AU2003302635A1 - Pyrazole derivatives useful as cox-i inhibitors - Google Patents

Description

WO 2004/050632 PCT/JP2003/014489 D E S C R I P T IO N PYRAZOLE DERIVATIVES USEFUL AS COX-I INHIBITORS 5 Technical Field This invention relates to pyrazole compounds having pharmacological activity, to a process for their production and to a pharmaceutical composition containing the same. 10 Background Art The presence of two cyclooxygenase isoenzymes, cyclooxygenase-I (COX-I) andcyclooxygenase-II (COX-II) is known (Proc. Nat. Acad. Sci. USA 88, 2692-2696 (1991)). Traditional non steroidal anti-inflammatory compounds 15 (NSAIDs) have inhibiting activities of both COX-I and COX-II (J. Biol. Chem., 268, 6610-6614 (1993) , etc) . The therapeutic use thereof involves undesired effects on the gastrointestinal tract, such as bleeding, erosions, gastric and intestinal ulcers, etc. 20 It was reported that selective inhibition of COX-II shows anti-inflammatory and analgesic activities comparable with conventional NSAIDs but with a lower incidence of some gastrointestinal undesired effects (Pro. Nat. Acad. Sci. USA, 91, 3228-3232(1994)). Accordingly, 25 various selective COX-II inhibitors have been prepared. However, it was reported that those "selective COX-II inhibitor" show some side-effects on kidney and/or insufficient efficacy on acute pains. Further, some compounds such as SC-560, mofezolac, etc, 30 which have certain selective inhibiting activity against COX-I. W098/57910 shows some compounds having such activity. However, their selectivity of inhibiting COX -I does not seem to be enough to use them as a clinically 1 WO 2004/050632 PCT/JP2003/014489 acceptable and satisfactory analgesic agent due to their gastrointestinal disorders. W002/055502 shows some pyridine derivatives having cyclooxygenase inhibiting activity, particularly 5 cyclooxygenase-I inhibiting activity. Further, W003/040110 shows some triazole derivatives having cyclooxygenase inhibiting activity, particularly cyclooxygenase-I inhibiting activity. And W099/51580 shows some triazole derivatives having an inhibiting 10 activity of cytokine production. Disclosure of Invention This invention relates to pyrazole compounds, which have pharmacological activity such as cyclooxygenase 15 (hereinafter described as COX) inhibiting activity, to a process for their production, to a pharmaceutical composition containing the same and to a use thereof. Accordingly, one object of this invention is to provide the pyrazole compounds, which have a COX inhibiting 20 activity. Another object of this invention is to provide a process for production of the pyrazole compounds. A further object of this invention is to provide a pharmaceutical composition containing, as active 25 ingredients, the pyrazole compounds. Still further object of this invention is to provide a use of the pyrazole compounds for manufacturing a medicament for treating or preventing various diseases. 30 The new pyrazole compounds of this invention can be represented by the following general formula (I): 2 WO 2004/050632 PCT/JP2003/014489

R

4 -Z-(X)m R1 NN > R2 N

R

3 y (I) wherein R2 is hydrogen or lower alkyl;

R

2 is lower alkyl optionally substituted with 5 halogen, hydroxy, lower alkoxyimino or lower alkoxy; lower alkenyl; cycloalkyl; cyano; lower alkanoyl; cycloalkylcarbonyl; N,N-di(lower)alkylcarbamoyl; carbamoyl; N-lower alkoxy-N-lower alkylcarbamoyl; amino; 10 di(lower)alkylamino; lower alkoxycarbonylamino; N,N-di(lower)alkylcarbamoylamino; N-(N,N-di(lower)alkylcarbamoyl)-N-lower alkylamino; halogen; hydroxy; carboxy; lower 15 alkoxycarbonyl; aroyl; heterocycliccarbonyl; heterocyclic group; lower alkylsulfonyl; lower alkoxy optionally substituted with lower alkoxy, N,N-di(lower)alkylcarbamoyl or halogen; cycloalkyloxy; lower alkylthio; or 20 lower alkylsufinyl;

R

3 is lower alkyl optionally substituted with amino, carbamoylamino or lower alkylsulfonylamino; halogen; cyano; hydroxy; lower alkanoyloxy; lower alkylenedioxy; lower alkoxy optionally 25 substituted with aryl, hydroxy, cyano, amino, lower alkoxycarbonylamino, lower alkylsulfonylamino or carbamoylamino; 3 WO 2004/050632 PCT/JP2003/014489 nitro; amino; hetrocyclic group; lower alkylthio; lower alkylsulfinyl; or lower alkylsufonyl;

R

4 is hydrogen; cyano; amino optionally substituted 5 with phthaloyl or lower alkyl; aryl; heterocyclic group; lower alkoxy; hydroxy; lower alkylsulfonyloxy; lower alkanoyloxy; lower alkyl substituted with tritylamino and lower alkoxycarbonyl, amino and lower 10 alkoxycarbonyl, amino and carboxy, amino and carbamoyl, or amino and hydroxy; N-lower alkoxycarbonyl-N-lower alkylamino; lower alkanoyl optionally substituted with halogen; carboxy; lower alkylsulfonyl; 15 sulfo; lower alkylsilyloxy; lower alkoxycarbonyl; sulfamoyl optionally substituted with lower alkyl; carbamoyl optionally substituted with lower alkyl; lower alkylthio; lower alkylsulfinyl; 20 carbamoyloxy; thioureido; or a group of the formula:

R

5

-G-J

in which G is -CO- or -SO 2 -; J is -N(R) 25 (wherein R 6 is hydrogen or lower alkyl); and R5 is amino optionally substituted with lower alkoxycarbonyl or lower alkyl; lower alkyl optionally substituted with hydroxy, lower 30 alkoxycarbonylamino, lower alkanoyloxy, amino or halogen; lower alkoxy; hydrogen; heterocyclic group; or aryl; 4 WO 2004/050632 PCT/JP2003/014489 X is 0, S, SO or S02; Y is CH or N; Z is lower alkylene or lower alkenylene; and m is 0 or 1; 5 provided that when R 4 is hydrogen; then R 3 is lower alkyl substituted with amino, carbamoylamino or lower alkylsulfonylamino; or lower alkoxy substituted with aryl, hydroxy, cyano, 10 amino, lower alkoxycarbonylamino, lower alkylsulfonylamino or carbamoylamino; or salts thereof. 15 The object compound (I) of the present invention can be prepared by the following processes. Process (1) R4-Z--(X)m

NHNH

2 R1

R

3 Y 0 0 20 (11) or its salt (Ill) or its salt 5 WO 2004/050632 PCT/JP2003/014489

R

4 -- Z-()m R' )0- R2 N N R3 Y (Ia) or its salt Process (2) 5 H-Xa RI N R 2 +

R

4 -Z-Q

R

3 y (V) or its salt (IV) or its salt

R

4 -Z-Xa N 2 N R

R

3 y (lb) or its salt In the above processes, R , R2, R', R4, X, Y, Z and m are each as defined above, Xa is 0 or S, and 10 Q is hyroxy or an acid residue. The compounds of formula (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers. This invention includes both 6 WO 2004/050632 PCT/JP2003/014489 mixtures and separate individual isomers. The compounds of the formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers. 5 The compounds of the formula (I) and its salts can be in a form of a solvate, which is included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate. Also included in the scope of invention are 10 radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies. In the above and subsequent description of the present specification, suitable examples of the various 15 definitions to be included within the scope of the invention are explained in detail in the following. The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided. So, the "lower alkyl" and lower alkyl moiety in the 20 terms "lower alkylthio", "lower aklylsufinyl", "lower alkylsulfonyl" and "lower alkylsulfonylamino" means a straight or branched chain aliphatic hydrocarbon, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isoamyl, hexyl, and the like, and it 25 is preferably (Ci-C 4 )alkyl, more preferably (C 1

-C

2 )alkyl, most preferably methyl. The "halogen" may include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and it is preferably a fluorine atom or a chlorine atom, more preferably a 30 chlorine atom. The "lower alkyl substituted with halogen" means a monovalent group in which the above lower alkyl is substituted by one or more (more preferably 1 to 5, most 7 WO 2004/050632 PCT/JP2003/014489 preferably 1 to 3) above halogen atom(s), such as fluoromethyl, chloromethyl, difluoromethyl, dichloro methyl, dibromomethyl, trifluoromethyl, trichloromethyl, fluoroethyl, chloroethyl, 2,2,2-trifluoroethyl, 5 2,2,2-trichloroethyl, 2,2,3,3,3-pentafluoroethyl, fluoropropyl, fluorobutyl, fluorohexyl, or the like, and it is preferably (Ci-C 4 )alkyl substituted with halogen, more preferably (Ci-C 2 ) alkyl substituted with halogen, more preferably (C 1

-C

2 )alkyl substituted with fluorine, more 10 preferably methyl substituted with fluorine, most preferably difluoromethyl or trifluoromethyl. The "lower alkyl substituted with hydroxy" means a monovalent group in which the above lower alkyl is substituted by a OH group, such as hydroxymethyl, 15 hydroxyethyl, hydroxypropyl, 1-hydroxyisopropyl, 2-hydroxyisopropyl, hydroxybutyl, hydroxyisobutyl, hydroxy-tert-butyl, hydroxyhexyl, or the like, and it is preferably (Ci-C 4 )alkyl substituted with hydroxy, more preferably (C1-C 3 )alkyl substituted with hydroxy. 20 The "lower alkenyl" means a straight or branched chain aliphatic hydrocarbon having more than one double bond between two carbon atom, such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like, and it is preferably (C 2

-C

4 )alkenyl, more 25 preferably (C 2

-C

3 )alkenyl. The "lower alkoxy" means a straight or branched chain aliphatic hydrocarbon oxy group, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, or the like, and it is preferably 30 (Ci-C 4 )alkoxy, more preferably (C1-C 2 )alkoxy, most preferably methoxy. The "cycloalkyl" and cycloalky moiety in the terms "cycloalkylcarbonyl" and "cycloalkyloxy" means C 3

-C

10 8 WO 2004/050632 PCT/JP2003/014489 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, and the like, and it is preferably C 3

-C

6 cycloalkyl, more preferably C3-C 5 cycloalkyl, most 5 preferably cyclopropyl or cyclopentyl. The "di (lower) alkylamino" means a amino group substituted by the same or different above (lower)alkyl groups, such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, 10 dipentylamino, dihexylamino, ethylmethylamino, methylpropylamino, butylmethylamino, ethylpropylamino, butylethylamino, or the like, and it is preferably [di(C1-C 4 )alkyl] amino, more preferably [di(C 1

-C

4 )alkyl] amino, most preferably dimethylamino. 15 The "lower alkoxycarbonyl" and lower alkoxycarbonyl moiety in the term "lower alkoxycarbonylamino" means a -C0 2 -[(lower)alkyl] group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, 20 pentoxycarbonyl, hexoxycarbonyl, and the like, and it is preferably [(Cl-C4)alkoxy]carbonyl, more preferably ethoxycarbonyl or tert-butoxycarbonyl. The "lower alkanoyl" means carbonyl group which is substituted by hydrogen or the above (lower)alkyl groups, 25 such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, or the like, and it is preferably (CI-C 5 ) alkanoyl, more preferably (C 2

-C

3 )alkanoyl, most preferably acetyl. The "cycloalkylcarbonyl" means a carbonyl group 30 substituted with cycloalkyl group mentioned above, such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, norbornylcarbonyl, 9 WO 2004/050632 PCT/JP2003/014489 adamantylcarbonyl, and the like, and it is preferably

[(C

3

-C

6 ) cycloalkyl] carbonyl, more preferably

[(C

3

-C

5 )cycloalkyl]carbonyl, most preferably cyclopropylcarbonyl. 5 The "N,N-di(lower)alkylcarbamoyl" and N,N-di(lower)alkylcarbamoyl moiety in the term "N,N-di(lower)alkylcarbamoylamino" means a carbamonyl group substituted with the same or different lower alkyl groups mentioned above, such as dimethylcarbamoyl, 10 diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl, diisobutylcarbamoyl, dipentylcarbamoyl, dihexylcarbamoyl, ethylmethylcarbamoyl, methylpropylcarbamoyl, butylmethylcarbamoyl, ethylpropylcarbamoyl, 15 butylethylcarbamoyl, and the like, and it is preferably [di(C 1

-C

4 )alkyl]carbamoyl, more preferably [di(Ci-C 2 )alkyl]carbamoyl, most preferably dimethycarbamoyl or ethylmethylcarbamoyl. The "lower alkoxy substituted with halogen" means a 20 monovalent group in which the above lower alkoxy is substituted by one or more (more preferably 1 to 5, most preferably 1 to 3) above halogen atom(s), such as fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, 25 trichloromethoxy, fluoroethoxy, chloroethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 2,2,3,3,3-pentafluoroethoxy, fluoropropoxy, fluorobutoxy, fluorohexyloxy, or the like, and it is preferably 30 (C1-C 4 )alkoxy substituted with halogen, more preferably

(C

1

-C

2 )alkoxy substituted. with halogen, more preferably

(C

1

-C

2 )alkoxy substituted with fluorine, more preferably ethoxy substituted with fluorine, most preferably 10 WO 2004/050632 PCT/JP2003/014489 2,2-difluoroethoxy. The "lower alkyl substituted with amino" means a monovalent group in which the above lower alkyl is substituted by a amino group, such as aminomethyl, 5 2-aminoethyl, aminopropyl, 1-aminoisopropyl, 2-aminoisopropyl, aminobutyl, aminoisobutyl, amino-tert-butyl, aminohexyl, or the like, and it is preferably (C 1

-C

4 )alkyl substituted with amino, more preferably (C 1

-C

2 )alkyl substituted with amino. 10 The "lower alkyl substituted with carbamoylamino" means a monovalent group in which the above (lower)alkyl is substituted by a carbamoylamino group (urea group), such as carbamoylaminomethyl, 2-(carbamoylamino)ethyl, carbamoylaminopropyl, 1-(carbamoylamino)isopropyl, 15 2-(carbamoylamino)isopropyl, carbamoylaminobutyl, carbamoylaminoisobutyl, carbamoylamino-tert-butyl, carbamoylaminohexyl, or the like, and it is preferably

(CI-C

4 )alkyl substituted with carbamoylamino, more preferably (C 1

-C

2 )alkyl substituted with carbamoylamino. 20 The "aryl" and ar moiety in the term "aroyl" means an aromatic hydrocarbon group, such as phenyl, naphtyl, indenyl, or the like, and it is preferably (C 6 -Cio) aryl, more preferably phenyl. The "aroyl" means a carbonyl group substituted with aryl 25 group mentioned above, such as benzoyl, naphthoyl, or the like, and it is preferably benzoyol. The "lower alkanoyloxy" means a monovalent group in which oxygen atom is substituted with lower alkanoyl group mentioned above, such as formyl, acetyl, propanoyl, 30 butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, or the like, and it is preferably [(C 1

-C

4 ) alkanoyl] oxy, more preferably

[(C

1

-C

2 )alkanoyl]oxy, most preferably acetoxy. 11 WO 2004/050632 PCT/JP2003/014489 The "lower alkylene" means a straight or branched chain aliphatic hydrocarbon divalent group, such as methylene, ethylene, 1-methylethylene, 2-methylethylene, propylene, methylpropylene, butylene, pentylene, hexylene, and the 5 like, and it is preferably (C 1

-C

4 )alkylene, more preferably

(C

1

-C

2 ) alkylene. The "lower alkylenedioxy" means -O- [(lower)alkylene] -0- group. That is, in this case, R 3 is divalent group and is also substituted at the next carbon 10 atom. This group may be exemplified by methylenedioxy, ethylenedioxy, methylethylenedioxy, propylenedioxy, and the like, and it is preferably [(C1-C4) alkylene] dioxy, more preferably [(C 1

-C

2 )alkylene]dioxy, most preferably methylenedioxy. 15 The "lower alkoxy substituted with aryl" means a monovalent group in which the above lower alkoxy is substituted by aryl group mentioned above. The "lower alkoxy substituted with hydroxy" means a monovalent group in which the above lower alkoxy is 20 substituted by hydroxy. The "lower alkoxy substituted with cyano" means a monovalent group in which the above (lower)alkoxy is substituted by a cyano group, such as cyanomethoxy, cyanoethoxy, cyanopropoxy, cyanobutoxy, and the like, and 25 it is preferably (Cl-C4)alkoxy substituted with cyano, more preferably (Cl-C2)alkoxy substituted with cyano, most preferably cyanomethoxy. The "lower alkoxy substituted with amino" means a monovalent group in which the above lower alkoxy is 30 substituted with amino. The "lower alkoxy substituted with lower alkoxycarbonylamino means a lower alkoxy substituted with amino group mentioned above substituted with lower 12 WO 2004/050632 PCT/JP2003/014489 alkoxycarbonyl group mentioned above. The "lower alkoxy substituted with lower alkylsulfonylamino means a monovalent group in which the above lower alkoxy is substituted with lower 5 alkylsulfonylamino group mentioned above. The "lower alkoxy substituted with carbamoylamino" means a monovalent group in which the above lower alkoxy is substituted by a (carbamoyl)amino (urea) group, such as [(carbamoyl)amino]methoxy, [(carbamoyl)amino]ethoxy, 10 [(carbamoyl)amino]propoxy, [(carbamoyl)amino]cyanobutoxy, and the like, and it is preferably (Cl-C4)alkoxy substituted with [(carbamoyl) amino], more preferably (C 1

-C

2 ) alkoxy substituted with [(carbamoyl)amino], most preferably 15 carbamoylaminomethoxy. The "lower alkokycarbonylamino" means an amino group substituted with lower alkokycarbonyl group mentioned above. The "lower alkylsulfonylamino means a sulfonylamino 20 group substituted with lower alkyl group mentioned above. Suitable "heterocyclic group" may be one containing at least one hetero atom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group, and 25 preferable heterocyclic group may be N-containing heterocyclic group such as unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl 30 [e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.], tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; saturated 3 to 7-membered heteromonocyclic group 13 WO 2004/050632 PCT/JP2003/014489 containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, etc.]; unsaturated condensed heterocyclic group containing 1 to 5 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, imidazopyridyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g. tetrazolo[1,5-b]pyridazinyl, etc.], quioxalinyl, etc.; 10 unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; saturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, 15 1H-tetrahydropyranyl, tetrahydrofuranyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms, for example, thienyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, 20 for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.], oxazolinyl [e.g. 2-oxazolinyl, etc.], etc.; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms 25 [e.g. morpholinyl, etc.]; unsaturated condensed heterocyclic group containing 1 to 2 -oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzofurazanyl, benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 3 to 6-membered heteromonocyclic group 30 containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.], etc.; 14 WO 2004/050632 PCT/JP2003/014489 saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g. thiazolidinyl, etc.]; unsaturated condensed heterocyclic group containing 1 to 5 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g. benzothiazolyl, benzothiadiazolyl, etc.]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms [e.g. benzofuranyl, benzodioxolyl, chromanyl, etc.] and the like. 10 Said "heterocyclic group" may be substituted with lower alkyl as exemplified above or oxo, in which preferable one is pieridyl, pyrrolyl , 3-metyl-1,2,4-oxadiazol-5-yl, isoindole-1,3-dione-2-yl or 1-methyl-1H-imidazolyl. The heterocyclic moiety in the term 15 "heterocycliccarbonyl" means heterocyclic group mentioned above and, it is preferably piperidyl. The "lower alkylsulfonyloxy" means a sulfonyloxy group substituted with lower alkyl group mentioned above. The "lower alkanoyl substituted with halogen" means 20 a lower alkanoyl group mentioned above substituted with halogen mentioned above, such as trifluoroacetyl, and the like. The "lower alkylsilyloxy" means silyloxy group substituted by the same or different above (lower)alkyl 25 groups, such as trimethylsilyloxy, triethylsilyloxy, tert-butyldimethylsilyloxy, or the like, and it is preferably tert-butyldimethylsilyloxy. The "acid residue" means halogen (e.g. fluoro, chloro, bromo, iodo), arenesulfonyloxy (e.g. benzenesulfonyloxy, 30 tosyloxy, etc.), alkanesulfonyloxy (e.g. mesyloxy, ethanesulfonyloxy, etc.), and the like. Preferred compound (I) is one having hydrogen for R 1 ; lower alkyl optionally substituted with halogen; 15 WO 2004/050632 PCT/JP2003/014489 cycloalkyl; halogen; or lower alkoxy optionally substituted with halogen for R 2 ; lower alkoxy for R 3 ;

R

5 -G-J- (wherein -CO- or -S02- for G, -NH- for J, amino or lower alkyl for R 5 ) for R 4 ; 0 for X; CH or N for Y; lower 5 alkylene for Z; and 0 or 1 for m. Suitable salts of the compounds (I) are pharmaceutically acceptable conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.) and an alkaline earth 10 metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc.), an organic acid salt (e.g., acetate, maleate, tartrate, methanesulfonate, 15 benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt with an amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.), or the like. 20 The processes for preparing the object compounds are explained in detail in the following. Process (1) 25 The object compound (Ia) or its salt can be prepared by reacting a compound (II) or its salt with a compound (III) or its salt in the acidic condition, for example, by using acetic acid. Suitable salts of the compounds (Ia) and (III) may be 30 the same as those exemplified for the compound (I). Suitable salt of the compound (IT) may be acid addition salt exemplified for the compound (I). The reaction is carried out in a conventional solvent 16 WO 2004/050632 PCT/JP2003/014489 such as water, an alcohol (e.g. methanol, ethanol, propanol, isopropanol, etc.), tetrahydrofuran, dioxane, etc. or a mixture of thereof. The reaction temperature is not critical and the 5 reaction is usually carried out under cooling to heating. According to the starting material, the heterocyclic ring is formed but not to form pyrazole ring. In this case, the dehydration process is need to form pyrazole ring. The hydration process is carried out under the higher 10 temperature. Process (2) The object compound (Ib) or its salt can be prepared by reacting a compound (IV) or its salt with a compound (V) 15 or its salt. Suitable salts of the compounds (Ia), (IV) and (V) may be the same as those exemplified for the compound (I). When the compound (V) having halogen for Q is used in this reaction, the reaction is preferably carried out in 20 the presence of a base such as alkali metal (e.g. sodium, potassium, etc.) , an alkaline earth metal (e.g. magnesium, calcium, etc. ), the hydride or hydroxide or carbonate or bicarbonate thereof. When the compound (V) having hydroxy for Q is used in 25 this reaction, the reaction is preferably carried out in the presence of diethyl azodicarboxylate and triphenylphosphine. The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction 30 such as water, dioxane, a alcohol (e.g. methanol, ethanol, etc.), acetonitrile, tetrahydrofuran, acetic acid, N,N-dimethylformamide, or a mixture thereof. The reaction temperature is not critical and the 17 WO 2004/050632 PCT/JP2003/014489 reaction can be carried out under cooling to heating. In order to illustrate the usefulness of the object compounds (I), the pharmacological test data of the com 5 pounds (I) are shown in the following. [A] ANALGESIC ACTIVITY Effect on adjuvant arthritis in rats 10 (i) Test Method : Analgesic activity of a single dose of agents in arthritic rats was studied. Arthritis was induced by injection of 0.5 mg of Mycobacterium tuberculosis (Difco Laboratories, Detroit, 15 Mich.) in 50.4l of liquid paraffin into the right hind footpad of Lewis rats aged 7 weeks. Arthritic rats were randomized and grouped (n=10) for drug treatment based on pain threshold of left hind paws and body weight on day 22. Drugs (Test compounds) were administered and the pain 20 threshold was measured 2hrs after drug administration. The intensity of hyperalgesia was assessed by the method of Randall - Selitto. The mechanical pain threshold of the left hind paw (uninjected hind paw) was determined by compressing the ankle joint with a balance pressure 25 apparatus (Ugo Basile Co.Ltd., Varese, Italy). The threshold pressure of rats squeaking or struggling was expressed in grams. The threshold pressure of rats treated with drugs was compared with that of non-treated rats. A dose showing the ratio of 1.5 is considered to be the 30 effective dose. 18 WO 2004/050632 PCT/JP2003/014489 (ii) Test Results: Test compound Dose The coefficient of (Example No.) (mg/kg) analgesic 23 3.2 > 1.5 28 3.2 > 1.5 61 3.2 > 1.5 181 3.2 >= 1.5 240 3.2 >= 1.5 248 3.2 >= 1.5 250 3.2 >= 1.5 254 3.2 >= 1.5 267 3.2 >= 1.5 [B] Inhibiting activity against COX-I and COX-II 5 (Whole Blood Assay): (i) Test Method : Whole blood assay for COX-I Fresh blood was collected by syringe without anticoagulants from volunteers with consent. The subjects 10 had no apparent inflammatory conditions and had not taken any medication for at least 7 days prior to blood collection. 500l Aliquots of human whole blood were immediately incubated with 2l of either dimethyl sulfoxide vehicle is or a test compound at final concentrations for lhr at 37 C to allow the blood to clot. Appropriate treatments (no incubation) were used as blanks. At the end of the incubation, 5/tl of 250mM Indomethacin was added to stop the reaction. The blood was centrifuged at 6000 x g for 20 5min at 4*C to obtain serum. A 100 I1 aliquot of serum was mixed with 400l1 methanol for protein precipitation. The 19 WO 2004/050632 PCT/JP2003/014489 supernatant was obtained by centrifuging at 6000 x g for 5min at 4 0 C and was assayed for TXB 2 using an enzyme immunoassay kit according to the manufacturer's procedure. For a test compound, the results were expressed as percent 5 inhibition of thromboxane B 2

(TXB

2 ) production relative to control incubations containing dimethyl sulfoxide vehicle. The data were analyzed by that a test compound at the indicated concentrations was changed log value and was applied simple linear regression. IC 5 o value was 10 calculated by least squares method. Whole blood assay for COX-II Fresh blood was collected in heparinized tubes by syringe from volunteers with consent. The subjects had no 15 apparent inflammatory conditions and had not taken any medication for at least 7 days prior to blood collection. 500/Ll aliquots of human whole blood were incubated with either 2al dimethyl sulfoxide vehicle or 2/Ll of a test compound at final concentrations for 15 min at 37 C. 20 This was followed by incubation of the blood with 10Ll of 5mg/mi lipopolysaccharide for 24hrs at 370C for induction of COX-II. Appropriate PBS treatments (no LPS) were used as blanks. At the end of the incubation, the blood was centrifuged at 6000Xg for 5 min at 4r0 to obtain plasma. 25 A 100tl aliquot of plasma was mixed with 400I1l methanol for protein precipitation. The supernatant was obtained by centrifuging at 600OXg for 5min at 400 and was assayed for prostaglandin E 2

(PGE

2 ) using a radioimmunoassay kit after conversion of PGE 2 to its methyl oximate derivative 30 according to the manufacturer's procedure. For a test compound, the results were expressed as percent inhibition of PGE 2 production relative to control incubations containing dimethyl sulfoxide vehicle. The 20 WO 2004/050632 PCT/JP2003/014489 data were analyzed by that a test compound at the indicated concentrations was changed log value and was applied simple linear regression. IC 50 value was calculated by least squares method. 5 (ii) Test Results: Test Compound COX-I COX-II (Example No.) IC50 (PM) IC50 (pM) 23 < 0.01 > 0.1 28 < 0.01 > 0.1 61 < 0.01 > 0.1 181 < 0.01 > 0.1 240 < 0.01 > 0.1 248 < 0.01 > 0.1 250 < 0.01 > 0.1 254 < 0.01 > 0.1 267 < 0.01 > 0.1 It appeared, from the above-mentioned Test Results, that the compound (I) or pharmaceutically acceptable salts 10 thereof of the present invention have an inhibiting activity against COX, particularly a selective inhibiting activity against COX-I. [C] Inhibiting activity on aggregation of platelet 15 (i) Methods Preparation of platelet-rich plasma Blood from healthy human volunteers was collected into plastic vessels containing 3.8% sodium citrate (1/10 volume). The subject had no taken any compounds for at 20 least 7days prior to blood collection. Platelet-rich plasma was obtained from the supernatant fraction of blood 21 WO 2004/050632 PCT/JP2003/014489 after centrifugation at 1200rpm. for 10min. Platelet-poor plasma was obtained by centrifugation of the remaining blood at 3000rpm for 10min. 5 Measurement of platelet aggregation Platelet aggregation was measured according to the turbidimetric method with an aggregometer (Hema Tracer) In the cuvette, platelet-rich plasma was pre-incubated for 2min at 37 0 C after the addition of compounds or vehicle. 10 In order to quantify the inhibitory effects of each compound, the maximum increase in light transmission was determined from the aggregation curve for 7min after the addition of agonist. We used collagen as agonist of platelet aggregation in this study. The final concentration of 15 collagen was 0.Spg/mL. The effect of each compound was expressed as percentage inhibition agonist-induced platelet aggregation compared with vehicle treatment. Data are presented as the mean i S.E.M. for six experiments. The IC 50 value was obtained by linear regression, and is 20 expressed as the compound concentration required to produce 50% inhibition of agonist-induced platelet aggregation in comparison to vehicle treatment. It appeared, from the above-mentioned Test Result, that 25 the compound (I) or pharmaceutically acceptable salts thereof of the present invention have an inhibiting activity against platelet aggregation. Therefore, the compound (I) or pharmaceutically acceptable salts thereof are useful for preventing or treating disorders induced by 30 platelet aggregation, such as thrombosis. Additionally, it was further confirmed that the compounds (I) of the present invention lack undesired side-effects of non-selective NSAIDs, such as 22 WO 2004/050632 PCT/JP2003/014489 gastrointestinal disorders, bleeding, renal toxicity, cardiovascular affection, etc. As shown above, the object compound (I) or pharmaceutically acceptable salts thereof of this 5 invention possesses COX inhibiting activity and possesses strong anti-inflammatory, antipyretic, analgesic, antithrombotic, anti-cancer activities, and so on. The object compound (I) and pharmaceutically 10 acceptable salt thereof, therefore, are useful for treating and/or preventing COX mediated diseases, inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunological diseases, thrombosis, cancer and neurodegenerative diseases in human beings or is animals by using administered systemically or topically. More particularly, the object compound (I) and pharmaceutically acceptable salts thereof are useful for treating and/or preventing inflammation and acute or chronic pain in joint and muscle [e.g. rheumatoid arthritis, 20 rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, scapulohumeral periarthritis, cervical syndrome, etc.]; lumbago; inflammatory skin condition [e.g. sunburn, burns, eczema, dermatitis, etc.]; inflammatory eye condition [e.g. conjunctivitis, etc.]; 25 lung disorder in which inflammation is involved [e.g. asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.]; condition of the gastrointestinal tract associated with inflammation [e.g. aphthous ulcer, Chrohn's disease, atopic gastritis, gastritis varioloid, 30 ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.]; gingivitis; menorrhalgia; inflammation, pain and tumescence after operation or injury [pain after odontectomy, etc.] ; pyrexia, pain and other 23 WO 2004/050632 PCT/JP2003/014489 conditions associated with inflammation, particularly those in which lipoxygenase and cyclooxygenase products are a factor, systemic lupus erythematosus, scleroderma, polymyositis, tendinitis, bursitis, periarteritis nodose, 5 rheumatic fever, Sjogren's syndrome, Behcet disease, thyroiditis, type I diabetes, nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin's disease, Alzheimers disease, or the like. 10 Additionally, the object compound (I) or a salt thereof is expected to be useful as therapeutical and/or preventive agents for cardiovascular or cerebrovascular diseases, the diseases caused by hyperglycemia and hyperlipemia. The object compound (I) and a salt thereof can be used 15 for prophylactic and therapeutic treatment of arterial thrombosis, arterial sclerosis, ischemic heart diseases [e.g. angina pectoris (e.g. stable angina pectoris, unstable angina pectoris including imminent infarction, etc.), myocardial infarction (e.g. acute myocardial 20 infarction, etc.), coronary thrombosis, etc.], ischemic brain diseases [e.g. cerebral infarction (e.g. acute cerebral thrombosis, etc.), cerebral thrombosis (e.g. cerebral embolism, etc.), transient cerebral ischemia (e.g. transient ischemic attack, etc.), cerebrovascular spasm 25 after cerebral hemorrhage (e.g. cerebrovascular spasm after subarachnoid hemorrhage, etc.), etc.], pulmonary vascular diseases (e.g. pulmonary thrombosis, pulmonary embolism etc.), peripheral circulatory disorder [e.g. arteriosclerosis obliterans, thromboangiitis obliterans 30 (i.e. Buerger's disease), Raynaud's disease, complication of diabetes mellitus (e.g. diabetic angiopathy, diabetic neuropathy, etc.), phiebothrombosis (e.g. deep vein thrombosis, etc.), etc.], complication of tumors (e.g. 24 WO 2004/050632 PCT/JP2003/014489 compression thrombosis), abortion [e.g. placental thrombosis, etc.], restenosis and reocclusion [e.g. restenosis and/or reocclusion after percutaneous transluminal coronary angioplasty (PTCA), restenosis and 5 reocclusion after the administration of thrombolytic drug (e.g. tissue plasminogen activator (TPA), etc.)], thrombus formation in case of vascular surgery, valve replacement, extracorporeal circulation [e.g. surgery (e.g. open heart surgery, pump-oxygenator, etc.) hemodialysis, etc.) or 10 transplantation, disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia, essential thrombocytosis, inflammation (e.g. nephritis, etc.), immune diseases, atrophic thrombosis, creeping thrombosis, dilation thrombosis, jumping thrombosis, mural thrombosis, 15 etc.. The object compound (I) and a salt thereof can be used for the adjuvant therapy with thrombolytic drug (e.g. TPA, etc.) or anticoagulant (e.g. heparin, etc.). And, the compound (I) is also useful for inhibition 20 of thrombosis during extra corporeal circulation such as dialysis. Particularly, the following diseases are exemplified: pains caused by or associated with rheumatoid arthritis, osteoarthritis, lumbar rheumatism, rheumatoid spondylitis, 25 gouty arthritis, juvenile arthritis, etc; lumbago; cervico-omo-brachial syndrome; scapulohumeral periarthritis; pain and tumescence after operation or injury; etc.. And on the commercial package comprising the 30 pharmaceutical composition mentioned above, the matter, which states above mentioned effects, may be written. For therapeutic purpose, the compound (I) and a pharmaceutically acceptable salt thereof of the present 25 WO 2004/050632 PCT/JP2003/014489 invention can be used in a form of pharmaceutical preparation containing said compounds as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid 5 or liquid excipient suitable for oral, parenteral or external administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, inhalant, suppositories, solution, lotion, suspension, emulsion, ointment, gel, cream, or the like. If desired, there may 10 be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives. For therapeutic purpose, the analgesic agent of the present invention can be used in a form of pharmaceutical 15 preparation suitable for oral, parenteral or external administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, inhalant, suppositories, solution, lotion, suspension, emulsion, ointment, gel, or the like. 20 Particularly, the analgesic agent of this invention is useful for treating or preventing acute or chronic pains associated with acute or chronic inflammations in human beings or animals by using administered systemically or topically. 25 While the dosage of therapeutically effective amount of the compound (I) will vary depending upon the age and condition of each individual patient, an average single dose of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be 30 effective for treating the above-mentioned diseases. In general, amounts between 0.01 mg/body and about 1,000 mg/body may be administered per day. 26 WO 2004/050632 PCT/JP2003/014489 In the above and subsequent description of the present specification, the following abbreviations and acronyms mean ones as shown in the following table. Abbreviations and Acronyms Full Name AcOEt or EtOAc ethyl acetate AcOH acetic acid BuOH, t-BuOH, butanol, t-butyl alcohol, etc. etc. DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide Et3N triethylamine EtOH ethanol IPE diisopropyl ether MeOH methanol PrOH, i-PrOH propanol, isopropyl alcohol, etc. or IPA, etc. TFA trifluoroacetic acid THF tetrahydrofuran EDCI or WSCD 1-ethyl-3-[3'-(dimethylamino)propyllcar bodiimide HOBt or HOBT 1-hydroxybenztriazole Pd/C palladium on carbon MCBA or mCPBA 3-Chloroperoxybenzoic acid or mcpba deg 0 C=degree centigrade min minute(s) hr or h hour(s) conc. concentrated aq aqueous (ex. aq NaHCO3 solution) 27 WO 2004/050632 PCT/JP2003/014489 The following Examples and Preparations are given only for the purpose of illustrating the present invention in more detail. 5 Example 1-1 (1E) -1- [4- (Methoxymethoxy) phenyl] -4-methyl-l-penten-3 one 1M Sodium hydroxide aqueous solution (5.4ml) was added 10 to a solution of 4-mehoxymethoxybenzaldehyde (4.52g) and 3-methyl-2-butanone (4.69g) in ethanol (27ml), and the mixture was stirred at room temperature overnight. Themixture partitionedbetween ethyl acetate anddwater. The organic layer was washed with water, saturated aqueous 15 sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with 10% ethyl acetate/n-hexane to give the title compound (4.03g, 63.2%) as an oil. 20 1HNMR (CDCl 3 ) : 6 1.18(6H, d, J=6.7Hz) , 2.92(lH, m) , 3.48 (3H, s), 5.21 (2H, s), 6.71 (1H, d, J=16.OHz), 7.05 (2H, d, J=8.8Hz), 7.51(2H, d, J=8.8Hz), 7.58(lH, d, J=16.OHz). MS (ESI+) : m/z 257 (M+Na). 25 Example 1-2 (lS,2R)- and (lR,2S)-1,2-epoxy-l-[4-(methoxymethoxy) phenyl]-4-methyl-3-pentanone 30% H 2 0 2 (1.7ml) and3Msodiumhydroxide aqueous solution 30 (1.7ml) was added to a solution of (lE)-1-[4-(methoxymethoxy)phenyll-4-methyl-l-penten-3 one obtained by Example 1-1 (2.00g) in ethanol:acetone=3:1 28 WO 2004/050632 PCT/JP2003/014489 (34ml). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, and partitioned between ethyl acetate and water. The organic layer was 5 washed with water, saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give the target compound (2.03g, 95%) as an oil. 1H NMR (DMSO-d6) : 6 1.05(6H, d, J=6.9Hz), 2.85(lH, m), 10 3.36(3H, s), 3.93(lH, d, J=1.9Hz), 4.00(lH, d, J=1.9Hz), 5.20(2H, s), 7.03(2H, d, J=8.6Hz), 7.30(2H, d, J=8.6Hz). MS (ESI) : m/z 273 (M+Na). Example 1-3 15 4-[3-Isopropyl-l-(4-methoxyphenyl)-1H-pyrazol-5-yl] phenol A mixture of (1S,2R)- and (1R,2S)-1,2-epoxy-1-[4 (methoxymeth-oxy)phenyl)-4-methyl-3-pentanone obtained 20 by Example 1-2 (2.10g) and 4-methoxyphenylhydrazine hydrochloride (1.76g) in ethanol:acetic acid=20:1 (20ml) was stirred at 60'C for 3hrs. The mixture was concentrated in vacuo. To the residue was added ethyl acetate and 1M hydrochloric acid. The whole 25 mixture was treated with activated carbon, and was filtered through a celite pad. The filtrate was partitioned. The organic layer was washed successively with IM hydrochloric acid, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over 30 magnesium sulfate, and concentrated in vacuo. The residual solid were collected and washed with ethyl acetate to give the target compound (322.2mg, 12.5%) as a white powder. 29 WO 2004/050632 PCT/JP2003/014489 1H NMR (CD.Cl 3 ) : 1.33 (6H, d, J=7.OHz), 3.07 (1H, m), 3.80 (3H, s), 5.18 (1H, s), 6.26(1H, s), 6.72 (2H, d, J=8.8Hz), 6.83(2H, d, J=9.0Hz), 7.08(2H, d, J=8.8Hz), 7.20(2H, d, J=9.0Hz). 5 MS (ESI+) : m/z 309 (M+H) Example 2 tert-Butyl 2-{4-[3-isopropyl-l-(4-methoxyphenyl)-1H pyrazol-5-yl]-phenoxylethylcarbamate 10 Diethylazodicarboxylate (259mg) was added to a mixture of 4-[3-isopropyl-l-(4-methoxyphenyl)-lH pyrazol-5-yl]phenol obtained by Example 1-3 (305mg), 2-t-butoxycarbonylaminoethanol (479mg), and 15 triphenylphosphine (390mg) in tetrahydrofuran (3ml). After stirring at room temperature for 7hrs, diethylazod icarboxylate (17mg) and triphenylphosphine (26mg) was ad ded to the reaction mixture. After stirring at roomtemperature for lhr, the reaction 20 mixture was concentratedinvacuo. The residue waspurified by silica gel column chromatography eluted with 30% ethyl acetate/n-hexane to give the target compound (396mg, 88.5%) as a solid. 25 1H NMR (CDC1 3 ) : 1.34 (6H, d, J=7.0Hz), 1.45(9H, s) , 3.07 (1H, m) , 3.48-3.57 (2H, m) , 3.80 (3H, s), 3.97-4.03(2H, m), 4.97 (1H, br-s), 6.26(1H, s), 6.76-6.87 (4H, m), 7.14 (2H, d, J=8.9Hz), 7.20(2H, d, J=9.0 Hz). 30 Example 3 2-{4-[3-Isopropyl-l-(4-methoxyphenyl)-1H-pyrazol-5-yl] phenoxy}ethanamine hydrochloride 30 WO 2004/050632 PCT/JP2003/014489 4M Hydrochloric acid/dioxane (2ml) was added to a solution of tert-butyl 2-{4-[3-isopropyl-1-(4-methoxy phenyl)-1H-pyrazol-5-yl]-phenoxy}ethylcarbamate 5 obtained by Example 2 (382mg) in dichloromethane (3ml) at 0 0 C. After stirring at room temperature for lhr, the reaction mixture was concentrated in vacuo. The residue was crystallized from a mixture of isopropanol and ethyl acetate 10 to give the target compound (311mg, 94.7%) as a powder. 1H NMR (DMSO-d6) :& 1.27(6H, d, J=6.9Hz), 2.95(lH, m), 3.14-3.22(2H, m), 3.76(3H, s), 4.14-4.20(2H, m), 6.41(1H, s), 6.93(4H, d, J=8.9Hz), 7.16(4H, d, J=8.9Hz), 8.22(2H, 15 br-s) MS (ESI+) : m/z 352 (M+H). Example 4 N-(2-{4-[3-Isopropyl-l-(4-methoxyphenyl)-lH-pyrazol-5 20 yl]phenoxy}-ethyl)methanesulfonamide Methanesulfonyl chloride (32.2mg) was added to a solution of 2-{4-[3-isopropyl-1-(4-methoxyphenyl)-1H pyrazol-5-yllphenoxy}ethanamine hydrochloride obtained 25 by Example 3 (90.9mg) and triethylamine (71.1mg) in dichloromethane (2ml). The mixture was stirred at room temperature for 2hrs. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and a mixture of 1M 30 hydrochloric acid and brine. The aqueous layer was reextracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, 31 WO 2004/050632 PCT/JP2003/014489 and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was crystallized from a mixture of ethyl acetate and isopropylether to give the target compound (78.0mg, 77.5%) 5 as a white powder. MP : 162-163 0 C. 1H NMR (DMSO-d6) :5 1.26(6H, d, J=6.9Hz), 2.94(3H, s), 2.94(1H, m), 3.25-3.39(2H, m), 3.76(3H, s), 3.98-4.04(2H, 10 m), 6.40 (1H, s), 6.90 (2H, d, J=8.8Hz), 6.93(2H, d, J=8.9Hz), 7.13(2H, d, J=8.8Hz), 7.15(2H, d, J=8.9Hz), 7.27(1H, s). IR (KBr) : 3122, 2966, 2897, 2871, 1614, 1514cm Example 5 15 N-(2-{4-[3-Isopropyl-l-(4-methoxyphenyl)-lH-pyrazol-5 yl]phenoxy}ethyl)urea Trimethylsilylisocyanate (41.4mg) was added to a solution of 2-{4-[3-isopropyl-l-(4-methoxyphenyl)-1H 20 pyrazol-5-yllphenoxy}ethanamine hydrochloride obtained by Example 3 (93.0mg) and triethylamine (72.8mg) in dichloromethane (3ml) and the mixture wasstirred at room temperature for 3hrs. Trimethylsilylisocyanate (8.3mg) was added and the mixture was stirred at room 25 temperature for 1.5hrs. Trimethylsilylisocyanate (13.8 mg) and triethylamine (12.1mg) was added and the mixture was stirred at room temperature for 1.5hrs. The mixture was concentrated in vacuo, and the residue was partitioned between chloroform and a mixture of IM 30 hydrochloric acid and brine. The aqueous layer was extracted with chloroform. The combined organic layer was washed with saturated aqueous sodium bicarbonate solution 32 WO 2004/050632 PCT/JP2003/014489 and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by 10% methanol/chloroform. The 5 separated silica gel was extracted with 10% methanol/chloroform and the solvent was evaporated in vacuo. The residue was crystallized from a mixture of ethyl acetate and isopropylether to give the target compound (85.7mg, 90.6%) as a white powder. 10 MP : 100-104 0 C. 1H NMR (DMSO-d6) : 1.26(6H, d, J=6.9Hz), 2.94(1H, m), 3.27-3.36 (2H, m), 3.76 (3H, s) , 3.89-3. 96 (2H, m) , 5.52 (2H, s), 6.14(1H, t, J=5.6Hz), 6.39(1H, s), 6.89(2H, d, J=8.7Hz), 15 6.93(2H, d, J=8.9Hz), 7.12(2H, d, J=8.7Hz), 7.15(2H, d, J=8.9Hz). IR (KBr) : 3371, 3190, 2964, 2873, 1738, 1684, 1639, 1614, 1543, 1512cm 1 . MS (ESI+) : m/z 395 (M+H). 20 Example 6 tert-Butyl 2-{4-[3-(l-hydroxy-1-methylethyl)--(4 methoxyphenyl)-lH-pyrazol-5-yllphenoxy}ethylcarbamate 25 tert-Butyl 2-{4-[3-ethoxycarbonyl-1-(4-methoxy phenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate (1.37g) in tetrahydrofuran (10ml) was added dropwise to 0.93M solution of methyl magnesium bromide in tetrahydrofuran (16ml) at 24-27-C with cooling in a waterbath. 30 After stirring at room temperature for 1hr, the mixture was poured into a mixture of saturated aqueous ammonium chloride solution and ice. The mixture was extracted with 33 WO 2004/050632 PCT/JP2003/014489 ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuc. The residue was purified by silica gel column chromatography eluted with 5 70% ethyl acetate/n-hexaneto give the target compound (1.17g, 88%) as an amorphous powder. MS (ESI+) : m/z 468 (M+H) 1H NMR (CDCl 3 ) : 6 1.45(9H, s), 1.65(6H, s), 2.78(1H, s), 10 3.48-3.57(2H, m), 3.81(3H, s), 3.97-4.03(2H, m), 4.97(1H, br), 6.36(lH, s), 6.78-6.89(4H, m), 7.13(2H, d, J=8.7Hz), 7.21(2H, d, J=8.9Hz). Example 7 15 tert-Butyl 2-{4-[3-isopropenyl-l-(4-methoxyphenyl)-lH pyrazol-5-yljphenoxy}ethylcarbamate Methanesulfonyl chloride (367mg) and triethylamine (649mg) were added successively to a solution of tert 20 butyl 2-{4-[3-(1-hydroxy-1-methylethyl)-1-(4-methoxy phenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate obtained by Example 6 (1.0g) and N,N-dimethylformamide (91.5mg) in dichloromethane (10ml) and the mixture was stirred at room temperature for 2hrs. Additional methanesulfonyl 25 chloride and triethylamine were added until all starting material was consumed with stirring at the same temperature. The reaction mixture was partitioned between ethyl acetate and 1M hydrochloric acid, and the organic layer was 30 washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue 34 WO 2004/050632 PCT/JP2003/014489 was purified by silica gel column chromatography eluted with 30%ethylacetate/n-hexanetogivethetargetcompound (900mg, 93.6%) as an amorphous powder. 5 1H NMR (CDCl 3 ) :. 6 1.45(9H, s), 2.21(3H, s), 3.48-3.57(2H, m), 3.81 (3H, s), 3. 97-4.03 (2H, m) , 4.98 (1H, br-s), 5.12 (1H, br-s), 5.59(lH, br-s), 6.56(1H, s), 6.77-6.87(4H, m), 7.14(2H, d, J=8.7Hz), 7.22(2H, d, J=8.9Hz). MS (ESI+) : m/z 450 (M+H). 10 Example 8 tert-Butyl 2-{4-[3-isopropyl-l-(4-methoxyphenyl)-1H pyrazol-5-yl]phenoxylethylcarbamate 15 A mixture of 10% Pd-C 50% wet (65mg) and tert-butyl 2-{4-[3-isopropenyl-l-(4-methoxyphenyl)-1H pyrazol-5-yllphenoxylethylcarbamate obtained by Example 7 (645mg) in tetrahydrofuran (2ml) and methanol (4ml) was hydrogenated under H 2 latm at room temperature for 3hrs. 20 The catalyst was removed by filtration. The filtrate and combined washings were concentrated in vacuo. The residue was crystallized from a mixture of ethyl acetate and isopropyl ether to give the target compound (370mg, 57.1%) as a white powder. 25 1HNMR (CDCl 3 ) 6 1.34 (6H, d, J=7.0Hz), 1.45(9H, s), 3.07 (1H, m), 3.48-3.57 (2H, m), 3.80(3H, s), 3.97-4.03(2H, m), 4.97 (1H, br-s), 6.26(1H, s), 6.76-6.87 (4H, m) , 7.14 (2H, d, J=8.9Hz), 7.20(2H, d, J=9.OHz). 30 MS (ESI+) : m/z 452 (M+H). Example 9 35 WO 2004/050632 PCT/JP2003/014489 tert-Butyl 2-{4-[3-(l-hydroxy-l-methylethyl)-1-(6 methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl carbamate 5 The title compound (624.4mg, 42.9%) was prepared as an amorphous powder from tert-butyl 2-{4- [3- (1-hydroxy-1 methylethyl)-l-(6-methoxy-3-pyridinyl)-1H-pyrazol-5 yl]phenoxy}ethylcarbamate in a similar manner to that of Example 6. 10 1H NMR (CDCl 3 ) 6 1.45(9H, s), 1.65(6H, s), 3.49-3.57(3H, m), 3.93(3H, s), 3.98-4.04 (2H, m), 4.98 (1H, br), 6.39(1-H, s), 6.72(1H, d, J=8.8Hz), 6.83(2H, d, J=8.8Hz), 7.15(2H, d, J=8.8Hz), 7.54(1H, dd, J=2.8, 8.8Hz), 8.07(1H, d, 15 J=2.8Hz). MS(ESI+) : 469 (M+H). Example 10 tert-Butyl 2-{4-[3-isopropenyl-l-(6-methoxy-3 20 pyridinyl)-lH-pyrazol-5-yl]phenoxylethylcarbamate The title compound (495mg, 85.7%) was prepared as an oil from tert-butyl 2-{4-[3-(l-hydroxy-1-methylethyl) 1-(6-methoxy-3-pyridinyl)-lH-pyrazol-5-yl]phenoxy} 25 ethylcarbamate obtained by Example 9 in a similar manner to that of Example 7. 1HNMR (CDCl 3 ) :6 1.45(9H, s), 2.20(3H, s), 3.49-3.57(2H, m), 3.92(3H, s), 3.98-4.04(2H, m), 4.99(1H, br-s), 5.15(1H, 30 br-s), 5.60(1H, br-s), 6.58 (1H, s), 6.72(1H, d, J=8.8Hz), 6.83(2H, d, J=8.7Hz), 7.15(2H, d, J=8.7Hz), 7.55(1H, dd, J=2.6, 8.8Hz), 8.09(1H, d, J=2.6Hz). 36 WO 2004/050632 PCT/JP2003/014489 MS (ESI+) : m/z 451 (M+H). Example 11 tert-Butyl 2-{4-[3-isopropyl-l-(6-methoxy-3-pyridinyl) 5 1H-pyrazol-5-yl]phenoxy}ethylcarbamate The title compound (220mg, quant.) was prepared as a n amorphous powder from tert-butyl 2-{4-[3-isopropenyl 1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy} 10 ethylcarbamate obtained by Example 10 in a similar manne r to that of Example 8. 1HNMR (CDCl 3 ) : & 1.34 (6H, d, J=6.8Hz), 1.45(9H, s), 3.07(1H, m), 3.48-3.57 (2H, m), 3. 92 (3H, s) , 3.98-4.04 (2H, m), 4.98 (1H, 15 br), 6.28 (1H, s), 6.71(1H, d, J=8.9Hz), 6.82(2H, d, J=8.9Hz), 7.14 (2H, d, J=8.9Hz), 7.56(1H, dd, J=2.6, 8.9Hz), 8.05(1H, d, J=2.6Hz). MS (ESI+) : m/z 453 (M+H). 20 Example 12 2-{4-[3-Isopropyl-l-(6-methoxy-3-pyridinyl)-1H-pyrazol 5-yl]phenoxylethanamine dihydrochloride The title compound (257mg, quant.) was prepared as a 25 n amorphous powder from tert-butyl 2-{4-[3-isopropyl-1 (6-methoxy-3-pyridinyl)-1H-pyrazol-5-yllphenoxylethyl carbamate obtained by Example 11 in a similar manner to that of Example 3. 30 1H NMR (DMSO-d6) : 1.27(6H, d, J=6.9Hz), 2.96(1H, m), 3.15-3.23(2H, m), 3.85(3H, s), 4.15-4.21(2H, m), 6.47(1H, s), 6.86(lH, d, J=8.8Hz), 6.97(2H, d, J=8.8Hz), 7.20(2H, 37 WO 2004/050632 PCT/JP2003/014489 d, J=8.8Hz), 7.62(lH, dd, J=2.7, 8.8Hz), 8.01(lH, d, J= 2.7Hz), 8.19(2H, s). MS (ESI+) : m/z 353 (M+H) 5 Example 13 N-(2-{4-[3-Isopropyl-l-(6-methoxy-3-pyridinyl)-lH pyrazol-5-yl]phenoxy}ethyl)urea The title compound (49.9mg, 51.6%) was prepared as a 10 white powder from 2-{4-[3-isopropyl-1-(6-methoxy-3 pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethanamine obtained by Example 12 in a similar manner to that of Example 5. MP : 106-107"C. 15 1H NMR (DMSO-d6) : 6 1.27(6H, d, J=6.9Hz), 2.96(1H, m), 3.27-3.36 (2H, m), 3.85(3H, s), 3.94(2H, t, J=5.5Hz), 5.52(2H, s), 6.15(1H, t, J=5.6Hz), 6.45(1H, s), 6.85(1H, d, J=8.8Hz), 6.93(2H, d, J=8.7Hz), 7.16(2H, d, J=8.7Hz), 7.60(1H, dd, 20 J=2.6, 8.8Hz), 8.02(1H, d, J=2.6Hz). IR (KBr) 3400, 3390, 3379, 3352, 2960, 1657, 1608, 154 7, 1512, 1500cm 1 . MS (EST+) m/z 396 (M+H). 25 Example 14-1 5-[4-(Benzyloxy)phenyl]-1-(4-methoxyphenyl)-4,5 dihydro-lH-pyrazol-3-amine 30 Sodium (3.19g) was addedportionwisetoethanol (160ml) After all sodium was dissolved, 4-methoxyphenylhydrazine hydrochloride (14.5g) was added in one portion to the 38 WO 2004/050632 PCT/JP2003/014489 solution. The mixture was stirred at room temperature for 10min. To this mixture was added 3-(4-benzyloxyphenyl)acrylonitrile (16.3g) inoneportion, and the mixture was refluxed for days. 5 Insoluble matter was filtered off, and the filtrate was concentrated in vacuo. Ethyl acetate and water were added to the residue and the mixture was stirred at room temperature for 1hr. Precipitates were collected and washed successively with water, ethyl acetate, and air dried 10 to give the target compound (12.57g, 48.6%) as a powder. 1HNMR (DMSO-d6) : 6 2.49(1H, dd, J=8.3, 16.lHz), 3.29(lH, dd, J=10.2,16.lHz), 3.60(3H, s), 4.69(1H, dd, J=8.3,10.2Hz), 5.06(2H, s), 5.62(2H, s), 6.65(4H, s), 6.97(2H, d, J=8.6Hz), 15 7.25(2H, d, J=8.6Hz), 7.31-7.48(SH, m). MS : (ESI+) : m/z 374 (M+H). Example 14-2 5-[4-(Benzyloxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol 20 3-amine MnO 2 (3.5g) was added to a solution of 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-4,5 dihydro-lH-pyrazol-3-amine obtained by Example 14-1 25 (12.54g) in N,N-dimethylformamide (65ml) and the mixture was stirred at 60"C for 2hrs. MnO 2 (5.3g) was added and the mixture was stirred at 6 0 C for lhr. The mixture was filtered through a celite pad and the pad was washed with N,N-dimethylformamide. To the filtrate 30 were added ethyl acetate and water, and the mixture was stirred at room temperature for lhr. Precipitates were collected and washed with water and air dried. The obtained 39 WO 2004/050632 PCT/JP2003/014489 powder was suspended in hot isopropylether cooled with stirring, collected and washed with isopropylether to give the target compound (ll.70g, 93.8%) as a powder. 5 1H NMR (DMSO-d6) : 6 3.74(3H, s), 4.84(2H, s), 5.08 (2H, s), 5.73(1H, s), 6.87 (2H, d, J=9.0Hz), 6.96(2H, d, J=9.OHz), 7.03-7.13(4H, m), 7.34-7.47(5H, m). MS (ESI+) : m/z 372 (M+H). 10 Example 15 5-[4-(Benzyloxy)phenyl]-1-(4-methoxyphenyl)-N,N dimethyl-1H-pyrazol-3-amine 37% Aqueous formamide solution (6ml) and sodium 15 cyanoborohydride (1.39g) were added successively to a so lution of 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl) 1H-pyrazol-3-amine obtained by Example 14-2 (2.75g) in methanol 30ml. The reaction mixture was stirred at room temperature for 3days, occasionally adding 37% aqueous 20 formamide solution and sodium cyanoborohydride appropriate amount to consume all starting material. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium 25 chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 20% ethyl acetate/chloroform to give the target compound (0.88g, 29.8%) as an oil. 30 1H NMR (DMSO-d6) : 2.81(6H, s), 3.75(3H, s), 5.08(2H, s), 6.03(1H, s), 6.90(2H, d, J=8.9Hz), 6.97(2H, d, J=8.8Hz), 40 WO 2004/050632 PCT/JP2003/014489 7.06-7.16(4H, m), 7.32-7.46(5H, m). MS (ESI+) : m/z 400 (M+H). Example 16 5 4-[3-(Dimethylamino)-1-(4-methoxyphenyl)-lH-pyrazol-5 yl]phenol A mixture of 5-[4-(benzyloxy)phenyl] -1-(4-methoxy phenyl)-N,N-dimethyl-lH-pyrazol-3-amine obtained by 10 Example 15 (0.83g) and 10% Pd-C 50% wet (160mg) in acetic acid (8ml) was hydrogenated under H 2 latm at room temperature for 10hrs. The catalyst was removed by filtration. The filtrate and combined washings were concentrated in vacuo. The 15 residue was purified by silica gel column chromatography eluted with 20% ethyl acetate/chloroform and was crystallized from a mixture of isopropylether and ethyl acetate to give the target compound (455mg, 70.8%) asawhite powder. 20 1H NMR (DMSO-d6) : 6 2.80(6H, s), 3.74(3H, s), 5.96(lH, s), 6.69(2H, d, J=8.5Hz), 6.89(2H, d, J=9.0Ez), 7.01(2H, d, J=8.5Hz), 7.09(2H, d, J=9.OHz), 9.64(1H, s). MS (ESI+) : m/z 310 (M+H). 25 Example 17 tert-Butyl 2-{4-[3-(dimethylamino)-1-(4-methoxyphenyl) 1H-pyrazol-5-yllphenoxy}ethylcarbanate 30 The title compound (477.1mg, 99.7%) was prepared as an oil from 4-[3-(dimethylamino)-l-(4-methoxyphenyl) 1H-pyrazol-5-yl]phenol obtained by Example 16 in a 41 WO 2004/050632 PCT/JP2003/014489 similar manner to that of Example 2. 1H NMR (CDCl 3 ) : 6 1.45(9H, s), 2.93(6H, s), 3.48-3.54 (2 H, m), 3.79(3H, s), 3.97-4.03(2H, m), 4.97 (1H, br), 5.85 5 (1H, s), 6.79(2H, d, J=8.7Hz), 6.81(2H, d, J=9.OHz), 7.1 0-7.27(4H, m). Example 18 5-[4-(2-Aminoethoxy)phenyl]-1-(4-methoxyphenyl)-N,N 10 dimethyl-lH-pyrazol-3-amine hydrochloride The title compound (454mg, quant.) was prepared as an amorphous from tert-butyl 2-{4-[3-(dimethylamino)-l (4-methoxyphenyl).-1H-pyrazol-5-yljphenoxy}ethyl 15 carbamate obtained by Example 17 in a similar manner to that of Example 3. 1H NMR (DMSO-d6) : 6 2.83(6H, s), 3.16-3.25(2H, m), 3.7 5(3H, s), 4.13-4.18(2H, m), 6.06(1H, s), 6.91(2H, d, J=9. 20 0Hz), 6.94 (2H, d, J=8.8Hz), 7.12(2H, d, J=9.OHz), 7.17(2 H, d, J=8.8Hz), 8.05(2H, br-s). MS (ESI+) : m/z 353 (M+H). Example 19 25 N-(2-{4-[3-(Dimethylamino)-1-(4-methoxyphenyl)-1H pyrazol-5-yllphenoxy}ethyl)urea The title compound (116mg, 55.7%) was prepared as an amorphous from 5-[4-(2-aminoethoxy)phenyl]-1-(4 30 methoxyphenyl)-N,N-dimethyl-1H-pyrazol-3-amine hydrochloride obtained by Example 18 in a similar manner to that of Example 75 described later. 42 WO 2004/050632 PCT/JP2003/014489 1H NMR (DMSO-d6) : 2.81(6H, s), 3.29-3.34(2H, m), 3.7 4(3H, s), 3.92(2H, t, J=5.6Hz), 5.53(2H, s), 6.03(1H, s), 6.15(1H, t, J=5.6Hz), 6.88-6.92(4H, m), 7.04-7.14(4H, 5 m). IR (neat) : 3344, 3330, 3321, 1658, 1651, 1643, 1612, 1579, 1564, 1554, 1529, 1514cm 1 . MS (ESI+) : m/z 396 (M+H). 10 Example 20-1 5- [4- (Methoxymethoxy)phenyl] -1- (4-methoxyphenyl) -4,5 dihydro-lH-pyrazol-3-amine The title compound (4.0g, 57.8%) was prepared as a 15 powder from 3-(4-methoxymethoxyphenyl)acrylonitrile in a similar manner to that of Example 14-1. 1H NMR (DMSO-d6) : 5 2.49(1H, dd, J=8.3, 16.1Hz), 3.30(1H, dd, J=10. 3, 16.1Hz), 3.36 (3H, s), 3.59 (3H, s), 4.70 (1H, dd, 20 J=8.3, 10.3Hz), 5.16(2H, s), 5.62 (2H, s), 6.65(4H, s), 6.97(2H, d, J=8.6Hz), 7.25(2H, d, J=8.6Hz). MS (ESI+) : m/z 328 (M+H). Example 20-2 25 5-[4-(Methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-iH pyrazol-3-amine The title compound (4.80g, quant.) was prepared as an oil from 5-[4-(methoxymethoxy)phenyl]-1-(4-methoxy 30 phenyl) -4, 5-dihydro-1H-pyrazol-3-amine obtained by Example 20-1 in a similar manner to that of Example 14-2. 43 WO 2004/050632 PCT/JP2003/014489 1H NMR (DMSO-d6) : 3.36(3H, s), 3.74 (3H, s), 4.85(2H, s), 5.18(2H, s), 5.74(1H, s), 6.88(2H, d, J=9.OHz), 6.96 (2H, d, J=8.8Hz), 7.02-7.13(4H, m). 5 MS (EST+) : m/z 326 (M+H). Example 21 3-Chloro-5- [4- (methoxymethoxy) phenyl] -1- (4-methoxy phenyl)-lH-pyrazole 10 A mixture of 5- [4- (methoxymethoxy)phenyl] -1- (4 methoxyphenyl) -lH-pyrazol-3-amine obtained by Example 20-2 (3.79g), lithium chloride (2.47g), and copper(II) chloride (3.13g) in acetonitrile (60ml) was stirred at 15 room temperature for 10min. To this mixture was added isoamyl nitrite (2.73g), and the mixture was stirred at room temperature for 1hr. The mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic 20 layer was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 30% ethyl acetate/n-hexane. The solvent was 25 evaporated in vacuo. The residue was crystallized from a mixture of isopropyl ether and ethyl acetate to give the target compound (2.38g, 59.3%) as a white powder. 1H NMR (CDCl 3 ) : 6 3.48(3H, s), 3.82(3H, s), 5.17(2H, s), 30 6.36(1H, s), 6.85(2H, d, J=9.OHz), 6.95(2H, d, J=8.9Hz), 7.12(2H, d, J=8.9Hz), 7.20(2H, d, J=9.OHz). MS (ESTI+) : m/z 345(M+H). 44 WO 2004/050632 PCT/JP2003/014489 Example 22 4-[3-Chloro-1-(4-methoxyphenyl)-lH-pyrazol-5-yl]phenol 5 To a solution of 3-chloro-5-[4-(methoxymethoxy) phenyl]-1-(4-methoxyphenyl)-lH-pyrazole obtained by Example 21 (2.35g) in tetrahydrofuran (10ml) and methanol (10ml) was added 36% hydrochloric acid (0.34ml) . The reaction mixture was stirred at room temperature for lhr, 10 at 50 C for 1.5hrs, and at 60 0 C for 1.5hrs. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue solid was collected and 15 washed with a mixture of isopropylether and n-hexane to give the target compound (1.99g, 97.1%) as a white powder. 1H NMR (DMSO-d6) : 6 3.78 (3H, s), 6.62(1H, s), 6.71(2H, d, J=8.7Hz), 6.96(2H, d, J=9.0Hz), 7.03(2H, d, J=8.7Hz), 20 7.19(2H, d, J=9.0Hz), 9.80(lH, s). 200MHz 1H NMR (CDC1 3 ) : 3.82 (3H, s), 5.24 (1H, s), 6.35(1H, s), 6.75(2H, d, J=8.6Hz), 6.84(2H, d, J=9.OHz), 7.07(2H, d, J=8.6Hz), 7.18(2H, d, J=9.OHz). MS (ESI+) : m/z 301 (M+H) 25 Example 23 2-{4-[3-Chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl] phenoxylethanol 30 Sodium hydride 60% dispersion in mineral oil (31.1mg) was added to a solution of 4- [3-chloro-1- (4-methoxyphenyl) 1H-pyrazol-5-yl]phenol obtained by Example 22 (180mg) in 45 WO 2004/050632 PCT/JP2003/014489 N,N-dimethylformamide (2ml) under cooling in an ice bath. The reaction mixture was stirred at room temperature for lhr. To the reaction mixture was added a solution of 2-bromoethyl tert-butyl(dimethyl)silyl ether (258mg) in 5 N,N-dimethylformamide (2ml). After stirring at room temperature overnight, the mixture was poured into ice water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over 10 magnesium sulfate, and concentrated in vacuo. The residue was dissolvedinethanol (3.6ml). Tothissolutionwas added 36% aqueous hydrochloric acid (0.3ml) . After stirring at room temperature for 3 hrs, the mixture was concentrated invacuo. The residue was partitioned between ethyl acetate 15 and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed 20 by 70% ethyl acetate/n-hexane. The separate silica gel was extracted with 10% methanol/chloroform and the solvent was evaporated in vacuo. The residue was crystallized from a mixture of isopropylether and ethyl acetate to give the target compound (136.4mg, 66.1%) as a white powder. 25 MP : 114.7-115.5C. 1HNMR (DMSO-d6) : 6 3.64-3.73(2H, m), 3.77(3H, s), 3.97(2H, t, J=4.9Hz), 4.86(lH, t, J=5.4Hz), 6.68(1H, s), 6.91(2H, d, J=8.9Hz), 6.96(2H, d, J=8.9Hz), 7.15(2H, d, J=8.9Hz), 30 7.20(2H, d, J=8.9Hz). IR(KBr) : 3521, 1610, 1518cm-. MS (ESI+) : m/z 345 (M+H). 46 WO 2004/050632 PCT/JP2003/014489 Example 24 tert-Butyl 2-{4-[3-chloro-l-(4-methoxyphenyl)-lH pyrazol-5-yl]phenoxy}ethylcarbamate 5 The title compound (329.5mg, 22.3%) was prepared as an amorphous from 4-[3-chloro-l-(4-methoxyphenyl)-1H pyrazol-5-yl]phenol obtained by Example 22 in a similar manner to that of Example 73 described later. 10 1HNMR (CDCl 3 ) : 1.45(9H, s), 3.48-3.57(2H, m), 3.81(3H, s), 4.00(2H, t, J=5.lHz), 4.96(lH, br), 6.35(1H, s), 6.81( 2 H, d, J=8.8Hz), 6.84(2H, d, J=8.9Hz), 7.12(2H, d, J=8.8Hz), 7.18(2H, d, J=8.9Hz). 15 MS (ESI+) : m/z 444 (M+H). Example 25 tert-Butyl 2-{4-[3-chloro-1-(4-methoxyphenyl)-1H pyrazol-5-yl]phenoxylethylcarbamate 20 The title compound (1.31g, 97.8%) was prepared from 4-[3-chloro-l-(4-methoxyphenyl)-lH-pyrazol-5-yl]phenol obtained by Example 22 in a similar manner to that of Example 2. 25 MS (ESI+) : m/z 444 (M+H). Example 26 2-{4-[3-Chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl] 30 phenoxylethanamine hydrochloride The title compound (605.2mg, 85.4%) was prepared as 47 WO 2004/050632 PCT/JP2003/014489 a white powder from tert-butyl 2-{4-[3-chloro-1-(4 methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate obtained by Example 25 in a similar manner to that of Example 3. 5 1H NMR (DMSO-d6) : 3.14-3.23(2H, m), 3.78 (3H, s), 4.14-4.20(2H, m), 6.70 (1H, s), 6.96(2H, d, J=8.8Hz), 6.97 (2H, d, J=8.9Hz), 7.19(2H, d, J=8.8Hz), 7.21(2H, d, J=8.9Hz), 8.19 (2H, br-s) . 10 MS (ESI+) : m/z 344 (M+H). Example 27 N-(2-{4-[3-chloro-l-(4-methoxyphenyl)-lH-pyrazol-5-yl] phenoxyIethyl)methanesulfonamide 15 The title compound (137.8mg, 82.8%) was prepared as a white powder from 2-{4-[3-chloro-l-(4-methoxyphenyl) 1H-pyrazol-5-yl]phenoxy)ethanamine hydrochloride obtained by Example 26 in a similar manner to that of 20 Example 4. MP : 117-119 0 C. 1HNMR (DMSO-d6) : 5 2.94 (3H, s) , 3.27-3.34 (2H, m) , 3.76(3H, s), 4.02(2H, t, J=5.5Hz), 6.69(1H, s), 6.90-7.01(4H, m), 25 7.14-7.25(4H, m), 7.28(lH, t, J=5.7Hz). IR (KBr) 1612, 1516cm1. MS (ESI+) m/z 422(M+H). Example 28 30 N-(2-{4-[3-Chloro-l-(4-methoxyphenyl)-lH-pyrazol-5-yl] phenoxylethyl)urea 48 WO 2004/050632 PCT/JP2003/014489 The title compound (174.6mg, 85.8%) was prepared as a white powder from 2-14-[3-chloro-l-(4-methoxyphenyl) 1H-pyrazol-5-yl]phenoxy}ethanamine hydrochloride obtain ed by Example 26 in a similar manner to that of Example 5 75 described later. MP : 144.8-145.40C. 1HNMR (DMSO-d6) : 6 3.27-3.34(2H, m), 3.77 (3H, s), 3.93 (2H, t, J=5.5Hz), 5.52(2H, s), 6.15(1H, t, J=5.7Hz), 6.68(1H, 10 s), 6.92(2H, d, J=9.0Hz), 6.97(2H, d, J=9.0Hz), 7.15(2H, d, J=9.0Hz), 7.20(2H, d, J=9.0Hz). IR (ATR) : 3423, 3402, 3203, 3143, 3010, 2976, 2943, 2885, 1651, 1610, 1583, 1516cm- 1 . MS (ESI+) : m/z 387 (M+H). 15 Example 29-1 5-[4-(Methoxymethoxy)phenyl]-1-(6-methoxy-3-pyridinyl) 4,5-dihydrc-lH-pyrazol-3-amine 20 The title compound (1.63g, 41.2%) was prepared as a powder from 3-(4-methoxymethoxyphenyl)acrylonitrile and 2-methoxy-5-pyridinylhydrazine dihydrochloride in a similar manner to that of Example 14-1. 25 H NMR (DMSO-d6) : 6 2.48-2.60(1H, dd, overlapping), 3.23-3.34(1lH, dd, overlapping), 3.36(3H, s), 3.68(3H, s), 4.75(lH, dd, J=8.6, 10.0Hz), 5.16(2H, s), 5.77(2H, s), 6.56(1H, d, J=8.8Hz), 6.98(2H, d, J=8.6Hz), 7.15(1H, dd, J=2.8, 8.8Hz), 7.27(2H, d, J=8.6Hz), 7.49(1H, d, J=2.8Hz). 30 MS (ESI+) : m/z 329 (M+H). Example 29-2 49 WO 2004/050632 PCT/JP2003/014489 5-[4-(Methoxymethoxy)phenyl]-1-(6-methoxy-3-pyridinyl) 1H-pyrazol-3-amine The title compound (1.77g, quant.) was prepared as 5 an oil from 5-[4-(methoxymethoxy)phenyl]-1-(6-methoxy 3-pyridinyl)-4,5-dihydro-1H-pyrazol-3-amine obtained by Example 29-1 in a similar manner to that of Example 14 2. 10 1H NMR (DMSO-d6) :5 3.37(3H, s), 3.83(3H, s), 4.97(2H, s), 5.19 (2H, s), 5.78 (1H, s), 6.81 (1H, d, J=8.9Hz), 6.99(2H, d, J=8.8Hz) , 7.15 (2H, d, J=8.8Hz) , 7.51 (1H, dd, J=2.7, 8.9Hz), 7.92(lH, d, J=2.7Hz). MS (ESI+) : m/z 327 (M+H). 15 Example 30 5-{3-Chloro-5-[4-(methoxymethoxy)phenyl]-1H-pyrazol-l yl}-2-methoxypyridine 20 The title compound (981.7mg, 57.9%) was prepared as a powder from 5-[4-(methoxymethoxy)phenyl]-l-(6 methoxy-3-pyridinyl)-1H-pyrazol-3-amine obtained by Example 29-2 in a similar manner to that of Example 21. 25 1H NMR (CDCl 3 ) : & 3.48 (3H, s), 3.93(3H, s), 5.18(2H, s), 6.39(1H, s), 6.74(lH, d, J=8.8Hz), 6.99(2H, d, J=8.8Hz), 7.13(2H, d, J=8.8Hz), 7.55(1H, dd, J=2.7, 8.8Hz), 8.05 (1H, d, J=2.7Hz). MS (ESI+) : m/z 346 (M+H). 30 Example 31 4-[3-Chloro-1-(6-methoxy-3-pyridinyl)-lH-pyrazol-5-yl] 50 WO 2004/050632 PCT/JP2003/014489 phenol The title compound (2.15g, 80.5%) was prepared as a white powder from 5-{3-chloro-5-[4-(methoxymethoxy) 5 phenyl]-1H-pyrazol-1-yl}-2-methoxypyridine obtained by Example 30 in a similar manner to that of Example 22. 1H NMR (DMSO-d6) : 6 3.87(3H, s), 6.68(1H, s), 6.74 (2H, d, J=8.6Hz), 6.89(1H, d, J=8.8Hz), 7.07(2H, d, J=8.6Hz), 10 7.65(lH, dd, J=2.7, 8.8Hz), 8.09(1H, d, J=2.7Hz), 9.86 (1H, br-s). MS (ESI+) : m/z 302 (M+H). Example 32 15 2-{4-[3-Chloro-l-(6-methoxy-3-pyridinyl)-1H-pyrazol-5 yl]phenoxy}ethanol The title compound (140.9mg, 86%) was prepared as a white powder from 4-[3-chloro-1-(6-methoxy-3 20 pyridinyl)-1H-pyrazol-5-yl]phenol obtained by Example 31 in a similar manner to that of Example 23. MP : 136.5-138.2 0 C. 1H NMR (DMSO-d6) : 6 3.65-3.74(2H, m), 3.87(3H, s), 3.9 25 8(2H, t, J=4.9Hz), 4.87(1H, t,, J=5.5Hz), 6.74 (lH, s), 6. 86-6.98(3H, m), 7.19(2H, d, J=8.8Hz), 7.67 (11, dd, J=2.8, 8.8Hz), 8.10(1H, d, J=2.8Hz). IR (KBr) 3369, 2960, 1610, 1502cma. MS (ESI+) m/z 346 (M+H). 30 Example 33 tert-Butyl 2-{4-[3-chloro-l-(6-methoxy-3-pyridinyl)-lH 51 WO 2004/050632 PCT/JP2003/014489 pyrazol-5-yl]phenoxylethylcarbamate The title compound (964mg, 93.4%) was prepared as a white solid from 4-[3-chloro-l-(6-methoxy-3-pyridinyl) 5 1H-pyrazol-5-yl]phenol obtained by Example 31 in a similar manner to that of Example 2. IH NMR (DMSO-d6) : 6 1.37(9H, s), 3.22-3.33(2H, m), 3.8 7(3H, s), 3.95(2H, t, J=5.7Hz), 6.74(lH, s), 6.86-7.04(4 10 H, m), 7.19(2H, d, J=8.7Hz), 7.67 (1H, dd, J=2.7, 8.8Hz), 8.11(1H, d, J=2.7Hz). MS (ESI+) : m/z 445 (M+H). Example 34 15 2-{4-[3-Chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5 yl]phenoxy}-ethanamine dihydrochloride The title compound (842mg, 98.6%) was prepared as an amorphous from tert-butyl 2-{4-[3-chloro-1-(6-methoxy 20 3-pyridinyl)-1H-pyrazol-5-yl]phenoxylethylcarbamate obtained by Example 33 in a similar manner to that of Example 3. 1H NMR (DMSO-d6) : 3.15-3.24(2H, m), 3.87(3H, s), 4.1 25 9(2H, t, J=4.9Hz), 6.76(lH, s), 6.90(1H, d, J=8.8Hz), 6. 99(2H, d, J=8.8Hz), 7.23(2H, d, J=8.8Hz), 7.68(1H, d, J= 2.7, 8.8Hz), 8.10(1H, d, J=2.7Hz), 8.20(2H, br-s). MS (ESI+) : m/z 345 (M+H). 30 Example 35 N-(2-{4-[3-Chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol 52 WO 2004/050632 PCT/JP2003/014489 5-yl]phenoxylethyl)urea The title compound (119.5mg, 62.4%) was prepared as a white powder from 2 -{4-[3-chloro-l-(6-methoxy-3 5 pyridinyl)-lH-pyrazol-5-yl]phenoxy}ethanamine dihydrochloride obtained by Example 34 in a similar manner to that of Example 75 described later. MP : 155.6-157.9 0 C. 10 1H NMR (DMSO-d6) : & 3.27-3.34(2H, m), 3.87(3H, s), 3.9 4(2H, t, J=5.5Hz), 5.53(2H, s), 6.15(1H, t, J=5.5Hz), 6. 75(1H, s), 6.89(1H, d, J=8.8Hz), 6.95(2H, d, J=8.8Hz), 7. 19(2H, d, J=8.8Hz), 7.66(1H, dd, J=2.7, 8.8Hz), 8.11(lH, d, J=2.7Hz). 15 IR (KBr) : 3425, 3415, 3319, 1657, 1610, 1591, 1581, 1574, 1500cm~1. Example 36 5-[4-(Benzyloxy)phenyl]-3-isopropoxy-l-(4-methoxy 20 phenyl)-1H-pyrazole A mixture of 5-[4-(benzyloxy)phenyl]-3-hydroxy-l (4-methoxyphenyl)-lH-pyrazol (2.4g), 2-iodopropane (5.4 8g), and potassium carbonate (2.67g) in N,N-dimethyl 25 formamide (10ml) was stirred at 100 0 C for 3hrs. The reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate. Theorganiclayer was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated 30 in vacuo. The residue was purified by silica gel column chromatography eluted with 20% ethyl acetate/n-hexane and the solvent was evaporated in vacuo. The residue was 53 WO 2004/050632 PCT/JP2003/014489 recrystallized from a mixture of ethyl acetate and n-hexane togive the target compound (2.14g, 80.1%) asawhite powder. 1H NMR (DMSO-d6) : & 1.31(6H, d, J=6.lHz), 3.76(3H, s), 5 4.75(1H, m), 5.08 (2H, s), 6.00(1H, s), 6.92(2H, d, J=9.OHz), 6.97(2H, d, J=8.9Hz), 7.10-7.16(4H, m), 7.34-7.43(5H, m). MS (ESI+) : m/z 415 (M+H). Example 37 10 4-[3-Isopropoxy-l-(4-methoxyphenyl)--1H-pyrazol-5-yll phenol To a solution of ammonium formate (954mg) in water (2ml) were added ethanol (10ml), a solution of 5-[4-(benzyl 15 oxy)phenyl]-3-isopropoxy-l-(4-methoxyphenyl)-lH pyrazole obtained by Example 36 (2. 09g) in tetrahydrofuran (10ml), and 10% palladium on carbon 50% wet (200mg) successively. The mixture was refluxed for lhr. The catalyst was removed by filtration and washed with 20 ethyl acetate. The filtrate and combined washings were concentrated in vacuo. Ethyl acetate and water were added totheresidue. Precipitateswere collectedandwashedwith water and ethyl acetate to give the first crop of the target compound (419mg) as a white powder. The filtrate was 25 partitioned, and the organic layer was saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated invacuo. The residue crystals were collected and washed with isopropylether to give the second crop of the target compound (1.19g, 72.5%) as a white powder. 30 1H NMR (DMSO-d6) 6 1.31(6H, d, J=6.2Hz), 3.75(3H, s), 4.75(1H, m), 5.93(1H, s), 6.70(2H, d, J=8.6Hz), 6.91(2H, 54 WO 2004/050632 PCT/JP2003/014489 d, J=9.OHz), 7.01(2H, d, J=8.6Hz), 7.11(2H, d, J=9.OHz), 9.70(1H, s). MS (ESI+) : m/z 325 (M+H) 5 Example 38 2

-{

4

-[

3 -Isopropoxy-l-(4-methoxyphenyl)-H-pyrazol-5 yl]phenoxylethanol The title compound (147.3mg, 88.2%) was prepared as 10 an oil from 4

-[

3 -isopropoxy-1-(4-methoxyphenyl)-lH pyrazol-5-yl]phenol obtained by Example 37 in a similar manner to that of Example 23. 1H NMR (CDCl 3 ) : ( 1.40(6H, d, J=6.2Hz), 2.02(lH, t, J=5. 15 8Hz), 3.79(3H, s), 3.94-4.00(2H, m), 4.04-4.10(2H, m), 4. 87(1H, m), 5.85(lH, s), 6.81(2H, d, J=9.0Hz), 6.82(2H, d, J=8.9Hz), 7.10-7.21(4H, m). IR (neat) : 3400, 3369, 2974, 2933, 1612, 1514cm-1. MS (ESI+) : m/z 369 (M+H). 20 Example 39 tert-Butyl 2

-{

4

-[

3 -isopropoxy-l-(4-methoxyphenyl)-lH pyrazol-5-yl]phenoxy}ethylcarbamate 25 The title compound (520mg, 72.2%) was prepared as a white powder from 4-[3-isopropoxy-1-(4-methoxyphenyl) 1H-pyrazol-5-yl]phenol obtained by Example 37 in a similar manner to that of Example 2. 30 1H NMR (DMSO-d6) : 5 1.31(6H, d, J=6.2Hz), 1.37(9H, s), 3.22-3.31(2H, m), 3.75(3H, s), 3.90-3.97(2H, m), 4.76(1H, m), 5.99(H, s), 6.86-6.96(4H, m), 7.01(lH, t, J=5.6Hz), 55 WO 2004/050632 PCT/JP2003/014489 7.09-7.15(4H, m). MS (EST+) : m/z 467 (M+H). Example 40 5 2-{4-[3-Isopropoxy-l-(4-methoxyphenyl)-1H-pyrazol-5 yl]phenoxy}ethanamine hydrochloride The title compound (557mg, quant.) was prepared as an amorphous from tert-butyl 2-{4-[3-isopropoxy-l-(4 10 methoxyphenyl)-1H-pyrazol-5-yllphenoxy)ethylcarbamate obtained by Example 39 in a similar manner to that of Example 3. 1H NMR (DMSO-d6) 0 1.31(6H, d, J=6.1Hz), 3.12-3.28 (2H, 15 m), 3.76(3H, s), 4.00-4.18(2H, m), 4.76(lH, m), 6.01(1H, s), 6.92(2H, d, J=9.0Hz), 6.94(2H, d, J=8.7Hz), 7.10-7. 19(4H, m), 8.06(2H, br-s). MS (EST+) : m/z 368 (M+H). 20 Example 41 N-(2-{4-[3-Isopropoxy-l-(4-methoxyphenyl)-lH-pyrazol-5 yl]phenoxy}ethyl)methanesulfonamide The title compound (125mg, 79.8%) was prepared as a 25 white powder from 2-{4-[3-isopropoxy-l-(4-methoxy phenyl)-lH-pyrazol-5-yl]phenoxylethanamine hydrochloride obtained by Example 40 in a similar manner to that of Example 4. 30 MP : 167.9-168.0 0 C. 1H NMR (DMSO-d6) 0 1.31(6H, d, J=6.1Hz), 2.94 (3H, s), 3.27-3.36 56 WO 2004/050632 PCT/JP2003/014489 (2H, m), 3.75(3H, s), 3.98-4.05(2H, m), 4.76(1H, m), 6.0 0(1H, s), 6.88-6.94(4H, m), 7.12(2H, d, J=9.OHz), 7.14(2 H, d, J=8.9Hz), 7.29(1H, t, J=5.8Hz). IR (KBr) 3132, 2979, 2939, 1612, 1556, 1518cm-. 5 MS (ESI+) m/z 446 (M+H). Example 42 N-(2-{4-[3-Isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5 yllphenoxylethyl)urea 10 The title compound (76.3mg, 50.1%) was prepared as a white powder from 2-{4-[3-isopropoxy-1-(4-methoxy phenyl)-1H-pyrazol-5-yl]phenoxy}ethanamine hydrochlorid e obtained by Example 40 in a similar manner to that of 15 Example 75 described later. MP : 139-140 0 C. 1H NMR (DMSO-d6) : 1.31(6H, d, J=6.1Hz), 3.27-3.35(2H, m), 3.75(3H, s), 3.89-3.96(2H, m), 4.76(1H, m), 5.53(2H, 20 s), 6.00(1H, s), 6.15(1H, t, J=5.7Hz), 6.90(2H, d, J=8. 9Hz), 6.92(2H, d, J=9.0Hz), 7.08-7.15(4H, m). IR (KBr) : 3388, 3350, 3332, 1658, 1612, 1579, 1562, 1554, 1518cm. 25 MS (ESI+) : m/z 411 (M+H) Example 43 5-[4-(Benzyloxy)phenyl]-1-(6-methoxy-3-pyridinyl)-1H pyrazol-3-ol 30 To a solution of 3-(4-benzyloxyphenyl)propiolic acid (lg) and 1-hydroxybenzotriazole hydrate (643mg) in 57 WO 2004/050632 PCT/JP2003/014489 N-methylpyrrolidone (10ml) was added WSCD-HC1 (912mg) and the mixture was stirred at room temperature for 10min. In another flask, diisopropylethylamine ( 2

.

3 1g) was added to a suspension of 5-hydrazino-2-methoxypyridine 5 dihydrochloride (1.26g) in N-methylpyrrolidone (4ml) and stirred at room temperature until all 5-hydrazino-2-methoxypyridine dihydrochloride was dissolved. Thus obtained hydrazine solution was added to the reaction flask and the mixture was stirred at room 10 temperature for 1.5hrs. The mixture was partitioned between ethyl acetate and 0. 1M hydrochloric acid, and the aqueous layer was reextracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and 15 saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in dichloroethane (15ml) and tetrakis(triphenylphosphine)palladium(0) (45.8mg) was added. The mixture was refluxed for 1hr and then 20 concentrated in vacuo. The residue was crystallized from ethyl acetate to give the target compound (739,mg, 49.9%) as a powder. 1H NMR (DMSO-d6) : 3.84(3H, s), 5.10(2H, s), 5.87(lH, 25 s), 6.83(1H, d, J=8.7Hz), 7.00(2H, d, J=8.7Hz), 7.16(2H, d, J=8.7Hz), 7.29-7.48(5H, m), 7.54(lH, dd, J=2.6, 8.7Hz), 7.97(lH, d, J=2.6Hz), 10.13(1H, s). MS (ESI+) : m/z (M+H). 30 Example 44 5-{5-[4-(Benzyloxy)phenyll-3-isopropoxy-1H-pyrazol-l yl}-2-methoxypyridine 58 WO 2004/050632 PCT/JP2003/014489 The title compound (1.33g, quant.) was prepared as a powder from 5-[4-(benzyloxy)phenyl]-1-(6-methoxy-3 pyridinyl)-1H-pyrazol-3-ol obtained by Example 43 in a 5 similar manner to that of Example 36. 1H NMR (CDCl 3 ) : 5 1.40(6H, d, J=6.2Hz), 3.92(3H, s), 4. 86(lH, m), 5.05(2H, s), 5.87(1H, s), 6.69(1H, d, J=8.8H z), 6.91(2H, d, J=8.8Hz), 7.15(2H, d, J=8.8Hz), 7.35-7.4 10 3(5H, m), 7.51(lH, dd, J=2.7, 8.8Hz), 8.04(1H, d, J=2.7H z). MS (ESI+) : m/z 416 (M+H). Example 45 15 4-[3-Isopropoxy-1-(6-methoxy-3-pyridinyl)-lH-pyrazol-5 yl]phenol The title compound (442.5mg, 54.9%) was prepared as a powder from 5-{5-[4-(benzyloxy)phenyl]-3-isopropoxy 20 1H-pyrazol-1-yl}-2-methoxypyridine obtained by Example 44 in a similar manner to that of Example 37. 1H NMR (CDCl 3 ) : 1.40(6H, d, J=6.2Hz), 3.91 (3H, s), 4. 84(1H, m), 5.80(1H, s), 5.87(1H, s), 6.71(1H, d, J=8.8H 25 z), 6.75(2H, d, J=8.6Hz), 7.08 (2H, d, J=8.6Hz), 7.55(1H, dd, J=2.7, 8.8Hz), 8.00(1H, d, J=2.7Hz). MS (ESI+) : m/z 326 (M+H). Example 46 30 2-{4-[3-Isopropoxy-l-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl]phenoxylethanol 59 WO 2004/050632 PCT/JP2003/014489 The title compound (94.6mg, 52.2%) was prepared as a white powder from 4-[3-isopropoxy-1-(6-methoxy-3 pyridinyl) -1H-pyrazol-5-yll phenol obtained by Example 45 in a similar manner to that of Example 23. 5 MP 74-75 0 C. 1H NMR (CDCl 3 ) : 1.40(6H, d, J=6.1Hz), 1.99(1H, t, J=6. 1Hz), 3.91(3H, s), 3.94-4.00(2H, m), 4.05-4.11(2H, m), 4. 86(1H, m), 5.88(1H, s), 6.69(1H, d, J=8.7Hz), 6.85(2H, d, 10 J=8.7Hz), 7.15(2H, d, J=8.7Hz), 7.51(1H, dd, J=2.7, 8.7 Hz), 8.03(1H, d, J=2.7Hz). IR (KBr) 3350, 1612, 1512, 1500cm'. MS (ESI+) m/z 370 (M+H). 15 Example 47 tert-Butyl 2-{4-[3-isopropoxy-l-(6-methoxy-3 pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate The title compound (515.3mg, 87.6%) was prepared as 20 a powder from 4-[3-isopropoxy-l-(6-methoxy-3 pyridinyl) -1H-pyrazol-5-yl]phenol obtained by Example 45 in a similar manner to that of Example 2. 1H NMR (DMSO-d6) : 1.32(6H, d, J=6.2Hz), 1.37(9H, s), 25 3.22-3.34(2H, m), 3. 84(3H, s), 3.92(2H, t, J=5.7Hz), 4.7 7(1H, m), 6.06(1H, s), 6.84(1H, d, J=8.8Hz), 6.91(2H, d, J=8.8Hz), 7.01(1K, t, J=5.5Hz), 7.16(2H, d, J=8.8Hz), 7. 58(1H, dd, J=2.7, 8.8Hz), 7.99(1K, d, J=2.7Hz). 30 Example 48 2-{4-[3-Isopropoxy-l-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl]phenoxy}ethanamine dihydrochloride 60 WO 2004/050632 PCT/JP2003/014489 The title compound (531mg, quaint ) was prepared as an amorphous from tert-butyl 2-{4-[3-isopropoxy-l-(6 methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxylethyl 5 carbamate obtained by Example 47 in a similar manner to that of Example 3. 1H NMR (DMSO-d6) : 6 1.32(6H, d, J=6.lHz), 3.15-3.24(2H, m), 3.84(3H, s), 4.19(2H, t, J=4.9Hz), 4.77(lH, m), 6.0 10 7(1H, s), 6.85(lH, d, J=8.8Hz), 6.97(2H, d, J=8.8Hz), 7. 21(2H, d, J=8.8Hz), 7.60(lH, dd, J=2.7, 8.8Hz), 7.99(1H, d, J=2.7Hz), 8.22(2H, br-s). MS (ESI+) : m/z 369 (M+H). 15 Example 49 N-(2-{4-[3-Isopropoxy-l-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl]phenoxylethyl)urea The title compound (81.4mg, 60.2%) was prepared as a 20 white powder from 2 -{4-[3-isopropoxy-l-(6-methoxy-3 pyridinyl)-lH-pyrazol-5-yl]phenoxy}ethanamine dihydrochloride obtained by Example 48 in a similar manner to that of Example 75 described later. 25 MP : 120 0 C. 1H NMR (DMSO-d6) : 1.32(6H, d, J=6.2Hz), 3.27-3.36(2H, m), 3.84 (3H, s), 3.94(2H, t, J=5.5Hz), 4.77(1H, m), 5.5 2(2H, s), 6.06(1H, s), 6.15(lH, t, J=5.6Hz), 6.84(lH, d, J=8.8Hz), 6.93(2H, d, J=8.8Hz), 7.17(2H, d, J=8.8Hz), 7. 30 58(1H, dd, J=2.7, 8.8Hz), 7.99(lH, d, J=2.7Hz). IR (KBr) 3400, 3330, 1658, 1612, 1514, 1500cm . MS (ESI+) m/z 412 (M+H). 61 WO 2004/050632 PCT/JP2003/014489 Example 50 N-(2-{4-[3-Isopropoxy-l-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide 5 The title compound (94.4mg, 58.4%) was prepared from 2-{4-[3-isopropoxy-l-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl]phenoxylethanamine dihydrochloride obtained by Example 48 in a similar manner to that of 10 Example 4. MP : 121.0-121.6 0 C. 1H NMR (DMSO-d6) : 1.32(6H, d, J=6.1Hz), 2.94(3H, s), 3.29-3.34(2H, m), 3.84(3H, s), 4.00-4.06(2H, m), 4.77(1H, 15 m), 6.06(lH, s), 6.85(lH, d, J=8.7Hz), 6.94(2H, d, J=8. 8Hz), 7.18(2H, d, J=8.8Hz), 7.28(1H, br-s), 7.58(lH, dd, J=2.7, 8.7Hz), 7.99(lH, d, J=2.7Hz). IR (KBr) 3242, 1612, 1514, 1502cm'. MS (ESI+) m/z 447 (M+H). 20 Example 51 2-{4-[1-(4-Chlorophenyl)-3-(trifluoromethyl)-lH pyrazol-5-yl]phenyl}ethyl methanesulfonate 25 To a solution of 2-{4-[1-(4-chlorophenyl)-3 (trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanol (2.72 g) and triethylamine (1.55ml) in dichloromethane (30ml) was added dropwise methanesulfonyl chloride (0.86ml) under ice-cooling. The reaction mixture was allowed to 30 warm to room temperature and stirred for lhr. The reaction mixture was quenched with water. The organic layer was separated and washed with lN hydrochloric 62 WO 2004/050632 PCT/JP2003/014489 acid and water, dried over sodium sulfate, filtered and evaporated under reduced pressure to give the target compound (3.25g, 98.5%). 5 1 HNMR (CDCl 3 ) : 5 2.929( 3H, s), 3.072(2H, t, J=6.7Hz), 4.427(2H, t, J=6.7Hz), 6.739(1H, ), 7.175(2H, d, J=8.4H z), 7.234(2H, d, J=8.4Hz), 7.253(2H, d, J=8.9Hz), 7.344 (2H, d, J=8.8Hz). MS (ESI+): m/z 467 (M+Na). 10 Example 52 2-(2-{4-[1-(4-Chlorophenyl)-3-(trifluoromethyl)-lH pyrazol-5-yl]phenyl}ethyl)-1H-isoindole-1,3(2H)-dione 15 A mixture of 2-{4-[1-(4-chlorophenyl)-3-(trifluorom ethyl)-lH-pyrazol-5-yl]phenyl}ethyl methanesulfonate obtained by Example 51 (3.2g) and Potassium phthalimide (1.6g) was stirred at 80 C for 5hrs. After cooling, the mixture was diluted with water and 20 ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (twice). The combined organic layer was washed with water (twice) and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the target compound (1.55g, 43.5%) as a 25 powder. 1H NMR (CDCl 3 ) : 1-59(3H, s ), 3.02(2H, t, J=7.3Hz), 3. 94(2H, t, J=7.3Hz), 6.71(lH, s), 7.11(2H, d, J=8.2Hz), 7. 21(2H, d, J=7.6Hz), 7.24(2H, d, J=8.4Hz), 7.32(2H, d, J= 30 8.9Hz), 7.70-7.86(4H, m). MS (ESI+) : m/z 518 (M+Na). 63 WO 2004/050632 PCT/JP2003/014489 Example 53 2-{4-[1-(4-Chlorophenyl)-3-(trifluoromethyl)-lH pyrazol-5-yl]phenyl}ethanamine 5 A mixture of 2-(2-{4-[1-(4-chlorophenyl)-3 (trifluoromethyl)-lH-pyrazol-5-yl]phenyl}ethyl)-1H isoindole-1,3(2H)-dione obtained by Example 52 (1.5g) and hydrazine (2.93ml) in acetonitrile (30ml) was stirred at 60 C for 5hrs. 10 After cooling, the mixture was filtered and washed with acetonitrile. The filtrate was evaporated under reduced pressure to give the target compound (1.lg, quant.) as an oil. 15 1H NMR (CDCl 3 ): 6 3.09(2H, dd, J=5.6Hz, 9.3Hz), 3.24(2H, dd, J=5.6Hz, 8.6Hz), 5.47(2H, s), 6.69(lH, s), 7.12(lH, d, J=8.2Hz), 7.21(lH, d, J=8.2Hz), 7.22(1H, d, J=8.9Hz), 7.32(1H, d, J=8.9Hz). MS (ESI+) : m/z 366 (M+1). 20 Example 54 N-(2-{4-[l-(4-Chlorophenyl)-3-(trifluoromethyl)-IH pyrazol-5-yl]phenyl}ethyl)methanesulfonamide 25 To a solution of 2-{4-[1-(4-chlorophenyl)-3 (trifluoromethyl)-lH-pyrazol-5-yllphenyl}ethanamine obtained by Example 53 (400mg) and triethylamine (0.46ml) in dichloromethane (20ml) was added dropwise methanesulfonyl chloride (0.25ml) at room temperature. 30 After stirring for lhr, the reaction mixture was quenched with 1N hydrochloric acid. The aqueous layer was separated and extracted twice with chloroform. The 64 WO 2004/050632 PCT/JP2003/014489 combined organic layer was washed with lN hydrochloric acid, sodiumhydrogencarbonate solution, water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was column chromatographed on silica gel 5 (chloroform/methanol=4:1) to give the target compound (166mg, 34.2%) as an oil. 1H NMR (CDCl 3 ): 5 2.899(3H, s), 2.904(2H, t, J=6.9Hz), 3. 417(2H, dt, J=6.7 ,6.8Hz), 4.272(lH, t, J=6.lHz), 6.737 10 (1H, s), 7.178(2H, d, J=8.4Hz), 7.21(2H, d, J=8.4Hz), 7. 255(2H, d, J=8.8Hz), 7.35(2H, d, J=8.8Hz). IR (Film) : 3346, 1657, 1597, 1552, 1496, 1471, 1236, 1163, 1136, 1092, 978, 835, 756 cm~-. MS (ESI-) : 442 (M-1). 15 Example 55 N-(2-{4-[1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H pyrazol-5-yl]phenyl}ethyl)urea 20 To a solution of 2-{4-[1-(4-chlorophenyl)-3 (trifluoromethyl)-lH-pyrazol-5-yl]phenyl)ethanamine obtained by Example 53 (300mg) and triethylamine (0.57ml) in dichloromethane (10ml) was added dropwise trimethylsilyl isocyanate (0.555ml) at room 25 temperature. After stirring overnight, the reaction mixture was quenched with 1N hydrochloric acid. Aqueous layer was separated and extracted twice with chloroform. The combined organic layer was washed with lN hydrochloric acid, 30 sodium hydrogencarbonate solution, water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was column chromatographed on silica gel 65 WO 2004/050632 PCT/JP2003/014489 (chloroform/methanol=4:1) to give the target compound (205mg, 61.1%) as an amorphous. IH NMR (CDCl 3 ): 65 2.83(2H, t, J=7Hz), 3.43(2H, dt, J=6.6 5 Hz, 6.8Hz), 4.41(2H, s), 4.61(1H, t, J=5.4Hz), 6.72(1H, s), 7.16(4H, s), 7.25(2H, d, J=8.8Hz), 7.34(2H, d, J=8.8 Hz). IR (Film): 3346, 1657, 1597, 1552, 1496, 1471, 1448, 1375, 1271, 1236, 1163, 1136, 1092, 978, 835, 756 cm- 1 . 10 MS (ESI+) : m/z 431 (M+Na). Example 56 4-[l-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol 5-yl]benzonitrile 15 A mixture of 4-(4,4,4-trifluoro-3-oxobutanoyl) benzonitrile (1.0g), 4-methoxyphenylhydrazine hydrochloride (760mg), and sodium acetate (357mg) in acetic acid (10ml) was stirred at 80 C for 4hrs. 20 After cooling, the reaction mixture was poured into water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic layers were washed with saturated sodium hydrogencarbonate solution (twice), water and brine, dried over sodium sulfate, and 25 evaporated under reduced pressure to give crude product. The crude product was column chromatographed on silica gel (50ml, n-hexane:ethyl acetate=5:1-4:1) and triturate with petroleum ether to give the target compound (553mg, 38.8%). 30 1H NMR (CDCl 3 ) : 5 3.84 (3H, s), 6.82(1H, s), 6.9(2H, d, J=9Hz), 7.2(2H, d, J=9Hz), 7.33(2H, d, J=8.6Hz), 7.62(2H, d, J=8.6Hz). 66 WO 2004/050632 PCT/JP2003/014489 IR (Film) : 2229, 1610, 1512, 1468, 1240, 1161, 1132, 839 cm-f. MS (ESI+) : m/z 366 (M+Na). 5 Example 57 4-[l-(4-Methoxyphenyl)-3-(trifluoromethyl)-lH-pyrazol 5-yl]benzyl-amine hydrochloride A mixture of 4-[1-(4-methoxyphenyl)-3-(trifluoro 10 methyl) -1H-pyrazol-5-yl]benzonitrile obtained by Example 56 (430mg), Pd/C (100mg) and 1N hydrochloric acid (1.3ml) in methanol (43ml) was stirred under Hydrogen atmosphere for 5hrs. The reaction mixture was filtered with paper filter, 15 and filtrate was evaporated. After dissolving in methanol, the solution was filtered with membrane filter. The filtrate was evaporated to give the target compound (450mg, 93.6%) as crystals. 20 1H NMR (CDCl 3 ) : & 3.79(3H, s), 4.04(2H, br-s), 6.69(1H, s), 6.85(2H, d, J=8.9Hz), 7.13(2H, d, J=8.9Hz), 7.24(2H, d, J=9Hz), 7.42(2H, d, J=9Hz). IR (Film) : 2964, 1512, 1468, 1238, 1161, 1130, 976, 837 cm . 25 MS (ESI+) : m/z 331 (M-Cl-NH 3 ). Example 58 N-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-lH pyrazol-5-yllbenzyl}methanesulfonamide 30 To a solution of 4-[1-(4-methoxyphenyl)-3 (trifluoromethyl)-1H-pyrazol-5-yl]benzylamine 67 WO 2004/050632 PCT/JP2003/014489 hydrochloride obtained by Example 57 (100mg) and triethylamine (0.073ml) in chloroform (10ml) was added dropwise methanesulfonyl chloride (0.04ml) at room temperature. 5 After stirring for lhr, the reaction mixture was partitioned between chloroform and water. The organic layer was washed with water, sodium bicarbonate solution, brine, driedovermagnesiumsulfate, filteredandevaporated under reduced pressure to give the target compound (90mg, 10 81.2%) as an oil. 1H NMR (CDCl 3 ) : 2.93(3H, s), 3.82(3H, s), 4.32(2H, d, J=6.2Hz), 4.71(1H, t, J=6.2Hz), 6.73(lH, s), 6.86(2H, d, J=9Hz), 7.21(2H, d, J=9Hz), 7.21(2H, d, J=8.3Hz), 7.31 15 (2H, d, J=8.3Hz). IR (Film) : 3282, 1514, 1321, 1240, 1151, 974, 837cm 1 . MASS (ESI+) : m/z 426 (M+1). Example 59 20 4-[3-(Difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5 yl]benzonitrile The title compound (4.5g, 20.6%) was prepared from 4

-(

4

,

4 -difluoro-3-oxobutanoyl)benzonitrile in a similar 25 manner to that of Example 56. 1H NMR (CDC1 3 ) : 5 3.84(3H, s), 6.77(1H, t, J=54.9Hz), 6. 8(1H, s), 6.9(2H, d, J=9Hz), 7.19(2H, d, J=9Hz), 7.33(2H, d, J=8.6Hz), 7.61(2H, d, J=8.6Hz). 30 MS (ESI+) : m/z 348 (M+Na). Example 60 68 WO 2004/050632 PCT/JP2003/014489 1-{4-[3-(Difluoromethyl)-1-(4-methoxyphenyl)-lH pyrazol-5-yl]phenyl}methanamine hydrochloride The title compound (510mg, 45.4%) was prepared from 5 4

-[

3 -(difluoromethyl)-l-(4-methoxyphenyl)-lH-pyrazol-5 yl]benzonitrile obtained by Example 59 in a similar manner to that of Example 57. 1H NMR (DMSO-d6) : 6 3.35(3H, s), 3.79(2H, s), 7.1(1H, t, 10 J=54.5Hz), 6.95(1H, s), 6.99(2H, d, J=8.8Hz), 7.26(2H, d, J=8.8Hz), 7.3(2H, d, J=8.3Hz), 7.49(2H, d, J=8.3Hz). MS (ESI-): m/z 365 (M-HCl). Example 61 15 N-{4-[3-(Difluoromethyl)-l-(4-methoxyphenyl)-lH pyrazol-5-yl]benzyl}methanesulfonamide The title compound (146mg, 65.5%) was prepared from 1-14-[3-(difluoromethyl)-1-(4-methoxyphenyl)-lH-pyrazol 20 -5-yi]phenyllmethanamine hydrochloride obtained by Example 60 in a similar manner to that of Example 58. 1H NMR (CDCl 3 ) : 6 2.90(3H, s), 3.82 (3H, s), 4.31(2H, d, J=6.2Hz), 4.73(1H, t, J=6.2Hz), 6.72(lH, s), 6.77(lH, t, 25 J=55Hz), 6.86(2H, d, J=9Hz), 7.19(2H, d, J=9Hz), 7.22(2 H, d, J=8.4Hz), 7.30(2H, d, J=8.4Hz). IR (film) : 3143, 1518, 1508, 1452, 1325, 1244, 1151, 10 74, 1022, 972, 843, 793 cm-. 30 MS (ESI-) : m/z 406 (M-1) Example 62 69 WO 2004/050632 PCT/JP2003/014489 N-{4-[3-(Difluoromethyl)-1-(4-methoxyphenyl)-1H pyrazol-5-yl]benzyl}urea To a solution of 1-{4-[3-(difluoromethyl)-l-(4 5 methoxyphenyl)-lH-pyrazol-5-yl]phenyl}methanamine hydrochloride obtained by Example 60 (100mg) in dichloromethane (lml) was added dropwise triethylamine (0.163ml) and trimethylsilyl isocyanate (0.11ml) at room temperature. 10 The mixture was stirred at room temperature overnight and quenched by adding saturated sodium hydrogencarbonate solution (0.5ml). The mixture was filtered by Chemelute. The elution was evaporated and purified by preparative thin layer chromatography (0.5mm, 10% methanol/chloroform) to 15 give solid. The solid was added ethyl acetate and n-hexane, and the precipitate was collected by filtration to give the target compound(160mg, 62.9%). 1HNMR (CDCl 3 ) : 6 3.82(3H, s), 4.35(2H, d, J=6Hz), 4.46( 2H, 20 br-s) , 4.99(1H, t, J=6Hz), 6.69(1H, s) , 6.76(1H, t, J=55.1Hz), 6.86(2H, d, J=9Hz), 7.14-7.21(6H, m). MS (ESI+) m/z 395 (M+Na). IR (film) 1657, 1608, 1593, 1550, 15120, 1510, 1467, 1338, 1252, 1171, 1088, 1030, 837, 796cm'. 25 Example 63 4-[l-(4-Methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-5 yl]benzonitrile 30 The title compound (942mg, 86.8%) was prepared from 4-(4,4,4-trifluoro-3-oxobutanoyl)benzonitrile in a similar manner to that of Example 56. 70 WO 2004/050632 PCT/JP2003/014489 1H NMR (CDCl 3 ) 6 2.39(3H, s), 6.82(1H, s), 7.15(2H, d, J=8.9Hz), 7.21(2H, d, J=8.8Hz), 7.33(2H, d, J=8.3Hz), 7. 62(2H, d, J=8.3Hz). 5 MS (ESI+): m/z 328 (M+1). Example 64 1-{4-[1-(4-Methylphenyl)-3-(trifluoromethyl)-1H pyrazol-5-yl]phenyllmethanamine hydrochloride 10 The title compound (414mg, 92.1%) was prepared from 4-[1-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5 yl]benzonitrile obtained by Example 63 in a similar manner to that of Example 57. 15 1H NMR (DMSO-d6) : 6 2.35(3H, d, J=4.2Hz), 3.35(2H, s), 7.17(1H, s), 7.17-7.29(4H, m), 7.32(2H, d, J=8.lHz), 7.5 1(2H, d, J=8.2Hz). MS (ESI+): m/z 332 (M+1). 20 Example 65 N-{4-[1-(4-Methylphenyl)-3-(trifluoromethyl)-IH pyrazol-5-yl]benzyllurea 25 The title compound (81mg, 31.8%) was prepared from 1-(4-[1-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol -5-yl]phenyl}methanamine hydrochloride obtained by Example 64 in a similar manner to that of Example 62. 30 1H NMR (CDCl 3 ) : 6 2.36(3H, s), 4.35(2H, d, J=5.9Hz), 4. 50(2H, br-s), 5.02(1H, t, J=5.5Hz), 6.71(1H, s), 7.16(4H, s), 7.20(4H, d, J=5.77Hz). 71 WO 2004/050632 PCT/JP2003/014489 IR (film) : 3344, 1658, 1600, 1552, 1518, 1236, 1159, 11 34cm'. MS (ESI+) : m/z 397 (M+Na) 5 Example 66 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-1 yl]benzonitrile The title compound (1.05g, 73.8%) was prepared from 10 4-methyl-1- (4,4, 4 -trifluoro-3-oxobutanoyl)benzene in a similar manner to that of Example 69 described later. MP : 125.0-125.5 0 C. 1H NMR (CDC13) : 5 2.39(3H, s), 6.74( 1H, s), 7.10 (2H, d, 15 J=8.lHz), 7.19(2H, d, J=8.2Hz), 7.45(2H, d, J=8.7Hz), 7. 65(2H, d, J=8.7Hz). MASS (ESI+) : m/z 350 (M+Na). Example 67 20 1-{4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H pyrazol-1-yl]phenyllmethanamine hydrochloride The title compound (830mg, 92.3%) was prepared from 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol 25 1- yl]benzonitrile obtained by Example 66 in a similar manner to that of Example 70 described later. 1H NMR (DMSO-d6) : 2.30 (3H, d, J=2.3Hz), 4.07(2H, s), 30 7.15(1H, s), 7.15(2H, d, J=9.OHz), 7.21(2H, d, J=8.9Hz), 7.39(2H, d, J=8.5Hz), 7.58(2H, d, J=8.5Hz). MS (ESI+) : m/z 332 (M+1). 72 WO 2004/050632 PCT/JP2003/014489 Example 68 N-{4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-lH pyrazol-1-yl]benzyl}urea 5 The title compound (65mg, 31.9%) was prepared from 1-{4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH pyrazol-1-yl] phenyl}methanamine hydrochloride obtained by Example 67 in a similar manner to that of Example 72 described 10 later. 1H NMR (CDCl 3 ) 6 2.34 (3H, s), 4.34(2H, d, J=5.8Hz), 4. 56(2H, br-s), 5.23(lH, t, J=5.8Hz), 6.71(lH, s), 7.07(2H, d, J=8.7Hz), 7.13(2H, d, J=8.7Hz), 7.24(4H, s). 15 IR (film) 3344, 1658, 1604, 1552, 1234, 1159, 1134cm-1. MS (ESI+) 397 (M+Na). Example 69 4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-lH-pyrazol 20 1-yl]benzonitrile A mixture of 4-methoxy-1-(4,4,4-trifluoro-3 oxobutanoyl)benzene (1.0g), 4-methoxyphenylhydrazine hydrochloride (758mg) and sodium acetate (367mg) in 25 acetic acid (5ml) was stirred overnight at room temperature. After then, the reaction mixture was poured into water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic layers were washed 30 with water, saturated sodium hydrogencarbonate (twice) and brine, dried over sodium sulfate, and evaporated under reduced pressure to give crude product. The crude product 73 WO 2004/050632 PCT/JP2003/014489 was column chromatographed on silica gel (50ml, n-hexane:ethyl acetate=10:1-5:1) to give the target compound (930mg, 66.7%). 5 1H NMR (CDCl 3 ) : 6 3.84(3H, s), 6.72(lH, s), 6.9(2H, d, J=8.9Hz), 7.14(2H, d, J=8.9Hz), 7.46(2H, d, J=8.7Hz), 7.66(2H, d, J=8.7Hz). MS (ESI+) : m/z 366 (M+Na). 10 Example 70 4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol 1-yl]benzylamine hydrochloride A mixture of 4-[5-(4-methoxyphenyl)-3-(trifluoro 15 methyl)-lH-pyrazol-1-yl]benzonitrile obtained by Example 69 (400mg) and 50% wet pd/C (400mg) in ethanol (10ml) and 1N hydrochloric acid (1.2ml) was stirred under hydrogen atmosphere for 8hrs. The mixture was filtered and filtrate was evaporated 20 under reduced pressure. The residue was washed with isopropyl ether to give the target compound (400mg, 89.4%) as a powder. 1H NMR (CDCl 3 ) 6 3.36(s, 3H), 3.76(d, J=2.4, 2Hz), 6.9 25 4(d, J=8.7, 2Hz), 7.12(s, 1H), 7.23(d, J=8.7, 2Hz), 7.39 (d, J=8.4, 2Hz), 7.59(d, J=8.4, 2Hz). MS (ESI+) : m/z 348 (M+1). Example 71 30 N-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-lH pyrazol-1-yl]benzyl}methanesulfonamide 74 WO 2004/050632 PCT/JP2003/014489 To a solution of 4-[5-(4-methoxyphenyl)-3 (trifluoromethyl)-lH-pyrazol-1-yl]benzylamine hydrochloride obtained by Example 70 (150mg) and triethylamine (0.lml) in dichloromethane (10ml) was 5 added dropwise methanesulfonyl chloride (0.06ml) under ice cooling. After stirring for 1hr, the reaction mixture was quenched and partitioned between chloroform and water. The aqueous layer was extracted with chloroform. The combined 10 organic layer was washed with water, 1N hydrochloric acid, saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed by high performanced thin layer chromatography to give the target 15 compound (67mg, 40.3%). 1H NMR (CDCl 3 ) : 5 2.91(3H, s), 3.82(s, 3H), 4.35(2H, d, J=6. 1Hz) , 4. 69 (1H, t, J=6. lHz) , 6. 69 (1H, s) , 6. 84 (2H, d, J=8.6Hz), 7.13(2H, d, J=8.6Hz), 7.32(2H, d, J=9Hz), 7.3 20 7(2H, d, J=9Hz). IR (film) 3207, 1479, 1456, 1323, 1252, 1234, 1146, 1122, 984, 968, 962, 841, 802cm 1 . MS (ESI+) m/z 448 (M+Na). 25 Example 72 N-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H pyrazol-1-yllbenzyl}urea To a solution of 4-[5-(4-methoxyphenyl)-3 30 (trifluoromethyl)-1H-pyrazol-1-yl]benzylamine hydrochloride obtained by Example 70 (150mg) in water (8ml) and ethanol (4ml) was added sodium cyanate (100mg) 75 WO 2004/050632 PCT/JP2003/014489 under ice cooling. After stirring for 3hrs, the reaction mixture was partitioned between chloroform and water. The aqueous layer was extracted with chloroform. The combined organic 5 layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed by high performanced thin layer chromatography to give the target compound (105mg, 69%). 10 1H NMR (CDCl 3 ) : 3.80(3H, s), 4.35(2H, d, J=5.9Hz), 4. 53(2H, br-s), 5.171(1H, t, J=5.7Hz), 6.68(1H, s), 6.84(2 H, d, J=8.7Hz), 7.12(2H, d, J=8.7Hz), 7.25(4H, s). MS (ESI+) : m/z 413 (M+Na). 15 Example 73 tert-Butyl 2

-{

4 -[1-(4-methoxyphenyl)-3-(trifluoro methyl)-lH-pyrazol-5-yljphenoxy}ethylcarbamate 20 To solution of 4 -[1-(4-methoxyphenyl)-3-trifluoro methyl-lH-pyrazol-5-yl]phenol (500g) in N,N-dimethyl formamide (1.5L) was added sodium hydride (dispersion in mineral oil, 77.8g) over 25min under ice cooling. The mixture was warmed to room temperature over 10min 25 and then stirred at room temperature for 30min. A solution of 2 -tert-butoxycabonylaminoethyl bromide (469 g) (prepared by reacting di-ter-butyl dicarbonate with 2 bromoethylamine hydrobromide) reaction in N,N-dimethylformamide (300ml) was added to the mixture 30 over 10min at 25-28 0 C, and the whole mixture was stirred at 600 for 6hrs. After allowed to stand overnight, themixture was poured 76 WO 2004/050632 PCT/JP2003/014489 into a mixture of water (4. 5L) and toluene (3L) . The organic layer was separated, and the aqueous layer was extracted with toluene (1.5L). The combined organic layers were washed with water (1.5LX3) and brine (1.5L), dried over 5 magnesium sulfate, filtered and evaporated to give the oil (1.02kg). The oil was purified with silica gel column chromatography [5L, n-hexane (10L), 50% ethyl acetate/n-hexane (30L)] to give the target compound (680g, 95%) as a pale yellow oil. 10 MP : 104.7-105.10C. 1HNMR (CDCl 3 ) : 1.45(3H, s), 3.53(2H, dt, J=4Hz), 3.82 (3H, s), 4.01(2H, t, J=4Hz), 6.67(lH, s), 6.83(2H, d, J=8Hz), 6.8 15 7(2H, d, J=8Hz), 7.13(2H, d, J=8Hz), 7.23(2H, d, J=8Hz). Example 74 2-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H pyrazol-5-yl]phenoxy}ethanamine hydrochloride 20 To a solution of hydrogen chloride in ethyl acetate (4N, 1.OL) was added powdered tert-Butyl 2-{4-[1-(4-meth oxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl] phenoxy}ethylcarbamate obtained by Example 73 (500g) at 25 5 0 C over 20min. After stirring at the same temperature for 30min and then at room temperature for lhr, the mixture was evaporated to give oil (543.12g). The oil was dissolved in toluene (1. 5L) . And then, n-hexane (20 Oml) and the target compound 30 (as seeds for crystallization) were added to the solution. The mixture was stirred at room temperature overnight. And the precipitate was filtered, washed with toluene (500ml 77 WO 2004/050632 PCT/JP2003/014489 X2) andisopropylether (650ml), anddriedtogive the target compound (420.5g, 97%) as a white powder. MP : 166.8-168.0"C. 5 1HNMR (DMSO-d6) : & 3.185(2H, t, J=5Hz), 3.8(3H, s), 4. 215(2H, t, J=5Hz), 6.96-7.05(4H, m), 7.1(lH, s), 7.22-7. 33(4H, m). Example 75 10 N-(2-{4-[l-(4-Methoxyphenyl)-3-(trifluoromethyl)-lH pyrazol-5-yllphencxylethyl)urea 2-{4-[l-(4-Methoxyphenyl)-3-(trifluoromethyl)-lH pyrazol-5-yl]phenoxylethanamine hydrochloride obtained 15 by Example 74 (400g) and sodium acetate (159g) was dissolved in a mixture of N,N-dimethylformamide (1.4L) and water (0.52L) at 50 0 C. A solution of potassium cyanate (157g) in water (520ml) was added dropwise to the solution over 15min at 38-40 C. The whole solution 20 was stirred at 50"C for 2hrs. The solution was filtered and washed with N,N-dimethylformamide (0. 68L) at the same temperature. The filtrate was cooled to room temperature, and then water (0.4L) and the target compound (A04 type crystal) was added 25 as seeds for crystallization to the filtrate, and themixture was stirred at room temperature for 30min. Then water (2.76L) was added dropwise to the mixture over 30min, and the mixture was stirred at room temperature for 30min. The precipitate was filtered, washed with water (0.8LX3), and 30 dried under reduced pressure at 45 0 C overnight to give the target compound (A04 type crystals, 442.01g) as a white powder. 78 WO 2004/050632 PCT/JP2003/014489 1HNMR (CDCl 3 ) 6 3.555(2H, dt, J=5, 6Hz), 3.81(3H, s), 3.995(2H, t, J=5Hz), 4.67 (2H, s) , 5.37(1H, t, J=6Hz), 6.66(1H, br-s), 6.79(2H, d, J=8Hz), 6.845(2H, d, J=6Hz), 7.11(2H, 5 d, J=8Hz), 7.19(2H, d, J=8Hz). 1HNMR (DMSO-d6) : & 3.28-3.36(2H, m) , 3.79(3H, s), 3.945(2H, t, J=5Hz), 5.54 (2H, br-s), 6.165(1H, t, J=5Hz), 6.92-7.08 (5H, m), 7.2(2H, d, J=8Hz), 7.28(2H, d, J=8Hz). 10 Example 76 2-Hydroxy-N-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl) -lH-pyrazol-5-yl]benzyl}acetamide To a solution of 4-[1-(4-methoxyphenyl)-3 15 (trifluoromethyl)-1H-pyrazol-5-yl]benzylamine hydrochloride obtained by Example 57 (46.5mg) in dichloromethane (1.5ml) was added diisopropylethylamine (1351IL) and acetoxyacetylchloride (41.6/IL) at 0C. After stirring at room temperature for 3hrs, the mixture 20 was quenched with water. The whole mixture was extracted withethyl acetate. The organic layerwaswashedwithbrine, dried over magnesium sulfate, filtered and evaporated to give oil (67mg). The oil was dissolved in methanol (1.5ml). Potassiumcarbonate (55mg) was addedto the solution. After 25 stirring at room temperature for 3hrs, the mixture was filtered and evaporated to give oil which was purified with preparative thin layer chromatography (0.5mmX2, 10% methanol/chloroform) to give colorless oil (42.5mg) . The oil was crystallized from a mixture of ethyl acetate, 30 diisopropylether, and n-hexane with stirring at room temperature. Theprecipitate was filtered and dried to give the target compound (33.9mg, 64.8%) as a white powder. 79 WO 2004/050632 PCT/JP2003/014489 1HNMR (CDCl 3 ) : 2.32 (1H, t, J=5.2Hz), 3.83(3H, s), 4.2 O(2H, d, J=5.2Hz), 4.51(2H, d, J=6.lHz), 6.72(1H, s), 6. 87 (2H, d, J=8.9Hz), 7.16-7.24(6H, m) 5 MS (ESI+) : 428.2(M+Na). Example 77 2- Hydroxy-N-(2-{4-[1-(4-methoxyphenyl)-3-(trifluoro methyl)-1H-pyrazol-5-yl]phenyl}ethyl)ethanesulfonamide 10 To a solution of 2-{4-[1-(4-methoxyphenyl)-3 (trifluoromethyl)-lH-pyrazol-5-yl]phenyl}ethanamine hydrochloride and triethylamine in chloroform was added methanesulfonyl chloride at room temperature. 15 After stirring for lhr, the reaction mixture was poured into water and chloroform. The aqueous layer was separated and extracted with chloroform. The combined organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The 20 residue was column chromatographed on silica gel and crystallized to give the target compound (27.7mg, 23.5%) 1HNMR (CDCl 3 ) : 6 2.78-2.91(2H, m), 3.16(2H, t, J=5.lHz), 3.32-3. 43 (2H, m), 3.82 (3H, s), 3.96 (2H, t, J=5.Hz), 4.65(1H, 25 t, J=6.2Hz), 6.72(1H, s), 6.87 (2H, d, J=9.OHz) , 7.12-7.27 (6H, m). MS(LC, ESI+), 470.21(MH+), 511.17(MHMeCN). Example 78-1 30 tert-Butyl 2-(4-acetylphenoxy)ethylcarbamate To a solution of 4-hydroxyacetophenone (10g) and 80 WO 2004/050632 PCT/JP2003/014489 2-tert-butoxycarbonylaminoethylbromide (24.7g) in N,N-dimethylformamide (50 ml) was added potassium iodide (12.2g) and potassium carbonate (15.2g). After stirring at 50*C overnight, the mixture was 5 quenched with water and extracted with ethyl acetate (3 times). The combined organic layers were washed with 1N sodium hydroxide aqueous solution (2 times) and brine, dried over magnesium sulfate, and evaporated to give oil. The oilwaspurifiedwith silicagel column chromatography [500ml, 10 20% ethyl acetate/n-hexane (1000ml), 30% ethyl acetate/n-hexane (1000ml)] to give the target compound (19.89g, 96.9%) as a white solid. 1HNMR(CDCl 3 ) : & 1.46(9H, s), 2.56(3H, s), 3.52-3.60(2H, 15 m), 4.09(2H, t, J=5.lHz), 6.93(2H, d, J=8.9Hz), 7.93(2H, d, J=8.9Hz). MS (ESI+) : 280.09(MH+). Example 78-2 20 tert-Butyl 2-[4-(4,4,4-trifluoro-3-oxobutanoyl) phenoxy]ethylcarbamate A mixture of tert-butyl 2-(4-acetylphenoxy)ethyl carbamate obtained by Example 78-1 (15g), trifluoroacetic 25 acid (8.95ml), andsodiumethoxide (8.77g) in ethanol (45ml) was stirred at 700C for 2.5hrs. The mixture was poured into a mixture of aqueous hydrogen chloride solution (1N) and ethyl acetate. The whole mixture was extracted with ethyl acetate (2 times) . The organic 30 layer was separated, washed with saturated sodium hydrogencarbonate and brine, dried over magnesium sulfate, and evaporated to give oil (25g) . The oil was purified with 81 WO 2004/050632 PCT/JP2003/014489 silica gel column chromatography [500ml, 30% ethyl acetate/n-hexane (1000ml)] to give oil. The oil was dissolved in ethyl acetate (5ml) underheatingbywaterbath. n-Hexane (100ml) was added to the solution, and the solution 5 was cooled to room temperature over 30min under stirring. And n-hexane (100ml) was added to the mixture. The precipitate was filtered and dried to give the target compound (15.956g, 79.2%) as an orange powder. 10 1HNMR (CDCl 3 ) : 3.40-3.70(2H, m), 4.00-4.20(2H, m), 5.00(1H, br-s), 6.50(1H, s), 6.98 (2H, d, J=8.6Hz), 7.93(2H, d, J=8.6Hz). Example 78-3 15 tert-Butyl 2-{4-[1-(4-methoxyphenyl)-3-(trifluoro methyl)-lH-pyrazol-5-yllphenoxy)ethylcarbamate Toasuspensionof 4-methoxyaniline (100mg) inamixture of acetic acid (2ml) and concentrated hydrogen chloride 20 (0.4ml) was added dropwise a solution of sodium nitrite (61.6mg) in water (0.lml) over 5min at 3-C, and the mixture was stirred at 3"C for lhr. To the mixture was added dropwise a solution of tin chloride (641mg) in concentrated hydrogen chloride (0.3ml) at 0"C over 10min, and then the mixture 25 was stirred at 00C for lhr. Acetic acid (5ml) was added dropwise to the mixture at between -20 and -10"C over 2min, and then the mixture was quenched with a solution of sodium hydroxide (336mg) in water (2.24ml) at -10 0 C over 2min and warmed to room temperature to give a solution containing 30 4-methoxyphenylhydrazine hydrochloride. A solution of tert-butyl 2-[4-(4,4,4-trifluoro-3 oxobutanoyl) -phenoxy] ethylcarbamate obtained by Example 82 WO 2004/050632 PCT/JP2003/014489 78-2 (305mg) was added to the former solution at -10"C, and then the mixture was stirred at room temperature for 3hrs. The mixture was poured into a mixture 5 of saturated sodium hydrogen carbonate aqueous solution (150ml) and ethyl acetate (100ml), and adjusted pH to basic by sodium hydrogencarbonate powder. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50mlX2) . The combined 10 organic layers were washed with saturated sodium hydrogen carbonate aqueous solution and brine, dried over magnesium sulfate, filtered, andevaporated togive oil (450mg). The oil was purified with silica gel column chromatography [35 ml, 15% ethyl acetate/n-hexane (800 ml)] to give an oil. 15 (343.2mg, 88.5%). The oil was dissolved in isopropylether (2ml), and then n-hexane (6ml) was added to the solution. The whole mixture was stirred at room temperature for lhr. And then the precipitate was filtered, washed with n-hexane (10ml), and dried under reduced pressure for 2hrs to give 20 the target compound (280.6 mg, 72.4%) as a white powder. 1HNMR (CDCl 3 ) data was identical to authentic sample. 1HNMR (CDCl 3 ) : & 1.45(3H, s), 3.53(2H, dt, J=4.4Hz), 3.82(3H, s), 4.01(2H, t, J=4Hz), 6.67(lH, s), 6.83(2H, d, 25 J=8Hz), 6.87(2H, d, J=8Hz), 7.13(2H, d, J=8Hz), 7.23(2H, d, J=8Hz). Example 79-1 1-[4-(Benzyloxy)phenyllhydrazine hydrochloride 30 To the suspension of 4-benzyloxyaniline (10g) in concentrated hydrogen chloride (100ml) was added dropwise 03 WO 2004/050632 PCT/JP2003/014489 a solution of sodium nitrite (3.2g) in water (10ml) over 10min at between -15 and -10 C, and then the mixture was stirred at 39C for lhr. To the mixture was added dropwise a solution of tin chloride (33.5g) in concentrated hydrogen 5 chloride (80ml) at between -20 and -10*C over 30min, and then the mixture stirred at 0 C for lhr. After cooling to -20*C, the precipitate was filtered, washed with water (25ml), ethanol (25ml) and ether (50ml), and dried to give the target compound (10.637g, 100%) as 10 a pale brown powder. NMR (DMSO-d6) : 5. 05 (2H, s) , 6. 93-7. 03 (4H, m), 7.46-7.28 (4H, m). 15 Example 79-2 2-{4-[1-(4-Benzyloxyphenyl)-3-(trifluoromethyl)-1H pyrazol-5-yl]phenoxyl ethanamine hydrochloride The title compound (12.9g, 87.5%) was prepared from 20 1-[4-(benzyloxy)phenyl]hydrazine hydrochloride obtained by Example 79-1 and tert-butyl 2-[4-(4,4,4-trifluoro-3 oxobutanoyl)phenoxy]ethylcarbamate obtained by Example 78-2 in a similar manner to that of Example 78-3. 25 1HNMR (DMSO-d6) : & 3.10-3.30(2H, m), 4.19 (2H, t, J=6.3Hz), 5.14(2H, s), 6.98(2H, d, J=8.7Hz), 7.09(lH, s), 7.09(2H, d, J=8.9Hz), 7.49-7.22(9H, m). Example 80 30 N-(2-{4-[l-[4-(Benzyloxy)phenyl]-3-(trifluoromethyl) 1H-pyrazol-5-yl]phenoxy)ethyl)urea 84 WO 2004/050632 PCT/JP2003/014489 The title compound (10.57g, 84.3%) was prepared from 2-{4-[1-(4-benzyloxyphenyl)-3-(trifluoromethyl)-lH pyrazol-5-yl]phenoxyl}-ethanamine hydrochloride obtained by Example 79-2 in a similar manner to that of 5 Example 75. 1HNMR (CDCl 3 ) : 3.57 (2H, td, J=5.7, 5.0Hz), 4.01(2H, t, J=5.OHz), 4.57 (1H, br-s), 5.06(2H, s), 5.20 (1H, t, J=5.7Hz), 6.66(1H, s), 6.80(2H, d, J=8.7Hz), 6.93(2H, d, J=9.OHz), 10 7.12(2H, d, J=8.7Hz), 7.21(2H, d, J=9.OHz), 7.35-7.42(5H, m). Example 81 N-(2-{4-[1-(4-Hydroxyphenyl)-3-(trifluoromethyl)-lH 15 pyrazol-5-yl]-phenoxylethyl)urea To a solution of N-(2-{4-[1-[4-(benzyloxy)phenyl] 3-(trifluoromethyl)-lH-pyrazol-5-yl]phenoxy}ethyl)urea obtained by Example 80 (10.33g) in methanol (100ml) was 20 added palladium on carbon (10% wet, 2g), and the mixture was stirred vigorously at room temperature under hydrogen atmosphere for 3hrs. The whole mixture was fil tered and evaporated to give oil (8.23g). The oil was purified with silica gel column chromatography [250ml, 25 3% methanol/chloroform (500ml), 5% methanol/chloroform (500ml), and 10% methanol/chloroform (500ml)] to give the target compound (8.07g, 95.4%) as an oil. 1HNMR (DMSO-d6) : & 3.28-3.33(2H, m), 3.94(2H, t, J=5.5 30 Hz), 5.52(2H, br-s), 6.14(1H, br-t, J=5.7Hz), 6.80(2H, d, J=8.7Hz), 6.93(2H, d, J=8.9Hz), 7.05(1H, s), 7.14(2H, d, J=8.7Hz), 7.19(2H, d, J=8.9Hz). 85 WO 2004/050632 PCT/JP2003/014489 MS (ESI+) : 407.10(MH+). Example 82 4-[5-(4-{2-[ (Aminocarbonyl)amino]ethoxyphenyl)-3 5 (trifluoromethyl)-1H-pyrazol-1-yl]phenyl acetate To a mixture of N-(2-{4-[1-(4-hydroxyphenyl) -3 (trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea obtained by Example 81 (148.5mg) in dichloromethane (1.5 10 ml) was added pyridine (163pL) and acetic anhydride (45p L), and the mixture was stirred at room temperature for lhr and stirred'under reflux for 3hrs. After evaporation, the mixture was purified with preparative thin layer chromatography (1.0mm, 10% 15 methanol/chloroform) to give oil. The oil was crystallized from a mixture of dichloromethane and isopropylether at room temperature to give the target compound (138.6mg, 84.6%) as a white powder. 20 1HNMR (CDC1 3 ) : 5 2.30(3H, s), 3.59(2H, td, J=5.5, 4.9H z), 4.04(2H, t, J=4.9Hz), 4.51(2H, br-s), 5.22(1H, br-t, J=5.5Hz), 6.69(1H, s), 6.84(2H, d, J=8.7Hz), 7.10(2H, d, J=8.8Hz), 7.14(2H, d, J=8.7Hz), 7.31(2H, d, J=3.9Hz). MS(LC, ESI+) : 449.24(MH'), (ESI-) 492.5(M-H+HCO2) 25 Example 83-1 1-(1,3-Benzodioxol-5-yl)hydrazine hydrochloride The title compound (1.811g, quant.) was prepared from 30 3,4- (methylenedioxy) aniline in a similar manner to that of Example 79-1. 86 WO 2004/050632 PCT/JP2003/014489 1HNMR (DMSO-d6) 6 5.94 (2H, s), 6.53(1H, dd, J=2.2 8.2 Hz), 6.80(1H, s), 6.83(lH, d, J=8.2Hz). MS(LS, ESI+): 153.9(MH+) 193.99(MH+CH 3 CN) 5 Example 83-2 tert-Butyl 2-{4-[l-(1,3-benzodioxol-5-yl)-3-(trifluoro methyl)-1H-pyrazol-5-yllphenoxy}ethylcarbamate The title compound (371.3mg, 56.7%) was prepared 10 from tert-butyl 2-[4-(4,4,4-trifluoro-3-oxobutanoyl) phenoxy]ethylcarbamate obtained by Example 78-2 and 1-(1,3-benzodioxol-5-yl)hydrazine hydrochloride obtained by Example 83-1 in a similar manner to that of Example 78-3. 15 NMR (CDCl 3 ) MA12.048 6 1.75(9H, s), 3.45-3.60(2H, m), 4.02(2H, t, J=5.lHz), 6.02(2H, s), 6.66-6.88(1H, m), 7.1 6(2H, d, J=8.8Hz). MS(LC, ESI+) : 492.22 (MH+), 533.26 (MHMeCN+). 20 Example 84 2-{4-[1-(1,3-Benzodioxol-5-yl)-3-(trifluoromethyl)-1H pyrazol-5-yllphenoxy)ethanamine 25 The title compound (181.2mg, 61.5%) was prepared from tert-butyl 2-{4-[1-(1,3-benzodioxol-5-yl)-3-(tri fluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate obtained by Example 83-2 in a similar manner to that of Example 74. 30 1HNMR (CDCl 3 ) 6 1.75(9H, s), 3.45-3.60(2H, m), 4.02(2H, t, J=5.1Hz), 6.02(2H, s), 6.66-6.88(1H, m), 7.16(2H, d, 87 WO 2004/050632 PCT/JP2003/014489 J=8.8Hz) . MS (LC, ESI+) : 392.09(MH+), 433.16(MHMeCN+). Example 85 5 N-(2-{4-[1-(1,3-Benzodioxol-5-yl)-3-(trifluoromethyl) 1H-pyrazol-5-yl]phenoxylethyl)urea The title compound (181.2mg, 90.1%) was prepared from 2-{4-[1- (1,3-benzodioxol-5-yl)-3-(trifluoro 10 methyl)-1H-pyrazol-5-yl]phenoxy}ethanamine obtained by Example 84 in a similar manner to that of Example 75. 1HNMR (CDC1 3 ) : 5 3.6(2H, td, J=5.0, 5.0Hz), 4.045(2H, t, J=5Hz), 4.5(2H, br-s), 5.095(1H, br-t, J=5Hz), 6.01(2H, 15 s), 6.66(1H, s), 6.75-6.86(3H, m), 6.84(2H, d, J=8Hz), 7.16(2H, d, J=8Hz). MS (LC, ESI+) : 435.08 (MH+). Example 86 20 tert-Butyl 2-({4-[1-(4-methoxyphenyl)-3-(trifluoro methyl)-lH-pyrazol-5-yl]benzyl}amino)-2-oxoethyl carbamate A mixture of 4-[1-(4-methoxyphenyl)-3-(trifluoro 25 methyl)-lH-pyrazol-5-yl]benzylamine hydrochloride obtained by Example 57, N-tert-butoxycarbonyl-glycine, WSCD and 1-hydroxybenzotriazole hydrate in triethylamine and dichloromethane was stirred at room temperature. 30 After stirring for 15hrs, the reaction mixture was poured onto water and chloroform. The aqueous layer was separated and extracted with chloroform. The combined 88 WO 2004/050632 PCT/JP2003/014489 organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was column chromatographed on silica gel and crystallized to give the target compound (93.5mg, 5 88.9%). 1HNMR (CDCl 3 ) : 1.43(9H, s), 3.82(3H, s), 3.82-3.85(2H, m), 4.475(2H, d, J=6Hz), 6.71(lH, s), 6.87(2H, d, J=8Hz), 7.14-7.26(6H, m). 10 MS (ESI+) : 505(MH+). Example 87 2-Amino-N-{ 4-[l- (4-methoxyphenyl) -3- (trifluoromethyl) 1H-pyrazol-5-ylIbenzyl}acetamide hydrochloride 15 The title compound (62.3mg, 82.9%) was prepared from tert-butyl 2-({4-[1-(4-methoxyphenyl)-3-(trifluoro methyl)-lH-pyrazol-5-yl]benzyl}amino)-2-oxoethyl carbamate obtained by Example 86 in a similar manner to 20 that of Example 74. 1HNMR (DMSO-d6) : 6 3.61(2H, s), 3.79(3H, s), 4.345(2H, d, J=6Hz), 7.005(2H, d, J=lOHz), 7.15(lH, s), 7.22-7.32 (6H, m), 8.09(2H, br-s), 8.93(lH, br-t, J=6Hz). 25 MS (ESI+) : 405.33 (free, MH+). Example 88 N-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-IH pyrazol-5-yl]benzyllacetamide 30 To a solution of 4-[1- (4-methoxyphenyl) -3- (trifluoro methyl)-lH-pyrazol-5-yl]benzylamine hydrochloride 89 WO 2004/050632 PCT/JP2003/014489 obtained by Example 57 and triethylamine in dichloromethane was added dropwise acetyl chloride at 0 C. After stirring at room temperature for lhr, the mixture was quenched with saturated sodium hydrogen carbonate 5 aqueous solution andextractedwith ethyl acetate (3 times). The combined organic layers were washed with lN hydrochloric acid, water, and brine, dried over magnesium sulfate, and evaporated to give oil, which was purified with silica gel column chromatography (eluted with 50% ethyl 10 acetate/n-hexane) to give oil. The oil was crystallized from a mixture of ethyl acetate and n-hexane at 50 C to give the target compound (52.2mg, 69.3%) as a solid. 1HNMR (CDCl 3 ) : 6 2.04 (3H, s), 3.83(3H, s), 4.435(2H, d, 15 J=6Hz), 6.71(1H, s), 6.87 (2H, d, J=8Hz), 7.15-7.26(6H, m) IR (KBr) 1647cm. MS (ESI+) 412.1(M+Na). Example 89 20 N-(2-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-lH pyrazol-5-yl]-phenyllethyl)-l-methyl-lH-imidazole-4 sulfonamide The title compound (72mg, 70.8%) was prepared from 25 2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-lH pyrazol-5-yl]phenyl)ethanamine hydrochloride in a similar manner to that of Example 77. 1HNMR (CDCl 3 ) : 6 2.83(2H, t, J=8Hz), 3.26(2H, dt, J=6H 30 z), 3.75(3H, s), 3.83(3H, s), 5.005(lH, t, J=6Hz), 6.7(1 H, s), 6.88 (2H, d, J=8Hz), 7.13(4H, s), 7.22(2H, d, J=8H z), 7.45-7.47(2H, m). 90 WO 2004/050632 PCT/JP2003/014489 MS (ESI+) : 528.1 (MNa+). Example 90 N-((lR)-2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl) 5 1H-pyrazol-5-yl]phenoxy}-l-methylethyl)urea To a solution of (1R)-2-{4-[1-(4-methoxyphenyl)-3 (trifluoromethyl)-lH-pyrazol-5-yllphenoxy}-1-methyl ethanamine hydrochloride in dichloromethane was added 10 triethylamine and trimethylsilyl isocyanate at 0 0 C. After stirring for 5hrs, the mixture was quenched with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give oil, 15 which was purified with preparative thin layer chromatography (1mm, ethyl acetate) to give oil. The oil was crystallized from a mixture of isopropyl ether, ethyl acetate, and n-hexane to give the target compound as a white solid (22.8mg, 88.1%). 20 1HNMR (CDCl 3 ) 6 1.29(3H, d, J=8Hz), 3.82(3H, s), 3.87 3.94(2H, m), 4.07-4.19(lH, m), 4.51(2H, s), 4.87(lH, d, J=8Hz), 6.67(1H, s), 6.8-6.89(4H, m), 7.12(2H, d, J=8Hz), 7.215(2H, d, J=lOHz). 25 MS (ESI+) : 435.3 (MH+), 476.3(MH+MeCN). Example 91 N-(2-{4-[1-(6-Methoxy-3-pyridinyl)-3-(trifluoromethyl) 1H-pyrazol-5-yllphenoxy}ethyl)methanesulfonamide 30 The title compound (130mg, 71.8%) was prepared from 2-{4-[l-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-lH 91 WO 2004/050632 PCT/JP2003/014489 pyrazol-5-yl]phenoxy}ethanamine dihydrochloride in a similar manner to that of Example 77. 1HNMR (CDCl 3 ) : 5 3.03(3H, s), 3.555(2H, dt, J=5, 5Hz), 5 3.94(3H, s), 4.115(2H, t, J=5Hz), 4.785(1H, br-t, J=5Hz), 6.71(lH, s), 6.76(lH, d, J=8Hz), 6.85(2H, d, J=8Hz), 7. 16(2H, d, J=BHz), 7.555(2H, dd, J=8, 2Hz), 8.085(1H, d, J=2Hz). MS (EST+) : 479.1 (M+Na)+. 10 Example 92 4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-lH-pyrazol 1-yl]phenol 15 A mixture of 4-methoxy-1-(4,4,4-trifluoro-3-oxo butanoyl)benzene (5.Og) and p-hydroxyphenyl hydrazine hydrochloride (3.59g) in acetic acid (30ml) was stirred at room temperature. After stirring for 15hrs, toluene and water was added. 20 The aqueous layer was separated and extracted twice with toluene. The combined organic layer was washed with water (twice) and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was column chromatographed on silica gel to give the target compound 25 (4.88g, 71.9%) as crystals. 1H NMR (CDCl 3 ) 6 3.80(3H, s), 6.68(lH, s), 6.72(2H, d, J=8.8Hz), 6.83(2H, d, J=8.8Hz), 7.12(2H, d, J=8.8Hz), 7.13(2H, d, J=8.8Hz). 30 MS (ESI+) : m/z 357 (M+Na) Example 93 92 WO 2004/050632 PCT/JP2003/014489 2-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-lH pyrazol-1-yllphenoxylethanol A suspension of 4-[5-(4-methoxyphenyl)-3-(tri 5 fluoromethyl)-1H-pyrazol-1-yl]phenol obtained by Example 92 (500mg), potassium carbonate (1.24g), potassium iodide (1.49g), and 2-chloro-1-ethanol (0.60m 1) was stirred at 80 0 C for 5hrs. After cooling, the reaction mixture was poured into 10 water. Themixture was extracted twice with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was column chromatographed on silica gel to give the target compound (545mg, 96.4%). 15 1H NMR (CDCl3) : 2.03(1H, t, J=5.8Hz), 3.81(3H, s), 3. 94-4.01(2H, m), 4.09(2H, dd, J=3.5 ,4.6Hz), 4.52(3H, s), 6.68(1H, s), 6.84(2H, d, J=8.9Hz), 6.89(2H, d, J=9Hz), 7.13(2H, d, J=8.9Hz), 7.24(2H, d, J=9Hz). 20 MASS (ESI+) : m/z 401 (M+Na) Example 94 {4-[5-(4-Mathoxyphenyl)-3-(trifluoromethyl)-lH-pyrazol 1-yl]phenoxy}acetonitrile 25 A suspension of 4-[5-(4-methoxyphenyl)-3-(tri fluoromethyl)-lH-pyrazol-1-yl]phenol obtained by Example 92 (2.Og), potassium carbonate (992mg), potassium iodide (993mg), and chloroacetonitrile (0.57m 30 1) was stirred at 80 0 C for 4hrs. After cooling, the reaction mixture was poured into water. Themixture was extracted twice with ethyl acetate, 93 WO 2004/050632 PCT/JP2003/014489 washed with water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was column chromatographed on silica gel to give the target compound (1.75g, 78.3%) as an oil. 5 1H NMR (CDCl 3 ) : 3.81(3H, s), 4.79(2H, s), 6.69(1H, s), 6.86(2H, d, J=8.8Hz), 6.96(2H, d, J=9Hz), 7.14(2H, d, J =8.8Hz), 7.31(2H, d, J=9Hz). MS (APCI+) : m/z 374 (M+1). 10 Example 95 tert-Butyl 2-{4-[5-(4-methoxyphenyl)-3-(trifluoro methyl)-lH-pyrazol-1-yl]phenoxylethylcarbamate 15 The title compound (420mg, 21%) was prepared from 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-lH-pyrazol 1-yl]phenol obtained by Example 92 in a similar manner to that of Example 73. 20 1H NMR (CDCl 3 ) : 6 1.46(9H, s), 3.501-3.58 (2H, m), 4.02 (2H, t, J=5.lHz), 4.99(lH, br-s), 6.67(lH, s), 6.84(2H, d, J=8.9Hz), 6.85(2H, d, J=9Hz), 7.13(2H, d, J=8.9Hz), 7. 23 (2H, d, J=9Hz). MS (ESI+) : m/z 500 (M+Na). 25 Example 96 2-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-lH pyrazol-1-yl]phenoxy}ethanamine hydrochloride 30 The title compound (0.35g, 96.2%) was prepared from tert-butyl 2-{4-[5-(4-methoxyphenyl)-3-(trifluoro methyl)-1H-pyrazol-1-yl]phenoxy}ethylcarbamate obtained 94 WO 2004/050632 PCT/JP2003/014489 by Example 95 in a similar manner to that of Example 74. 1H NMR (CDCl 3

+CD

3 0D) : 6 3.2-3.5(4H, m), 3.81(3H, s), 4. 2-4.35(2H, m), 6.70(lH, s), 6.84 (2H, d, J=8.6Hz), 6.95(2 5 H, d, J=8.6Hz), 7.13(2H, d, J=8.6Hz), 7.25(2H, d, J=8.6H z). MS (ESI+) : m/z 378 (M-Cl). Example 97 i N-(2-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-lH pyrazol-1-yllphenoxylethyl)methanesulfonamide To a solution of 2-{4-[5-(4-methoxyphenyl)-3 (trifluoromethyl)-lH-pyrazol-1-yl]phenoxy}ethanamine 15 hydrochloride obtained by Example 96 (100mg) in dichloromethane (5ml) and triethylamine (0.1ml) was added dropwise methanesulfonyl chloride (3841) at room temperature. After stirring for 2hrs, the reaction mixture was 20 partitioned between chloroform and water. The aqueous layer was extracted with chloroform. The combined organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified with high performanced thin layer 25 chromatography to give the target compound (35mg, 31.8%) as crystals. 1H NMR (CDCl 3 ) 6 3.03(3H, s), 3.56(2H, dt, J=5 ,5.7Hz), 3.81(3H, s), 4.11(2H, t, J=5Hz), 4.82(lH, t, J=5.7Hz), 30 6.68(lH, s), 6.85(2H, d, J=7.9Hz), 6.85(2H, d, J=8.7Hz), 7.13(2H, d, J=8.7Hz), 7.24(2H, d, J=7.9Hz). MS (ESI+) : m/z 478 (M+Na). 95 WO 2004/050632 PCT/JP2003/014489 Example 98 N-(2-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-lH pyrazol-1-yll-phenoxylethyl)urea 5 To a solution of 2-{4-[5-(4-methoxyphenyl)-3-(tri fluoromethyl)-lH-pyrazol-1-yl]phenoxy}ethanamine hydrochloride obtained by Example 96 (200mg) in water (10ml) and ethanol (5ml) was added sodium cyanate (314m 10 g) at room temperature. After stirring for 15hrs, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, dried over sodium 15 sulfate, filtered and evaporated under reduced pressure. The residue was column chromatography by high performanced thin layer chromatography (chloroform:methanol=8:1) to give the target compound (0.148g, 72.8%). 20 1H NMR (CDCl 3 ) ': 5 3.60(21, dt, J=5.6, 5.0Hz), 3.81(3H, s), 4.04 (2H, t, J=5.OHz), 4.50 (2H, br-s), 5.12 (1H, t, J=5.6Hz), 6.68(lH, s), 6.84(2H, d, J=8.8Hz), 6.85(2H, d, J=8.9Hz), 7.13(2H, d, J=8.8Hz), 7.22(2H, d, J=8.9Hz). MS (ESI+) : m/z 443 (M+Na). 25 Example 99 N-(2-{4-[3-(Difluoromethyl)-1-(4-methoxyphenyl)-lH pyrazol-5-yl]phenyllethyl)-2-hydroxyethanesulfonamide 30 To a solution of 2-(2-{4-[1-(4-methoxyphenyl)-3 difluoromethyl-lH-pyrazol-5-yl]phenyl}ethyl)-1H isoindole-1,3(2H)-dione in acetonitrile was added 96 WO 2004/050632 PCT/JP2003/014489 hydrazine monohydrate. After stirring at 60 C overnight, the mixture was filtered. And the filtrate was evaporated to give 2-{4 [1-(4-methoxyphenyl)-3-(difluoromethyl)-lH-pyrazol-5 5 yl]phenyl}ethanamine as an orange oil. To a solution of the oil and triethylamine in chloroform was added 2-hydroxyethanesulfonyl chloride at room temperature. After stirring for lhr, the reaction mixture was poured 10 onto water and chloroform. The aqueous layer was separated and extracted with chloroform. The combined organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was column chromatographed on silica gel and 15 crystalized to give the target compound (220mg, 76.1%). 1H NMR (CDC1 3 ) :5 2.875(2H, t, J=7Hz), 2.91-3.19(2H, m), 3.395(2H, dt, J=6Hz), 3.83(3H, s), 3.985(2H, t, J=5Hz), 4.44(1H, br-t, J=6Hz), 6.7(lH, s), 6.765(lH, t, J=55Hz), 20 6.875(2H, d, J=lHz), 7.12(6H, s). MS (ESI+) : 452.19(MH+). Preparation 1 25 T To a suspension of AlCl3 (45.9g) was added dropwise acetyl chloride (13.4ml) (About 5 0 C), and then I (25.7g) mentioned above under ice-cooling(5-10 C) . After stirring for 8 hours, the reaction 97 WO 2004/050632 PCT/JP2003/014489 mixture was poured onto ice-water. The organic layer was separatedandwashedwithwater(twice) and 1NHCl, sat.NaHCO3 and brine, dried over MgSO4, filtered and evaporated under reduced pressure to give crude product. The product was 5 distilled under reduced pressure to give 105.8g (84%) of the following compound (P0001) 0_ 0 (P0001) TLC Check: Ninhydrin/UV 10 b.p. 1> 91-117 'C /0.7mmHg. E111271-1 12.6g 2> 117 OC /0.7mmHg. E111271-2 105.8g Preparation 2 0 0 0 15 (P0002) The above compound P0002 was prepared in a similar manner to that of P0001. Mass (API-ES positive) : 243 (M+Na)+ 20 200MHz 1H NMR (CDC13, d) : 1.91-2.05(2H, m), 2.06(3H, s), 2.59(3H, s), 2.76(2H, t, J=7.7 Hz), 4.09(2H, t, J=6.5 Hz), 7.28(2H, d, J=8.2 Hz), 7.90(2H, d, J=8.2 Hz) Preparation 3 25 98 WO 2004/050632 PCT/JP2003/014489 F 0 (P0003) 60% Sodium hydride 427mg was added to a solution of the compound P0001 (2g) and ethyl trifluoroacetate 2. 6ml in DMF 5 10mlportionwise (in threeportions) under ice bath cooling. The reaction mixture was stirred at same temperature for 45minutes. Then ice bath was replaced to water bath. The temperature of reaction mixture was raised to 24. 5'C, then slowly fall down to 22'C over hour. The mixture was stirred 10 at r.t. for hour, then poured into a mixture of 1M HCl 12ml and ice 40ml. The whole mixture was extracted with AcOEt 20ml. The organic layer was washed with H20 30ml, saturated aqueous sodium chloride solution, dried over magnesium sulfate, concentrated in vacuo. The residue was purified 15 by silica gel column chromatography eluted with toluene. Obtained crystals were washed with chilled n-hexane 10ml and petroleum ether 5ml by decantation to give a compound P0003 as white crystals. mp. 87-88'C 20 Mass (API-ES negative) 301(M-H)+ 200MHz 1H NMR (DMSO-d6, d) 3.00(2H, t, J=6.7 Hz), 4.27 (2H, t, J=6.7 Hz), 6.99(1H, s), 7.48(2H, d, J=8.3 Hz), 8.08 (2H, d, J=8.3 Hz) 25 Preparation 4 F F OF -O O 0 (P0004) 99 WO 2004/050632 PCT/JP2003/014489 P0004 was prepared in a similar manner to that of P0003 as shown in Preparation 3. Mass (API-ES negative) 315 (M-H)+ NMR JA24.112 5 200MHz 1H NMR (CDCl3, d) 1. 92-2. 0 6 (2H, m) , 2. 0 6 (3H, s) , 2.74-2.82(2H,m), 4.10(2H, t, J=6.5Hz), 6.55(1H, s), 7.33(2H, d, J=8.3 Hz), 7.89(2H, d, J=8.3 Hz) Preparation 5 HO 0 1 0/' 10 0 0 (P0005) P0005 was prepared in a similar manner to that of P0003 as shown in Preparation 3. yellow crystals 15 Mass (API-ES positive) 259 (M+Na)+ 400MHz 1H NMR (CDC13, d) 1.41(3H, t, J=7.1 Hz), 4.40(2H, q, J=7.1 Hz), 6.93(2H, d, J=8.9 Hz), 7.02(1H, s), 7.96(2H, d, J=8.9 Hz) 20 Preparation 6 0 F O F (P0006) P0006 was obtained according to a similar manner to that of P0003. (PREPARATION 3) 25 100 WO 2004/050632 PCT/JP2003/014489 Preparation 7 HO F F F F 0 o P0007) 60% Sodium hydride 233mg was added to a solution of P0001 5 lg and ethyl pentafluoropropionate 0. 93ml in three portions under ice bath cooling. The reaction mixture was stirred at 24-27'C with cooling in a water bath for several hours, then poured into a mixture of ice and IM HC1 50ml. The whole mixture was extracted with AcOEt twice. The combined organic 10 layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give P0007 1.94g as an oil. Mass (API-ES negative) : 309 (M-H)+ 200MHz 1H NMR (CDCl3, d) : 2.90-3.05(2H, m), 3.85-4.00(2H, 15 m), 6.62(lH, s), 7.39(2H, d, J=8.3 Hz), 7.92(2H, d, J=8.3 Hz) Preparation 8 HO 0 OO O O 20 (P0008) 20% solution of sodium ethoxide in EtOH 18ml was added dropwise to a solution of P0001 (4.00g) and diethyl oxalate 5. 95g in DMF 12ml at 4-6'C. After stirring at same temperature for hour, the reaction mixture was poured into a mixture 25 of ice-water 100ml and conc.HCl 5ml, andextractedwithAcOEt. The organic layer was washed successively with 1M HCl, H20, and saturated aqueous sodium chloride solution, dried over 101 WO 2004/050632 PCT/JP2003/014489 magnesium sulfate, treated. with activated carbon, then filtered through a Si02 (20ml) pad. The pad was washed with AcOEt. The filtrate and combined washings were concentrated in vacuo to give P0008 (6.05g) as an oil. 5 Mass (API-ES positive) 287(M+Na)+, (API-ES negative) 263 (M-H) + 200MHz 1H NMR (CDCl3, d) 1.42 (3H, t, J=7.lHz), 2.96(2H, t, J=6.5 Hz), 3.93 (2H, t, J=6.5 Hz), 4.40(2H, q, J=7.lHz), 10 7.06(1H, s), 7.38(2H, d, J=8.3 Hz), 7.96(2H, d, J=8.3Hz) Preparation 9 Ho F F 0 F P0009) 15 To a solution of 4-Hydroxybenzophenone (160 g), Ethyl trifluoroacetate (182 ml), and ethanol (11 ml) in N,N-dimethylformamide (670 ml) was added portionwise sodium hydride (suspension in mineral oil, 103 g) over 15 minutes at 0 - 35 0 C. The mixture was stirring at room temperature 20 for 2 hours, and then at 35 - 40 0 C for 3 hours. The mixture was poured into a mixture of ice and concentrated hydrogen chloride (320 ml) (aqueous layer total 4L) and diisopropyl ether (2 L). The aqueous layer was separated and extracted with diisopropyl ether (500 ml x '2) . The 25 combined organic layers were washed with water (500 ml x 4) and brine, dried over magnesium sulfate, and evaporated to give 415 g of solid. The solid was dissolved in diisopropyl ether (200 ml) at 65'C. The solution was added dropwise hexane (1.5 L) under stirring at room temperature. 102 WO 2004/050632 PCT/JP2003/014489 After stirring at room temperature for 1 hour, The suspension was filtered and dried under reduced pressure to give solid (first crop, 109.53 g, 40%). The mother liquid evaporated and similarly treated diisopropyl ether (20 ml) and hexane 5 (250 ml) to give second crop (71.11 g, 26%). P0009 (first corp and second corp total, 66.2%). NMR(CDCl3); 5.65(1H, brs), 6.50(1H, s), 6.94(2H, d, J=8.8 Hz), 7.91(2H, d, J=8.8 Hz). MS(ESI+), 255.1(M+Na)+. 10 Preparation 10 HO 0 0 (P0010) This compound was obtained according to a similar manner 15 to that of P0009 (S0203744) as a powder (56.195 g, 102%). NMR(CDCl3); 6.01(1H, t, J=54 Hz), 6.49(1H, s), 6.92 (2H, d, J=8.8 Hz), 7.90(2H, d, J=8.8 Hz). MS(ESI-), 213.3(M-H)+ 20 Preparation 11 F HO F ( P0011) A mixture of P0009 (100 g), 4-Methoxyphenylhydrazine hydrochloride (82. 4 g) , and sodium acetate (42. 6 g) in acetic 103 WO 2004/050632 PCT/JP2003/014489 acid (550 ml) was stirring at 70'C for 3 hours. After cooling to room temperature, the mixture was poured into water (4 L) andstirredatroomtemperature forlhour. Theprecipitate was filtered, washed with water (250 ml x 3) and Hex(500 5 ml x 2), and dried at room temperature overnight to give powder (157.86 g). The powder was purified by recrystallization fromethyl acetate andhexane to give P0011 as a powder 121.34G (77%). NMR (CDC13) ; 3.82 (3H, s), 5.08 (1H, brs), 6.67 (1H, s), 6.77 (2H, 10 d, J=8.6 Hz), 6.87 (2H, d, J=9.0 Hz), 7.09(2H, d, J=8.6 Hz), 7.23(2H, d, J=9.0 Hz). MS(ESI+); 357.1(M+Na)+. Preparation 12 F 15\ P0012) This compound was obtained according to a similar manner to that of P0011 as a solid (3.2028 g, 72%). NMR (DMSO-d6) ; 3. 88 (3H, s) , 6. 74 (2H, d, J=8. 6 Hz) , 6.82 (1H, 20 s), 6.90(lH, d, J=8.6 Hz), 7.10(2H, d, J=8.6 Hz), 7.09(lH, t, J=55 Hz), 7.68 (1H, dd, J=8.6, 2.7 Hz), 8.12 (1H, d, J=2.7 Hz). MS(ESI+); 316.1(M-H)+, 633.3(2M-H). 25 Preparation 13 104 WO 2004/050632 PCT/JP2003/014489 F X HO \C /d. Ho (P0013) This compound was obtained according to a similar manner to that of P0011. 5 Preparation 14 HO y~ N F 0N (P0014) To a solution of 4-methoxyphenylhydrazine hydrochloride 10 (3.43 g) in water (7.7 ml) was added a solution of P0009 in acetic acid (50 ml). The mixture was then allowed to stand at room temperature overnight. The mixture was poured into water (500 ml) and stirred at room temperature for 1 hour. The precipitate was filtered, washed with water (100 ml), 15 and dried at room temperature to give P0014 as a brown solid (3.26 g, 90%). NMR(DMSO-d6); 3.88 (3H, s), 6.75(2H, d, J=8.6 Hz), 6.92(1H, d, J=8.5 Hz), 7.06-7.15 (3H, m) , 7.73(lH, dd, J=8.5, 2.8 Hz), 8.16(1H, d, J=2.8 Hz),. 9.86(lH, s, OH). 20 MS(ESI-); 334.1(M-H)+, 669.2(2M-1)+. Preparation 15 105 WO 2004/050632 PCT/JP2003/014489 HO 0 (P0015) This compound was obtained according to a similar manner to that of P0014 as a pale brown powder (13.58 g, 91.7%). 5 NMR(DMSO-d6); 3.94(3H, s), 6.67(1H, s), 6.75(1H, t, J=55 Hz), 6.73-6.80(3H, m), 7.09(2H, d, J=8.6 Hz), 7.57(1H, dd, J=8.6, 2.6 Hz), 8.07(lH, d, J=2.6 Hz). MS(ESI-); 316.1(M-H), 633.3(2M-H). 10 Preparation 16 Si \I/ 0 CHO (P0016) (P0016-1) 1M NaOH 1ml was added to a solution of P0016-1 (reported inW09427973) 1.31gandinEtOH5mlandthemixturewas stirred 15 at amibient temperature overnight. The mixture partitioned between AcOEt and H20. The organic layer was washed with H20, saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 20 AcOEt / n-hexane to give P0016 (900mg) as an oil. Mass (ESI+) : 331 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : -0.05(6H, s), 0.82(9H, s), 0.94 (4H, d, J=6.0 Hz), 2.38-2.52(1H, m), 2.78 (2H, t, J=6.6 Hz), 3.79(2H, t, J=6.6 Hz), 7.01(1H, d, J=16.2 Hz), 7.29 (2H, 25 d, J=8.1 Hz), 7.65(2H, d, J=8.1 Hz), 7.65 (1H, d, J=16.2 Hz) 106 WO 2004/050632 PCT/JP2003/014489 Preparation 17 00 (P0017) P00176.41gwaspreparedinasimilarmannertothatofP0016. 5 Mass (API-ES positive) 255 (M+Na)+ 200MHz 1H NMR (CDCl3, d) 0.90-1.01(2H, m), 1.11-1.20(2H, m) , 2.22 (1H, m), 3.49 (3H, s) , 5.21 (2H, s), 6.78 (1H, d, J=16.0 Hz), 7.05(2H, d, J=8.7 Hz), 7.52(2H, d, J=8.7 Hz), 7.58(1H, d, J=16.0 Hz) 10 Preparation 18 Si\I 0 (P0018) 30%H2020.64mland3MNaOHO.64mlwasaddedtoa0.25Msolution 15 of P0016 1.03g in EtOH:acetone=3:1. The mixture was stirred at ambient temperature overnight. The mixture was concentrated in vacuo, and partitioned between AcOEt and H20. The organic layerwaswashedwithHE20, saturated aqueous sodiumchloride solution, driedovermagnesiumsulfate, and 20 concentrated in vacuo to give P0018 (792mg) as an oil. Mass (ESI+) : 347 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) -0.05(6H, s), 0.82(9H, s), 0.92-1.04 (4H, m), 2.24(1H, m), 2.75(2H, t, J=6.7 Hz), 3.76(2H, t, J=6.7 Hz), 3.86(1H, d, 25 J=1.9 Hz), 4.19(1H, d, J=1.9 Hz), 7.24(2H, d, J=8.4 Hz), 7.30(2H, d, J=8.4 Hz) 107 WO 2004/050632 PCT/JP2003/014489 Preparation 19 00 0 (P0019) P0019 1.082g was prepared fromP0017 1.Ogina similarmanner 5 to that of P0018. Mass (API-ES positive) : 271(M+Na)+ 200MHz 1H NMR (DMSO-d6, d) : 0. 90-1. 04 (4H, m) , 2. 24 (1H, m) , 3.37 (3H, s), 3.88(1H, d, J=1.9 Hz), 4.17 (1H, d, J =1.9 Hz), 5.20(2H, s), 7.03(2H, d, J=8.7 Hz), 7.32(2H, d, J=8.7 Hz) 10 200MHz 1H NMR (CDC13, d) : 0.90-1.07(2H, m), 1.12-1.26(2H, m), 2.18 (1H, m) , 3.48 (3H, s), 3.58 (1H, d, J=1.9 Hz), 4.05 (1H, d, J=1.9 Hz), 5.18(2H, s), 7.04 (2H, d, J=8.7 Hz), 7.23(2H, d, J=8.7 Hz) 15 Preparation 20 HO 0I (P0020) P0005 17. 0Og was dissolved in warm EtOH 68ml and AcOH 170ml at 70'C. To this solution was added P0005, suspended in H20 20 20ml, in one portion. The mixture was stirred at 70'C for 1.5hours and then poured into a mixture of ice 500ml and conc.HCl 10ml. Diisopropyl ether 100ml was added and the mixture was stirred at ambient temperature for 20minutes. The precipitates were collected and washed successively with 25 1M HC1, H20, and diisopropylether. This was air dried 108 WO 2004/050632 PCT/JP2003/014489 overnight to give P0020 21.28g was a pale yellow powder. Mass (ESI+) : 339 (M+H)+ 400MHz 1H NMR (CDC13, d) : 1.41(3H, t, J=7. 1 Hz), 3.82 (3H, s), 4.44 (2H, q, J=7.1 Hz), 6.76(2H, d, J=8.7 Hz), 6.85 (2H, 5 d, J=9.0 Hz), 6.96(1H, s), 7.08 (2H, d, J=8.7 Hz), 7.24 (2H, d, J=9.0 Hz) Preparation 21 HO 00 N~ y N 10 (P0021) P0021 was prepared from P0005 in a similar manner to that of P0020. white powder Mass (ESI+) : 340 (M+H)+ 15 200MHz 1H NMR (DMSO-d6, d) : 1.31(3H, t, J=7.1 Hz) , 3.88 (3H, s), 4.32 (2H, q, J=7.1 Hz), 6.74 (2H, d, J=8.6 Hz), 6.92(1H, d, J=8.8 Hz), 7.00(1H, s), 7.09(2H, d, J=8.6 Hz), 7.71(1H, dd, J=8.8,2.7 Hz), 8.13(1H, d, J=2.7 Hz), 9.82(1H, s) 20 Preparation 22 (P0022) A solution of triphenylphosphine 831mg in THF 5m1 was added dropwise to a solution of E0118 521.8mg and carbon 109 WO 2004/050632 PCT/JP2003/014489 tetrabromide 1.15g in THF 5ml at ambient temperature. The reacion mixture was stirred at ambient temperaturer for hour. Carbon tetrabromide 573mg and triphenylphosphine 415mg were added in one portion and stirred for further hour. Unsoluble 5 matter was filtered off and washed with THF. The filtrate andcombinedwashingswereconcentratedinvacuo. Theresidue was purified by silica gel column chromatography eluted with AcOEt / n-hexane = 5%, then 25% to give P0022 647.2mg as pale yellow wax. 10 mp.60-70'C Mass (API-ES positive) : 425,427 (M+H)+ , 447,449 (M+Na) + 200MHz 1H NMR (CDCl3, d) : 3.12-3.19(2H, m), 3.52-3.60(2H, m), 3.82(3H, s), 6.72(lH, s), 6.87(2H, d, J=9.0 Hz), 7.16-7.30(6H, m) 15 Preparation 23 B, (P0023) P0023 was prepared in a similar manner to that of P0022. 20 colorless oil Mass (API-ES positive) 448,450 (M+Na)+ 400MHz 1H NMR (DMSO-d6, d) 3.14(2H, t, J=7.2 Hz), 3.74(2H, t, J=7.2 Hz), 3.88 (3H, s), 6.92(1H, d, J=8.8 Hz), 7.20(1H, s), 7.27 (2H, d, J=8.4 Hz), 7.32(2H, d, J=8.4 Hz), 7.76(1H, 25 dd, J=2.7,8.8 Hz), 8.19(1H, d, J=2.7 Hz), Preparation 24 110 WO 2004/050632 PCT/JP2003/014489 0 H F O 0 F (P0024-0) (P0024) To a solution of P0001 (20.0g) and P0024-0 (53.4g) in DMF (200ml) was added portionwise NaH (4.27g) under 5 ice-cooling. The reaction mixture was warmed at room temperature and the temperature was kept under 40 C. After stirring for 5 hours, the reaction mixture was poured onto ice-cooled dilHCl and extracted twise with ethylacetate. The combined organic layer was washed with water (twice) 10 and brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was column chromatographed on silica gel (500ml, Hex:EtOAc) to give 12.12g of P0024 as crystal. mp: 52.6-53.6'C 15 Example 100 (E0100) To a solution of 4-hydroxybenzophenone (4.16g) and 20 chloromethyl methyl ether (2.46g) in N,N-dimethylacetoamide (15ml) was added portionwise sodium hydride (suspension in mineral oil (60%), 1.22g) over 15 minutes at 0 C. The mixture was stirred for 30 minutes at ambient temperature. To the reaction mixture was added 111 WO 2004/050632 PCT/JP2003/014489 2-propanole (0.5ml) , carbon disulfide (2.56g) and portionwise sodium hydride (suspension in mineral oil (60%), 2.50g) over 15 minutes at 250C. The mixture was stirred at ambient temperature for 1.5 hours,diluted with toluene 5 (20ml) and poured into a mixture of ice and concentrated hydrogen chloride (8 ml) (aqueous layer total 68ml) . The resultant mixture was extracted with ethyl acetate , washed with brine,dried over magnesium sulfate, and evaporated. To the mixture of the resultant residue and sodium hydrogen 10 carbonate (13g) in ethyl acetate (30ml) and water (20ml) was added portionwise the solution of iodine (3.88g) and sodium iodide (8.0g) in water at 00C. To the mixture was added portionwise 4-Methoxyphenylhydrazine hydrochloride (3.80g) at 0 C under nitrogen. The mixture was stirred at 15 ambient temperature for 3 hours and the organic layer was seperated, washed with water and brine, dried over magnesium sulfate, and evaporated. To the solution of the residue in ethyl acetate (30ml) was added methyl iodide (4.0ml) and triethylamine (10ml) at 00C. The mixture was stirred for 20 30 minutes at ambient temperature, washed with water and aqueous potassium carbonate, dried over magnesium sulfate, and evaporated. The residue was column chromatographed on silica gel (80g) ,eluting with a mixture of ethyl acetate andtoluene (1:20) togive7.56gof 5-[4-(methoxymethoxy) 25 phenyl]-1-(4-methoxyphenyl)-3-(methylthio)-lH-pyrazole. To the solution of methyl sulfide (7.56g) in dichloromethane (30 ml) was added a solution of m-chloroperbenzoic acid (80%,4.4g) in dichloromethane (15ml) at 0 C, and the mixture was stirred at 0 0 C for hour. 30 The mixture was washed with aqueous potassium carbonate , dried over magnesium sulfate, and evaporated. The residue was column chromatographed on silica gel (80g) ,eluting with 112 WO 2004/050632 PCT/JP2003/014489 ethyl acetate to give 5.43g of 5-[4-(methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-3 (methylsulfinyl)-lH-pyrazole (EO100). mp.136.9-137.3 0 C 5 Mass; 373 (M+l) IR(KBr);1054cm-1 NMR(CDCl3,5) ; 3.00(H, s), 3.48 (H, s), 3.83(H, s), 5.17(H, s), 6.88 (H, d, J=9.0 Hz), 6.92(H, s), 6.97 (H, d, J=8.8 Hz), 7.14(H, d, J=8.8 Hz), 7.22(H, d, J=9.0 Hz), 10 Example 101 (E0101) To the solution of 5-[4-(methoxymethoxy)phenyl]-l-(4 15 methoxyphenyl)-3-(methylsulfinyl)-lH-pyrazole (7.56g) in dichloromethane (20 ml) was added m-chloroperbenzoic acid (60%,3.76g) at 0 0 C, and the mixture was stirred at 0 0 C for 3 hour. The mixture was washed with aqueous sodium hydrogen carbonate , dried over magnesium sulfate, and evaporated. 20 The residue was purified by recrystallization with toluene to give 5.07g of 5-[4-(methoxymethoxy)phenyll-1-(4-methoxyphenyl) 3-(methylsulfonyl)-1H-pyrazole(EO101). mp.128.0-128.1 0 C 25 Mass;389(M+l) IR(KBr) ;1300cm-1 NMR (CDCl3, 5) ; 3. 29 (3H, s) , 3.48 (3H, s) , 3.83 (3H, s) , 5.17 (2H, s), 6.88(2H, d, J=9.0 Hz), 6.93(1H, s), 6.98 (2H, d, J=8.8 113 WO 2004/050632 PCT/JP2003/014489 Hz), 7.13(2H, d, J=8.8 Hz), 7.24(2H, d, J=9.0 Hz), Preparation 25 0 \\ 5 (P0024) To the solution of 5- [4- (methoxymethoxy)phenyl) -1- (4-methoxyphenyl) 3-(methylsulfonyl)-1H-pyrazole (0.93g) in a mixture of tetrahydrofuran (10ml) andisopropyl alcohol (5ml) was added 10 hydrogen chloride aqueous solution (20%,8ml) at ambient temperature. The solution was stirred for 3 hours, extracted with ethyl acetate , washed with brine, dried over magnesium sulfate,and evaporated to give 0.82g of 4-[1-(4-methoxyphenyl)-3-(methylsulfonyl)-lH-pyrazol 15 5-yl]phenol (P0025). Mass;345 (M+1) NMR(DMSO-d6,5);3.32(3H, s), 3.79(3H, s), 6.73(2H, d, J=8.6 Hz), 7.01(2H, d, J=8.9 Hz), 7.05(1H, s), 7.08 (2H, d, J=8.6 Hz), 7.27(2H, d, J=8.9 Hz), 9.84(1H, s), 20 Preparation 26 O-Br HO Br (P0026-0) (P0026) To a solution of P0026-0 (5.0g) and imidazole (3.3g) in 25 DMF (40ml) was added portionwise TBDMSC1 (6.69g) at room 114 WO 2004/050632 PCT/JP2003/014489 temperature. After stirring overnight, water and hexane was added. The aqueous layer was separated and extracted twice with hexane. The combined organic layer was washed with water (twice) and brine, dried over MgSO4, filtered 5 and evaporated under reduced pressure to give 9.49g (98.3%) of P0026. IR (film): 2952.5, 2935.1, 1467.6, 1255.4, 1124.3, 1097.3, 838.9, 777.2 cm-1. 10 Preparation 27 0 O BnO OMe 0 0 0 (P0027-0) (P0027) To a solution of P0027-0 (10g) and dimethylcarbonate 5.97g in DMF was added sodium methoxide 4.77g. The mixture was 15 stirred at ambient temperature for 2hours. The mixture was poured into water with 8 ml of conc. HCl, and extracted with AcOEt. The organic layer was dried over magnesium sulfate, andconcentratedinvacuo. The residue was purifiedby silica gel column chromatography to give orange solid. Which was 20 recrystallized from MeOH to give P0027 as white crystals. NMR (200 MHz, CDCl3) 3.75(3H, s), 3.96(2H, s), 5.14 (211, s), 7.02(2H, d, J=8.9 Hz), 7.34-7.45(5H, m), 7.93(2H, d, J=8.9 Hz) 25 Mass ESI 285(M+H)+ (file platform 7366-1) Preparation 28 Ph O ~ - CO 2 Me 115 WO 2004/050632 PCT/JP2003/014489 (P0028) To a solution of triphenylphosphin oxide 294mg in 1, 2-dichloroethane 3ml was added trifluoromethanesulfonic anhydride 198mg dropwise under cooling in an ice bath. The 5 mixture was stirred at same temperature for 15minutes, when white precipitates were came out. To this mixture was added P0027 (300mg) in 1,2-dichloroethane 2ml dropwise, followed byadditionof Et3N214mg. Themixturewasrefluxedfor2hours. The mixture was allowed to cool to ambient temperature and 10 was washed with H20, sat.aq NaCi, dried over MgSO4, concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / n-hexane = 5%, and 10%. The residue was crystallized from IPE to give P0028 (166mg) as a white powder. 15 Mass (ESI+) : 289 (M+Na)+ 200MHz 1HNMR (DMSO-d6, d) : 3.76 (3H, s), 5.18 (.2H, s) , 7.11 (2H, d, J=8.8 Hz), 7.33-7.48(5H, m), 7.62(2H, d, J=8.8 Hz) Preparation 29 20 Ph-/ \- CO 2 H (P0029) Solid KOH 124mg was dissolved in EtOH 5ml at 50'C. To this solution was added P0028 (196mg). After stirring at same 25 temperature for 2hours, the reaction mixture was allowed to cool to ambient temperature. The mixture was partitioned between 1M HC1 and CHCl3. The aqueous layer was reextracted with CHCl3. The combined organic layers were dried over MgSO4, evaporated in vacuo. The residual crystals were collected 30 and washed with IPE to give 1st crop of P0029 (87mg) as a white powder. The mother liqour was concentrated in vacuo 116 WO 2004/050632 PCT/JP2003/014489 and the residual crystals were collected and washed with n-hexane to give 2ndcropof P0029 (39mg) asaslightlyreddish powder. Mass (ESI-) : 251 (M-H)+ 5 200MHz 1H NMR (CDCl3, d) : 5.10 (3H, s), 6.97 (2H, d, J=8.9 Hz), 7.34-7.43(5H, m), 7.56(2H, d, J=8.9 Hz) Preparation 30 10 Ph'-O O'D yH Ph - 1O 0 H C0 2 Et (P0030-0) (P0030) To a solution of P0030-0 (2g) and triethylphosphonoacetate 2.32g in DMF 20ml was added 60% NaH 490mg in two portions 15 with cooling on ice bath. The mixture was stirred at same temperature for lhour, and then poured into ice water containing NH4Cl. The mixture was stirred for a while, and white precipitates were collected and washed with water and 10% aqueous IPA to give P0030. 20 200MHz 1H NMR (CDCl3, d) 1.33(3H, t, J=7.2 Hz), 4.25 (2H, q, J=7.2 Hz), 5.10(2H, s), 6.31(1H, d, J=16.0 Hz), 6.97(2H, d, J=8.7 Hz), 7.32-7.50(7H, m), 7.64(1H, d, J=16.0 Hz) 25 Preparation 31 Ph O Br

CO

2 Et Br (P0031) 117 WO 2004/050632 PCT/JP2003/014489 Toasolutionof P0030 (2.79g) inCH2Cl228mlwasaddedbromine 1.66g dropwise under ice bath cooling. The mixture was stirred at same temperature for 30minutes. The reaction mixture was poured into 5% aqueous solution of Na2S203, and 5 partitioned. The organic layerwas washedwith sat.aqNaHCO3, sat.aqNaCl, dried over MgSO4, concentrated in vacuo. The residual crystals were collected and washed with n-hexane to give P0031 (3.07g) as a pale yellow powder. 200MHz 1H NMR (CDCl3, d) : 1.38 (3H, t, J=7.2 Hz), 4.35 (2H, 10 q, J=7.2 Hz), 4.81(1H, d, J=ll.8 Hz), 5.07 (2H, s), 5.35(1H, d, J=1l.8 Hz), 6.98 (2H, d, J=8.7 Hz), 7.34 (2H, d, J=8.7 Hz), 7.32-7.45(5H, m) Preparation 32 15 Ph-O~- CO2H (P0032) 85% solid KOH 1.73g was dissolved in 95% aqueous EtOH 20ml at50 0 C. P0031 (3.05g) wasaddedinoneportionandthemixture was refluxed for 9hours. To this mixture was added a solution 20 of 85% KOH 0.32g dissolved in 95% aqueous EtOH 10ml and refluxed for 5hours. The mixture was cooled in an ice bath, precipitates were collected and washed with EtOH. The crystals were suspended in AcOEt and H20, cooled in an ice bath, acidified by 3M HCl and 1M HCl. The mixture was 25 partitioned and the organic layer was washed with H20, dried over MgSO4, concentrated in vacuo. The residual solid was collected andwashedwith IPE-n-hexane to give P0032 (0.67g) as a white powder. 30 200MHz 1H NMR (CDCl3, d) : 5.10(3H, s), 6.97 (2H, d, J=8.9 Hz), 7.34-7.43(5H, m), 7.56(2H, d, J=8.9 Hz) 118 WO 2004/050632 PCT/JP2003/014489 Example 102 Ph O ,1 HOH C1H MeO 5 (E0102-0) (E0102) To a solution of P0032(99.9mg) and HOBT 64.2mg in N-methylpyrrolidone 1ml was added WSCD-HCl 91.1mg and the mixture was stirred at ambient temperature for 20minutes. In another flask, diisopropylethylamine 76.8mg was added 10 to a suspension of E0102-0 (83.0mg) in N-methylpyrrolidone iml and stirred at ambient temperature until all E0102-0 was dissolved. The solution of E0102-0 was added to the reaction flask and the mixture was stirred at ambient temperature for hour. The mixture was partitioned between 15 AcOEt and H20, washed with sat.aqNaHCO3, sat.aqNaCl, dried over MgSO4, and concentrated in vacuo.The residue was dissolved in CH2Cl2 3ml, and stirred at ambient temperature for 24hours. The mixture was concentrated in vacuo. The residual crystals were suspended in hot AcOEt, cooled with 20 stirring, collected and washed with AcOEt to give E0102 (90.9mg) as a white powder. Mass (EST+) : 373 (M+H)+ 200MHzlHNMR (DMSO-d6, d) :3.75(3H, s), 5.08 (2H, s), 5.81(1H, s), 6.90(2H, d, J=9.0 Hz), 6.96(2H, d, J=9.0 Hz), 7.10(2H, 25 d, J=9.0 Hz), 7.12(2H, d, J=9.0 Hz), 7.32-7.47(5H, m), 10.00(lH, s) Example 103 119 WO 2004/050632 PCT/JP2003/014489 Ph OMe N N MeO (E0103) To a suspension of E0102 (20.9mg) and K2CO3 23.3mg in DMSO 0.5ml was added dimethylsulf ate 10.6mg and the mixture was 5 stirred at ambient temperature for hour. The mixture was partitioned between AcOEt and H20, and the organic layer was washed with sat.aqNaCl, dried over MgSO4, concentrated in vacuo. The residue was purified by preparative thin layer chromatography developed with AcOEt / n-hexane = 25%. The 10 obtained crystals were crystallized from IPE to give E0103 (12.0mg) as white crystals. Mass (ESI+) : 387 (M+H)+ 200MHz lHNMR (DMSO-d6, d) : 3.76 (3H, s), 3.83(3H, s), 5.08 (2H, s), 6.04(lH, s), 6.92(2H, d, J=9.0 Hz), 6.97(2H, d, J=9.0 15 Hz), 7.11-7.17(4H, m), 7.30-7.50(5H, m) 200MHzlHNMR (CDCl3, d) : 3.80(3H, s), 3.97(3H, s), 5.04(2H, s), 5.88(1H, s), 6.82(2H, d, J=9.0 Hz), 6.88 (2H, d, J=8.9 Hz), 7.11-7.21(4H, m), 7.34-7.43(5H, m) 20 Example 104 PhO -. OMe N'N MeO (E0104) To suspension of E0102 (818mg) and K2CO3 911mg in DMF 6ml was added dimethylcarbonate 0.56ml. The mixture was 120 WO 2004/050632 PCT/JP2003/014489 stirred at 1200C for 2hours. Additional dimethylcarbonate 1ml was added and stirred at 1200C for 8hours. The mixture was partitioned between AcOEt and H20, and the aq layer was reextracted with AcOEt. The combined organic layers were 5 washed with sat.aqNaCl, dried over MgSO4, concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / n-hexane = 30%. The residue was crystallized from AcOEt 2.5ml and n-hexane 5ml to give E0104 (583mg) as white crystals. 10 200MHz lHNMR (DMSO-d6, d) : 3.76 (3H, s) , 3.83 (3H, s), 5.08 (2H, s), 6.04 (1H, s), 6.92(2H, d, J=9.0 Hz), 6.97(2H, d, J=9.0 Hz), 7.11-7.17(4H, m), 7.30-7.50(5H, m) 200MHz 1H NMR (CDCl3, d) : 3.80 (3H, s), 3.97 (3H, s), 5.04 (2H, s), 5.88 (1H, s), 6.82(2H, d, J=9.0 Hz), 6.88 (2H, d, J=8.9 15 Hz), 7.11-7.21(4H, m), 7.34-7.43(5H, m) Preparation 33 HO NZ /OMe NN MeO (P0033) 20 Amixture of 10% Pd-C 50% wet 50mg and E0104 (261mg) inAcOEt 2ml and MeOH 2ml was hydrogenated under H2 latm at ambient temperature for lday. The additional 10% Pd-C 50% wet 50mg was added and the mixture was hydrogenated under H2 3.5atm at ambient temperature for 3hours. The catalyst was filtered 25 off and the filtrate and combined washings were concentrated in vacuo. The residue was dissolved in AcOEt, dried over MgSO4, and concentrated in vacuo. The residue was crystallized from AcOEt-n-hexane to give P0033 (146mg) as 121 WO 2004/050632 PCT/JP2003/014489 a white powder. Mass (ESI+) : 297 (M+H)+ 200MHz1H NMR (DMSO-d6, d) : 3.75(3H, s), 3.83(3H, s), 5.98 (lH, s), 6.70(2H, d, J=8.6 Hz), 6.91(2H, d, J=8.9 Hz), 7.01(2H, 5 d, J=8.6 Hz), 7.12(2H, d, J=8.9 Hz), 9.69(lH, s) Preparation 34 HO N/OMe

N

MeO (P0034) 10 To a solution of ammonium formate 455mg in H20 1ml was added EtOH 6ml, E0104 (558mg), THF lml, and 10% Pd-C 50% wet 60mg successively. The mixture was refluxed for hour. The catalyst was removed by filtration. The filtrate and combined washings were concentrated in vacuo. The residue was 15 partitioned between AcOEt and H20, and the organic layer was washed with sat.aqNaCl, dried over MgSO4, concentrated in vacuo. The residual crystals were recrystallized from AcOEt 3ml and n-hexane 3ml to give P0034 (335mg) as white crystals. 20 Mass (ESI+) : 297 (M+H)+ Example 105 0 F (E0105) 122 WO 2004/050632 PCT/JP2003/014489 A mixture of P0003 (2.9g) and 4-methoxyphenylhydrazine (1. 68g) in acetic acid (30ml) was stirred at roomtemperature for 15 hours. After addition of water, the mixture was extracted twice with toluene. The combined organic layer 5 was washed with water (twice), sat.NaHCO3, water and brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was column chromatographed on silica gel ( Hex/EtOAc = 8:1-4:1) to give 2.2g (57%) of E0105 as an oil. 10 IR (film): 1737.6, 1511.9, 1240.0, 1159.0, 1130.1 cm-1. Example 106 F N (E0106) 15 E0106 was prepared from P0004 in a similar manner to that of E0105. Mass (ESI+) : 420 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.79-1.94 (2H, m), 1.98 (3H, s), 2. 60-2. 68 (2H, m) , 3.88 (3H, s) , 3. 98 (2H, t, J=6.5 Hz) , 6. 92 (1H, 20 d, J=8.9 Hz), 7.18(1H, s), 7.24(4H, s), 7.75(1H, dd, J=2.7,8.9 Hz), 8.48(1H, d, J=2.7 Hz) Example 107 I F 123 WO 2004/050632 PCT/JP2003/014489 (E0107) E0107 (175.7mg) was prepared from P0007 (590mg) and 4-methoxyphenylhydrazine hydrochloride (332mg) in a similar manner to that of E0105. 5 Mass (ESI+) : 455 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.96(3H, s), 2.88 (2H, t, J=6.8 Hz), 3.79 (3H, s), 4.20(2H, t, J=6.8 Hz), 6.99(2H, d, J=8.9 Hz), 7.15(lH, s), 7.17-7.30(6H, m) 10 Example 108 F F i / F (E0108) E0108 was prepared from P0007 in a similar manner to that of E0105. 15 Mass (API-ES positive) 456 (M+H)+ , 478 (M+Na)+ 200MHz 1H NMR (DMSO-d6, d) :1.96(3H, s), 2.89(2H, t, J=6.8 Hz), 3.88 (3H, s), 4.21(2H, t, J=6.8 Hz), 6.92(1H, d, J=8.8 Hz), 7.15-7.35(4H, m) , 7.21(1H, s), 7.76(lH, dd, J=2.7,8.8 Hz), 8.17(1H, d, J=2.7 Hz) 20 Example 109 (EO109) E0109 was prepared in a similar manner to that of E0105. 124 WO 2004/050632 PCT/JP2003/014489 Mass (ESI+) 409(M+H)+, 431(M+Na)+ NMR: SE20.059 200MHz 1H NMR (DMSO-d6, d) : 1.31(3H, t, J=7.1 Hz), 1. 96 (3H, s), 2.87 (2H, t, J=6.8 Hz), 3.79 (3H, s), 4.20 (2H, t, J=6.8 Hz), 4.32(2H, q, J=7.1 Hz), 6.99(2H, d, J=9.0 Hz), 5 7.08(1H, s), 7.16-7.28(6H, m) Example 110 (EO110) 10 E0110 was prepared in a similar manner to that of E0105. Mass (ESI+) : 410 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) :1.32(3H, t, J=7.1Hz), 1.96(3H, s), 2.89(2H, t, J=6.8 Hz), 3.88 (3H, s), 4.21(2H, t, J=6.8 Hz), 4.33 (2H, q, J=7.1 Hz), 6.92 (1l, d, J=8.8 Hz), 7.12 (1H, 15 s), 7.19-7.32(4H, m), 7.73(1H, dd, J=2.7,8.8 Hz), 8.14 (1H, d, J=2.7 Hz) Example 111 oF 20 (E0111) E0111 was prepared in a similar manner to that of E0105. Mass (API-ES positive) 406(M+H)+ , 428(M+Na)+ 200MHz 1H NMR (DMSO-d6, d) 1.96(3H, s), 2.89(2H, t, J=6.7 Hz), 3.88 (3H, s), 4.21(2H, t, J=6.7 Hz), 6.92(1H, d, J=8.8 125 WO 2004/050632 PCT/JP2003/014489 Hz), 7.20(1H, s), 7.24(2H, d, J=8.7 Hz), 7.30(2H, d, J=8.7 Hz), 7.76(1H, dd, J=2.7, 8.8 Hz), 8.18 (1H, d, J=2.7 Hz) Example 112 0 N11/ 0N F 5 (E0112) E0112 was obtained according to a similar manner to that of E0105. 10 Example 113 o N F (E0113) E0113 was obtained according to a similar manner to that of E0105. 15 Example 114 F F (E0114) E0114 was obtained according to a similar manner to that 20 of E0105. 126 WO 2004/050632 PCT/JP2003/014489 Example 115 0F F (E0115) 5 E0115 was obtained according to a similar manner to that of E0105. Example 116 F < F 10 (E0116) E0116 was obtained according to a similar manner to that of E0105. Example 117 15 (E0117) E0117 was obtained according to a similar manner to that of E0105. 20 Example 118 127 WO 2004/050632 PCT/JP2003/014489 HO N (E0118) Amixture of E0105 (2.Og) and 1N NaOH (15ml) in THF (40ml) was stirred at room temperature for 5 hours. After the 5 reaction was completed, the mixture was neutralized with 1N HCl (15ml), extracted twice with ethylacetate, washed with 1N HCl, sat.NaHCO3, and brine, dried over NA2SO4, filtered and evaporated under reduced pressure. The residue was column chromatographed on silica gel (H/EA = 10 2:1-1:1) to give 1.14g (64%) of E0118 as a crystal. mp: 103-104'C IR (film): 3396.0, 1513.9, 1467.6, 1238.1, 1160.9, 1132.0 cm-1. 15 Example 119 HO N F (E0119) E0119 was prepared from E0217 in a similar manner to that of E0118. 20 IR (neat) : 3359, 3332, 3325, 1658, 1651, 1624, 1614, 1545, 1533, 1500cm-1 Mass (ESI+) : 421 (M+H)+ 200MHz1HNMR (DMSO-d6, d) :2.71-2.79(2H, m), 3.28-3.39(2H, m), 3.76(2H, brs), 3.88 (3H, s), 5.47(1H, br), 6.92(1H, d, 128 WO 2004/050632 PCT/JP2003/014489 J=8.9 Hz), 7.18(1H, s), 7.24(4H, s), 7.74(1H, dd, J=2.7, 8.9 Hz), 7.80(1H, t, J=5.9 Hz), 8.19(1H, d, J=2.7 Hz) Example 120 HOF N F 5N (E0120) E0120 was prepared from E0002 in a similar manner to that of E0118. IR (neat) : 3433, 3423, 3398, 3367, 2945, 1612, 1500cm-1 10 Mass (ESI+) : 378 (M+H)+ 200MHz lHNMR (DMSO-d6, d) :1.62-1.77 (2H, m), 2.57-3.65 (2H, m), 3.34-3.44(2H, m), 3.88 (3H, s), 4.48(1H, t, J=5.1 Hz), 6.92(1 , d, J=8.9 Hz), 7.17(1H, s), 7.23(4H, s), 7.76(1H, dd, J=8.9,2.8 Hz), 8.18(1H, d, J=2.8 Hz) 15 Example 121 HO O O N (EO121) E0121 was prepared from E0268 in a similar manner to that 20 of E0118. white powder mp. 91-92 0 C IR (KBr) : 3491, 3471, 3437, 2941, 2239, 1610, 1508cm-1 Mass (ESI+) : 336 (M+H)+ 129 WO 2004/050632 PCT/JP2003/014489 200MHz 1H NMR (DMSO-d6, d) 3.65-3.73(2H, m), 3.79(3H, s), 3.95-4.05(2H, m), 4.87(1H, t, J=5.4 Hz), 6.93(2H, d, J=8.8 Hz), 7.00(2H, d, J=9.0 Hz), 7.16(2H, d, J=8.8 Hz), 7.28 (2H, d, J=9.0 Hz), 7.32(1H, s) 5 Example 122 .NO E0122) E0122 was prepared from E0353 in a similar manner to that 10 of E0118. white powder mp. 158-159 0 C IR (KBr) : 3399, 2955, 1707, 1693, 1647, 1614, 1566, 1547, 1529, 1512cm-1 15 Mass (ESI+) : 393 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.44(3H, s), 3.66-3.74(2H, m), 3. 80 (3H, s) , 3. 96-4. 02 (2H, m) , 4. 88 (1H, t, J=5. 4 Hz) , 6. 94 (2H, d, J=8.7 Hz), 7.02(2H, d, J=8.9 Hz), 7.22(2H, d, J=8.7 Hz), 7.26(1H, s), 7.31(2H, d, J=8.9 Hz) 20 Example 123 HO o N ~

K

0 N (E0123) E0123 was prepared from E0358 in a similar manner to that 130 WO 2004/050632 PCT/JP2003/014489 of E0118. white powder mp. 105-107"C IR (KBr) : 3529, 3437, 2956, 1610, 1570, 1547, 1529cm-i 5 Mass (ESI+) : 337 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.65-3.73(2H, m), 3.88 (3H, s), 3.96-4.02(2H, m), 4.87(1H, t, J=5.3 Hz), 6.93(1H, d, J=8.8 Hz), 6.96(2H, d, J=8.7 Hz), 7.21(2H, d, J=8.7 Hz), 7.35(1H, s), 7.73(1H, dd, J=2.7,8.8 Hz), 8.20(1H, d, J=2.7 Hz) 10 Example 124 F F (E0124) E0124 was prepared from E0107 in a similar manner to that 15 of E0118. white powder mp. 97-98 0 C IR (KBr) : 3427, 2960, 1608, 1516cm-i Mass (ESI+) : 413 (M+H)+ 20 200MHz 1H NMR (DMSO-d6, d) : 2.71(2H, t, J=6.9 Hz), 3.54-3.65(2H,m), 3.79(3H, s), 4.64(1H, t, J=5.1Hz), 7.00(2H, d, J=9.0 Hz), 7.12(1H, s), 7.15-7.33(4H, m), 7.29(2H, d, J=9.0 Hz) 25 Example 125 131 WO 2004/050632 PCT/JP2003/014489 HO 0 (E0125) E0125 was prepared in a similar manner to that of E0118. IR (neat) : 3435, 3425, 3406, 3398, 3367, 1691, 1658, 1647, 5 1614, 1547, 1512cm-1 Mass (ESI+) 320 (M+H)+ , 361(M+CH3CN+H)+ 200MHz 1H NMR (DMSO-d6, d) 2.71(2H, t, J=6.8 Hz), 3.54-3.64(2H,m), 3.79(3H, s), 4.64(1H, t, J=5.2Hz), 7.00(2H, d, J=8.9 Hz), 7.15(2H, d, J=8.3 Hz), 7.23(2H, d, J=8.3 Hz), 10 7.29(2H, d, J=8.9 Hz), 7.34(1H, s) Example 126 N F F (E0126) 15 E0126 was prepared from E0111 in a similar manner to that of E0118. white powder mp. 89-92*C IR (KBr) : 3481, 2947, 1608, 1496cm-i 20 Mass (ESI+) 364 (M+H)+ 200MHz IH NMR (DMSO-d6, d) : 2.72(2H, t, J=6.8 Hz), 3.55-3.65(2H, m) , 3.88 (3H, s), 4.65 (1H, t, J=5.2Hz), 6. 92 (1H, d, J=8.8 Hz), 7.16(iH, s), 7.19-7.28(4H, m), 7.77(1H, dd, J=2.6,8.8 Hz), 8.19(1H, d, J=2.6 Hz) 132 WO 2004/050632 PCT/JP2003/014489 Example 127 HO F /F (E0127) 5 E0127 was prepared from E0108 in a similar manner to that of E0118. IR (neat) : 3400, 2951, 1610, 1502cm-1 Mass (API-ES positive) : 414 (M+H)+ , 436 (M+Na)+ 200MHz 1H NMR (DMSO-d6, d) : 2.72(2H, t, J=6.9 Hz), 10 3 .51- 3 .65 (2H, m) , 3.88 (3H, s), 4.65 (1H, t, J=5.1 Hz) , 6.93 (1H, d, J=8.8 Hz), 7.15-7.35(4H, m), 7.18 (1H, s), 7.77(1H, dd, J=2.7,8.8 Hz), 8.18(lH, d, J=2.7 Hz) Example 128 HO O N 15 (E0128) E0128 104.4mg was prepared in a similar manner to that of E0118. IR (neat) : 3433, 3423, 3398, 2947, 2873, 2243, 1608cm-i 20 Mass (ESI+) : 321 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.72(2H, t, J=6.8 Hz), 3

.

5 5

-

3 .65(2H,m),3.88(3H,s),4.65(1H,t,J=5.lHz),6.93(1H, d, J=8.8 Hz), 7.19(2H, d, J=8.4 Hz), 7.26(2H, d, J=8.4 Hz), 7

.

3 8 (1H, s), 7.76(1H, dd, J=2.7,8.8 Hz), 8.21(1H, d, J=2.7 133 WO 2004/050632 PCT/JP2003/014489 Hz) Example 129 HO ON 5 (E0129) E0129 was obtained according to a similar manner to that of E0118. Example 130 HO 10 N (E0130) E0130 was obtained according to a similar manner to that of E0118. 15 Example 131 F F HO - F (E0131) E0131 was obtained according to a similar manner to that of E0118. 20 134 WO 2004/050632 PCT/JP2003/014489 Example 132 HO F (E0132) E0132 was obtained according to a similar manner to that 5 of E0118. IR (film): 3392.2, 1494.6, 1236.2, 1160.9, 1133.9, 1095.4, 975.8, 833.1 cm-1. Example 133 HOF 10 E (E0133) E0133 was obtained according to a similar manner to that of E0118. TR (film) : 3374.8, 1511.9, 1471.4, 1274.7, 1232.3, 1160.9, 15 1133.9, 977.7, 842.7, 811.9 cm-1. mp: 82-83 'C Example 134 F 20 (E0134) 135 WO 2004/050632 PCT/JP2003/014489 E0134 was obtained according to a similar manner to that of E0118. IR (film) : 3386.4, 1511.9, 1471.4, 1236.2, 1159.0, 1132.0, 1047.2, 975.8, 817.7 cm-1. 5 Example 135 HO F 0 N Ff (E0135) E0135 was obtained according to a similar manner to that 10 of E0118. IR (film): 3399.9, 1610.3, 1513.9, 1459.9, 1251.6, 1172.5, 1083.8, 1033.7, 836.9, 802.2 cm-1. (FS7081) Example 136 HO NN 15 (E0136) P0018 (277mg) and 4-methoxyphenylhydrazine hydrochloride (209mg) in EtOH:AcOH=20:1 6ml was refluxed for 2hours. The mixture was partitioned between AcOEt and H20. The organic 20 layer was washed successively with 1M HCl, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / n-hexane = 136 WO 2004/050632 PCT/JP2003/014489 30%, 40%, 50%. Thepure fraction was collected and concentrated in vacuo. The residue was crystallized from AcOEt / n-hexane to give E0136 (95.6mg) as a white powder. mp. 111-112-C 5 IR (KBr) : 3325, 2931, 1707, 1693, 1685, 1658, 1647, 1564, 1549, 1514cm-1 Mass (ESI+) : 335 (M+H)+ 200MHzlHNMR (DMSO-d6, d) :0.69-0.77(2H, m), 0.86-0.96(2H, m) , 1. 93 (1H, m) , 2. 69 (2H, t, J=6. 9 Hz) , 3.53-3. 64 (2H, m) , 10 3.76(3H, s), 4.64 (1H, t, J=5.2 Hz), 6.28 (1H, s), 6.92(2H, d, J=9.0 Hz), 7.05-7.19(6H, m) Example 137 NN N 15 (E0137) E0137 was prepared from P0018 498.5mg in a similar manner to that of E0136. Preparation 34 HO 20 "o YN (P0034) P0034 was prepared in a similar manner to that of E0137. white powder Mass (ESI+) : 306 (M+H)+ 137 WO 2004/050632 PCT/JP2003/014489 200MHz 1H NMR (DMSO-d6, d) 0.67-0.76'(2H, m), 0.84-0.94 (2H, m), 1.91(1H, m), 3.76(3H, s), 6.18 (1H, s), 6.68 (2H, d, J=8.7 Hz), 6.91(2H, d, J=9.0 Hz), 6.98 (2H, d, J=8.7 Hz), 7.12 (2H, d, J=9.0 Hz), 9.63(1H, 5 s) Example 138 / F F

---

N (E0138) 10 To a solution of E0118 (1.Og) and Et3N (0.6ml) in CH2Cl2 (20ml) was added dropwisemethanesulfonyl chloride (0.2 6ml) under ice-cooling. After stirring for 1 hour, the reaction mixture was quenched with water and extracted with CHCl3. The organic layer was washed with water, dried over Na2SO4, 15 filtered and evaporated to give 1.2g (99%) of crude E0138 as an off-white solid. IR (film): 1513.9, 1469.5, 1351.9, 1240.0, 1166.7, 1130.1, 971.9, 835.0, 804.2cm-1. 20 Example 139 (E0139) E0139 was prepared in a similar manner to that of E00138. Mass (ESI+) : 459 (M+H)+ 138 WO 2004/050632 PCT/JP2003/014489 200MHz 1H NMR (DMSO-d6, d) 1.09-1.23(3H, m), 2.98,3.29(3H, s), 3.01(2H, t, J=6.6 Hz), 3. 09 (3H, s) , 3. 43-3. 77 (2H, m) , 3. 87 (3H, s) , 4. 42 (2H, t, J= 6 .6 Hz), 6.88-6.92(2H, m), 7.25(2H, d, J=8.3 Hz), 7.33(2H, d, 5 J=8.3 Hz), 7.65-7.73(1H, m), 8.15(1H, d, J=2.6 Hz) Example 140 a (E0140) 10 E0140 was prepared in a similar manner to that of E0138. Mass (APCI+) : 458 (M+H)+ 200MHzlHNMR (DMSO-d6, d) :1.05-1.25(3H, m), 2.96-3.03(2H, m), 2.98,3.29(3H, s), 3.08(3H, s), 3.40-3.85(2Hm), 3.78(3H, s), 4.42(2H, t, J=6.6 Hz), 6.86,6.88(1H, s), 6.98(2H, d, 15 J=8.9 Hz), 7.18-7.32(6H, m) Example 141 F F (E0141) 20 E0141 was prepared in a similar manner to that of E0138. Mass (ESI+) : 456 (M+H)+ 200MHz1HNMR (DMSO-d6, d) :1.89-2.04(2H, m), 2.52-2.73(2H, m), 3.16(3H, s), 3.88(3H, s), 4.19(2H, t, J=6.3Hz), 6.92 (1H, d, J=8.9 Hz), 7.18 (1H, s), 7.21-7.31(4H, m), 7.76(1H, dd, 139 WO 2004/050632 PCT/JP2003/014489 J=2.6,8.9 Hz), 8.19(1H, d, J=2.6 Hz) Example 142 F 5 (E0142) E0142 was obtained according to a similar manner to that of E0138. Example 143 10 (E0143) E0143 was obtained according to a similar manner to that of E0138. 15 Example 144 V 0F F - F (E0144) This compound was obtained according to a similar manner to that of E0138. 20 140 WO 2004/050632 PCT/JP2003/014489 Example 145 F F - / F (E0145) This compound was obtained according to a similar manner 5 to that of E0138. Example 146 F F O - F (E0146) 10 This compound was obtained according to a similar manner to that of E0138. Example 147 /,7 F N-N 15 (E0142) This compound was obtained according to a similar manner to that of E0138. Example 148 141 WO 2004/050632 PCT/JP2003/014489 (E0148) A mixture of E0138 (900mg) and potassium phthalimide (454mg) in DMF (18ml) was stirred at 60oC for 3.0 hours. 5 After addition of water, the reaction mixture was extracted with EtOAc and washed twice with water and with brine. The organic layer was dried over Na2SO4 ,filtered and evaporated under reduced pressure. The residue was column chromatographed on silica gel (50ml) to give 930mg (93%) 10 of E0148 as a powder. IR (film): 1772.3, 1712.5, 1240.0, 1160.9, 1130.1cm-1. Example 149 15 (E0149) E0149 was prepared from E0139 in a similar manner to that of E0148. amorphous powder Mass (ESI+) : 510 (M+H)+ 20 200MHz 1H NMR (DMSO-d6, d) 1.08-1.22(3H, m), 2.89-2.98(2H, m), 2.98,3.27(3H, s), 3.48,3.70(2H, q, J=7.1,6.9 Hz), 3.32(2H, t, J=7.3 Hz), 3.88 (3H, s) , 6.83-6.88 (2H, m), 7.23 (2H, d, J=8.7 Hz) , 7.18 (2H, d, J=8.7 Hz), 7.53-7.63(1H, m), 7.79-7.89(4H, m), 8.15(1H, 142 WO 2004/050632 PCT/JP2003/014489 d, J=2.6 H z) Example 150 5 (E0150) E0150 was prepared from E0140 in a similar manner to that of E0148. amorphous powder Mass (ESI+) : 509 (M+H)+ 10 200MHz 1H NMR (DMSO-d6, d) 1.12,1.18(3H, t, J=7.0,7.1 Hz), 2.92(2H, t, J=7.0 Hz), 2.97,3.28 (3H, s), 3.47,3.

7 1( 2 H, q, J=7.1,7.0 Hz), 3.78(3H, s), 3.81(2H, t, J=7.0 Hz), 6.82, 6.84 (1H, s), 6. 94 (2H, d, J=9.0 Hz), 7.11-7.20 (6H, m), 7.79-7.89(4H, m) 15 Example 151 a / (E0151) E0151 was prepared from E0038 in a similar manner to that 20 of E0148. Mass (ESI+) : 507 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.82-1.97 (2H, m), 2.59-2.67 (2H, m), 3.60(2H, t, J=7.0 Hz), 3.88(3H, s), 6.91(1H,. d, J=8.8 Hz), 7.14(1H, s), 7.20(2H, d, J=8.5 Hz), 7.26(2H, d, J=8.5 143 WO 2004/050632 PCT/JP2003/014489 Hz), 7.73(1H, dd, J=8.8,2.8 Hz), 7.78-7.89(4H, m) , 8.17 (1H, d, J=2.8 Hz) Example 152 5 o (EO152) This compound was obtained according to a similar manner to that of E0148. 10 Example 153 (E0153) This compound was obtained according to a similar manner to that of E0148. 15 Example 154 0F. F (E0154) This compound was obtained according to a similar manner 20 to that of E0148. 144 WO 2004/050632 PCT/JP2003/014489 Example 155 (E0155) 5 This compound was obtained according to a similar manner to that of E0148. Example 156 oF F F 10 (E0156) This compound was obtained according to a similar manner to that of E0148. Example 157 15 (E0157) This compound was obtained according to a similar manner to that of E0148. 20 Example 158 145 WO 2004/050632 PCT/JP2003/014489 H1 2 N F / F N-1N (E0158) To a solution of E0148 (800mg) in CH3CN (10ml) was added hydrazine hydroxide (87ul) at room temperature. After 5 stirring for 1 hour, the reaction mixture was filtered and evaporated. After addition of dichloromethane, the mixture was stirred for an hour, filtered and evaporated. The residue was treated with 4NHC1/EtOAc to give 518mg (80%) of E0158. 10 IR (Film); 3403.74, 1610.27, 1511.92, 1467.56, 1238.08, 1160.94, 1130.08, 1027.87, 975.80, 836.96, 806.10cm-1. Example 159 14,N F~ 15 (E0159) This compound was obtained according to a similar manner to that of E0158. Example 160 HgN F 20 146 WO 2004/050632 PCT/JP2003/014489 (E0160) This compound was obtained according to a similar manner to that of E0158. 5 Example 161 F HN F CIH N-N (E0161) This compound was obtained according to a similar manner to that of E00158. 10 IR (film): 3428.8, 1511.9, 1467.6, 1238.1, 1160.9, 1132.0cm-1. Example 162 - N H/N F 15 (E0162) This compound was obtained according to a similar manner to that of E0158. IR (film): 3371.0, 1511.9, 1471.4, 1272.8, 1230.4, 1160.9, 1133.9, 975.8, 842.7, 810.Ocm-1. 20 Example 163 147 WO 2004/050632 PCT/JP2003/014489 F F N F (E0163) This compound was obtained according to a similar manner to that of E0158. 5 mp: 163.1-165.1cC IR (film): 2973.7, 1511.9, 1471.4, 1236.2, 1159.0, 1133.9cm-1. Example 164 Hi2N F 10 (E0164) This compound was obtained according to a similar manner to that of E0158. IR(film): 3369.0, 1604.5, 1513.9, 1459.9, 1251.6, 1172.5, 15 1083.8, 1029.8,837.0, 800.3 cm-1. Example 165 H:N FF (E0165) 20 To a solution of E0395 (1.08 g) in acetonitril (15 ml) was 148 WO 2004/050632 PCT/JP2003/014489 added hydrazine monohydrate (0.53 ml). After stirring at 60*C overnight, the mixture was filtered. And the filtrate was evaporated to give E0165 as an orange oil (814 mg, 102%) . NMR(CDC13), 2.76(2H, t, J=6.5 Hz), 2.98(2H, t, J=6.5 Hz), 5 3.94 (3H, s), 6.73(1H, s), 6.76(1H, d, J=8.9Hz), 7.22-7.1 2

(

4 H, m), 7.57(1H, dd, J=8.9, 2.7 Hz), 8.09(1H, d, J=2.7 Hz). MS(ESI+);363.3(MH+). Example 166

H

2 N 0 N N N -\ 10 MeO N (EO166) E0166 was prepared from E0046 in a similar manner to that of E0165. Mass (ESI+) : 380 (M+H)+ 15 200MHz 1H NMR (DMSO-d6, d) 1.91-1.23(3H, m), 2.59-2.79(4H, m), 2.98,3.28(3H, s), 3.48,3.71(2H, q, J=7.2,7.0 Hz), 3.87(3H, s), 6.86-6.93(2H, m), 7.16-7.26(4H, m), 7.64-7.73(1H, m), 8.15(1H, d, J=2.5 Hz) 20 Example 167 HgN 7 1N "N (E0167) E0167 was prepared from E0150 in a similar manner to that 149 WO 2004/050632 PCT/JP2003/014489 of E0165. Mass (ESI+) : 379 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) 1.08-1.22(3H, m), 2.57-2.78(4H, m), 2.97,3.29(3H, s), 5 3.48,3.72(2H, q, J=7.2,7.0Hz), 3.78(3H, s), 6.83,6.85(1H, s), 6.98(2H, d, J=8.9 Hz), 7.06-7.26(6H, m) Example 168 H2N' / F 0 F 10 (E0168) E0168 was prepared from E0048 in a similar manner to that of E0165. Mass (ESI+) 377 (M+H)+ 200MHz1HNMR (DMSO-d6, d) :1.54-1.69(2H, m), 2.49-2.64(4H, 15 m), 3.88 (3H, s), 6.92(1H, d, J=8.7 Hz), 7.17 (1H, s), 7.22(4H, s), 7.75(1H, dd, J=8.7,2.6 Hz), 8.18(1H, d, J=2.6 Hz) Example 169 7 F 20 (E0169) To a solution of E0165 (180 mg) in tetrahydrofuran (2 ml) was added triethylamine (0.242 ml) and t-butoxycarbonyl anhydride (325 mg) at room temperature. After stirring at room temperature overnight, the mixture was quenched with 150 WO 2004/050632 PCT/JP2003/014489 water and extracted with ethyl acetate (x3) . The organic layer was washed with hydrogen chloride aqueous solution (lN), saturated sodium hydrogen carbonate aqueous solution, and brine, dried over magnesium sulfate, and evaporated to 5 giveoil, whichwaspurifiedwithcolumnchromatography (SiO2 25 ml, 20% ethyl acetate/hexane) to give E0169 as an oil (224 mg , 97.5%). NMR(CDCl3); 1.35(9H, s), 2.69(2H, t, J=7.7 Hz), 3.09-3.19 (2H, m) , 3.88 (3H, s), 6.91(1H, d, J=8.8 Hz), 7.17 (1H, 10 s), 7 .18-7.27(4H, m), 7.75(1H, dd, J=8.8, 2.7 Hz), 8.19(1H, d, J=2.7 Hz). MS(ESI+); 485.2(M+Na). Example 170 HN /N F 15 (E0170) This compound was obtained according to a similar manner to that of E0169. NMR(CDCl3), 1.45(9H, s), 3.49-3.57(2H, m), 3.82(3H, s), 4.01(2H, t, J=5.1 Hz), 6.67(1H, s), 6.82(2H, d, J=8.7 Hz), 20 6.87(2H, d, J=9.0 Hz), 7.13(2H, d, J=8.7 Hz), 7.22(2H, d, J=9.0 Hz). MS(ESI+), 500.2(M+Na). Example 171 151 WO 2004/050632 PCT/JP2003/014489 H N F (E0171) A mixture of E0158 (650mg) , Boc2O (428mg) and 1NNaOH (3.3ml) in THF (20ml) was stirred at room temperature for 5 15 hours. Water and EtOAc was added and the aqueous layer was separated and extracted with EtOAc. The combined organic layer was washed with sat NaHCO3, water and brine, dried over NA2SO4, filtered and evaporated under reduced pressure. The residue was column chromatographed on silica 10 gel (Hex/EtOAc) to give 700mg (93%) of E0171 as an oil. Example 172 O F 0/ F (E0172) 15 This compound was obtained according to a similar manner to that of E0171. Example 173 F 0 20 (E0173) 152 WO 2004/050632 PCT/JP2003/014489 This compound was obtained according to a similar manner to that of E0171. Example 174 0 N-N 5 0 (E0174) This compound was obtained according to a similar manner to that of E0171. IR (film): 1702.8, 1513.9, 1241.9, 1164.8, 1132.0cm-1. 10 Example 175 o F 'P N-N (E0175) To a solution of E0171 (200mg) and MeI (0.14ml) in THF 15 (20ml) was addedportionwise NaH (35mg) at roomtemperature. Then the reaction mixture was heated at 70o0C for 1 hour. Almost no reaction. MeI (0.3ml) and NaH (40mg) was added, and DMF was added. The mixture was stirred at 70'C for 12 hours, and then 20 cooled, quenched with water. The aqueous layer was extracted twice with EtOAc. The combined organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was column chromatographed on silica gel to give 151mg (73%) of E0175 as an oil. 153 WO 2004/050632 PCT/JP2003/014489 Example 176 0 N--N (E0176) 5 This compound was obtained according to a similar manner to that of E0175. Example 177 F F N N CIH 10 (E0177) To a mixture of E0158 (150mg) and HO (46ul) in Et3N (53ul) and CH3CN (5ml) was added portionwise NaBH(OAc)2 (240mg) at room temperature. After stirring for 15 hours, the mixture was quenched with water and extracted three times 15 withEtOAc. The combinedorganiclayerwaswashedwithwater and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was column chromatographed on silica gel (CHCl3/MeOH) and treated with 4NHCl/dioxane to give 108mg (70%) of E0177. 20 Example 178 154 WO 2004/050632 PCT/JP2003/014489 0f (E0178) Methylisocyanate 36.2mg was added to a solution of E0165 (199.3mg) and triethylamine 48.6mg in CH2C12 2ml under ice 5 bath cooling. The reaction mixture was stirred at same temperature for hour and concentrated in vacuo. The residue was partitioned between AcOEt and 1M HC1. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, 10 dried over magnesium sulfate, and concentrated in vacuo. The residue was recrstallizedfromAcOEt-n-hexane. Obtained powder was dissolved in CHCl3 and further purified by preparative thin layer silica gel chromatography developed byMeOH/CHCl3=10%. The seaparatedsilica gelwas extracted 15 with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residual solid was collected and washed with diisopropyl ether to give E0178 (101.3mg) as a white powder. mp. 149'C IR (KBr) : 3348, 2947, 2885, 1626, 1583, 1529, 1500cm-1 20 Mass (ESI+) : 420 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.49-2.53(3H, overlapping), 2.64-2.72(2H, m), 3.15-3.26(2H, m), 3.88 (3H, s), 5.72(1H, q, J=4.5 Hz), 5.89(1H, t, J=5.7 Hz), 6.92(1H, d, J=8.8 Hz), 7.17(lH, s), 7.24(4H, s), 7.76(lH, dd, J=2.7, 8.8 Hz), 25 8.19(lH, d, J=2.7 Hz) Example 179 155 WO 2004/050632 PCT/JP2003/014489 I (E0179) E0179 80.7mg was prepared from E0166 in a similar manner to that of E0178. 5 amorphous powder IR (neat) : 3350, 2950, 2930, 1707, 1691, 1674, 1645, 1641, 1622, 1614, 1566, 1549, 1533, 1510cm-1 Mass (ESI+) : 437 (M+H)+ 200MHz1HNMR (DMSO-d6, d) : 1.09-1.23(3H, m) , 2.49-2.54(3H, 10 overlapping), 2.67(2H, t, J=7.2 Hz), 2.98,3.28(3H, s), 3.15-3.28 (2H, m) , 3.48,3.71 (2H, q, J=6.8,6.9 Hz), 3.88 (3H, s), 5.73(1H, q, J=4.6 Hz), 5.90(1H, t, J=5.6 Hz), 6.86-6.93(2H, m), 7.22(4H, s), 7.64-7.73(1H, m), 8.15(1H, d, J=2.6 Hz) 15 Example 180 /F F (E0180) E0180 was prepared from E0294 in a similar manner to that 20 of E0178. white powder mp. 155-157 0 C IR (KBr) :3336, 2968, 1707, 1693, 1674, 1621, 1576, 1533cm-1 Mass (ESI+) (M+H)+ 156 WO 2004/050632 PCT/JP2003/014489 200MHz 1H NMR (DMSO-d6, d) : 0.96(3H, t, J=7.1 Hz), 2.64-2.72(2H, m), 2.91-3.05(2H, m), 3.15-3.26(2H, m), 3.88 (3H, s) , 5.76-5.84 (2H, m) , 6.92 (1H, d, J=8.8 Hz) , 7.17 (1H, s), 7.24(4H, s), 7.76(1H, dd, J=8.8,2.7 Hz), 8.19(1H, d, 5 J=2.7 Hz) Example 181 F

H

2 N F -NH (E0181) 10 This compound was obtained according to a similar manner to that of E0178. IR (film) :3343.9, 1658.5, 1608.3, 1513.9, 1457.9, 1249.6, 1029.8, 836.9 cm-1. 15 Example 182 2DN F F o F N (E0182) This compound was obtained according to a similar manner to that of E0178. 20 IR (Film): 1659.0, 1608.8, 1554.8, 1485.4, 1470.0, 1240.4, 1165.1, 1134.3, 1097.6, 835.3cm-1. Example 183 157 WO 2004/050632 PCT/JP2003/014489 'F F Hz~ N O F (E0183) This compound was obtained according to a similar manner to that of E0178. 5 IR (film): 3249.8, 1658.5, 1608.3, 1554.3, 1469.5, 1240.0, 1164.8, 1133.9, 1097.3, 975.8, 835.0 cm-1. Example 184 H N F N F 10 (E0184) AcC1 23.3mg was added to E0158 (107.4mg) and triethylamine 68.3mg in CH2Cl2 2ml with cooling in an ice bath. After stirring at same temperature for hour, the reaction mixture was concentrated in vacuo. The residue was partitioned 15 between AcOEt and 1M HCl. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residual solid were collected and washed with diisopropyl ether to give E0184 20 (84mg) as a white powder. mp. 79-80'C IR (KBr) : 3307, 3221, 3093, 2964, 1689, 1639, 1554, 1514cm-i Mass (ESI+) : 404 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.76(3H, s), 2.65-2.73(2H, m), 158 WO 2004/050632 PCT/JP2003/014489 3.18-3.31 (2H, m) 3.79 (3H, s), 6.99 (2H, d, J=8.9Hz), 7.12 (IH, s), 7.20(4H, s), 7.28(2H, d, J=8.9 Hz), 7.92(1H, t, J=5.4 Hz) 5 Example 185 0 HN HFF \ F N (E0185) E0185 (143.4mg) was prepared from E0232 (155.3mg), methyl chloroformate 35.8mg, and triethylamine 105mg in a similar 10 manner to that of E0184. amorphous powder IR (neat) : 3319, 2954, 1718, 1711, 1668, 1660, 1612, 1545, 1533, 1500cm-1 Mass (ESI+) : 178 (M+H)+ 15 200MHz1HNMR (DMSO-d6, d) :2.67-2.75(2H, m), 3.22-3.33(2H, m), 3.50-3.60(2H, overlapping), 3.53(3H, s), 3.88 (3H, s), 6.92(1H, d, J=8.8 Hz), 7.18(1H, s), 7.24(4H, s), 7.28 (1H, t, J=6 Hz), 7.75 (iH, dd, J=2.7,8.8 Hz), 7.94(1H, t, J=5.6 Hz), 8.19(1H, d, J=2.7 Hz) 20 Example 186 N F (E0186) E0186 (59.3mg) was prepared from E0158 (96.2mg), methyl 159 ~ WO 2004/050632 PCT/JP2003/014489 chioroformate 25.1mg and triethylamine 61.2mg in a similar manner to that of E0184. mp. 78-80'C IR (KBr) : 3352, 1739, 1695, 1658, 1647, 1549, 1514cm-i 5 Mass (ESI+) : 420 (M+H)+ 200MHz1HNMR (DMSO-d6, d) :2.66-2.74(2H, m), 3.14-3.25(2H, m) , 3. 49 (3H, s), 3.79 (3H, s) , 6.99-(2H, d, J=8.9 Hz) , 7.12 (1H, s), 7.12-7.32(1H, m), 7.20(4H, s), 7.28 (2H, d, J=8.9 Hz) 10 Example 187 0) / F (E0187) E0187 (63.4mg) was prepared from E0165 (113.6mg), acetyl chloride29.5mg, andtriethylamine41.2mginasimilarmanner 15 to that of E0184. white powder mp. 97-98 0 C IR (KBr) : 3311, 2956, 1674, 1641, 1543, 1500cm-1 Mass (ESI+) : 405 (M+H)+ 20 200MHz 1HNMR (DMSO-d6, d) : 1.76(3H, s), 2.66-2.74(2H, m), 3.19-3.30 (2H, m) , 3.88 (3H, s), 6.92 (1H, d, J=8.8 Hz), 7.18 (1H, s), 7.24(4H, s), 7.75(1H, dd, J=8.8,2.6 Hz), 7.92(1H, t, J=5.3 Hz), 8.19(1H, d, J=2.6 Hz) 25 Example 188 160 WO 2004/050632 PCT/JP2003/014489 F (E0188) E0188 was prepared from E0165 in a similar manner to that of E0184 . 5 IR (neat) : 3338, 3020, 2951, 1716, 1610, 1527, 1500cm-i Mass (ESI+) : 421 (M+H)+ 200MHzlHNMR (DMSO-d6, d) :2.67-2.75(2H, m), 3.14-3.25(2H, m), 3.49(3H, s), 3.88(3H, s), 6.92(1H, d, J=8.9 Hz), 7.15-7.35(5H, m), 7.18 (1H, s), 7.75(1H, dd, J=2.7,8.9 Hz), 10 8.19(1H, d, J=2.7 Hz) Example 189 (E0189) 15 E0189 was prepared from E0294 in a similar manner to that of E0184. IR (neat) : 3352, 2939, 1691, 1639, 1533, 1500cm-1 Mass (ESI+) : 434 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.67-2.74(2H, m), 2.74(6H, s), 20 3.15-3.26 (2H, m) , 3.88 (3H, s) , 6. 34 (1H, t, J=5. 4 Hz) , 6. 92 (1H, d, J=8.9 Hz), 7.17(1H, s), 7.23(4H, s), 7.75(1H, dd, J=8.9,2.7 Hz), 8.19(1H, d, J=2.7 Hz) 161 WO 2004/050632 PCT/JP2003/014489 Example 190 HN F F -NHF 0-0 HO N O (E0190) This compound was obtained according to a similar manner 5 to that of E0189. NMR (CDCl3) ; 2.78 (3H, d, J=5. O Hz) , 3.56-3.64 (2H, m), 3.82 (3H, s), 4. 03 (2H, t, J=5.1 Hz), 4.2-4.4 (1H, m, NH), 4. 6-4.9 (1H, m, NH), 6.67(1H, s), 6.80-6.91(4H, m), 7.13(2H, d, J=8.8 Hz), 7.22(2H, d, J=9.0 Hz). 10 MS(ESI+).457.1(M+Na). IR(NBr), 1627.6cm-i Example 191 SFF 0-K- F 15 (E0191) This compound was obtained according to a similar manner to that of E0184. IR (film): 3299.6, 1658.5, 1550.5, 1515.8, 1467.6, 1240.0, 20 1164.8, 1132.0, 975.8, 829.2, 755.9 cm-1. Example 192 162 WO 2004/050632 PCT/JP2003/014489 HN H DN N F (E0192) E0158 (250mg) was suspended in AcOEt 5ml and was partitioned between AcOEt and saturated aqueous sodium bicarbonate 5 solution. The organic layer was washed with aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in dimethoxyethane 5ml, sulfamide 181mg was added and ref luxed for 2days. The reacion mixture was concentrated in vacuo, 10 and the residue was purified by silica gel column chromatography eluted with MeOH / CHCl3 = 1%, 2%, then 3%. Obtained amorphous powder was crystallized from EtOH-diisopropyl ehter to give E0192 153mg as a white powder. mp. 127-128'C 15 IR (KBr) : 3357, 1707, 1693, 1647, 1564, 1549, 1529, 1514cm-1 Mass (ESI+) : 441 (M+H)+ 400MHz 1HNMR (DMSO-d6, d) : 2.76-2.80 (2H, m), 3.06-3.11(2H, m) , 3.79 (3H, s) , 6.53 (2H, s) , 6.53-6.61 (1H, broad) ,7.00 (2H, d, J=8.9 Hz), 7.12(1H, s), 7.21(2H, d, J=8.5 Hz), 7.24 (2H, 20 d, J=8.5 Hz), 7.29(2H, d, J=8.9 Hz) Example 193 H'N H N F S N F (E0193) 163 WO 2004/050632 PCT/JP2003/014489 E0193 was prepared from E0294 in a similar manner to that of E0192. white powder mp. 114-115 C 5 IR (KBr) : 3489, 3469, 3458, 3435, 3425, 3398, 3363, 3280, 1647, 1500cm-i Mass (ESI+) : 442 (M+H)+ 200MHz1HNMR (DMSO-d6, d) :2.75-2.83(2H, m), 3.00-3.20(2H, m), 3.88(3H, s), 6.45-6.67(3H, m), 6.92(1H, d, J=8.7 Hz), 10 7.18 (1H, s), 7.21-7.31(4H, m), 7.76(1H, dd, J=2.6,8.7 Hz)., 8.19(1H, d, J=2.6 Hz) Example 194 H2N o 15 (E0194) E0194 was prepared from E0322 in a similar manner to that of E0192. white powder mp. 142-143*C 20 IR (KBr) : 3415, 3323, 3111, 3093, 3010, 2962, 1614, 1516cm-i Mass (ESI+) : 429 (M+H)+ 200MHz1HNMR (DMSO-d6, d) :0.68-0.76(2H, m), 0.85-0.95(2H, m) , 1. 92 (1H, m) , 3.15-3. 31 (2H, m) , 3.76 (3H, s) , 4. 00-4. 07 (2H, m) , 6.25 (1H, 1), 6. 60 (2H, brs), 6.72 (1H, brs), 6. 86-6. 96 (4H, 25 m), 7.10(2H, d, J=8.7 Hz), 7.13(2H, d, J=8.9 Hz) Example 195 164 WO 2004/050632 PCT/JP2003/014489 (E0195) This compound was obtained according to a similar manner to that of E0192. 5 NMR(CDC13), 3.50-3.59(2H, m), 3.82(3H, s), 4.14(2H, t, J=4.9 Hz), 6.68 (1H, s), 6.80-6.90(4H, m), 7.15(2H, d, J=8.8 Hz), 7.22(2H, d, J=9.0 Hz). IR(KBr); 1612, 1552cm-1. MS(ESI+), 479.1(M+Na) 10 Example 196 / sFF O (E0196) To a solution of E0158 (100mg) and Et3N (53ul) in CHC13 15 (10ml) was added MsC1 (29ul) at room temperature. After stirring for 1 hour, the reaction mixture was poured onto water and CHC13. The aqueous layer was separated and extracted with CHCl3. The combined organic layer was washed with water and brine, dried over Na2SO4, filtered and 20 evaporated under reduced pressure. The residue was column chromatographedon silica gel (50ml) and crystalized to give 75mg (68%) of E0196 as a powder. IR (film): 3284.2, 1513.9, 1319.1, 1240.0, 1151.3, 973.9cm-1. 165 WO 2004/050632 PCT/JP2003/014489 Example 197 0 (E0197) 5 E0197 was prepared from E0166 in a similar manner to that of E0196. mp.137-1380C IR (KBr) : 3222, 1691, 1684, 1658, 1645, 1610, 1566, 1547, 1531cm-1 10 Mass (ESI+) : 458 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) 1.09-1.22(3H, m), 2.73-2.81(2H, m), 2.80(3H, s), 2.98,3.28(3H, s), 3.09-3.30(2H, m), 3.48,3.71(2H, q, J=7. 0, 6.8 Hz) , 3. 87 (3H, s) , 6. 88-6. 93 (2H, m) , 7. 10 (1H, brs) , 15 7. 22 (2H, d, J=8. 5 Hz) , 7.28 (2H, d, J=8. 5 Hz) , 7. 64-7.73 (1H, m), 8.15(1H, d, J=2.5 Hz) Example 198 0/ 20 (E0198) E0198 was prepared from E0167 in a similar manner to that of E0196. mp.162-163 C IR (KBr) : 3224, 1610, 1547, 1512cm-1 166 WO 2004/050632 PCT/JP2003/014489 Mass (ESI+) : 457 (M+H)+ 200MHz 1H1 NMR (DMSO-d6, d) 1.08-1.22(3H, m), 2.76(2H, t, J=7.2 Hz), 2.80(3H, s), 2.98,3.29(3H, s), 3.12-3.23(2H, m), 3.48,3.73(2H, q, 5 J=7.2,6.9 Hz), 3.78 (3H, s), 6.84,6.87(1H, s), 6.98(2H, d, J=9.0 Hz), 7.09(1H, t, J=5.7 Hz), 7.16-7.26(6H, m) Example 199 N 10 (E0199) E0199 was prepared from E0234 in a similar manner to that of E0196. white powder, mp. 1550C 15 IR (KBr) : 3265, 2974, 2937, 1682, 1612, 1512cm-1 Mass (ESI+) : 458 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.15(6H, d, J=6.8 Hz), 2.94(3H, s), 3.27-3.36(2H, m), 3.68(1H, m), 3.79(3H, s), 4.03(2H, t, J=5.5 Hz), 6.93(2H, d, J=8.8 Hz), 6.98 (1H, s), 7.00(2H, 20 d, J=8.9 Hz), 7.19(2H, d, J=8.8 Hz), 7.28 (2H, d, J=8.9 Hz), 7.17-7.30(1H, overlapping) Example 200 167 WO 2004/050632 PCT/JP2003/014489 (E0200) E0200 was prepared from E0235 in a similar manner to that of E0196. white powder 5 mp. 149-153 0 C IR (KBr) : 3321, 1693, 1658, 1647, 1610, 1547, 1510cm-1 Mass (ESI+) : 413 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2. 93 (3H, s) , 3.27-3.35 (2H, m) , 3.79(3H, s), 4.03(2H, t, J=5.5 Hz), 6.95(2H, d, J=8.7 Hz), 10 7.01(2H, d, J=9.0 Hz), 7.18(2H, d, J=8.7 Hz), 7.28(2H, d, J=9.0 Hz), 7.31(1H, s), 7.15-7.31(1H, overlapping) Example 201 /? 15 (E0201) E0201 was prepared from E0294 in a similar manner to that of E0196. IR (neat) : 3298, 2952, 2885, 1612, 1566, 1547, 1529cm-1 Mass (ESI+) : 470 (M+H)+ 20 200MHz 1H NMR (DMSO-d6, d) : 2.56(6H, s), 2.71-2.79 (2H, m), 3.07-3.17 (2H, m) , 3.88 (3H, s) , 6.92 (1H, d, J=8.7 Hz) , 7.18 (1H, s), 7 .1 9

-

7 .30 (5H, m), 7.77(1H, dd, J=8.7,2.6 Hz), 8.18(1H, d, J=2.6 Hz) 25 Example 202 168 WO 2004/050632 PCT/JP2003/014489 K N (E0202) E0202 was prepared from E0322 in a similar manner to that of E0196. 5 white powder mp. 166-168 0 C IR (KBr) : 3093, 2964, 2873, 2854, 1614, 1516cm-i Mass (ESI+) : 428 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 0.68-0.76(2H, m), 0.85-0.95 (2H, 10 m), 1.

9 2 (1IH, m), 2.93(3H, s), 3.27-3.36(2H, m), 3.76(3H, s), 3.98-4.04(2H, m), 6.25(lH, s), 6.90(2H, d, J=8.7 Hz), 6.92(2H, d, J=8.9 Hz), 7.11(2H, d, J=8.7 Hz), 7.13(2H, d, J=8.9 Hz), 7.27(1H, t, J=5.8 Hz) 15 Example 203 F / F K' F (E0203) This compound was obtained according to a similar manner to that of E00196. 20 MS(ESI+); 454.1(MH+). IR(KBr); 1612.2, 1 5 15.8cm-1. NMR(CDCl3), 3.03(3H, s), 3.51-3.59(2H, m), 3.82(3H, s), 4.10 (2H, t, J=4.9 Hz), 6.68 (1H, s), 6.82 (1H, d, J=8.7 Hz), 6.88(1H, d, J=8.9 Hz), 7.15(1H, d, J=8.7 Hz), 7.22(1H, d, 169 WO 2004/050632 PCT/JP2003/014489 J=8. 9 Hz). Example 204 0 7' F 5 (E0204) This compound was obtained according to a similar manner to that of E0196. NMR(DMSO-d6); 2.80(3H, s), 2.73-2.84(2H, m), 3.13-3.22(2H, m), 3.88(3H, s), 6.92(1H, d, J=9.0 Hz), 7.08-7.13(1H, m), 10 7.19(1H, s), 7.22-7.33(4H, m), 7.76(1H, dd, J=9.0, 2.6 Hz), 8.19(1H, d, J=2.6 Hz). MS(ESI+),463.1(M+Na). IR(KBr), 3136, 1614, 1554, 1144cm-1. 15 Example 205 O 0 / F N-N N (E0205) This compound was obtained according to a similar manner to that of E0196. 20 Example 206 170 WO 2004/050632 PCT/JP2003/014489 (E0206) This compound was obtained according to a similar manner to that of E0196. 5 mp: 134.2-134.5'C IR (film) : 3284. 2, 1610 .3, 1513. 9, 1457. 9, 1321. 0, 1251. 6, 1151.3, 1083.8, 1031.7, 838.9, 802.2, 757.9 cm-1. Example 207 10 0 /d N-N 10 (E0207) This compound was obtained according to a similar manner to that of E00196. IR (film): 3286.11, 1606.41, 1513.85, 1457.92, 1319.07, 15 1251.58, 1153.22, 1081.87, 1029.80, 836.955 cm-1. Example 208 IF (E0208) 20 This compound was obtained according to a similar manner 171 WO 2004/050632 PCT/JP2003/014489 to that of E0196. IR(film): 3284.2, 1513.9, 1317.1, 1240.0, 1153.2cm-1. Example 209 FF 0 N 5 F (E0209) This compound was obtained according to a similar manner to that of E0196. IR (film): 3286.1, 1511.9, 1321.0, 1230.4, 1155.2, 975.8, 10 842.7, 756.0cm-1. Example 210 F F (E0210) 15 This compound was obtained according to a similar manner to that of E0196. IR (film): 3284.2, 1511.9, 1469.5, 1321.0, 1236.2, 1153.2, 975.8, 821.5, 756.0cm-1. 20 Example 211 172 WO 2004/050632 PCT/JP2003/014489 F -- LNH F o \ / N (E0211) This compound was obtained according to a similar manner to. that of E0196. 5 IR (film) : 3289.9, 1612.2, 1513.9, 1322.9, 1251.6, 1155.1, 1085.7, 1029.8, 975.8, 836.9, 796.4 cm-1. Example 212 F F 10 (E0212) This compound was obtained according to a similar manner to that of E0196. IR (film): 3266.8, 1612.2, 1469.5, 1321.0, 1240.0, 1153.2, 1097.3, 975.8, 835.0 cm-1. 15 Example 213 0 F F (E0213) This compound was obtained according to a similar manner 173 WO 2004/050632 PCT/JP2003/014489 to that of E0196. IR (film): 3288.0, 1612.2, 1322.9, 1240.0, 1153.2, 975.8, 946.9 cm-i. 5 Example 214 F F (E0214) A mixture of E0158 (180mg), formic acid (38ul), and WSCD (155mg) in Et3N (0.3ml) and THF (5ml) was stirred at room 10 temperature for 1 hour. After addition of water andEtOAc, the aqueous layer was separated and extracted twice with EtOAc. The combined organic layer was washed with INHC1, sat.NaHCO3, water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was 15 column chromatographedon silica gel (Hex/EtOAc=2:1) togive 136mg (70%) of E0214 as a powder. IR (film): 1670.1, 1513.9, 1238.1, 1160.9, 1130.1cm-1. Example 215 0 HNY F 20 0 F (E0215) A mixture of E0158 (250mg), BocGly (132mg) , WSCD (127mg) andHOBt (110mg) inEt3N (114ul) andCH2Cl2 (30ml) was stirred at room temperature. After stirring for 15hour, the reaction 174 WO 2004/050632 PCT/JP2003/014489 mixture was poured onto water and CHC13. The aqueous layer was separated and extracted with CHC13. The combined organic layer was washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. 5 The residue was column chromatographed on silica gel (50ml) and crystalized to give 325mg (99%) of E0215 as an oil. Example 216 HO N. ,M 10 (E0216) E0216 was prepared in a similar manner to that of E0215. oil IR (neat) :3431, 3421, 3404, 3400, 2939, 1614, 1570, 1547cm-1 Mass (ESI+) : 381(M+H)+ 15 200MHz 1H NMR (DMSO-d6, d) 1.09-1.23(3H, m), 2.72(2H, t, J=6.9Hz), 2.98,3.29(3H, s), 3.42-3.77(4H, m), 3.88(3H, s), 6.86-6.93(2H, m), 7.19(2H, d, J=8.5 Hz), 7.24(2H, d, J=8.5 Hz), 7.65-7.74(1H, m), 8.15(1H, d, J=2.6 Hz) 20 Example 217 N F (E0217) E0217 was prepared from E0294 and acetoxyacetic acid in a 175 WO 2004/050632 PCT/JP2003/014489 similar manner to that of E0215. oil Mass (ESI+) : 463(M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.07 (3H, s), 2.69-2.77(2H, m), 5 3.24-3.33 (2H, m), 3.88 (3H, s), 4.40 (2H, s), 6. 92 (1H, d, J=8.7 Hz), 7.18 (1H, s), 7.24 (4H, s), 7.75 (1H, dd, J=2.7,8.7 Hz), 8.10(1H, t, J=5.6 Hz), 8.19(1H, d, J=2.7 Hz) Example 218 N 10F (E0218) E0218 was prepared from E0294 and N-tert-butoxycarbonyl glycine in a similar manner to that of E0215 using N-methylmorpholine 55.8mg instead of triehtylamine. 15 amorphous powder IR (neat) : 3315, 1707, 1693, 1684, 1676, 1658, 1649, 1624, 1614, 1564, 1547, 1533, 1510, 1500cm-1 Mass (ESI+) : 520 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.37(9H, s), 2.67-2.75(2H, m), 20 3.22-3.33(2H, m), 3.47(2H, d, J=6.0 Hz), 3.88(3H, s), 6.80-7.00(1H, overlapping), 6.92(1H, d, J=8.8 Hz), 7.17(1H, s), 7.24(4H, s), 7.75(1H, dd, J=8.8,2.7 Hz), 7.86(1H, t, J=5.6 Hz), 8.19(1H, d, J=2.7 Hz) 25 Example 219 176 WO 2004/050632 PCT/JP2003/014489 HO N N N N (E0219) E0219 was prepared in a similar manner to that of E0215. oil 5 IR (KBr) 3329, 3313, 3303, 1620, 1564, 1547, 1512 cm-1 Mass (ESI+) : 380 (M+H)+ 200MHz 1H NMR (DMSO-d6, d): 1.08-1.22(3H, m) , 2.71 (2H, t, J=6.9 Hz) , 2.97, 3.29 (3H, s), 3. 42-3.78 (4H, m) , 3. 78 (3H, s), 4.65 (1H, t, J=5.1 Hz), 6.82,6.85(1H, s), 6.98 (2H, d, J=8.9 10 Hz), 7.12-7.27(6H, m) Example 220 o NN NA, (E0220) 15 E0220 was prepared in a similar manner to that of E0215. Example 221 HO o O N NH N (E0221) 20 E0221 was prepared in a similar manner to that of E0215. 177 WO 2004/050632 PCT/JP2003/014489 white powder mp. 95-101 0 C IR (KBr) : 3421, 1693, 1647, 1603, 1566, 1549, 1516cm-1 Mass (ESI+) : 396 (M+H)+ 5 200MHz 1H NMR (DMSO-d6, d) : 1. 08-1.22 (3H, m) , 2. 97, 3. 29 (3H, s), 3.42-3.74(4H,m), 3.78(3H, s), 3.95-4.00(2H,m), 4.86(1H, t, J=5.4 Hz), 6.78,6.81(1H, s), 6.91(2H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.16(2H, d, J=8.8 Hz), 7.23(2H, d, J=8.8 Hz) 10 Example 222 0 HO (E0222) E0222 was prepared in a similar manner to that of E0215. 15 white powder Mass (ESI+) : 398 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.38 (3H, s), 3.65-3.74(2H, m), 3.77 (3H, s), 3.78 (3H, s), 3.95-4.01(2H, m), 4.87(1H, t, J=5.4 Hz), 6.89(1H, s), 6.92(2H, d, J=8.8 Hz), 6.99(2H, s, J=8.9 20 Hz), 7.17(2H, d, J=8.8 Hz), 7.24(2H, d, J=8.9 Hz) Example 223 HO o N (E0223) 1278 WO 2004/050632 PCT/JP2003/014489 E0223 was prepared in a similar manner to that of E0215. white powder mp. 110-111 0 C IR (KBr) : 3425, 2979, 2945, 1606, 1570, 1549cm-1 5 Mass (ESI+) 397 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) 1.09-1.23(3H, m), 2.98,3.28(3H, s), 3.42-3.73(4H, m), 3.87(3H, s), 3.96-4.02(2H, m), 4.87(1K, t, J=5.3 Hz), 6.82-6.97 (4H, m) , 7.21 (2H, d, J=8.7 Hz), 7.63-7.72(1H, m), 10 8.14(lH, d, J=2.6 Hz) Example 224 HO / NN (E0224) 15 E0224 was prepared in a similar manner to that of E0215. white powder Mass (ESI+) : 399 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.37(3H, s), 3.66-3.74(2H, m), 3.77 (3H, s) , 3.88 (3H, s) , 3.96-4.02 (2H, m) , 4.87 (1H, t, J=5.5 20 Hz), 6.88-6.97(4H, m), 7.21(2H, d, J=8.7 Hz), 7.69(1H, dd, J=2.7,8.8 Hz), 8.16(1H, d, J=2.7.Hz) Example 225 179 WO 2004/050632 PCT/JP2003/014489 (E0225) E0225 was prepared in a similar manner to that of E0215. white powder Mass (ESI+) : 495(M+H)+ 5 400MHz 1H NMR (DMSO-d6, d) 1. 12,1.18 (3H, t, J=7.0 Hz), 1.37 (9H, s), 2.97,3.29(3H, s), 3.24-3.28(2H, m), 3.48,3.45(2H, q, J=7.0 Hz), 3.78 (3H, s), 3.95(2H, t, J=5.7 Hz), 6.78,6.81(1H, s), 6.91(2H, d, J=8.8 Hz), 6. 98 (2H, d, J=8.8 Hz), 7.00 (1H, overlapping) , 10 7.16(2H, d, J=8.8 Hz), 7.23(2H, d, J=8.9 Hz) Example 226 (E0226) 15 E0226 was prepared in a similar manner to that of E0215. white powder Mass (ESI+) : 497 (M+H)+ 400MHz 1H NMR (DMSO-d6, d) : 1.37 (9H, s), 3.25-3.29(2H, m), 3.37 (3H, brs), 3.76(3H, s), 3.78 (3H, s), 3. 95 (2H, t, J=5.7 20 Hz), 6.88 (1H, s), 6.91 (2H, d, J=8.8 Hz), 6.99 (2H, d, J=8.9 Hz), 6.97-7.00(1H, br), 7.17(2H, d, J=8.8 Hz), 7.24 (2H, d, J=8.9 Hz) Example 227 180 WO 2004/050632 PCT/JP2003/014489 0 0O

N

(E0227) E0227 was prepared in a similar manner to that of E0215. white powder 5 Mass (ESI+) : 498 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) 1.37(9H, s), 3.22-3.33(2H, m), 3.37(3H, s), 3.77(3H, s), 3.88 (3H, s), 3.93-3.99(2H, m), 6.88-7.05(5H, m), 7.22(2H, d, J=8.6 Hz), 7.69(1H, dd, J=2.7,8.8 Hz) , 8.16(1H, d, J=2.7 10 Hz) Example 228 H O Boc.N-N-o'O H 1 MeON-N CF 3 (E0228) 15 This compound was obtained according to a similar manner to that of E0215 as an oil (371.9 mg, 96%). NMR(CDC13); 1.43(9H, s), 3.65-3.73(2H, m), 3.79-3.82(2H, m), 3.82(3H, s), 4.03(2H, t, J=5.2 Hz), 6.67(1H, s), 6.79-6.89(4H, m), 7.14 (2H, d, J=8.7 Hz), 7.22 (2H, d, J=9.0 20 Hz). MS(ESI+); 557.2(M+Na). Example 229 181 WO 2004/050632 PCT/JP2003/014489 HN

H

2 N F N F F (E0229) This compound was obtained according to a similar manner to that of E0289 as a white powder. 5 NMR(DMSO-d6),3.49-3.63(4H, m), 3.79(3H, s), 4.03(2H, t, J=4.8Hz) , 6.92-7.08 (5H, m) , 7.21 (2H, d, J=8.7 Hz) , 7.28 (2H, d, J=8.9 Hz). MS (ESI-) , 433. 2 (M-H) IR(KBr); 1683cm-1 10 Example 230

HN

NF +0 (E0230) This compound was obtained according to a similar manner 15 to that of E0215. IR (film): 3320.82, 1706.69, 1668.12, 1515.77, 1249.65, 1168.65, 1031.73 cm-1. Example 231 o H H2N F CH FF 20 o 182 WO 2004/050632 PCT/JP2003/014489 (E0231) A mixture of E0215 (300mg) and 4NHC1 in dioxane (5.8ml) was stirred at room temperature for 1.0 hour. After then, the reaction mixture was evaporated under reduced pressure 5 to give 260mg (99%) of E0231 as an amorphous. IR(film): 3226.3, 1679.7, 1513.9, 1251.6, 1083.8, 1029.8, 837.0cm-1. Example 232 H2N Ci F 10 o (E0232) E0232 was prepared in a similar manner to that of E0231. white powder IR (KBr) : 3458, 3435, 3404, 3244, 3078, 3026, 1671, 1614, 15 1579, 1566, 1554, 1500cm-1 Mass (ESI+) : 420 (M+H)+ 200MHz1HNMR(DMSO-d6,d) :2.71-2.79(2H,m), 3.30-3.41(2H, m), 3.44-3.54(2H, m), 3.88(3H, s), 6.93(1H, d, J=8.7 Hz), 7.22(1H, s), 7.22-7.33(4H, m), 7.77(1H, dd, J=2.7,8.7 Hz), 20 8.10(2H, br), 8.19(1H, d, J=2.7 Hz), 8.55(1H, t, J=5.4 Hz) Example 233 CIH O N (E0233) 183 WO 2004/050632 PCT/JP2003/014489 E0233 was prepared in a similar manner to that of E0231. white powder mp. 207-209'C IR (KBr) : 2966, 2933, 2871, 2750, 1606, 1566, 1549, 1512cm-1 5 Mass (ESI+) : 395 (M+H)+ 200MHzlHNMR (DMSO-d6, d) :1.08-1.22(3H, m), 2.97,3.29(3H, s), 3.17-3.22(2H, m), 3.40-3.80(2H, m), 3.78(3H, s), 4.14-4.20(2H, m), 6.80,6.83(lH, s), 6.94-7.01(4H, m), 7.18-7.26(4H, m), 8.13(2H, brs) 10 Example 234 HeN o CIH 0 N (E0234) E0234 was prepared in a similar manner to that of E0231. 15 white powder mp. 129-142'C IR (KBr) : 3471, 3437, 2968, 2933, 1674, 1639, 1631, 1612, 1545, 1512cm-1 Mass (ESI+) : 380 (M+H)+ 20 200MHz 1H NMR (DMSO-d6, d) 1.15(6H, d, J=6.9 Hz), 3.16-3.22(2H, m), 3.68(1H, m), 3.79(3H, s), 4.15-4.20(2H, m), 6.94-7.05(5H, m), 7.22(2H, d, J=8.8 Hz), 7.29(2H, d, J=8.9 Hz), 8.15(2H, brs) 25 Example 235 184 WO 2004/050632 PCT/JP2003/014489 HeN o CIH N ~ N O N (E0235) E0235 was prepared and in a similar manner to that of E0231. white powder 5 mp. 186-189-C IR (KBr) :3209, 3136, 2968, 2873, 1647, 1610, 1547, 1512cm-1 Mass (ESI+) : 335 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.19 (2H, t, J=4.9 Hz), 3.79(3H, s), 4.18(2H, t, J=4.9 Hz), 6.96-7.05(4H, m), 7.21(2H, d, 10 J=8.8 Hz), 7.29(2H, d, J=9.0 Hz), 7.32(1H, s), 8.16(2H, brs) Example 236 HrN o HIN ClH O CIN (E0236) 15 E0236 was prepared in a similar manner to that of E0231. white powder Mass (ESI+) : 378 (M+H)+ 200MHz1H NMR (DMSO-d6, d) :1.04(4H, d, J=6.1Hz), 3.04(1H, m), 3.14-3.22(2H, m), 3.80(3H, s), 4.15-4.21(2H, m), 20 6.93-7.05(5H, m), 7.23(2H, d, J=8.6 Hz), 7.31(2H, d, J=8.9 Hz), 8.15(2H, brs) Example 237 185 WO 2004/050632 PCT/JP2003/014489 H2N NI (E0237) E0237 was prepared in a similar manner to that of E0231. amorphous powder 5 IR (KBr) : 3433, 3425, 3404, 3043, 3028, 3022, 2962, 1658, 1612cm-1 Mass (ESI+) : 336 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.15-3.24(2H, m), 3.88 (3H, s), 4.16-4.22(2H, m), 6.94(1H, d, J=8.8 Hz), 7.01(2H, d, J=,8.7 10 Hz), 7.25(2H, d, J=8.7 Hz), 7.36(1H, s), 7.75(lH, dd, J=2.6,8.8 Hz), 8.10-8.30(2H, br), 8.20(lH, d, J=2.6 Hz) Example 238 CIH 0 7I N 15 (E0238) E0238 was prepared in a similar manner to that of E0231. white powder mp. 156-161 0 C IR (KBr) : 2970, 1676, 1647, 1612, 1550, 1500cm-1 20 Mass (ESI+) : 381 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.16(6H, d, J=6.9 Hz), 3.15-3.24(2H, m), 3.68(1H, m), 3.88(3H, s), 4.16-4.22(2H, m), 6.91-7.06(4H, m), 7.26(2H, d, J=8.7 Hz), 7.75(1H, dd, J=2.7,8.9 Hz), 8.18(1H, d, J=2.7 Hz), 8.22(2H, brs) 186 WO 2004/050632 PCT/JP2003/014489 Example 239 H2Nr OIHF N N (E0239) 5 This compound was obtained according to a similar manner to that of E0231. IR (film): 3220.5, 1679.7, 1513.9, 1461.8, 1251.6, 1081.9, 1029.8, 837.0, 800.3 cm-1. 10 Example 240 NH F (E0240) To a solution of E0267 (75.2 mg) in dichloromethane (1 ml) 15 was added triethylamine (30.4 ml) and trimethylsilyl isocyanate (36.9 ml) at 0 0 C. After stirring for 5 hours, the mixture was quenched with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated 20 under reduced pressure to give oil, which was purified with preparative TLC (1 mm, ethyl acetate) to give oil. The oil was crystallized from a mixture of isopropyl ether, ethyl acetate, and hexane to give E0240 as a white solid (39.1 mg, 51.2%). 187 -e' - -mnTmT " ,TTTV/TTTT TAnN WO 2004/050632 PCT/JP2003/014489 NMR(DMSO-d6); 3.27-3.32(2H, m), 3.79(3H, s), 3.94(2H, t, J=5.6 Hz), 5.52(2H, brs, NH2), 6.15(1H, t, J=5.6 Hz, NH), 6.94(2H, d, J=8.8 Hz), 7.00(2H, d, J=8.9 Hz), 7.07(1H, s), 7.20(2H, d, J=8.8 Hz), 7.28(2H, d, J=8.9 Hz). 5 MS(ESI+); 443.2(M+Na). IR(KBr), 1685.5, 1656.6cm-1. Example 241 0,0 F N F 10 (E0241) E0241 was prepared from E0194 in a similar manner to that of E0240. white powder mp. 139-140 0 C 15 IR (KBr) : 3458, 3342, 1691, 1647, 1604, 1572, 1529cm-1 Mass (ESI+) : 404 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.28-3.36(2H, m), 3.87 (3H, s), 3.92-3.98(2H, m), 5.52(2H, brs), 6.15(1H, t, J=5.5 Hz), 6.88-6.98 (4H, m), 7.10 (1H, t, J=54.4 Hz), 7.22 (2H, d, J=8.7 20 Hz), 7.69(1H, dd, J=2.7,8.8 Hz), 8.14(1H, d, J=2.7 Hz) Example 242 0 FN4 N N 188 WO 2004/050632 PCT/JP2003/014489 (E0242) E0242 was prepared in a similar manner to that of E0240. white powdermp. 108-113'C IR (KBr) : 3492, 3435, 3425, 3359, 3298, 1647, 1614, 1564, 5 1549, 1512cm-1 Mass (ESI+) : 438 (M+H)+ 200MHz1HNMR(DMSO-d6,d) :1.08-1.22(3H,m),2.97,3.29(3H, s), 3.20-3.85(4H, m), 3.78 (3H, s), 3.94 (2H, t, J=5.5 Hz), 5.53(2H, s), 6.15(1H, t, J=5.6Hz), 6.79,6.81(1H, s), 6.92(2H, 10 d, J=8.8 Hz), 6.99(2H, d, J=8.9 Hz), 7.17 (2H, d, J=8.8 Hz), 7.23(2H, d, J=8.9 Hz) Example 243 0 H2N 0 N 15 (E0243) E0243 was prepared from E0234 in a similar manner to that of E0240. white powder mp. 144-145'C 20 IR (KBr) : 3435, 3369, 3176, 2970, 1674, 1612, 1547, 1514cm-1 Mass (ESI+) : 423 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.15(6H, d, J=6.9 Hz), 3.27-3.36(2H, m), 3.68(1H, m), 3.79(3H, s), 3.90-3.97(2H, m), 5.53(2H, s), 6.15(1H, t, J=5.6 Hz), 6.92 (2H, d, J=8.7 25 Hz), 6.98 (1H, s), 7.00(2H, d, J=8.9 Hz), 7.18 (2H, d, J=8.7 Hz), 7.28(2H, d, J=8.9 Hz) 189 WO 2004/050632 PCT/JP2003/014489 Example 244 H2N

N-

(E0244) E0244 was prepared from E0235 in a similar manner to that 5 of E0240. white powder mp. 187-190 0 C IR (KBr) : 3379, 3201, 1649, 1614, 1579, 1527, 1506cm-i Mass (ESI+) : 378 (M+H)+ 10 200MHz 1H NMR (DMSO-d6, d) : 3.27-3.34(2H, m), 3.79(3H, s), 3.94 (2H, t, J=5.5 Hz), 5.52 (2H, brs), 6.14 (1H, t, J=5.6 Hz), 6.94(2H, d, J=8.8 Hz), 7.00(2H, d, J=9.0 Hz), 7.17(2H, d, J=8.8 Hz), 7.24-7.31(3H, m) 15 Example 245 NKN (E0245) E0245 was prepared in a similar manner to that of E0240. white powder 20 mp. 136-137'C IR (KBr) : 3433, 3342, 3221, 1658, 1612, 1581, 1549, 1512cm-1 Mass (ESI+) : 421 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.04(4H, d, J=6.2 Hz), 3.03(1H, 190 WO 2004/050632 PCT/JP2003/014489 m), 3.27-3.36(2H, m), 3.80(3H, s), 3.90-3.97(2H,m), 5.52(2H, s), 6.14 (1H, t, J=5.6 Hz), 6.93(2H, d, J=8.8 Hz), 6.97 (1H, s), 7.01(2H, d, J=8.9 Hz), 7.19(2H, d, J=8.8 Hz), 7.30(2H, d, J=8. 9 Hz) 5 Example 246 N (E0246) E0246 was prepared in a similar manner to that of E0240. 10 white powder mp. 173-176'C IR (KBr) : 3473, 3334, 1630, 1624, 1601, 1583cm-1 Mass (ESI+) : 379 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.27-3.36(2H, m), 3.88 (3H, s), 15 3.92-3.98 (2H,m), 5.52(2H, s), 6.14(1H, t, J=5.7Hz), 6.93(1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.21(2H, d, J=8.8 Hz), 7.35(1H, s), 7.73(1H, dd, J=2.7,8.8 Hz), 8.20(1H, d, J=2.7 Hz) 20 Example 247 (E0247) E0247 was prepared in a similar manner to that of E0240. white powder 191 WO 2004/050632 PCT/JP2003/014489 mp. 145-147 0 C IR (KBr) : 3367, 3174, 2972, 1689, 1674, 1610, 1566, 1502cm-i Mass (ESI+) : 424 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.16(6H, d, J=6.9 Hz), 5 3.28-3.37(2H, m), 3.68 (1H, m), 3.88(3H, s), 3.92-3.98 (2H, m), 5.52(2H, s), 6.15(1H, t, J=5.6 Hz), 6.93(1H, d, J=8.7 Hz), 6.95 (2H, d, J=8.8 Hz), 7.02(1H, s), 7.22(2H, d, J=8.8 Hz), 7.73(1H, dd, J=2.7,8.7 Hz), 8.19(1H, d, J=2.7 Hz) J 10 Example 248 0N (E0248) E0248 was prepared in a similar manner to that of E0240. white powder 15 mp. 150.8-151.0'C IR (KBr) : 3496, 3361, 3294, 1705, 1674, 1647, 1603, 1581, 1568, 1554, 1516cm-i Mass (ESI+) : 393 (M+H)+ 200MHz lHNMR (DMSO-d6, d) :0.71-0.77(2H, m), 0.85-0.92(2H, 20 m), 1.92(1H, m), 3.27-3.37(2H, m), 3.76(3H, s), 3.92(2H, t, J=5.5 Hz), 5.51(2H, s), 6.14 (1H, t, J=5.5 Hz), 6.24(1H, s), 6.86-6.96(4H, m), 7.07-7.15(4H, m) Example 249 192 WO 2004/050632 PCT/JP2003/014489 0 H2N H0 F F N F (E0249) This compound was obtained according to a similar manner to that of E0240 as an amorphous. 5 NMR(CDC13), 3.56-3.64 (2H, m) , 3.94 (3H, s), 4.04 (2H, t, J=4.9 Hz) , 4. 50 (2H, brs, NH2) , 6. 69 (lH, s) , 6. 76 (1H, d, J=8. 8 Hz) , 6.84(2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 7.58 (1H, dd, J=8.8, 2.8 Hz), 8.05(1H, d, J=2.8 Hz). MS(ESI+), 444.1 (M+Na)+. IR(KBr); 1650.8, 1608.3cm-1. 10 LCMS(ESI+), 422.27(MH+). Example 250 H2N F

N-

(E0250) 15 This compound was obtained according to a similar manner to that of E0240 as a white powder. NMR(CDCl3), 3.55-3.63(2H,m), 3.93(3H, s), 4.04(2H, t, J=5.1 Hz) , 4.55 (2H, brs, NH2), 5.23 (1H, brt, J=5.4 Hz, NH) , 6.67 (lH, s), 6.75(lH, t, J=55 Hz), 6.75(1H, d, J=8.4 Hz), 6.88(2H, 20 d, J=8.8 Hz) , 7.13 (2H, d, J=8.8 Hz) , 7.56 (1H, d, J=8. 4, 2. 9 Hz), 8.04(1H, d, J=2.9 Hz). LC'MS(ESI+), 404.39(MH+). IR(KBr) 1649cm-1 MP, 141.5 - 142.10C. 193 WO 2004/050632 PCT/JP2003/014489 Example 251 F N F (E0251) 5 This compound was obtained according to a similar manner to that of E0240 as a powder. NMR(CDCl3), 3.56-3.64 (2H, m), 3.82 (3H, s), 4.03 (2H, t, J=5.0 Hz), 4.42(2H, brs), 6.65(lH, s), 6.76(1H, t, J-55 Hz), 6.79-6.89(4H, m), 7.14(2H, d, J=8.7 Hz), 7.20(2H, d, J=9.0 10 Hz). MS(ESI+), 425(M+Na)+. Example 252 NN F 15 (E0252) To a solution of E0267 (15. 3 g) in ethanol (75 ml) and hydrogen chloride aqueous solution (lN, 220 ml) was added dropwise a solution of sodium cyanate (14.4 g) in water (300 ml) at 45 0 C over 5 minutes. After stirring at 45'C for 4 hours, 20 the mixture was quenched with saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate-. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to give powder. The powder was crystallized from ethyl acetate and hexane at 194 WO 2004/050632 PCT/JP2003/014489 room temperature - 70'C to give E0252 as a powder (12.628 g, 81.2%). The physical data of this compound was identical to previously obtained authentic sample. 5 Example 253 N F ~N F (E0253) To a solution of E0267 (200 mg) in methanol (1 ml) was added 10 sodium methoxide methanol solution (5.2M, 0.1 ml) at room temperature. After stirring for 20 minutes, the mixture was evaporated to give residue. To the residue was added tetrahydrofuran, and the mixture was filtered and evaporated to give oil. The oil was dissolved in ethyl formate (2 ml) 15 and stirred at room temperature overnight. The mixture was evaporated and purified with preparative TLC (1 mm, 50% ethyl acetate/hexane) to give oil, which was crystallized from isopropyl ether, ethyl acetate, and hexane to give E0253 as a white powder (162.8 mg, 83%). 20 NMR(CDCl3), 3.68-3.76(2H, m), 3.82(3H, s), 4.06(2H, t, J=5.0 Hz), 6.68(1H, s), 6.80-6.89(4H, m), 7.14(2H, d, J=8.7 Hz), 7.22(2H, d, J=9.0 Hz), 8.22(1H, s). MS(ESI+), 428.2(M+Na). IR(KBr), 1660.4, 1614.lcm-1. 25 Example 254 195 WO 2004/050632 PCT/JP2003/014489 / F (E0254) To a solution of E0267 (800 mg) and triethylamine (0.7 ml) in dichloromethane (9 ml) was added dropwise acetyl chloride 5 (0.18 ml) at 0 0 C. After stirring at room temperature for 1 hour, the mixture was quenched with saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate (x3) . The combined organic layers were washed with hydrogen chloride aqueous solution (IN), water, and brine, 10 dried over magnesium sulfate, and evaporated to give oil, which was purified with column chromatography (SiO2 100 ml, eluted with 50% ethyl acetate/hexane) to give oil. The oil was crystallized from a mixture of ethyl acetate and hexane at 50 0 C to give E0254 as a solid (768.6 mg, 94.8%). 15 NMR(CDCl3). 2.01(3H, s), 3.62-3.70('2H, m), 3.82(3H, s), 4.03(2H, t, J=5.0 Hz) , 6.67 (lH, s) , 6.80-6.91 (4H, m), 7.14 (2H, d, J=8.7 Hz), 7.22(2H, d, J=9.0 Hz). MP; 109.8 - 110.2 0 C IR(KBr), 1649cm-1. 20 MS(ESI+).442.1(M+Na). Example 255 1 0 196 WO 2004/050632 PCT/JP2003/014489 (E0255) This compound was obtained according to a similar manner to that of E0254 as an oil. NMR(CDCl3), 3.69(3H, s), 3.65-3.73(2H, m)r 3.82(3H, s), 5 3.86(2H, d, J=5.9 Hz), 4.04 (2H, t, J=5.1 Hz), 6.67(1H, s), 6.80-6.89 (4H, m) , 7.14 (2H, d, J=8.5 Hz), 7.22 (2H, d, J=8.9 Hz), MS(ESI+).515.2(M+Na). IR(KBr, 20727-10), 1722.1, 1710.6, 1673.9cm-1. 10 Example 256 F (E0256) This compound was obtained according to a similar manner 15 to that of E0254 as an oil (82 mg, 78%). MS(ESI+).458.2(M+Na). IR(Neat), 1699cm-1. NMR(CDC13); 3.54-3.62(2H, m), 3.69(3H, s), 3.82(3H, s), 4.02 (2H, t) , 6.67 (1H, s) , 6.80-6.89 (4H, m) , 7.13 (2H, d, J=8 .9 20 Hz), 7.22(2H, d, J=9.0 Hz). Example 257 F 0 F / F N F 197 WO 2004/050632 PCT/JP2003/014489 (E0257) To a solution of E0275 (97.5 mg) and pyridine (0.14 ml) in dichloromethane (1 ml) was added trifluoroacetic anhydride (60.6 ml) at 0 0 C. After stirring at room temperature 5 overnight, the mixture was quenched with saturated sodium hydrogen carbonate aqueous solution (0.5 ml), filtered with chemelute1001 (Varian), andpurifiedwithpreparative TLC(1 mm, 50% ethyl acetate/hexane) to give E0257 as a solid (92.5 mg, 76%). 10 MS(ESI+), 496.1(M+Na). IR(KBr), 1705cm-1. NMR(CDCl3),3.75-3.87(2H, m), 3.82(3H, s), 4.10(4.8H, t), 6.68 (1H, s), 6.83 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.9 Hz), 7.16(2H, d, J=8.8 Hz), 7.22(2H, d, J=8.9 Hz). 15 Example 258 0 FOF N-N (E0258) To a solution of E0327 (400mg) in THF (5ml) was added 20 dropwise 1N NaOH (2.5ml) at room temperature. The mixture was stirred overnight, and then quenched with 1N HCl and CHCl3. The organic layer was separated and water layer was extracted twice with CHCl3. The combined organic layer was washed with water and brine, dried over Na2SO4, and 25 evaporated under reduced pressure. The residue was washed with IPE to give 273mg (70.7%) of E0258. IR (film): 2971.8, 1683.6, 1629.6, 1515.8, 1315.2, 1230.4, 1159.0, 1132.0, 977.7, 835.Ocm-1. 198 WO 2004/050632 PCT/JP2003/014489 Example 259 00 HO N 0 (E0259) 5 E0259 was prepared in a similar manner to that of E0258. white powder Mass (ESI+) : 355 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.63-3.78(2H, m), 3.79(3H, s), 3.95-4.00(2H, m), 4.86(1H, brs), 6.91(2H, d, J=8.7 Hz), 10 6.95(1H, s), 6.99(2H, d, J=8.9 Hz), 7.16(2H, d, J=8.7 Hz), 7.24(2H, d, J=8.9 Hz), 12.88(1H, brs) Example 260 HO OH

N

N N0 15 (E0260) E0260 was prepared in a similar manner to that of E0258. white powder Mass (ESI+) : 356 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.69-3.79(2H, m), 3.88 (3H, s), 20 3.96-4.02(2H, m), 4.87(1H, br), 6.89-7.00(4H, m), 7.20(2H, d, J=8.8 Hz), 7.70(1H, dd, J=2.6,8.8 Hz), 8.14 (1H, d, J=2.6 Hz), 12.97 (1H, br) Example 261 199 WO 2004/050632 PCT/JP2003/014489 Hoo 01 (E0261) E0261 was prepared from E0109 in a similar manner to that of E0258. 5 white powder Mass (ESI+) : 339(M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.70(2H, t, J=6.9 Hz), 3.59(2H, t, J=6.9 Hz), 3.79(3H, s), 4.64(lH, brs), 6.96-7.03(3H, m), 7.12-7.28(6H, m), 12.90(1H, br) 10 Example 262 (E0262) E0262 was prepared in a similar manner to that of E0258. 15 white powder Mass (ESI+) : 454 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.37(9H, s), 3.22-3.32(2H, m), 3.79(3H, s), 3.91-3.98(2H, m), 6.90(2H, d, J=8.7 Hz), 6.90-7.03(1H, overlapping), 6.95(1H, s), 6.99(2H, d, J=8.9 20 Hz), 7.16(2H, d, J=8.7 Hz), 7.24(2H, d, J=8.9 Hz) Example 263 200 WO 2004/050632 PCT/JP2003/014489 0 00 OH (E0263) E0263 was prepared in a similar manner to that of E0258. amorphous powder 5 Mass (ESI+) : 455 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.37 (9H, s), 3.22-3.32(2H, m), 3.88 (3H, s), 3.93-3.98 (2H, m), 6.89-7.05(5H, m), 7.20(2H, d, J=8.7 Hz), 7.70(1H, dd, J=2.7,8.8 Hz), 8.14(1H, d, J=2.7 Hz), 12.98(1H, br) 10 Example 264 NH (E0264) E0264 was prepared from E0006 in a similar manner to that 15 of E0258. white powder Mass (ESI+) : 340 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.71(2H, t, J=6.9 Hz), 3.56-3.64(2H, m), 3.88(3H, s), 4.64(1H, br), 6.92(1H, d, 20 J=8.8 Hz), 7.03(1H, s), 7.16-7.28(4H, m), 7.72(1H, dd, J=8.8,2.7 Hz), 8.15(1H, d, J=2.7 Hz), 12.94(1H, br) Example 265 201 WO 2004/050632 PCT/JP2003/014489 HO INN (E02 65) 4M HC1/AcOEt 0.4ml was added to a solution of E0378 (73mg) in AcOEt Im1. The mixture was concentrated and dried in vacuo 5 to give E0265 68.4mg as an amorphous powder. IR (neat) : 3440, 2960, 1739, 1707, 1691, 1674, 1647, 1624, 1614, 1566, 1549, 1533, 1500cm-1 Mass (ESI+) : 400 (M+H)+ 200MHz1HNMR (DMSO-d6, d) : 2.73(2H, t, J=6.9 Hz), 3.62(2H, 10 t, J=6.9 Hz), 3.89(3H, s), 6.94(1H, d, J=8.8 Hz), 7 .19-7.32(5H, m), 7.52-7.70(3H, m ), 7.80(1H, dd, J=8.8, 2

.

7 Hz), 8.22-8.28(3H, m) Example 266 HO NON 15' 0 CIH (E0266) E0266 was prepared in a similar manner to that of E0265. oil IR (neat) : 3435, 2966, 2935, 1678, 1662, 1649, 1612, 1581, 20 1566, 1547, 1533, 1500cm-1 Mass (ESI+) : 366 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) :1.16(6H, d, J=6.9 Hz), 2.72(2H, t, J=6.9 Hz), 3.54-3.75(3H, m), 3.89(3H, s), 6.93(1H, d, J=8.8 Hz), 7.05(1H, s), 7.13-7.35(4H, m), 7.76(1H, dd, 202 WO 2004/050632 PCT/JP2003/014489 J=2.7,8.8 Hz), 8.19(.1H, d, J=2.7 Hz) Example 267 HN 5 (E0267) To a solution of E0275 (765 mg) in ethyl acetate (1.9 ml) was added a solution of hydrogen chloride in ethyl acetate (4N, 0.56 ml) . The mixture was evaporated to give oil, which was crystallized from diisopropyl ether and ethyl acetate 10 at 65 0 C to give E0267 as a solid (766.8 mg, 91.4%). NMR(CDCl3), 3.30(2H, t, J=5.0 Hz), 3.79(3H, s), 4.18(2H, t, J=5.0 Hz), 6.62(1H, s), 6.83-6.88(4H, m), 7.10(2H, d, J=8.8 Hz), 7.18(2H, d, J=8.8 Hz). NMR(DMSO-d6), 3.19(2H,brs), 3.79(3H, s), 4.18(2H, t, J=5.0 15 Hz), 6.96-7.01(4H, m), 7.08(1H, s), 7.23-7.29(4H, m). MS(ESI+), 378.3(MH+, free). IR(KBr, 20727-2), 1612.2, 1513.9cm-1. Example 268 Nk / N , F 20 (E0268) A mixture of P0011 (30 g), chloroacetonitrile (8.52 ml), potassium iodide (4.47 g), and potassium carbonate (14.9 g) in acetone (150 ml) was stirring under reflux at 80 0 C 203 WO 2004/050632 PCT/JP2003/014489 for 2.5 hours. After cooling to room temperature, the mixture was quenched with water (600 ml) and extracted with ethyl acetate (300 ml x 2, 150 ml) . The combined organic layers were washedwithbrine (300ml), dried overmagnesium sulfate, 5 and evaporated to give solid (36.34 g). The solid was recrysallized fromdiisopropyl ether (60ml) andhexane (200 ml) at room temperature to give E0268 as a powder (31.5 g, 94%) NMR(CDCl3), 3.83(3H, s), 4.78(2H, s), 6.70(1H, s), 10 6.86-6.97(4H, m), 7.18-7.24(4H, m). IR(KBr), 2051.9cm-1. Example 269 N O 15 (E0269) E0269 was obtained according to a similar manner to that of E0268. white powder Mass (ESI+) 346(M+H)+ 20 200MHzlHNMR (DMSO-d6, d) : 0.69-0.77(2H, m), 0.86-0.96(2H, m), 1.92(1H, m), 3.76(3H, s), 5.16(2H, s), 6.30(lH, s), 6.93 (2H, d, J=9.0 Hz), 7.02(2H, d, J=8.8 Hz), 7.10-7.21 (4H, m) 25 Example 270 204 WO 2004/050632 PCT/JP2003/014489 (E0270) This compound was obtained according to a similar manner to that of E0268 as a powder. 5 NMR(CDCl3), 3.95(3H, s), 4.78(2H, s), 6.71(1H, s), 6.76(1H, t, J=55 Hz), 6.76(1H, d, J=8.4 Hz), 6.96(2H, d, J=8.9 Hz), 7.23(2H, d, J=8.9 Hz), 7.53(1H, dd, J=8.4, 2.6 Hz), 8.08 (1H, d, J=2.6 Hz). MS (ESI+) ,379 (M+Na). 10 Example 271 N - F (E0271) This compound was obtained according to a similar manner 15 to that of E0268. Example 272 F F - , F (E0272) 20 This compound was obtained according to a similar manner 205 WO 2004/050632 PCT/JP2003/014489 to that of E0268. IR (film): 1612.2, 1482.9, 1234.2, 1162.8, 1132.0, 1095.3, 973.8, 835.0 cm-1. 5 Example 273 F F (E0273) This compound was obtained according to a similar manner to that of E0268. 10 Example 274 OH (E0274) This compound was obtained according to a similar manner 15 to that of E0268. mp.96-99 0 C Mass;389 (M+1) NMR(CDC13,5); 1. 98 (1H, t, J=6. 1 Hz) , 3. 29 (3H, s) , 3. 83 (3H, s) , 3 . 93-4 . 01 (2H, 20 m), 4.06-4.11(2H, m), 6.86(2H, d, J=8.8 Hz), 6.88(2H, d, J=9.0 Hz), 6.93(1H, s), 7.14(2H, d, J=8.8 Hz), 7.23(2H, d, J=9.0 Hz) 206 WO 2004/050632 PCT/JP2003/014489 Example 275 - F (E0275) To a suspension of lithium aluminum hydride (250 mg) in ether 5 (14 ml) was added E0268 (1.38 g) in ether (5 ml) and tetrahydrofuran (1 ml) under ice-bath. The mixture was stirred at room temperature for 1 hour. Lithium aluminum hydride (50 mg) was added to the mixture under ice-bath., and then the mixture was stirred at room temperature for 10 1 hour. The mixture was quenched with water (0.3 ml), sodium hydroxide aqueous solution (15%, 0.3 ml), and water (0.9 ml), and then stirred at room temperature for 30 minutes. Magnesium sulfate and celite was added to the mixture, then the suspension was filtered and washed with ether. The 15 filtrate was evaporated to give 1.307 g of oil. The oil purified with column chromatography (SiO2, 100 ml, eluted with 20% methanol / chloroform (500 ml) ) to give E0275 as an oil (1.156 g, 82.9%). NMR(CDCl3), 3.09(2H, t, J=5.1 Hz), 3.82(3H, s), 3.99(2H, 20 t, J=5.1 Hz), 6.67(lH, s), 6.82-6.89(4H, m), 7.14(2H, d, J=8.9 Hz), 7.23(2H, d, J=9.0 Hz). MS(ESI+), 378 (MH+). Example 276 207 WO 2004/050632 PCT/JP2003/014489 N-lH F (E0276) To a solution of E0268 (27.43 g) in tetrahydrofuran (270 ml) was added borane methylsulfide complex (10M, 15 ml) at 5 roomtemperature. Themixturewasstirredatroomtemperature overnight. Then borane methylsulfide complex (7.5 ml) was added to the mixture. After stirring at room temperature overnight, the mixture was quenched with methanol (100 ml) and evaporated under reduced pressure to give oil. The oil 10 was dissolved in a mixture of tetrahydrofuran (150 ml) and hydrochloric acid (6N, 100 ml), and then stirred at 40 ~ 50'C for 1 hour. To the mixture was added dropwise aqueous sodium hydroxide solution (30%, 80 ml), and then sodium hydrogen carbonate, and sodium chloride. The mixture was 15 extracted with ethyl acetate (x4). The organic layer was evaporated to give oil (31.86 g), which was purified with column chromatography (SiO2, 1 L, eluted with 20% methanol/dichloromethane and concentrated ammonia/methanol/chloroform (0.025:1:4)) to give oil. 20 A solution of hydrogen chloride in ethyl acetate (4N, 22 ml) was added to the solution of the oil in ethyl acetate (50 ml), and the mixture was evaporated to give E0276 as an amorphous (22.87 g, 69.4%). 25 Example 277 208 WO 2004/050632 PCT/JP2003/014489 CIH NN 0 N (E0277) E0277 was prepared in a similar manner to that of E0276. white powder 5 mp. 229-231 0 C IR (KBr) : 3084, 2960, 2885, 2800, 2731, 2563, 2519, 2482, 1606, 1576, 1516cm-1 Mass (ESI+) : 350 (M+H)+ 200MHzlHNMR (DMSO-d6, d) : 0.69-0.77(2H,m), 0.84-0.96(2H, 10 m),1.93(1H,m), 3.14-3.22(2H,m), 3.76(3H, s), 4.14-4.20(2H, m), 6.26(1H, s), 6.94(4H, d, J=8.8 Hz), 7.14(4H, d, J=8.8 Hz), 8.21(2H, brs) Example 278 HNNNo 15 (E0278) This compound was obtained according to a similar manner to that of E0276 without formation of hydrogen chloride salt (oil). 20 NMR(CDC13), 3.09(2H, t, J=5.2 Hz), 3.94 (3H, s), 3.99(2H, t, J=5.2 Hz), 6.77 (1H, t, J=54.9 Hz), 6.67 (1H, s), 6.74 (2H, d, J=7.5 Hz), 6.87(2H, d, J=8.9 Hz), 7.15(2H, d, J=8.7 Hz), 209 WO 2004/050632 PCT/JP2003/014489 7.55(1H, dd, J=8.9, 2.8 Hz), 8.09(1H, d, J=2.8 Hz). MS (ESI+), 361 (MH+) Example 279 F ~N F 0C (E0279) This compound was obtained according to a similar manner to that of E0276. 10 Example 280 F F H2N -F CI (E0280) This compound was obtained according to a similar manner to that of E0276. 15 IR (film): 3423.0, 1612.2, 1469.5, 1240.0, 1164.8, 1132.0, 1095.4, 975.8, 836.9 cm-1. Example 281 H, \\ / 20 (E0281) 210 WO 2004/050632 PCT/JP2003/014489 This compound was obtained according to a similar manner to that of E0276. mp.104-106 C Mass;388 (M+1) 5 IR(KBr);1310cm-1 NMR(CDC13,5);3.09(2H, t, J=5.1 Hz), 3.29(3H, s), 3.83(3H, s), 3.99 (2H, t, J=5. 1 Hz), 6.83(2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.9 Hz), 6.93(1H, s), 7.13(2H, d, J=8.8 Hz), 7.24 (2H, d, J=8.9 Hz), 10 Example 282 0 N / F (E0282) (P0015-1) Diethylazodicarboxylate 82.3mg was added to a solution of 15 P0015 (100mg), P0015-1 (152mg), and triphenylphosphine 124mg in THF 2ml. After stirring at ambient temperature for 5 hours, Thereaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / CHC13 = 5% viscous oil to give E0282. 20 Mass (ESI+) : 461 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.37 (9H, s), 3.22-3.33(2H, m), 3.87 (3H, s), 3.93-3.99(2H, m), 6.88-7.04(5H, m), 7.10(1H, t, J=54.4 Hz), 7.21(2H, d, J=8.7 Hz), 7.69(1H, dd, J=2.7,8.8 Hz), 8.14(1B, d, J=2.7 Hz) 25 Example 283 211 WO 2004/050632 PCT/JP2003/014489 (E0283) E0283 was prepared from P0020 in a similar manner to that of E0282. 5 white powder Mass (ESI+) : 482 (M+H)+ 200MHz lH NMR (DMSO-d6, d) : 1.31(3H, t, J=7.1Hz), 1.37(9H, s), 3

.

2 2

-

3

.

3 2 (2H, m), 3.79(3H, s), 3.91-3.98 (2H, m), 4.32 (2H, q, J=7.1 Hz), 6.90(2H, d, J=8.7 Hz),6.95-7.06(1H, 10 overlapping), 6.99(2H, d, J=8.9 Hz), 7.01(1H, s), 7.17(2H, d, J=8.7 Hz), 7.25(2H, d, J=8.9 Hz) Example 284 15 (E0284) E0284 was prepared in a similar manner to that of E0282. white powder Mass (ESI+) : 483 (M+H)+ 200MHz1H NMR (DMSO-d6, d) : 1.31(3H, t, J=7.1 Hz), 1.37(9H, 20 s), 3.22-3.33(2H, m), 3.88 (3H, s), 3.96(2H, t, J=5.7 Hz), 4

.

3 3 (2H, q, J=7.1Hz), 6.89-7.05(1H, overlapping), 6.92(1H, d, J=8.9 H2), 6.93(2H, d, J=8.7 Hz), 7.05(1H, s), 7.21(2H, d, J=8.7 Hz), 7.72(1H, dd, J=2.7,8.9 Hz), 8.15(1H, d, J=2.7 Hz) 212 WO 2004/050632 PCT/JP2003/014489 Example 285 F N (E0285) 5 This compound was obtained according to a similar manner to that of E0282 as an oil. NMR(CDCl3), 1.45(9H, s), 3.50-3.58(2H, m), 3.94(3H, s), 4.02(2H, t, J=5.1 Hz), 6.70(1H, s), 6.75(1H, d, J=8.4 Hz), 6.85(2H, d, J=8.9 Hz), 7.15(2H, d, J=8.9 Hz), 7.56(1H, dd, 10 J=8.4, 2.9 Hz), 8.08(1H, d, J=2.9 Hz). MS(ESI+), 501.2(M+Na). Example 286 N F NN F 15 (E0286) This compound was obtained according to a similar manner to that of E0282 as a powder. NMR(CDCl3), 2.89(1H, d, J=10.4 Hz, NH), 3.23(3H, s), 3.67-3.78(1H, m) , 3.81(3H, s), 3.99(1H, dd, J=9.2, 6.4 Hz), 20 4.22(1H, dd, J=9.2, 5.0 Hz), 6.67(1H, s), 6.81(2H, d, J=8.9 Hz), 6.86(2H, d, J=6.0Hz), 7.10-7.29(13H,m), 7.49-7.54(6H, MS (ESI+), 678.4 (MH+). 213 WO 2004/050632 PCT/JP2003/014489 Example 287 - F N N F (E0287) 5 This compound was obtained according to a similar manner to that of E0282 as an oil. NMR(CDCl3), 1.28(3H, d, J=6.6 Hz), 1.45(9H, s), 3.82(3H, s), 3.92(2H, d, J=4.1 Hz), 3.90-4.14(1H, m), 6.67 (1H, s), 6.84(2H, d, J=8.9 Hz), 6.86(2H, d, J=9.0 Hz), 7.13(2H, d, 10 J=8.9 Hz), 7.23(2H, d, J=9.0 Hz). MS(ESI+), 514.2(M+Na). Example 288 15 (E0288) This compound was obtained according to a similar manner to that of E0282 as an oil. NMR(CDCl3), 1.28(3H, d, J=6.6 Hz), 1.45(9H, s), 3.82(3H, s), 3.92 (2H, d, J=4.1 Hz), 3.90-4.14(1H, m), 6.67 (1H, s), 20 6.84(2H, d, J=8.9 Hz), 6.86(2H, d, J=9.0 Hz), 7.13(2H, d, J=8.9 Hz), 7.23(2H, d, J=9.0 Hz). MS(ESI+), 514.2(M+Na). 214 WO 2004/050632 PCT/JP2003/014489 Example 289 CFH CIH N F (E0289) 5 4M HCl/AcOEt 1ml was added to a solution of E0282 (129mg) in AcOEt 1ml, and the mixture was stirred at ambient temperature for Ihour. The supernatant.was removed by decantation. The residual oily solid was washed with AcOEt 1ml by decantation. To the residue was added acetone 2ml, 10 and oily residual solid became white powder on stirring. This was stirred at ambient temperature for 20minutes. The precipitates were collected and washed with acetone to give E0289 (91.4mg) as a white powder. IR (neat) : 2964, 1705, 1668, 1660, 1614, 1581, 1566, 1531, 15 1512cm-1 Mass (ESI+) : 361 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.11-3.23(2H, m), 3.87(3H, s), 4.12-4.28 (2H, m), 6.90-7.02(4H, m), 7.11(1H, t, J=54.3 Hz), 7.26(2H, d, J=8.6 Hz), 7.71(1H, dd, J=2.7,8.8 Hz), 8.14 (1H, 20 d, J=2.7 Hz), 8.24(2H, brs) Example 290 NH 21F 215 WO 2004/050632 PCT/JP2003/014489 (E0290) This compound was obtained according to a similar manner to that of E0289 as a white powder. NMR(DMSO-d6), 3.17-3.21(2H, m), 3.95(3H, s), 4.19(2H, t, 5 J=5.0 Hz), 6.93(1H, d, J=8.8 Hz), 7.00(2H, d, J=8.8 Hz), 7.15(1H, s), 7.28 (2H, d, J=8.8 Hz), 7.76(1H, dd, J=8.8, 2.6 Hz), 8.18 (1H, d, J=2.6 Hz). MS(ESI+), 379.1(MH+). IR(KBr), 1612.2cm-1. 10 Example 291 H 0 IHF (E0291) This compound was obtained according to a similar manner 15 to that of E0289 as a white powder. NMR(DMSO-d6), 2.60(3H, s), 3.28-3.33(2H, m), 3.79(3H, s), 4.25(2H, t, J=4.7 Hz), 7.04-6.96(4H, m), 7.09(1H, s), 7.22-7.31(4H, m). MS(ESI-), 426.2 (M+Cl)+. 20 IR(KBr); 1610.2, 1515.8cm-1. MP; 189 - 189.2 0 C. Example 292 216 WO 2004/050632 PCT/JP2003/014489 0 z (E0292) This compound was obtained according to a similar manner to that of E0289 as a white amorphous. 5 NMR(DEMSO-d6),1.04(3H, d, J=6.0 Hz), 3.5-3.7(1H, m), 3.79(3H, s), 3.98(1H, dd, J=10.1, 6.9 Hz), 4.11(1H, dd, J=10.1, 6.5 Hz), 6.96-7.04 (4H, m), 7.09 (1H, s) ,7.22-7.31(4H, m)). MS(ESI+), 392.2(MH+). 10 Example 293 HaN 0 Ks/ F CIH F (E0293) This compound was obtained according to a similar manner 15 to that of E0289 as a white amorphous. NMR(DEMSO-d6),1.04(3H, d, J=6.0 Hz), 3.5-3.7(1H, m), 3.79(3H, s), 3.98(1H, dd, J=10.1, 6.9 Hz), 4.11(1H, dd, J=10.1, 6.5Hz), 6.96-7.04 (4H, m), 7.09(1H, s), 7.227. .31(4H, m). 20 MS(ESI+), 392.2(MH+). IR(Neat) 1612.2cm-1. Example 294 217 WO 2004/050632 PCT/JP2003/014489 H2N (E0294) This compound was obtained according to a similar manner to that of E0289 as a white powder. 5 NMR(DMSO-d6); 2.84-3.20(4H, m), 3.88(3H, s), 6.93(1H, d, J=8.

9 Hz),7.19(lH,s),7.30-7.36(4H,m),7.86(lH,ddJ=8.9, 2.7 Hz), 8.19(lH, d, J=2.7 Hz). MS(ESI+); 363.3(MH+). IR(KBr); 1612.2, 1500.3cm-1. 10 Example 295 NIO N F (E0295) A mixture of P0012 (0.5 g), chloroacetonitrile (0.2 ml), 15 potassium iodide (525mg), and potassium carbonate (437 mg) in N,N-dimethylformamide (6 ml) was stirring at 75'C for 6 hours. After cooling to room temperature, the mixture was quenched with water, and extracted with ethyl acetate (x3). The combined organic layers were washed with water (x3) and 20 brine, dried over magnesium sulfate, and evaporated to give E0295 as a solid (631.6 mg, 112%). NMR(CDCl3), 3.83(3H, s), 4.77(2H, s), 6.69(1H, s), 6.76(1H, t, J=55 Hz), 6.96-6.86(4H, m), 7.18-7.24(4H, m). MS(ESI+), 378.1(M+Na). 218 WO 2004/050632 PCT/JP2003/014489 Example 296 so F N (E0296) 5 This compound was obtained according to a similar manner to that of E0295 as an oil. NMR (CDC13) ; 1. 63 (1H, t, J=5.2 Hz) , 1. 99-2. 11 (2H, m) , 3. 82 (3H, s), 3.82-3.91(2H, m), 4.12(2H, t, J=6.0 Hz), 6.67 (1H, s), 6.84(2H, d, J=8.8 Hz), 6.87(2H, d, J=8.9 Hz), 7.13(2H, d, 10 J=8.8 Hz), 7.32(2H, d, J=8.9 Hz). TR(Neat); 1612, 1514cm-1. MS(ESI+); 393.1(MH+), 415.1(M+Na). Example 297 F N_ N F 15 (E0297) This compound was obtained according to a similar manner to that of E0205 as an oil. NMR(CDC l3);3.03(3H, s), 3.83(3H, s), 4.97(2H, s), 6.70(1H, 20 s), 6.88(2H, d, J=9.0 Hz), 7.01(2H, d, J=8.8 Hz), 7.17-7.26(4H, m). IR(KBr); 1612.2, 1513.9 cm-1. MS(ESI+),449.1(M+Na). 219 WO 2004/050632 PCT/JP2003/014489 Example 298 HO NF O F (E0298) This compound was obtained according to a similar manner 5 to that of E0295 as a white solid. NMR(DMSO-d6), 3.65-3.73(2H, m), 3.79(3H, s), 3.98(2H, t, J=4.7 Hz), 4.87(1H, t, J=5.4 Hz), 6.93(2H, d, J=8.7 Hz), 7.00(2H, d, J=8.9 Hz), 7.07(1H, s), 7.19(2H, d, J=8.7 Hz), 7.28(2H, d, J=8.9 Hz). 10 MS(ESI+), 401.2(M+Na). IR(KBr); 1610.3, 1511.9cm-1. Example 299 HO 15 (E0299) This compound was obtained according to a similar manner to that of E0295 as a white solid. NMR(CDC13), 2.01(1H, t, J=6.1Hz), 3.82(3H, s), 3.93-4.10 (4H, m), 6.66(1H, s), 6.76(1H, t, J=55.1 Hz), 6.85(2H, d, J=8.7 20 Hz), 6.87 (2H, d, J=9.0 Hz), 7.15(2H, d, J=8.7 Hz), 7.21(2H, d, J=9.0 Hz). MS(ESI+); 383.2(M+Na). IR(KBr); 1610.3, 1513.9, 1454.1cm-1. 220 WO 2004/050632 PCT/JP2003/014489 Example 300 0F N NF (E0300) 5 This compound was obtained according to a similar manner to that of E0295 as a white powder. NMR(DMSO-d6); 3.78(3H, s), 4.43(2H, s), 6.80-7.53(12H, m, NH2), MS(ESI+);396.3(M+Na)+. 10 IR(KBr); 1681.6, 1606.4cm-1. Example 301 0 N (E0301) 15 Alkylation of this compound was achieved by a similar manner to that of E0295 to give salt free compound as an oil. Hydrogen chloride salt formation was achieved successively by a similar manner to that of E0172 to give E0301 as a white powder (498.7 mg, 49.6%). 20 NMR(DMSO-d6), 3.69(2H, t, J=5.0 Hz), 3.88 (3H, s), 3.99(2H, t, J=5.0 Hz), 6.92(1H, d, J=8.7 Hz), 6.96(2H, d, J=8.8 Hz), 7.13(1H, s), 7.23(2H, d, J=8.8 Hz), 7.53(1H, dd, J=8.7, 2.9 Hz), 8.18 (1H, d, J=2.9 Hz). 221 WO 2004/050632 PCT/JP2003/014489 MS(ESI+), 402.1(M+Na)+, (Free). IR(Neat), 1614, 1552cm-1. Example 302

"

2 N F N F 5N (E0302) This compound was obtained according to a similar manner to that of E0295 as a white solid. NMR (CDC13) ; 3.88 (3H, s), 4.45 (2H, s), 6.92 (1H, d, J=8.9 Hz), 10 6.96(2H, d, J=8.8 Hz), 7.14(1H, s), 7.26(2H, d, J=8.8 Hz), 7.41(1H, brs, NH2), 7.56(1H, brs, NH2), 7.76(1H, dd, J=8.9, 2.5 Hz), 8.18(1H, d, J=2.5 Hz). MS(ESI+); 415.1(M+Na). IR(KBr); 1693.2, 1608.3cm-1. 15 Example 303 HO aN!p (E0303) This compound was obtained according to a similar manner 20 to that of E0295 as an oil. NMR(CDCl3); 3.94(3H, s), 3.94-4.14(4H, m), 6.68(1H, s), 6.74 (1H, d, J=8.7 Hz), 6.86(1H, t, J=55.0 Hz), 6.88 (2H, d, J=8.9 Hz), 7.16(2H, d, J=8.9 Hz), 7.53(1H, dd, J=2.6, 8.7 Hz), 8.08 (1H, d, J=2.6 Hz). 222 WO 2004/050632 PCT/JP2003/014489 MS(ESI+); 384.2(M+Na). IR(KBr), 1805.1, 1612.2cm-1. Example 304 5 (E0304) This compound was obtained according to a similar manner to that of E0295 as a white powder. NMR(DMSO-d6); 3.88 (3H, s), 4.44(2H, s), 6.98-9.89(4H, m), 20 7.10(1H, t, J=54.3 Hz), 7.24(2H, d, J=8.8 Hz), 7.39(1H, brs, NH2), 7.54(1H, brs, NH2), 7.70(1H, dd, J=8.9, 2.8 Hz), 8.14(1H, d, J=2.8 Hz). MS(ESI-); 373 (M-H)+. IR(KBr); 1662.3, 1610.3cm-1. 15 Example 305 HO (E0305) This compound was obtained according to a similar manner 20 to that of E0298. IR (film): 3388.3, 1494.6, 1236.2, 1160.9, 1133.9, 1095.4, 975.8, 833.1 cm-1. Example 306 223 WO 2004/050632 PCT/JP2003/014489 NN Oy (E0306) This compound was obtained according to a similar manner to that of E0295. 5 Mass;384(M+1) Example 307

NH

2 CIH 0 F N F 0 (E0307) 10 Toa suspension of lithium aluminumhydride (250mg) in ether (5 ml) was added E0295 (630 mg) in tetrahydrofuran (1 ml) under ice-bath. After stirring at room temperature for 1 hour. the mixture was quenched with water (0.125 ml), sodium hydroxide aqueous solution (15%, 0.125ml), andwater (0.375 15 ml), and then stirred at room temperature for 30 minutes. Magnesium sulfate and celite was added to the mixture, then the suspension was filtered and washed with ether. The filtrate was evaporated to give 0.5 g of oil. The oil was purified with column chromatography (SiO2, 50 ml, eluted 20 with methanol / dichloromethane / concentrated ammonia water 224 WO 2004/050632 PCT/JP2003/014489 (1/10/0.05) ) to give oil (300 mg) . The oil was dissolved in ethyl acetate and added a solution of hydrogen chloride in ethyl acetate (4N, 1.6 ml) . The mixture was evaporated to give oil, which was crystallized from methanol and 5 diisopropyl ether to give E0307 as a powder (300 mg, 42.7%) NMR(DMSO-d6), 3.20(2H, t, J=4.9Hz), 3.78(3H, s), 4.16(2H, t, J=4.9 Hz), 6.85(1H, s), 6.94-7.01(4H, m), 7.08(1H, t, J=54.6 Hz), 7.20-7.26(4H, m). MS(ESI+), 360.3(MH+, free). 10 IR(KBr, 20727-7), 1612, 1513.9 cm-1. Example 308 F F

H

2 N F CIH N (E0308) 15 This compound was obtained according to a similar manner to that of E0307. IR (film): 3401.8, 1610.3, 1511.9, 1469.5, 1240.0, 1162.9, 1130.1, 975.8, 827.3 cm-1. 20 Example 309 HO o NF NF 225 WO 2004/050632 PCT/JP2003/014489 (E0309) Amixtureof P0011 (200mg), Chloromethylsulfonicacidsodium salt (274 mg), potassium iodide (298 mg), and potassium carbonate (248 mg) in 1-methyl-2-pyrrolidinone (2 ml) was 5 stirring at 1500C overnight. After cooling to room temperature, the mixture was poured into a mixture of aqueous hydrogen chloride solution (1 N), brine, and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (x3). The combined organic layers were dried over 10 magnesium sulfate, and evaporated under reduced pressure to give oil. The oil was purified with column chromatography (SiO2 10'0 ml, eluted with 15% methanol / dichloromethane) to give E0309 as a brown amorphous (154.3 mg, 60%) MS(ESI-); 427.1(M-H). 15 NMR(DMSO-d6), 3.79(3H, s), 4.52(2H, s), 7.00(2H, d, J=9.0 Hz), 7.01 (2H, d, J=8.9 Hz), 7.07 (lH, s), 7.18 (2H, d, J=9.0 Hz), 7.27(2H, d, J=8.9 Hz). Example 310 ' F F F 20 (E0310) To a solution of P0011 (1.0g) in DMF (10ml) under water cooling was added portionwise NaH (60%in Oil, 144mg) and stirred for 1 hour. After then, III (787mg) was added and 25 the reaction mixture was stirred at 5OoC for 5 hours. The mixture was quenched with water and extracted twice with 226 WO 2004/050632 PCT/JP2003/014489 EtOAc. The organic layer was washed three times with water and once with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was column chromatographed on silica gel (50ml) to give 803mg (55%) 5 of E0310 as a oil. Example 311 O N F (E0311) 10 This compound was obtained according to a similar manner to that of E0310. Example 312 HO o F F / N F 15 (E0312) ThemixtureofE0310 (800mg) and cHCl (100ul) inEtOH (10ml) was stirred at room temperature for 3 hours. Afteraddition of aqueous sodium bicarbonate, the mixture was evaporated, and extracted twice with EtOAc. The organic layer was 20 washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue (710mg) was column chromatographed on silica gel (50ml) to give 570mg (93%) of E0312. 227 WO 2004/050632 PCT/JP2003/014489 IR (film) : 3409.5, 1612.2, 1513.9, 1467.6, 1243.9, 1162.9, 1130.1, 835.0, 835.0 cm-1. 5 Example 313 (E0313) This compound was obtained according to a similar manner to that of E0312. 10 mp: 122.3-122.5'C IR (film): 3399.9, 1612.2, 1513.9, 1456.0, 1251.6, 1174.4, 1083.8, 1033.7, 836.9, 800.3 cm-1. Example 314 0 0 0 F N F 15 (E0314) 60% Sodium hydride 39.7mg was added to a solution of P0011 (255mg) in DMF 1.5ml. The mixture was stirred at ambient temperature for Ihour. To this was added ethyl bromoacetate 20 153mg. The reaction mixture was stirred at ambient temperature for hour, and then quenched by adding saturated ammonium chloride solution, and whole mixture was extracted 228 WO 2004/050632 PCT/JP2003/014489 with AcOEt. The organic layer was washed with H20, aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / n-hexane 5 30% to give E0314 (217mg) as an oil. Mass (ESI+) 421(M+H)+ 200MHz 1HNMR (DMSO-d6, d) : 1.94(3H, t, J=7.1 Hz), 3.79(3H, s), 4.15(2H, q, J=7.1 Hz), 4.79(2H, s), 6.92(2H, d, J=8.8 Hz), 6.99(2H, d, J=8.9 Hz), 7.09(1H, s), 7.20(2H, d, J=8.8 10 Hz), 7.28(2H, d, J=8.9 Hz) Example 315 HO--\ C F N N F 0 (E0315) 15 1M solution of diisobutylaluminum hydride in toluene 0.5ml was added dropwise to a solution of E0314 (98mg) in THF 3ml at -50 C. The mixture was stirred at -50*C for hour, then at 5oC for hour. Additional 1M solution of diisobutylaluminum hydride in toluene 0.5ml was added 20 dropwise. After stirring at 50C for one more hour, the reaction was quenched by adding 10% aqueous potassium sodium tartaric acid salt, and the mixture was filtered through a celite pad. The filtrate was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium 25 chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by 229 WO 2004/050632 PCT/JP2003/014489 preparative thin layer silica gel chromatography developed by AcOEt / n-hexane = 60%. The separated silica gel was extracted with 10% MeOH/CHC13 and the solvent was evaporated in vacuo to give E0315 (54.5mg) as an oi'l, which became solid 5 on standing. IR (KBr) : 3431, 2931, 1612, 1564, 1549, 1512cm-1 Mass (ESI+) : 379 (M+H)+ 400MHz 1H NMR (DMSO-d6, d) : 3.67-3.72(2H, m), 3.79(3H, s), 3.84-3.99(2H, m), 4.87 (1H, t, J=5.4 Hz), 6.93 (2H, d, J=8.7 10 Hz), 7.00(2H, d, J=8.9 Hz), 7.10(1H, s), 7.19(2H, d, J=8.7 Hz), 7.27(2H, d, J=8.9 Hz) Example 316 0 soJ N0 15 (E0316) 60% Sodium hydride 52mg was added to a solution of P0020 (200mg) in DMF 2ml under ice bath cooling. The mixture was stirred at same temperature for 30minutes. To this was added bromoacetic acid 90.3mg. The reaction mixture was stirred 20 at ambient temperature for 2hours, and then quenched by adding slM HCl 3ml. H20 3ml and diisopropyl ether 2ml were addedandthemixturewasstirredinanicebathfor30minutes. The precipitates were collected and washed with H20 and diisopropyl ether to give E0316 (231.2mg) as a white powder 25 Mass (ESI+) : 397 (M+H)+ 200MHz1HNMR (DMSO-d6, d) : 1.31(3H, t, J=7.lHz), 3.79(3H, s), 4.32(2H, q, J=7.1 Hz), 4.68(2H, s), 6.88(2H, d, J=8.8 230 WO 2004/050632 PCT/JP2003/014489 Hz), 7.00(2H, d, J=8.9 Hz), 7.02(1H, s), 7.18(2H, d, J=8.8 Hz), 7.26(2H, d, J=8.9 Hz), 13.05(1H, brs) Example 317 0 N 0 5N (E0317) E0317 was prepared in a similar manner to that of E0316. white powder Mass (ESI+) : 398 (M+H)+ 10 200MHz 1H NMR (DMSO-d6, d) : 1.31(3H, t, J=7.1 Hz), 3.88 (3H, s), 4.33(2H, q, J=7.1 Hz), 4.70(2H, s), 6.92(2H, d, J=8.8 Hz), 6.89-7.00(1H, m), 7.06(1H, s), 7.22(2H, d, J=8.8 Hz), 7.73(1H, dd, J=2.8,8.8 Hz), 8.15(1H, d, J=2.8 Hz), 13.04(1H, brs) 15 Example 318 0 HO N_ O N (E0318) E0318 was obtained according to a similar manner to that 20 of E0316. oil 231 WO 2004/050632 PCT/JP2003/014489 Mass (ESI+) : 365 (M+H)+ 200MHz1HNMR (DMSO-d6, d) :0.70-0.93(4H, m), 1.70-2.00(1H, m), 3.76(3H, s), 4.66(2H, s), 6.25(1H, s), 6.85 (2H, d, J=8.9 Hz), 6.92 (2H, d, J=9.0 Hz), 7.06-7. 16(4H, m), 13.00 (1H, brs) 5 Example 319

HO

N 0 (E0319) To a suspension of sodium borohydride 19. 1mg in THF 2ml was 10 added boron trifluoride diethyl etherate 89.5mg dropwise under ice bath cooling 2.5eg. The mixture was stirred at same temperature for 30minutes. E0316 (100mg) was added in one portion and the mixture was stirred at ambient temperature for hours. 1M HCl 5ml was added and the mixture 15 was stirredataambienttemperaturefor30minutes. Themixture was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was 20 crystallized from diisopropyl ether to give E0319 (68. 9mg) as a white powder. Mass (ESI+) : 383 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.31(3H, t, J=7.1 Hz), 3.65-3.73(2H, m), 3.79(3H, s), 3.94-4.00(2H, m), 4.32(2H, 25 q, J=7.1 Hz), 4.87(1H, t, J=5.5 Hz), 6.91(2H, d, J=8.8 Hz), 6.99(2H, d, J=8.9 Hz), 7.01 (1H, s), 7.17 (2H, d, J=8.8 Hz), 7.25(2H, d, J=8.9 Hz) 232 WO 2004/050632 PCT/JP2003/014489 Example 320 HO IO N 0 O N (E0320) 5 E0320 was prepared in a similar manner to that of E0319. white powder Mass (ESI+) : 384 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.31(3H, t, J=7.1 Hz), 3

.

6 5-3.74(2H, m), 3.88(3H, s), 3.96-4.02(2H, m), 4.33(2H, 10 q, J=7.1 Hz), 4.87(1H, t, J=5.4 Hz), 6.89-6.96(3H, m), 7 .05(1H, s), 7.21(2H, d, J=8.7Hz), 7.72(H, dd, J=2.7,8.8 Hz), 8.14(1H, d, J=2.7 Hz) Example 321 HO 15 0 (E0321) E0321 was prepared in a similar manner to that of E0319. white powder mp. 142-144'C 20 IR (KBr) : 3246, 2924, 1612, 1566, 1547, 1516cm-1 Mass (ESI+) : 351 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 0.68-0.77 (2H, m), 0.85-0. 95 (2H, 233 WO 2004/050632 PCT/JP2003/014489 m), 1.92(1H, m), 3.64-3.73(2H, m), 3.76(3H, s), 3.96(2H, t, J=4. 9 Hz) , 4 .85 (1H, t, J=5. 5 Hz) , 6. 24 (1H, s), 6.85-6.96(4H, m), 7.05-7.17(4H, m) 5 Example 322 HN K ( CIH (E0322) E0322 was prepared in a similar manner to that of E0319. white powder 10 mp. 228-231'C IR (KBr) : 3082, 2958, 2885, 2802, 2733, 2480, 1606, 1572, 1512cm-1 Mass (ESI+) : 350 (M+H)+ 200MHz1HNMR (DMSO-d6, d) :0.69-0.77(2H, m), 0.83-0.96(2H, 15 m),1.93(1H, m), 3.14-3.22(2H, m), 3.76(3H, s), 4.14-4.20(2H, m), 6.27 (1H, s), 6.93(4H, d, J=8.8 Hz), 7.14(4H, d, J=8.8 Hz), 8.24(2H, brs) Example 323 HO o F 20 (E0323) A solution of sodium sulfite 84.2mg in H20 1ml was added 234 WO 2004/050632 PCT/JP2003/014489 to a solution of P0022 (258.1mg) in EtOH 3ml and stirred at 700C for 2hours. At which time, white precipitates were appeared and H20 1ml was added to dissolve the precipitates. The mixture was stirred at 800C overnight to give a clear 5 solution. This was stirred at 800C further for 28hours. The reaction mixture was acidified by 1MHC1 0. 7ml, concentrated and dried under vacuo. The residue was dissolved in CHC13, dried over magnesium sulfate, all of unsoluble matter was filteredoff, and concentrated invacuo to give E0323 (245mg) 10 as an amorphous powder. Mass (API-ES negative) 425(M-H)+ 200MHzlHNMR (DMSO-d6, d) :2.61-2.69(2H, m), 2.78-2.91(2H, m) , 3.79(3H, s), 7.00 (2H, d, J=8.9Hz), 7.12 (iH, s), 7.17 (2H, d, J=8.6 Hz), 7.22 (2H, d, J=8.6 Hz), 7.29(2H, d, J=8.9 Hz) 15 Example 324 HO \ O S F N F F (E0324) E0324 was prepared from P0023 in a similar manner to that 20 of E0323. amorphous powder Mass (API-ES negative) : 426 (M-H)+ 200MHz 1HNMR (DMSO-d6, d) : 2.61-2.69(2H, m) , 2.83-2.92(2H, m) , 3.88 (3H, s), 6.92 (1H, d, J=8.8 Hz), 7.17 (1H, s), 7.23 (4H, 25 s), 7.75(lH, dd, J=8.8,2.7 Hz), 8.20(1H, d, J=2.7 Hz) 235 WO 2004/050632 PCT/JP2003/014489 Example 325 H2N F N F N F (E0325) DMF 41mg was added to a solution of E0319 (239mg) in thionyl 5 chloride 0.6ml and the mixture was stirred at 50'C for minutes. The reaction mixture was concentrated in vacuo. To the residue was added toluene 3ml, and concentrated in vacuo. The residue was dissolved in THF 10ml and was added dropwise to a solution of 28% aqoueous ammonium hydroxide 10 solution 0. 5ml and tetrabutylammonium hydrogensulfate 19mg in THF 4ml under ice bath cooling. After stirring at ambient temperature for 30minutes, the reaction mixture was partitioned between AcOEt and aqueous sodium chloride solution. The organic layer was washed with aqueous sodium 15 chloride solution, driedovermagnesium sulfate. The residue was purified by silica gel column chromatography eluted with MeOH / CHCl3 = 2%, 5%. Pure fraction was collected and concentratedinvacuo. The residual solidwas recrystallized fromEtOH-diisopropylether togive E0325 (72.6mg) asawhite 20 powder. mp. 131-132 0 C IR (KBr) : 3354, 3184, 3126, 1707, 1693, 1676, 1647, 1564, 1549, 1516cm-1 Mass (ESI+) : 426 (M+H)+ 25 200MHz 1HNMR (DMSO-d6, d) :2.95-3.04(2H, m), 3.21-3.30(2H, m) , 3.79 (3H, s), 6.87 (2H, s), 7.00 (2H, d, J=8.9 Hz), 7.14 (1H, s), 7.23-7.33(6H, m) 236 WO 2004/050632 PCT/JP2003/014489 Example 326 0 N O H _ F F N F (E0326) 5 E0326 was prepared in a similar manner to that of E0325. white powder mp. 139-140'C IR (KBr) : 3230, 3132, 1610, 1568, 1527, 1500cm-i Mass (ESI+) : 441 (M+H)+ 10 200MHz 1H NMR (DMSO-d6, d) : 2.58 (3H, s), 2.90-3.00(2H, m), 3.25-3.33 (2H, m) , 3.88 (3H, s), 6.93(1H, d, J=8.9Hz), 6.97 (1H, brs), 7.19(1H, s), 7.26(2H, d, J=8.3 Hz), 7.34(2H, d, J=8.3 Hz), 7.77(lH, dd, J=8.9,2.8 Hz), 8.19(1H, d, J=2.8 Hz) 15 Example 327 0 F F F P0 N-N OMe (E0327-0) (E0327-1) (E0327) A mixture of E0327-0 (800mg) and E0327-1 , methyl (triphenylphosphoranylidene)- acetate (850mg) in toluene 20 (10ml) was stirred under reflux condition for 5 hrs. The mixture was evaporated under reduced pressure and column chromatographed on silica gel (50ml, Hex:EtOAc=5: 1) to give 795mg(85.5%) of E0327. 237 WO 2004/050632 PCT/JP2003/014489 IR (film): 1718.3, 1637.3, 1513.9, 1241.9, 1166.7, 1132.0, 977.7, 837.0cm-1 Example 328 0 F H,/ F N-N (E0328) To a suspension of E0258 (180mg) in toluene (5ml) was adde thionylchloride (0.17ml) at room temperature. The reaction mixture was stirred at 100*C for 5 hours until the 10 mixture become clear solution. After then, the mixture was evaporated under reduced pressure. (become solid) THF was added, and then aqueous NH3 (37%) was added. The mixture was stirred for 1 hour, and quenched with water, and extracted twice with EtOAc. The combined organic layer 15 was washed with sat.NaHCO3, water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure to give 170mg (95%) of E0328 as a powder. IR (KBr): 3347.8, 1671.9, 1606.4, 1513.9, 1467.6, 1388.5, 1236.2, 1164.8, 1132.0, 979.7, 837.Qcm-1. 20 Example 329 0 F N F I/ F N-N 238 WO 2004/050632 PCT/JP2003/014489 (E0329) T a suspension of E0258 (200mg) in toluene (4ml) was added thionylchloride (0.19ml) at room temperature. The reaction mixture was stirred at 10"C for 5 hours until the 5 mixture become clear solution. After then, the mixture was evaporated under reduced pressure. (become solid) THF was added, and then Me2NH (116mg) was added. The mixture was stirred for Ihour, and quenchedwith water, and extracted twice with EtOAc. The combined organic layer was washed 10 with sat.NaHCO3, waterandbrine, driedoverNa2SO4, filtered and evaporated under reduced pressure to give 45mg (21%) of E0329 as a powder. Filtrate (58mg). mp: 118-120"C 15 IR (film): 1650.8, 1608.3, 1511.9, 1469.5, 1240.0, 1159.0, 1133. 9cm-1. Example 330 F HN F IF N-N 20 (E0330) A mixture of E0328 (125mg) and Pd/C (100mg) in EtOH (10m) was stirred under H2 atmosphere for 3.0 hours. After filtration, a filtratewas evaporatedunderreducedpressure. The residue was dissolved in EtOH and filtered with syringe 25 driven filter, and evaporated to give 85mg of E0330. IR (KBr): 3342.0, 1670.0, 1511.9, 1240.0, 1160.9, 1130.1cm-1. 239 WO 2004/050632 PCT/JP2003/014489 Example 331 F F - F (E0331) 5 A mixture of E0138 (300mg) and MeSNa (72mg) in DMF (6ml) was heated at 70'C for 5 hours. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was separated andextracted withEtOAc. Thecombined organic layer was washed with water (twice) and brine, dried 10 over Na2SO4, filtered and evaporated. The residue was column chromatographed on silica gel to give 270mg (quant) of E0331. Example 332 SNF NF 15 (E0332) E0332 was prepared from E0141 in a similar manner to that of E0331. oil 20 Mass (ESI+) : 408 (M+H)+ 240 WO 2004/050632 PCT/JP2003/014489 200MHz 1H NMR (DMSO-d6, d) : 1. 73-1. 89 (2H, m) , 2. 03 (3H, s) , 2.40-2.52(2H, m), 2.62-2.70(2H, m), 3.88(3H, s), 6.92(1H, d, J=8.8 Hz), 7.18(1H, s), 7.24(4H, s), 7.76(1H, dd, J=8.8,2.7 Hz), 8.18(lH, d, J=2.7 Hz) 5 Example 333 SFF S IF F (E0333) This compound was obtained according to a similar manner 10 to that of E0331. Example 334 /) (E0334) 15 This compound was obtained according to a similar manner to that of E0331. Example 335 241 WO 2004/050632 PCT/JP2003/014489 F F F / N F N -0 (E0335) This compound was obtained according to a similar manner to that of E0331 5 Example 336 ,F F S-F N-0 (E0336) This compound was obtained according to a similar manner 10 to that of E0331. Example 337 F F / N F (E0337) 242 WO 2004/050632 PCT/JP2003/014489 A mixture of E0331 (250mg) and mcpba (165mg) in CH2C12 was stirred under ice-cooling for 1 hour, and then mcpba (55mg) was added. After stirring for 1 hour under ice cooling, the reaction mixture was partitioned between CHC13 5 and sat.NaHCO3. The organic layer was separated , washed with sat.NaHC03, waterandbrine, driedoverNa2SO4, filtered and evaporated under reduced pressure. The residue was column chromatographed on silica gel (Hex/EtOAc) to give 141mg (52%) of E0337. 10 IR (film): 1511.9, 1303.6, 1240.0, 1130.1cm-1. Oxide: FR267958 NMR (CDC13): 2.599(s, 3H), 2.85-3.21(m, 4H), 3.828(s, 3H), 6.721(s, 1H), 6.872(d,J=9.0Hz,2H), 7.141(s, 4H), 7.179(d,J=9.0Hz, 2H). 15 MS: (M+Na)+ 431.1 (M110092-2) Example 338 F F FF (E0338) 20 This compound was obtained according to a similar manner to that of E0337. IR (film): 1511.9, 1469.5, 1311.4, 1282.4, 1236.2, 1126.2, 973.9, 823.5, 759.8 cm-1. 25 Example 339 243 WO 2004/050632 PCT/JP2003/014489 F F 0F N F (E0339) This compound was obtained according to a similar manner to that of E0337. 5 IR (film): 1511.9, 1469.5, 1311.4, 1282.4, 1236.2, 1128.2, 973.9, 823.5, 759.8cm-1. Example 340 F F \ F N 0 CIH -0 10 (E0340) This compound was obtained according to a similar manner to that of E0337. IR(film): 1673.9, 1616.1, 1498.4, 1477.2, 1467.6, 1390.4, 1307.5, 1290.1, 1240.0, 1160.9, 1132.0, 971.9, 756.0cm-1. 15 NMR (CDC13): 2.76-2.94(m, 4H), 3.927(s, 3H), 3.943(s, 3H), 6.728(s, 1H), 6.752(d, J=8.9Hz, 1H), 7.12-7.26(m, 4H), 7.46-7.59(m, 1H), 8.04-8.10(m, 1H). MASS (M+Na)+445.1 (FR267958-N) 20 Example 341 244 WO 2004/050632 PCT/JP2003/014489 F F F N (E0 341) To a solution of E0336 (450mg) in dichloromethane (45ml) was added MCPBA (306mg) at room temperature. After stirring 5 for 1 hour, the reaction mixture was washed with sat.NaHCO3 (twice) andwater, driedoverNa2SO4, filtered andevaporated under reduced pressure. The residue was column chromatographed on silica gel (50ml) to give 470mg of E0341 as an oil. 10 Example 342 N F N FF 0 N (E0342) E0342 was prepared in a similar manner to that of E0341. 15 white powder. mp. 92-93'C IR (KBr) : 3080, 2952, 1612, 1566, 1547, 1529, 1500cm-1 Mass (ESI+) : 424 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.87-2.00(2H, i), 2.51(3H, s), 20 2. 56-2.78 (4H, m) , 3. 88 (3H, s) , 6. 92 (1H, d, J=8. 9 Hz) , 7.19 (1H, s), 7.21-7.31(4H, m), 7.76(1H, dd, J=2.7,8.9 Hz), 8.19(1H, 245 WO 2004/050632 PCT/JP2003/014489 d, J=2.7 Hz) Example 343 0 'F F 0/ F -o 5 (E0343) To a solution of E0336 (450mg) in dichloromethane (45ml) was addedMCPBA (306mg) at room temperature. After stirring for 1 hour, the reaction mixture was washed with sat.NaHCO3 (twice) andwater, driedoverNa2SO4, filteredandevaporated 10 under reduced pressure. The residue was column chromatographed on silica gel (50ml) and recrystalized from EtOH to give 168mg (44%) of E0343. Example 344 N F 15 N (E0344) 3-Chloroperoxybenzoic acid (407mg) was added to a solution of E0342 (666.3mg) in CH2Cl2 6ml under ice bath cooling. The reaction mixture was stirred at ambient temperature for 20 lhour. The mixture was diluted with CHCl3, washed with 1M 246 WO 2004/050632 PCT/JP2003/014489 NaOH, 5% aqueous sodium thiosulfate solution, and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from AcOEt-n-hexane to give E0344 (565.2mg) 5 as a white powder. mp. 121-122'C IR (KBr) : 3120, 2954, 1707, 1693, 1647, 1612, 1566, 1547, 1529, 1500cm-1 Mass (ESI+) : 440 (M+H)+ 10 200MHz 1H NMR (DMSO-d6, d) : 1. 93-2. 06 (2H, m) , 2. 67-2.75 (2H, m), 2.96(3H, s), 3.04-3.13(2H, m), 3.88(3H, s), 6.92(1H, d, J=8.8 Hz), 7.19(lH, s), 7.19-7.31(4H, m), 7.76(1H, dd, J=8.8,2.8 Hz), 8.19(1H, d, J=2.8 Hz) 15 Example 345 <f N NH, O N (E0345) Oxalylchloride 286mg was added to a suspension of E0363 (0.43g) in CH2Cl2 3ml under ice bath cooling. DMF drop was 20 added and the mixture was stirred at same temperature for hour, and then concentrated in vacuo. To the residue, was added toluene and concentrated in vacuo. The residue was dissolved in THF 5ml and was added to a solution of aqueous ammoniumhydroxide solution 5ml with under ice bath cooling. 25 The mixture was stirred at same temperature for hour, 247 WO 2004/050632 PCT/JP2003/014489 diluted with AcOEt, washed successively with 1M HCl, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue 5 was purified by silica gel column chromatography eluted with AcOEt / n-hexane= 60%. The pure fraction was collected and concentrated in vacuo and the residue was crystallized from diisopropylether to give E0345 (287.8mg) as a white powder. Mass (ESI+) : 381 (M+H)+ 10 200MHz 1H NMR (DMSO-d6, d) : 1.97(3H, s), 2.89(2H, t, J=6.8 Hz), 3.87 (3H, s), 4.21 (2H, t, J=6.8 Hz), 6.91(1H, d, J=8.8 Hz), 6.98 (1H, s), 7.22(2H, d, J=8.4 Hz), 7.28(2H, d, J=8.4 Hz), 7.38(1H, brs), 7.63-7.75(1H, brs), 7.72(lH, dd, J=2.7,8.8 Hz), 8.16(1H, d, J=2.7 Hz) 15 Example 346 HO (E034 6) A mixture of E0109 (449.1mg) and sodium methoxide 238mg 20 in formamide 5ml was heated at 70*C for 5hours. The mixture was allowed to cool to ambient temperature, and was partitionedbetween ethyl acetate andH20. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. 25 The residue was purified by silica gel column chromatography eluted with CHCl3, then MeOH / CHCl3 = 2%, 5% to give E0346 (235.7mg) as a white powder. Mass (ESI+) : 338(M+H)+ 248 WO 2004/050632 PCT/JP2003/014489 400MHz 1H NMR (DMSO-d6, d) : 2.70(2H, t, J=6.9 Hz), 3.56-3.62 (2H, m) , 3.79(3H, s), 4.65(1H, t, J=5.1Hz), 6.92 (lH, s), 6.99(2H, d, J=8.9 Hz), 7.15(2H, d, J=8.3 Hz), 7.20(2H, d, J=8.3 Hz), 7.27(2H, d, J=8.9 Hz), 7.33(1H, s), 7.64 (1H, 5 s) Example 347 HO-O NH, N O -_/ 0 N (E0347) 10 E0347 was prepared in a similar manner to that of E0346. white powder Mass (ESI+) : 454 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.65-3.73(2H, m), 3.78(3H, s), 3.94-4.00 (2H, m) , 4.86(1H, t, J=5.5Hz), 6.88 (1H, s), 6.91 (2H, 15 d, J=8.8 Hz), 6.99(2H, d, J=8.9 Hz), 7.16(2H, d, J=8.8 Hz), 7.26(2H, d, J=8.9 Hz), 7.32(lH, s), 7.63(1H, s) Example 348 HOO

NH

2 N 0 N 20 (E0348) E0348 was prepared in a similar manner to that of E0346. 249 WO 2004/050632 PCT/JP2003/014489 white powder Mass (ESI+) : 355 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.65-3.74(2H, m), 3.87 (3H, s), 3.96-4.05(2H, m), 4.87(1H, t, J=5.5 Hz), 6.88-6.97(4H, m), 5 7.20(2H, d, J=8.7 Hz), 7.37(lH, brs), 7.67-7.73(lH, brs, overlapping), 7.71(1H, dd, J=2.6,8.8 Hz), 8.16(lH, d, J=2.6 Hz) Example 349 N HI 0 10 N NH, (E0349) E0349 was prepared in a similar manner to that of E0346. white powder Mass (ESI+) : 453 (M+H)+ 15 400MHz 1HNMR (DMSO-d6, d) : 1.37(9H, s), 3.24-3.29(2H, m), 3.78(3H, s), 3.94(2H, t, J=5.8 Hz), 6.88(lH, s), 6.90(2H, d, J=8.8 Hz), 6.99(2H, d, J=9.0 Hz), 6.97-7.00(lH, br), 7.16(2H, d, J=8.8 Hz), 7.25 (2H, d, J=9.0 Hz), 7.32 (lH, brs), 7.62(1H, brs) 20 Example 350 250 WO 2004/050632 PCT/JP2003/014489 00 NH O 7 N N NH 2 (E0350) E0350 was prepared in a similar manner to that of E0346. white powder 5 Mass (ESI+) : 454 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.37 (9H, s), 3.22-3.33(2H, m), 3.88(3H, s), 3.93-3.99(2H, m), 6.88-7.10(4H, m), 6.91(1H, s), 7.20(2H, d, J=8.7 Hz), 7.36(lH, brs), 7.68(1H, brs), 7.71(1H, dd, J=2.7,8.8 Hz), 8.16(1H, d, J=2.7 Hz) 10 Example 351 0 F N F 0 (E0351) E0351 was prepared in a similar manner to that of E0346. 15 mp. 168-169-C IR (KBr) : 3381, 3192, 1705, 1695, 1674, 1643, 1614, 1564, 1549, 1516cm-1 Mass (ESI+) : 392 (M+H)+ 400MHz 1H NMR (DMSO-d6, d) : 3. 79 (3H, s) , 4. 43 (2H, s) , 6. 93 (2H, 251 WO 2004/050632 PCT/JP2003/014489 d, J=8.9 Hz), 7.00(2H, d, J=9.0 Hz), 7.08 (1H, s), 7.21(2H, d, J=8.9 Hz), 7.28 (2H, d, J=9.0 Hz), 7.40 (1H, brs), 7.54 (1H, brs) 5 Example 352 HO 0N (E0352) A mixture of E0346 (433.5mg) and N,N-dimethylacetamide dimethyl acetal 856mg in toluene 5ml was heated at 100C 10 for 40minutes. The reactionmixture was concentrated invacuo. To the residue was added toluene and concentrated in vacuo. The residue was dissolved in toluene 5ml, hydroxylamine hydrochloride 893mg and AcOH 3ml was added and the mixture was heated at 1000C for hour. The mixture was cooled to 15 ambient temperature, and partitioned between AcOEt and H20, The organic layer was washed with H20, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica 20 gel column chromatography eluted with AcOEt / n-hexane = 40%, 60%, 80%. The pure fraction was collected and concentrated in vacuo. The residue was crystallized from AcOEt / n-hexane to give E0352 (203mg) as a white powder. mp. 148-150'C 25 IR (KBr) : 3431, 3425, 3406, 1614, 1547, 1510cm-1 Mass (ESI+) : 377 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.44(3H, s), 2.72 (2H, t, J=6.9 252 WO 2004/050632 PCT/JP2003/014489 Hz), 3.55-3.65(2H, m) , 3. 80 (3H, s), 4.66(1H, t, J=5.1 Hz), 7.02(2H, d, J=8.9 Hz), 7.20 (2H, d, J=9.0 Hz), 7.24(2H, d, J=9.0 Hz), 7.28-7.36(3H, m) 5 Example 353 0 NN (E0353) E0353 was prepared in a similar manner to that of E0352. oil 10 Mass (ESI+) : 435 (M+H)+ 200MHz1HNMR (DMSO-d6, d) : 2.03 (3H, s), 2.44 (3H, s), 3.80 (3H, s), 4.17-4.22(2H, m), 4.25-4.35(2H, m), 6.97 (2H, d, J=8.7 Hz), 7.02 (2H, d, J=9.0 Hz), 7.23 (2H, d, J=8.7 Hz), 7.27 (1H, s), 7.31(2H, d, J=9.0 Hz) 15 Example 354 00 'N N NHz! (E0354) Acetic anhydride 124mg was added to a solution of E0346 20 (102.6mg) and pyridine 241mg in CH2Cl2 1ml. The reaction 253 WO 2004/050632 PCT/JP2003/014489 mixture was stirred at ambient temperature for hour. Acetic anhydride 62mg and pyridine 1ml was added and stirred at ambient overnight. Acetic anhydride 62mg was added and stirred at ambient for 4hours. The mixture was concentrated 5 in vacuo, and the residue was partitioned between ethyl acetate and 1M HCl. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residual solid was 10 collected and washed with diisopropyl ether to give E0354 (76.3mg) as a white powder. Mass (ESI+) : 380 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.96(3H, s), 2.87(2H, t, J=6.8 Hz), 3.78 (3H, s), 4.20 (2H, t, J=6.8 Hz), 6.94 (1H, s), 6.98 (2H, 15 d, J=8.9 Hz), 7.15-7.30(6H, m), 7.33(lH, s), 7.64(lH, s) Example 355 0 00 0 N N O (E0355) 20 E0355 was prepared in a similar manner to that of E0354. white powder Mass (ESI+) : 397 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.03(3H, s), 3.87(3H, s), 4.16-4.21(2H, m), 4.29-4.34(2H, m), 6.88-6.98(4H, m), 25 7.21(2H, d, J=8.7 Hz), 7.37(1H, brs), 7.68-7.70(1H, 254 WO 2004/050632 PCT/JP2003/014489 brs,overlapping), 7.71(1H, dd, J=2.7,8.8 Hz), 8.16(1H, d, J=2.7 Hz) Example 356 0 r N ~~N N 0 (E0356) Phosphorus oxychloride 40.4mg was added to DMF 0.5ml under ice bath cooling. After stirring at same temperature for 5minutes, E0354 (50mg) was added in one portion. The reaction 10 mixture was stirred at same temperature for lhour, and quenched by adding aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with H20, saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated 15 in vacuo to give E0356 (45.0mg) as an oil. Mass (ESI+) : 403 (M+CH3CN+H)+ Mass (API-ES positive) 362 (M+H)+ , 384 (M+Na)+ 200MHz 1H NMR (DMSO-d6, d) :1.96(3H, s), 2.88(2H, t, J=6.8 Hz), 3.79(3H, s), 4.20(2H, t, J=6.8 Hz), 7.00(2H, d, J=8.9 20 Hz), 7.15-7.31(6H, m), 7.36(lH, s) Example 357 255 WO 2004/050632 PCT/JP2003/014489 0 N 0N (E0357) E0357 was prepared in a similar manner to that of E0356. oil 5 Mass (ESI+) 378 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.02(3H, s), 3.79(3H, s), 4.15-4.21(2H, m), 4.29-4.34(2H, m), 6.93-7.04(4H, m), 7.18(2H, d, J=8.8 Hz), 7.24-7.31(3H, m) 10 Example 358 0 0 N (E0358) E0358 was prepared in a similar manner to that of E0356. oil 15 Mass (ESI+) : 379 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.02(3H, s), 3.88(3H, s), 4.17-4.21(2H, m), 4.29-4.34(2H, m), 6.90-7.03(3H, m), 7.22(2H, d, J=8.8 Hz), 7.36(1H, s), 7.74(1H, dd, J=2.7,8.9 Hz), 8.20(lH, d, J=2.7 Hz) 20 256 WO 2004/050632 PCT/JP2003/014489 Example 359 ON 0 (E0359) E0359 was prepared in a similar manner to that of E0356. 5 amorphous powder Mass (EST+) : 435 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) :1.37 (9H, s) , 3.22-3.32 (2H, m), 3.79(3H, s), 3.92-3.98(2H, m), 6.90-7.08(1H, br,overlapping), 6.92(2H, d, J=8.8 Hz), 7.00(2H, d, J=9.0 10 Hz), 7.16(2H, d, J=8.8 Hz), 7.28(2H, d, J=9.0 Hz), 7.30(1H, s) Example 360 NN o/ N 0 N- 15 (E0360) E0360 was prepared in a similar manner to that of E0356. 257 WO 2004/050632 PCT/JP2003/014489 white powder Mass (ESI+) : 436 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.37(9H, s), 3.22-3.32(2H, m), 3.88 (3H, s), 3.93-3.99(2H, m), 6.90-7.01(1H, overlapping), 5 6.92 (lH, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 7.21(2H, d, J=8.8 Hz), 7.34(1H, s), 7.73(1H, d, J=2.7,8.8 Hz), 8.20(1H, d, J=2.7 Hz) Example 361 NN 0< N 10 (E0361) E0361 was prepared from E0345 in a similar manner to that of E0356. oil 15 Mass (ESI+) : 363 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) 1.96(3H, s), 2.89(2H, t, J=6.8 Hz), 3.88 (3H, s), 4.21(2H, t, J=6.8 Hz), 6.92(1H, d, J=8.8 Hz), 7.22 (2H, d, J=8.3 Hz), 7.30(2H, d, J=8.3 Hz), 7.41(1H, s), 7.75(1H, dd, J=8.8,2.7 20 Hz), 8.20(1H, d, J=2.7 Hz) Example 362 258 WO 2004/050632 PCT/JP2003/014489 0 Y 0 N N OH (E03 62) A solution of acetyl chloride 0. 28ml in was added to a solution of E0261 (441.6mg) in CH2Cl2 4ml and pyridine 2ml under ice 5 bath cooling. The reaction mixture was stirred at ambient temperature for Ihour. Acetyl chloride 0. 14ml was added and stirred at ambient temperature for hour. The reaction was quenched by adding aqueous sodium'bicarbonate solution and the mixture was stirred at ambient temperature overnight. 10 The mixture was acidified to pH 2 by 6M HCl and extracted with ethyl acetate. The organic layer was washed with H20 and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was crystallized from diisopropyl ether to give E0362 15 (405.3mg) as a white powder. Mass (ESI+) : 381(M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.96(3H, s), 2.87 (2H, t, J=6.8 Hz), 3.79(3H, s), 4.20(2H, t, J=6.8 Hz), 6.96-7.02(3H, m), 7.15-7.27(6H, m), 12.91(lH, br) 20 Example 363 259 WO 2004/050632 PCT/JP2003/014489 0

NN

N NOH (E0363) E0363 was prepared in a similar manner to that of E0362. oil 5 Mass (ESI+) : 382 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.04(3H, s), 2.94(2H, t, J=7.0 Hz), 3.95(3H, s), 4.29(2H, t, J=7.0 Hz), 6.76(1H, d, J=8.8 Hz), 7.08 (lH, s), 7.04-7.35(4H, m), 7.59(1H, dd, J=2.7,8.8 Hz), 8.12(lH, d, J=2.7 Hz) 10 Example 364 0 (E0364) Oxalyl chloride 264mg was added to a suspension of E0362 15 (395mg) in CH2Cl2 5ml under ice bath cooling. DMF drop was added and the mixture was stirred at ambient temperature for hour. The mixture was concentrated in vacuo. To the residue was added toluene, and concentrated in vacuo. The residue was 260 WO 2004/050632 PCT/JP2003/014489 dissolved in CH2C12 30ml, cooled in an ice bath, N,0-dimethylhydroxylamine hydrochloride 203mg and triethylamine 525mg were added and the mixture was stirred at ambient temperature overnight. The mixture was diluted 5 with AcOEt, washed successively with 1M HCl, aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with CHCl3, then AcOEt / CHCl3= 10%, 10 20% to give E0364 (418.4mg) as an oil. Mass (ESI+) : 424 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.97 (3H, s), 2.88(2H, t, J=6.8 Hz), 3.38 (3H, s), 3.77 (3H, s), 3.78 (3H, s), 4.20 (2H, t, J=6.8 Hz), 6.94-7.03(3H, m), 7.16-7.27(6H, m) 15 Example 365 0 O N

N

(E0365) E0365 was prepared fromE0363 andN, 0-dimethylhydroxylamine 20 hydrochloride in a similar manner to that of E0364. oil Mass (ESI+) : 425 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.97(3H, s), 2.89(2H, t, J=6.8 Hz), 3 .37 (3H, s), 3.77 (3H, s), 3.88 (3H, s) , 4.21(2H, t, J=6.8 25 Hz), 6.91(1H, d, J=8.8 Hz), 6.98(1H, s), 7.20-7.33(4H, m), 7.70(1H, dd, J=2.8,8.8 Hz), 8.15(1H, d, J=2.8 Hz) 261 WO 2004/050632 PCT/JP2003/014489 Example 366 HO N (E0366) 5 To a solution of 1. O phenylmagnesium bromide in THF 3. 4ml was added a solution of E0364 (106.5mg) in THF 2ml under ice bath cooling. After stirring at same temperature for hour, themixturewaspouredintosat.aqNH4Cl, andextracted with AcOEt. The organic layer was washed with saturated 10 aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / n-hexane = 30%, 40%, 50% to give E0366 (107mg )as an oil. IR (neat) 3469, 3435, 3425, 3406, 3398, 3369, 2937, 1647, 15 1606, 1512cm-1 Mass (ESI+) : 399 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.72(2H, t, J=6.9 Hz), 3 .56- 3 .66( 2 H,m),3.80(3H,s),4.65(1H,t,J=5.1Hz),7.02(2H, d, J=8.9 Hz), 7.20(1H, s), 7.22(4H, s), 7.34 (2H, d, J=8.9 20 Hz), 7.52-7.68(3H, m), 8.25(2H, d, J=8.5 Hz) Example 367 262 WO 2004/050632 PCT/JP2003/014489 HOO N 0 0 (E0367) E0367 was prepared in a similar manner to that of E0366. white powder 5 mp. 95-96'C IR (KBr) : 3498, 3476, 2966, 1678, 1649, 1612, 1547, 1512cm-1 Mass (ESI+) 381 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.15(6H, d, J=6.8 Hz), 3.61-3.75(3H, m), 3.79(3H, s), 3.95-4.00(2H, m), 4.87(1H, io t, J=5.3 Hz), 6.91(2H, d, J=8.7 Hz), 6.98(1H, s), 7.00(2H, d, J=8.9 Hz), 7.17 (2H, d, J=8.7 Hz), 7.28 (2H, d, J=8.9 Hz) Example 368 HOO 0 N 15 (E0368) E0368 was prepared in a similar manner to that of E0366. white powder mp.132-133 0 C IR (KBr) : 3390, 3334, 3288, 1707, 1670, 1612, 1564, 1549, 20 1512cm-1 263 WO 2004/050632 PCT/JP2003/014489 Mass (ESI+) : 379 (M+H)+ 200MHz 1HNMR (DMSO-d6, d) : 1.04(4H, d, J=6.2 Hz), 3.03(1H, m), 3.65-3.73(2H, m), 3.80(3H, s), 3.95-4.00(2H,m), 4.87(1H, t, J=5.4 Hz), 6.92(2H, d, J=8.7 Hz), 6.96(1H, s), 7.01(2H, 5 d, J=8.9 Hz), 7.18 (2H, d, J=8.7 Hz), 7.31(2H, d, J=8.9 Hz) Example 369 HO O N (E0369) 10 E0369 was prepared in a similar manner to that of E0366. white powder mp. 108-109,C IR (KBr) :3440, 2966, 1678, 1610, 1566, 1549, 1533, 1502cm-1 Mass (ESI+) : 382 (M+H)+ 15 200MHz 1H NMR (DMSO-d6, d) : 1.16(6H, d, J=6.9 Hz), 3.64-3.74 (3H, m), 3.88(3H, s), 3.96-4.02(2H, m), 4.87(1H, t, J=5.4 Hz), 6.93(1H, d, J=8.9 Hz), 6.94 (2H, d, J=8.7 Hz), 7.02 (1H, s), 7.21 (2H, d, J=8.7 Hz), 7.74 (1H, dd, J=2.7,8.9 Hz), 8.18 (1H, d, J=2.7 Hz) 20 Example 370 264 WO 2004/050632 PCT/JP2003/014489 HOO ONNN (E0370) E0370 was prepared in a similar manner to that of E0368. white powder 5 mp. 104-106'C IR (KBr) : 3367, 2947, 1668, 1610, 1566, 1549, 1531cm-1 Mass (ESI+) : 380 (M+H)+ 2500MHz 1HNMR (DMSO-d6, d) :1.05(4H, d, J=6.2 Hz), 3.04(1H, m), 3.65-3.73(2H, m), 3.89(3H, s), 3.96-4.02(2H, m), 4.87(1H, 10 t, J=5.4 Hz), 6.93(1H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 7.06(1H, s), 7.22 (2H, d, J=8.8 Hz), 7.76 (1H, dd, J=2. 6, 8.8 Hz), 8.21(1H, d, J=2.6 Hz) Example 371 15o (E0371) E0371 was prepared in a similar manner to that of E0366. white powder Mass (ESI+) : 480 (M+H)+ 20 200MHz 1H NMR (DMSO-d6, d) : 1.15(6H, d, J=6.9 Hz), 1.37(9H, 265 WO 2004/050632 PCT/JP2003/014489 s), 3.25-3.33(2H,m), 3.68(1H,m), 3.79(3H, s), 3.91-3.98 (2H, m), 6.90(2H, d, J=8.7 Hz), 6.90-7.05(1H, overlapping), 6.97(1H, s), 7.00(2H, d, J=8.9 Hz), 7.17(2H, d, J=8.7 Hz), 7.28(2H, d, J=8.9 Hz) Example 372

-

0 N (E0372) E0372 was prepared in a similar manner to that of E0368. 10 white powder Mass (ESI+) : 477 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.04 (4H, d, J=6. 2 Hz), 1.37 (9H, s), 3.04(1H, m), 3.22-3.33(2H, m), 3.80(3H, s), 3.95(2H, t, J=5.7 Hz), 6.88-7.03(1H, overlapping), 6.91(2H, d, J=8.7 15 Hz), 6.97(1H, s), 7.01(2H, d, J=8.9 Hz), 7.18 (2H, d, J=8.7 Hz), 7.31(2H, d, J=8.9 Hz) Example 373 N H NN 20 (E0373) 266 WO 2004/050632 PCT/JP2003/014489 E0373 was prepared in a similar manner to that of E0366. white powder Mass (ESI+) : 481 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.16(6H, d, J=6.9 Hz), 1.37(9H, 5 s), 3.22-3.32(2H, m), 3.68 (1H, m), 3.88(3H, s), 3.93-3.99(2H, m), 6.90-7.02(5H, m), 7.22 (2H, d, J=8.7 Hz), 7.73(lH, dd, J=2.7,8.8 Hz), 8.18(1H, d, J=2.7 Hz) Example 374 NN 100 10 N (E0374) E0374 was prepared in a similar manner to that of E0368. white powder Mass (ESI+) : 479 (M+H)+ 15 200MHz 1H NMR (DMSO-d6, d) : 1.05(4H, d, J=6.2 Hz), 1.37(9H, s) , 3. 04 (1H, m) , 3.23-3. 33 (2H, m) , 3.89 (3H, s) ,3. 93-3. 99 (2H, m), 6.89-7.08 (5H, m), 7.22(2H, d, J=8.7 Hz), 7.76(1H, dd, J=2.7,8.8 Hz), 8.21(1H, d, J=2.7 Hz) 20 Example 375 267 WO 2004/050632 PCT/JP2003/014489 0 (E0375) E0375 was prepared from E0364 in a similar manner to that of E0366. 5 oil IR (neat) : 3487, 3469, 3435, 3408, 3398, 3369, 2966, 2933, 1678, 1512cm-1 Mass (EST+) : 365 (M+H)+ 200MHz1HNMR (DMSO-d6, d) : 1.19(6H, d, J=7.9Hz), 2.70(2H, 10 t, J=6.9 Hz), 3.54-3.75(3H, m), 3.79(3H, s), 4.64(lH, t, J=5.1 Hz), 7.00(2H, d, J=8.9 Hz), 7.02(1H, s), 7.16(2H, d, J=8.6 Hz), 7.21(2H, d, J=8.6 Hz), 7.29(2H, d, J=8.9 Hz) Example 376 HO 15 (E0376) To a solution of 1.OM methylmagnesium bromide in diethyl ether 2.8ml was added a solution of E0364 (237.6mg) in THF 4ml dropwise under ice bath cooling. After stirring at same 20 temperature for 30minues the mixture was poured into 268 WO 2004/050632 PCT/JP2003/014489 sat.aqNH4Cl, and extracted with AcOEt. The organic layer was washed successively with a mixture of lMHCl and saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride 5 solution, dried over magnesium sulfate, and concentrated in vacuo.The residue was dissolved in THFlml, 1M NaOH 0.4ml was added and the mixture was stirred at ambient temperature for several hours. The mixture was neutralized with 1M HC1 0. 4ml, and partitioned between AcOEt and saturated aqueous 10 sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / n-hexane = 50% to give E0376 (139.1mg) as a white powder. 15 Mass (ESI+) : 337 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.54 (3H, s), 2.70(2H, t, J=6.9 Hz), 3.55-3.64(2H, m), 3.80(3H, s), 4.65(1H, t, J=5.1 Hz), 7.00(2H, d, J=8.9 Hz), 7.01(lH, s), 7.15 (2H, d, J=8.5 Hz), 7.21(2H, d, J=8.5 Hz), 7.29(2H, d, J=8.9 Hz) 20 Example 377 HO (E0377) E0377 was prepared in a similar manner to that of E0376. 25 oil Mass (ESI+) 366 (M+H)+ 269 WO 2004/050632 PCT/JP2003/014489 200MHz 1H NMR (DMSO-d6, d) : 1.16(6H, d, J=6.9 Hz), 2.72 (2H, t, J=6.9 Hz), 3.55-3.75(3H, m), 3.88(3H, s), 4.65(1H, t, J= 5.1Hz), 6.93 (1H, d, J=8.8 Hz), 7.05 (1H, s), 7.17-7.29 (4H, m), 7.76(1H, dd, J=8.8,2.7 Hz), 8.19(1H, d, J=2.7 Hz) 5 Example 378 HO N (E0378) E0378 was prepared in a similar manner to that of E0376. 10 oil 200MHz 1H NMR (DMSO-d6, d) : 2.73(2H, t, J=6.9 Hz), 3.57-3.66 (2H, m), 3.89 (3H, s) , 4. 66 (1H, t, J=5.0 Hz), 6.94 (lH, d, J=8.8 Hz), 7.23(1H, s), 7.15-7.35 (4H, m) , 7.52-7.72 (3H, m), 7.80(lH, dd, J=2.7,8.8 Hz), 8.23-8.32(3H, m) 15 Example 379 HO (E0379) E0379 was prepared in a similar manner to that of E0376. 270 WO 2004/050632 PCT/JP2003/014489 white powder Mass (ESI+) : 338 (M+H)+ 00MHz 1H NMR (DMSO-d6, d) : 2.55(3H, s), 2.71 (2H, t, J=6.9 Hz), 3.55-3.65(2H, m), 3.89(3H, s), 4.65(1H, t, J=5.1 Hz), 5 6.93(1H, d, J=8.8 Hz), 7.05(1H, s), 7.19(2H, d, J=8.6 Hz), 7.24(2H, d, J=8.6 Hz), 7.75(1H, dd, J=2.7,8.8 Hz), 8.19(1H, d, J=2.7 Hz) Example 380 HO 10 (E0380) A mixture of E0376 (127mg), 0-methylhydroxylamine hydrochloride 47.3mg and pyridine in EtOH 3ml was heated at 60 0 C for hour. The mixture was concentrated in vacuo 15 and the residue was purified by silica gel column chromatography eluted with AcOEt / n-hexane = 40%. The pure fractionwas collectedand concentrated in vacuo. The residue was crystallized from diisoprcpyl ether to give E0380 (103.2mg) as a white powder. 20 mp. 82-86'C IR (KBr) : 3359, 3269, 3246, 2939, 1549, 1512cm-1 Mass (ESI+) : 366(M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.20(3H, s), 2.70(2H, t, J=6.9 Hz), 3.54-3.65(2H, m), 3.78(3H, s), 3.92(3H, s), 4.65(1H, 25 t, J=5.0 Hz), 6.77(lH, s), 6.97(2H, d, J=8.9 Hz), 7.12-7.26(6H, m) 271 WO 2004/050632 PCT/JP2003/014489 Example 381 HO N 0O N O N (E0381) E0381 was prepared in a similar manner to that of E0380. 5 white powder mp.94-95 0 C IR (KBr) : 3469, 3433, 3423, 3404, 3400, 3371, 1647, 1549cm-1 Mass (ESI+) : 267(M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.20 (3H, s), 2.71 (2H, t, J=6.8 10 Hz), 3.55-3.65(2H, m), 3.87(3H, s), 3.92(3H, s), 4.65(1H, t, J=5.0 Hz), 6.81(1H, s), 6.90(1H, d, J=8.8 Hz), 7.18 (2H, d, J=8.7 Hz), 7.23(2H, d, J=8.7 Hz), 7.69(1H, dd, J=8.8,2.7 Hz), 8.11(1H, d, J=2.7 Hz) 15 Example 382

HN-

0F N F N_ F (E0382) 272 WO 2004/050632 PCT/JP2003/014489 To a solution of E0314 (100 mg) in methanol (21 ml) was added a solution of methyl amine in methanol (40%, 92 ml) . After stirring at room temperature overnight, the mixture was evaporated to give oil, which was purified with preparative 5 TLC (1 mm, 60% ethyl acetate / hexane) to give E0382 as an oil (97 mg, 100%). NMR(CDC13), 2.92 (3H, d, J=5.0 Hz), 3.83(3H, s), 4.49(2H, s), 6.69(1H, s), 6.82-6.91(4H, m), 7.14-7.24(4H, m). MS(ESI+); 428.2(M+Na). 10 IR(Neat, 20727-11), 1693.2cm-1. Example 383 H2N 0 F NF N F (E0383) 15 Trichloroacetyl isocyanate 62.4mg was added to a solution of E0118 100mg in CH2Cl2 2ml under ice bath cooling. After stirring at ambient temperature for 3hours, the reaction mixture was concentrated invacuo. The residue was dissolved in THF lml, MeOH lml, and H20 iml. Potassium carbonate 153mg 20 was added to the reaction mixture, and stirred at ambient temperature overnight. The reaction mixture was partitioned between AcOEt and H20. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residual 25 solid was recrystallized from AcOEt-n-hexane to give E0383 84.1mg as a white powder. mp. 169-170 0 C 273 WO 2004/050632 PCT/JP2003/014489 IR (KBr) : 3435, 3332, 3263, 3209, 1684, 1610, 1516cm-1 Mass (ESI+) : 406 (M+H)+ 400MHz 1H NMR (DMSO-d6, d) 2.84(2H, t, J=6.8 Hz), 3.79(3H, s), 4.10(2H, t, J=6.8 Hz), 6.30-6.70(2H, br), 7.00(2H, d, 5 J=9.0 Hz), 7.14 (1H, s), 7.21 (2H, d, J=8.4 Hz), 7.26(2H, d, J=8.4 Hz), 7.29(2H, d, J=9.0 Hz) Example 384 H2N)_ 0 F N F N F 10 (E0384) Trimethylsilyl isocyanate 42.7mg was added to a solution of E0158 98.2mg and triethylamine 30mg in CH2Cl2 Iml under ice bath cooling. The reaction mixture was stirred at same temperature for hour and concentrated in vacuo. The residue 15 was purified by preparative thin layer silica gel chromatography developedbyMeOH / CHCl3 = 10%. The separated silica gel was extracted with 10% MeOH/CHCl3, filtered, and the solvent was evaporated in vacuo.. The residue was crystallized from ethylacetate-diisopropyl ehter to give 20 E0384 (59.7mg) as a white powder. mp.157-158 C IR (KBr) : 3406, 3357, 3330, 3209, 1704, 1662, 1614, 1529, 1520cm-1 Mass (ESI+) : 405 (M+H)+ 25 200MHz 1H NMR (DMSO-d6, d) N006.067: 2.62-2.70(2H, m), 3.13-3.24(2H,m), 3.79(3H, s) , 5.42(2H, s), 5.93(1H, t, J=5.4 Hz), 7.00 (2H, d, J=8.8Hz), 7.12(lH, s), 7.21(4H, s), 7.29(2H, 274 WO 2004/050632 PCT/JP2003/014489 d, J=8.8 Hz) Example 385 F

H

2 N F N / ~-0 5 ( E0385) This compound was obtained according to a similar manner to that of E0384. IR (film): 3343.9, 1656.6, 1604.5, 1550.5, 1515.8, 1457.9, 1342.2, 1251.6, 1029.8 cm-1. 10 Example 386

NH

2 NH F F N ON F 0 (E0386) This compound was obtained according to a similar manner 15 to that of E0384. IR (film): 3345.9, 1654.6, 1604.5, 1556.3, 1513.9, 1465.6, 1240.0, 1160.9, 1132.0cm-1. 275 WO 2004/050632 PCT/JP2003/014489 Example 387 F F F N (E0387) This compound was obtained according to a similar manner 5 to that of E0384. IR (film): 3345.9, 1658.5, 1602.6, 1552.4, 1236.2, 1159.0, 1133. 9cm-1. Example 388 F F 0 H /N 10 (E0388) This compound was obtained according to a similar manner to that of E0384. IR(film) : 3345.9, 1658.5, 1602.6, 1552.4, 1517.7, 1236.2, 15 1159.0, 1133.9cm-l. Example 389 276 WO 2004/050632 PCT/JP2003/014489 'F F N F N N CIH ~~0 (E0389) A mixture of E0175 (150mg) and 6ml of 4N HC1/dioxane was stirred at room temperature. After 2 hours, the reaction 5 mixture was evaporated under reduced pressure to give 128mg (quant.). of E0389 as an oil. IR(film): 3403.7, 1513.9, 1467.6, 1241.9, 1162.9, 1130 - 1cm-1. 10 Example 390

H

2 N F CIH F N-N N O CIH (E0390) This compound was obtained according to a similar manner to that of E0389. 15 IR(film): 3428.8, 1662.34, 1612.2, 1500.4, 1461.8, 1390.4, 1292.1, 1166.7, 1087.7, 1029.8cm-1. Example 391 277 WO 2004/050632 PCT/JP2003/014489

H

2 N F Cid F N-N (E03 91) This compound was obtained according to a similar manner to that of E0389. 5 IR (film): 3403.74, 2965.98,1610.27, 1513.85, 1461.78, 1251.58, 1170.58, 1085.73, 1029.80, 836.955, 800.314 cm-1. Example 392 F F CIH N-N 10 (E0392) This compound was obtained according to a similar manner to that of E0389. IR (film): 3432.7, 1511.9, 1467.6, 1240.0, 1160.9, 1130.1cm-1. 15 Example 393 278 WO 2004/050632 PCT/JP2003/014489 0 F F N-N (E0393) A mixture of E0258 (100mg) and Pd/C (100mg) in EtOH (10m) was stirred under H2 atmosphere for 3.0 hours. After 5 filtration, a filtrate was evaporated under reducedpressure. The resudue was dissolved in EtOH and filtered with syringe driven filter, and evaporated to give 93mg (93%) of E0393. IR (film):3019.9, 1704.8, 1513.9, 1303.6, 1238.1, 1133. 9cm-1. 10 Example 394 0 F - N F F / F N-N (E0394) T a suspension of E0258 (200mg) in toluene (4ml) was added 15 thionylchloride (0.19ml) at room temperature. The reaction mixture was stirred at 1000C for 5 hours until the mixture become clear solution. After then, the mixture was evaporated under reduced pressure. (become solid) THF was added, and then aqueous MeNH2 (37%) was added. The 20 mixture was stirred for 1 hour, and quenched with water, and extracted twice with EtOAc. The combined organic layer was washed with sat.NaHCO3, water and brine, dried over 279 WO 2004/050632 PCT/JP2003/014489 Na2SO4, filtered and evaporated under reduced pressure to give 63mg (31%) of E0394 as a powder. mp: 155-157 0 C IR(film) 3297.7, 1662.3, 1617.9, 1513.9, 1236.2, 1162.9, 5 1133.9cm-1 Example 395 0 N 0< N F (E0395) 10 A suspension of E0399 (1.8 g) and potassium phtalimido (1.13 g) in N,N-dimethylformamide (6.6 ml) was stirred at 80'C for3hours. Themixturewasaddedwater (700ml) andextracted with a mixture of ethyl acetate and hexane (2:1) (x4). The combined organic layers were washed with aqueous sodium 15 hydroxide (lN) (x2) andbrine, dried over magnesium sulfate, and evaporated to give oil, which was purified with column chromatography (SiO2 100 ml, eluted with 30% ethyl acetate/hexane) to give oil (1.83g, 91.1%). Ethanol (15 ml) was added to the oil, then the mixture was stirred at room 20 temperature for 10 minutes. The precipitate was filtered, washed with ethanol (3 ml), and dried under reduced pressure to give E0395 as a white solid (1.16 g, 58%). NMR(CDCl3), 3.00(2H, t, J=7.6 Hz), 3.93(2H, t, J=7.6 Hz), 3.94 (3H, s), 6.73 (1H, s), 6.73 (1H, d, J=8.7 Hz), 7.13-7.26(4H, 280 WO 2004/050632 PCT/JP2003/014489 m), 7 .49(1H, dd, J=8 .7, 2.5 Hz), 7.70-7.86(4H, m), 8.10(1H, d, J=2.5 Hz). MS (ESI+), 515 (M+Na). 5 Example 396 CIH F o F NF (E0396) 6M HCl 0.045ml was added to a solution of E0168 (101.5mg) in AcOEt 1ml and EtOH Iml. The mixture was concentrated 10 and dried in vacuo to give E0396 (94.8mg) as an amorphous powder. IR (neat) : 3433, 3020, 2956, 1668, 1658, 1612, 1572, 1543, 1500cm-1 Mass (ESI+) : 377 (M+H)+ 15 200MHz1HNMR (DMSO-d6, d) :1.76-1.92(2H, m), 2.52-2.81(4H, m), 3

.

8 8

(

3 H,s),6.93( H,d,J=8.9Hz),7.19(lH,s),7.26(4H, s), 7.76(1H, dd, J=8.9,2.7 Hz), 8.19(1H, d, J=2.7 Hz) Example 397 F F 0 / N 20 -0 281 WO 2004/050632 PCT/JP2003/014489 (E0397) To a mixture of P0002 (5.0g) and CF3COOEt (3.5ml) in DMF (30ml) was added NaH (1.lg) under ice-cooling. The reaction mixture was allowed to warm to room temperature, and stirred 5 under 40oC for 1 hour. The reaction mixture was extracted twice with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue, sodium acetate ( 2 .23g) and 4-methoxyphenylhydrazine (3.96g) in acetic acid (20ml) was 10 stirred at room temperature for 15 hours. The mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water (twice), sat.NaHCO3, water and brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was column chromatographed 15 on silica gel ( Hex/EtOAc = 8:1-4:1) to give 2.58g (36%) of E0397 as an oil. Example 398 00 N F F N F 20 (E0398) To a solution of E0312 (326.7 mg) in ethyl acetate (3 ml) was added methanesulfonyl chloride (86.9 ml) and triethylamine (0.181 ml) at 00C. After stirring for 40 minutes at 0CC, the mixture was quenched with water and 25 extracted with ethyl acetate (x3). The combined organic layers were washed with water and brine, dried over sodium 282 WO 2004/050632 PCT/JP2003/014489 sulfate, and evaporated under reduced pressure to give E0398 as an oil (351.3 mg, 89%). NMR(CDCl3); 3.09(3H, s), 3.82(3H, s), 4.22-4.26(2H, m), 4.52-4.59 (2H, m), 6.68 (1H, s) , 6.75 (2H, d, J=8.7 Hz) , 6.87 (2H, 5 d, J=8.9 Hz), 7.16(2H, d, J=8.7 Hz), 7.22 (2H, d, J=8.9 Hz). Example 399 0 0 N (E0399) 10 This compound was obtained according to a similar manner to that of E0398 as a pale yellow oil (1.82 g, 98.6%). NMR(CDCl3), 2.91(3H, s), 3.07(2H, t, J=6.8 Hz), 3.94(3H, s), 4.43(2H, t, J=6.8 Hz), 6.75(1H, s), 6.78(lH, d, J=8.2 Hz), 7.17-7.26(4H, m), 7.58 (1H, dd, J=9.0, 2. 9 Hz) , 8.05(1H, 15 d, J=2.8 Hz). MS(EST+), 442.1(MH+), 464.0(M+Na). Example 400 F N F ON F 0 20 (E0400) A suspension of E0398 (351.3 mg) and sodium thiomethoxide 283 WO 2004/050632 PCT/JP2003/014489 (162mg) in N,N-dimethylformamide (3ml) was stirred at 60'C for 3.5 hours. The mixture was quenched with water and extracted with ethyl acetate (x3). The combined organic layerswerewashedwithwaterandbrine, dried overmagnesium 5 sulfate, and evaporated to give oil. The oil was purified with column chromatography (SiO2 50 ml, eluted with 10% ethyl acetate / hexane) to give E0400 as an oil (236.7 mg, 75.3%) . NMR(CDCl3); 2.24(3H, s), 2.88(2H, t, J=6.6 Hz), 3.82(3H, s), 4.15(2H, t, J=6.6 Hz), 6.67(lH, s), 6.83(2H, d, J=8.8 10 Hz), 6.88 (2H, d, J=9.0 Hz), 7.13 (2H, d, J=8.8 Hz), 7.23 (2H, d, J=9.0 Hz). MS(ESI+);431(M+Na). Example 401 0 0 F NF N F 15 (E0401) To a solution of E0400 (103.5 mg) in dichloromethane (1 ml) was added m-chloroperbenzoic acid (134 mg) at room temperature. After stirring at room temperature for 1 hour, 20 the mixture was added saturated sodium hydrogen sulfate aqueous solution (0.5 ml) and sodium thiosulfate pentahydrate (100 mg), and stirred for 30 minutes at room temperature. The mixture was filtered by Chemelut 1001 (Varian) and evaporated to give oil, which was purified 25 with preparative TLC (1 mm, 50% ethyl acetate/hexane) to give E0401 as an amorphous (105.9 mg, 94.9%). 284 WO 2004/050632 PCT/JP2003/014489 NMR(CDCl3);3.07(3H, s), 3.45(2H, t, J=5.3 Hz), 4.44(2H, t, J=5.3 Hz), 3.83(3H, s), 6.69(1H, s), 6.69-6.90(4H, m), 7.15-7.26(4H, M). MS(ESI+); 463.1 (M+Na)+. IR(KBr, 20727-8), 1612.2, 5 1515.8cm-1. Example 402 00 F N F (E0402) 10 To a solution of E0400 (104.8 mg) in dichloromethane (1 ml) was added m-chloroperbenzoic acid (44.7 mg) at 0 0 C, and the mixture was stirred at 0 0 C for 1 hour. Then m-chloroperbenzoic acid (35 mg) was added to the mixture. AfterstirringatO 0 Cfor30minutes, themixture was quenched 15 with saturated sodiumhydrogen sulfate aqueous solution (0.5 ml) andsodiumthiosulfatepentahydrate (100mg), andstirred for 30 minutes at room temperature. The mixture was filtered by Chemelut 1001 (Varian) and evaporated to give oil, which was purified with preparative TLC (1 mm, ethyl acetate) to 20 give 2 fractions of E0401 (TLC upper) as an amorphous (40.7 mg, 37.4%) and E0402 (TLC lower) as a powder (60 mg, 55%). NMR(CDC13); 2.70(3H, s), 2.99-3.27(2H, m), 3.83(3H, s), 4.40-4.46(2H, m), 6.68(lH, s), 6.84-6.90(4H, m), 7.15(2H, d, J=8.7 Hz), 7.22(2H, d, J=9.0 Hz). 25 MS(ESI+); 447.1 (M+Na). 285 WO 2004/050632 PCT/JP2003/014489 TR(KBr); 1612.2, 1513.9cm-1. Example 403 0 N F F 5 (E0403) To a solution of E0286 (500 mg) in dichloromethane (1.5 ml) was added successively anisol (0.5 ml) and triflutoroacetic acid (1 ml) . After stirring at room temperature for 2 hours, the mixture was quenched with saturated sodium hydrogen 10 carbonate aqueous solution and extracted with ethyl acetate (x3) . The organic layers were dried over magnesium sulfate and evaporated to give oil, which was purified with column chromatography (SiO2 50 ml, eluted with ethyl acetate) to give E0403 as an oil (302.5 mg, 94.2%). 15 NMR(CDCl3), 3.77(3H, s), 3.80(3H, s), 3.80-3.87(lH, m), 4.21-4.28(2H, m), 6.67(lH, s), 6.80-6.89(4H, m), 7.13(2H, d, J=8.7 Hz), 7.22(2H, d, J=8.9 Hz). MS(ESI+), 436.1(MH+). 20 Example 404 286 WO 2004/050632 PCT/JP2003/014489 0 F N F (E0404) Solution ofE0403 (104.6mg) inmethanol (3 ml) and sodium hydroxide aqueous solution (lN, 2 ml) was stirred at room 5 temperature for 3 hours. The mixture was evaporated, and methanol was added to the residue and evaporated to give white powder, which was purified with preparative TLC (1 mm, 20%methanol/chloroform) to give E0404 as a powder (29.9 mg, 29.5%). 10 NMR (DMSO-d6), 3.50-3.54 (1H, m), 3.79 (3H, s), 4.13-4.30 (2H, m), 6.91-7.07(5H, m), 7.21(2H, d, J=8.7 Hz), 7.27(2H, d, J=8.9 Hz). MS(EST-) .420.4(M-H). IR(KBr), 1641, 1616cm-1. 15 Example 405 f F N F 0 28 287 WO 2004/050632 PCT/JP2003/014489 (E0405) To a solution of E0403 (106.6 mg) in methanol (2 ml) was added concentrated ammonia solution (1 ml) . After stirring at room temperature overnight, the mixture was evaporated 5 to give solid, which was purified with preparative TLC (1 mm, 20%methanol/chloroform) to give E0405 as a solid (58.2 mg, 56.5%). NMR(CDCl3), 3.75-3.82(1H, m), 3.82(3H, s), 4.15-4.29(2H, m), 6.67 (1H, s), ~6.83-6.91(4H, m), 7.14 (2H, d, J=6.7 Hz), 10 7.22(2H, d, J=9.0 Hz). MS(ESI+).421.4(MH+), 462.4(MHMeCN)+. IR(KBr), 1658 cm-1. Example 406 HN O F -N F CIH 15 (E0406) To a solution of E0403 (87.5 mg) in tetrahydrofuran (1 ml) was added lithium aluminum hydride (30.5 mg) at room temperature. After stirring'at room temperature for 2 hours, 20 themixturewas quenchedwithwater (30ml), sodiumhydroxide aqueous solution (15%, 30 ml), and water (90 ml), and then stirred at roomtemperature for30minutes. Magnesiumsulfate and celite was added to the mixture, then the suspension was filtered and washed with tetrahydrofuran. 25 The filtrate was evaporated to give oil, which was purified 288 WO 2004/050632 PCT/JP2003/014489 with preparative TLC (0.5 mm, 20%methanol/chloroform) to give oil. To a solution of the oil in ethyl acetate was added a solution of hydrogen chloride in ethyl acetate (4N, 0.5 ml), and then 5 the mixture was evaporated to give E0406 as an oil (43.5 mg, 49%). NMR(CDCl3), 3.64-4.13(5H, m), 3.76(3H, s), 6.60(1H, s), 6.73-6.85(4H, m), 7.07(2H, d, J=8.5 Hz), 7.16(2H, d, J=8.9 Hz). 10 MS(ESI+) , 408.1(MH+) (Free) . IR(Neat, 20727-5), 1614.lcm-l. Example 407 NO 0 0 (E0407) 15 Toa suspension of sodiumhydride (34.8mg) interahydrofuran (2 ml) was added a solution of E0347 (208 mg) in tetrahydrof uran (1iml) at 00, and then the mixture was stirred at room temperature for 20 minutes. Then iodoinethane (54.2 ml) was added to the mixture. After stirring at room 20 temperature overnight, the mixture was quenched with water, extracted with ethyl acetate (x3) . The combined organic layers were washed with water (x3) and brine, dried over magnesium sulfate, and evaporated under reduced pressure to give oil, which was purified with preparative TLC (1 mam, 25 30% ethyl acetate/hexane) to give E0407 as an oil (160 mg, 289 WO 2004/050632 PCT/JP2003/014489 74.7%) . NMR (CDCl3) , 1. 45 (9H, s) , 2. 97 (3H, s) , 3. 59 (2H, t, J=5. 5 Hz), 3.82(3H, s), 4.0-4.15(2H, m), 6.67(1H, s), 6.80-6.91(4H, m), 7.13(2H, d, J=8.8 Hz), 7.23(2H, d, J=9.0 Hz). 5 MS(ESI+).514.2(M+Na). Example 408 0 00 NNHN (E0408) 10 AcC1 0.31ml was added to a suspension of E0347 (1.29g) and Et3N0.66mlinCH2Cl2 10mlundericebathcooling. Themixture was stirred at ambient temperature for 2hours. AcCl 0.31ml and Et3N 0. 66ml was added and stirred at ambient temperature for 3hours. To this mixture was added H20 and stirred at 15 ambient temperature for a while. White precipitates were appeared, which was collected and washed with H20 and diisopropyl ether to give E0408 (879.3mg) as awhite powder. Mass (ESI+) : 396(M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.03(3H, s), 3.78(3H, s), 20 4.15-4.19(2H, m), 4.29-4.33(2H, m), 6.89(lH, s), 6.93(2H, d, J=8.8 Hz), 6.98 (2H, d, J=8.9 Hz), 7.17 (2H, d, J=8.8 Hz), 7.26(2H, d, J=8.9 Hz), 7.32(lH, s), 7.63(1H, s) Example 409 290 WO 2004/050632 PCT/JP2003/014489 H2N ClH O o N (E0 4 0 9) To a solution of E0374 (61.4mg) in CH2Cl2 2ml was added trimethylsilyl trifluoromethanesulfonate 85.6mg at 0 0 C, 5 followed by an addition of triethylamine 39mg. The mixture was stirred at 0*C for 30minutes, and partitioned between AcOEt and H20. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was purified 10 by preparative thin layer silica gel chromatography developedby 28% NH3aq : MeOH : CHCl3 =1:10:100. The separated silica gel was extracted with 28% NH3aq : MeOH : CHC13 =1:10:100andthe solventwasevaporatedinvacuo. Theresidu was dried under vacuo and then dissolved in EtOH 3ml. To 15 this solution was added 1M HCl 0.0892ml and concentrated in vacuo. The residue was dried under vacuo to give E0409 (37mg) as an amorphous powder. IR (KBr) : 2958, 1668, 1662, 1612, 1581, 1568, 1549, 1531, 1500cm-1 20 Mass (ESI+) : 379 (M+H)+ 200MHz 1H NMR 1.05( 4 H, d, J=6.2Hz), 3.04(1H,m), 3.15-3.24(2Hm), 3.89( 3 H, s), 4.16-4.22(2H, m), 6.94(lH, d, J=8.8 Hz), 7.00(2H, d,

J=

8 .7 Hz), 7 .02(1H, s), 7.27(2H, d, J=8.7 Hz), 7.78 (1H, dd, 25 J=2.7,8.8 Hz), 8.14(2H, brs), 8.21(lH, d, J=2.7 Hz) 291 WO 2004/050632 PCT/JP2003/014489 Example 410

H

2 N OO 0 O N -0 (E0410) To a solution of 5 2 -{4-[l-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazol - 5-yl]phenoxy}ethanamine (133mg,0.342mmol) in methylene chloride(5ml) was added trimethylsilyl isocyanate (118mg,1.03mmol) and triethylamine(1.39mg,1.37mmol) at ambient temperature and stirred for two days. The reaction 10 mixture was washedwith water andbrine, driedovermagnesium sulfate, filtered and evaporated. Purification by column chromatography (silica gel, methylene chloride/methanol =20/1) followedbyrecrystallizationfromethylacetategave 102 mg (69%) of E0410 as white crystals. 15 mp.165-167*C Mass;431 (M+1) IR(KBr) ;1650, 1310CM-1 NMR(DMSO-d6,5);3.32(2H, q, J=5.5Hz), 3.33(3H, s), 3.

79

(

3 H, s), 3.94(2H, t, J=5.5 Hz), 5.52(2H, s), 6.14(1H, t, J=5.5 20 Hz), 6.94(2H, d, J=8.7 Hz), 7.01(2H, d, J=8.9 Hz), 7.11(1H, s), 7.20(2H, d, J=8.7 Hz), 7.28(2H, d, J=8.9 Hz), 292 WO 2004/050632 PCT/JP2003/014489 Example 411 0 HO O ~ OMe N'N MeO (E0411) A solution of P0034 64mg in DMF 1ml was added 60% NaH 11.4mg 5 at 4 0 C and the mixture was stirred at same temperature for 30minutes. To the mixture was added bromoacetic acid 33mg and the mixture was stirred at ambient temperature for 2hours. The reactionwas quenched by adding 1MHCl 2ml, andthemixture was extracted with AcOEt. The organic layer was washed with 10 H20, sat.aqNaCl, dried over MgSO4, concentrated in vacuo to give E0411 (73mg) as crystals. Mass (ESI+) : 355 (M+H)+ 200MHz1HNMR (DMSO-d6, d) :3.79(3H, s), 3.96(3H, s), 4.63(2H, s), 5.88(lH, s), 6.82(4H, d, J=9.0 Hz), 7.14(2H, d, J=9.0 15 Hz), 7.17(2H, d, J=9.0 Hz) Example 412 HO -O -OMe N'N MeO (E0412) 20 Boron trifluoride diethyl etherate 137mg was added to a suspension of sodium borohydride 29.3mg in THF 3ml with cooling in an ice bath, and the mixture was stirred at same temperature for 30minutes. To the reaction mixture was added E0411 (137mg) in THF 3ml in one portion and the mixture was 293 WO 2004/050632 PCT/JP2003/014489 stirred at ambient temperature for 4hours. The reacion was quenched by adding ice water containing 1M HCl 1ml, and the mixture was stirred at ambient temperature for hour. The mixture was extracted with AcOEt for 2 times, the combined 5 organic layers were washed with sat.aqNaHCO3, sat.aqNaCl, dried over MgSO4, evaporated in vacuo. The residue was purified by preparative thin layer chromatography developed with AcOEt / n-hexane = 50%. The residue was crystallized from IPE to give E0412 (79.2mg) as a white powder. 10 mp. 107-109"C IR (KBr) : 3334, 2935, 1693, 1612, 1564, 1520cm-1 Mass (ESI+) : 341 (M+H) + 200MHz 1H NMR (DMSO-d6, d) : 2.02(1H, t, J=6.1Hz), 3.80(3H, s), 3 .91- 3

.

9 9 (2H,m), 3.97(3H, s), 4.04-4.09(2Hm), 5.88(1H, 15 s), 6.82 (4H, d, J=9.0 Hz), 7.14 (2H, d, J=9.0 Hz), 7.17 (2H, d, J=9.0 Hz) Example 413 HO -- O N MeO / 20 (E0413) (E0413-0) To a solution of P0034 (237mg) in DMF 2ml was added 60% NaH 4 1.6mgwithcoolinginanicebath, andthemixturewas stirred at ambient temperature for hour. To the mixture was added E0413-0 (287mg) in DMF lml and the mixture was stirred at 25 ambient temperature for 13hours, and at 60 0 C for 3hours. The reaction was quenched by adding sat.NH4Claq, and the mixture was extracted with AcOEt. The organic layer was washedwithH20, sat.aqNaCl, driedoverMgSO4, concentrated 294 WO 2004/050632 PCT/JP2003/014489 invacuo. The residue was dissolvedinEtOH 4ml, andconc.HCl 40pL was added. After stirring at ambient temperature for 2hours, the mixture was concentrated in vacuo. The residue was partitioned between AcOEt and sat.aqNaHCO3, and the 5 organic layer was washed with sat.aqNaCl, dried over MgSO4, concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / n-hexane = 40%, 60%. The residue was crystallized from AcOEt 1ml and IPE2ml. The obtained crystals were recrystallized fromAcOEt 10 0.7mlandIPEl.5mltogiveEo413 (196.9mg) aswhitecrystals. mp. 114.9-116 (115) 'C Mass (ESI+) : 341 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.65-3.73(2H, m), 3.75(3H, s), 3

.

83 (3H, s), 3.94-3.99(2H,m), 4.86( 1H, t, J=5.4Hz), 6.04(lH, s), 6.87-6.96(4H, m), 7.10-7.16(4H, m) 15 Example 414 HO-'--O N z OMe 'N MeO (E0414) To a solution of P0034 (100mg) in DMF lml was added 60% NaH 20 17.5mg with cooling in an ice bath. The mixture was stirred at ambient temperature for hour. The mixture was cooled to 0 C. To the mixture was added 2-bromoethyl acetate 113mg and the mixture was stirred at ambient temperature for 24hours. The reaction was quenched by adding sat.NH4Claq, 25 and the mixture was extracted with AcOEt. The organic layer was washed with H20, sat.aqNaCl, dried over MgSO4, concentrated invacuo. The residue was dissolved in THF 0. 9ml and MeOH 0.9ml. To this solution was added 1M NaOH 0.4ml. 295 WO 2004/050632 PCT/JP2003/014489 The mixture was stirred at ambient temperature for hour. The mixture was partitioned between AcOEt and H20, and the aqueous layerwas reexractedwithAcOEt. The combinedorganic layers were washed with sat.aqNaCl, dried over MgSO4, 5 concentrated in vacuo. The residue was crystallized from AcOEt 0.3ml-IPE 0.9ml to give E0414 (82.4mg) as white crystals. Mass (ESI+) : 341 (M+H)+ (continued to the next page) 296 WO 2004/050632 PCT/JP2003/014489 Preparation 35 Toa solutionofN'- [5- [4- (benzyloxy)phenyl -1- (4-methoxy phenyl)-lH-pyrazol-3-yl]-N,N-dimethylurea (1.19g) inEtOH (10ml) and THF (10ml) were added a solution of ammonium 5 formate (509mg) in H20 (2ml) and 10% Pd-C 50% wet (150mg). The mixture was refluxed for hour. The catalyst was filtered off through a celite pad and the pad was washed with EtOH. The filtrate and combined washings were concentrated invacuo. To the residue were added AcOEt and H20. White precipitates 10 were appeared and collected and washed with H20 and IPE successively to give N'-[5-(4-hydroxyphenyl)-l-(4 methoxyphenyl)-lH-pyrazol-3-yl]-N,N-dimethylurea (555mg) as a white powder. Mass (ESI+) : 353 (M+H)+ 15 200MHzlHNMR (DMSO-d6, d) :2.91(6H, s), 3.76(3H, s), 6.57 (1H, s), 6.71(2H, d, J=8.6 Hz), 6.93(2H, d, J=9.0 Hz), 7.01(2H, d, J=8.6 Hz), 7.14(2H, d, J=9.0 Hz), 8.99(1H, s), 9.68 (lH, S) 20 The following compound(s) was (were) obtained in a similar manner to that of Preparation 35. Preparation 36 N-[5-(4-hydroxyphenyl)-1-(4-methoxyphenyl)-lH-pyrazol 25 3-yl]-N,N',N'-trimethylurea white powder Mass (ESI+) : 367 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) 2.78 (6H, s), 3.11(3H, s), 3.76(3H, s), 6.19 (lH, s), 6.70 (2H, 30 d, J=8.6 Hz), 6.93(2H, d, J=9.0 Hz), 7.03(2H, d, J=8.6 Hz), 7.15(2H, d, J=9.0 Hz), 9.72(lH, s) 297 WO 2004/050632 PCT/JP2003/014489 Preparation 37 4-[3-ethoxy-l-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol powder Mass (ESI+) : 311(M+H)+ 5 200MHz 1H NMR (DMSO-d6, d) : 1.32(3H, t, J=7.0 Hz), 3.75(3H, s), 4.16(2H, q, J=7.0 Hz), 5.96(1H, s), 6.70 (2H, d, J=8.6 Hz), 6.91(2H, d, J=8.9 Hz), 7.01(2H, d, J=8.6 Hz), 7.11(2H, d, J=8.9 Hz), 9.74(1H, brs) 10 Preparation 38 4-[3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yll phenol white powder Mass (ESI+) : 339 (M+H)+ 15 200MHz 1H NMR (CDCl3, d) : 1.02(6H, d, J=6.6 Hz), 2.10(1H, m), 3.79(3H, s), 3.98 (6.6H, d, J=2 Hz), 5.38 (1H, s), 5.87(1H, s), 6.72(2H, d, J=8.6 Hz), 6.81(2H, d, J=9.0 Hz), 7.07 (2H, d, J=8.6 Hz), 7.16(2H, d, J=9.0 Hz) 20 Preparation 39 4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol 5-yl]phenol white powder Mass (ESI+) : 341 (M+H)+ 25 200MHz 1H NMR (DMSO-d6, d) : 3.30(3H, s), 3.62-3.67(2H, m), 3.75 (3H, s) , 4.21-4.26 (2H, m), 5. 98 (1H, s) , 6.70 (2H, d, J=8.6 Hz), 6.91(2H, d, J=9.0 Hz), 7.01(2H, d, J=8.6 Hz), 2.12(2H, d, J=9.0 Hz), 9.69(1H, s) 30 Preparation 40 4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5 yl] phenol 298 WO 2004/050632 PCT/JP2003/014489 white powder Mass (ESI+) : 355 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.13(3H, t, J=7.0 Hz), 3.49(2H, q, J=7.0 Hz), 3.65-3.71(2H, m), 3.75(3H, s), 4.20-4.25(2H, 5 m), 5.99(1H, s), 6.70(2H, d, J=8.6 Hz), 6.91(2H, d, J=9.0 Hz), 7.01(2H, d, J=8.6 Hz), 7.12(2H, d, J=9.0 Hz), 9.72(1H, s) Preparation 41 10 2-{[5-(4-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazol 3-yl]oxyl-N,N-dimethylacetamide white powder Mass (ESI+) : 368 (M+H)+ 200MHz1HNMR (DMSO-d6, d) : 2.84(3H, s) , 2.97 (3H, s) , 3.75(3H, 15 s), 4.87(2H, s), 6.01(1H, s), 6.70(2H, d, J=8.6Hz), 6.92(2H, d, J=9.0 Hz), 7.01(2H, d, J=8.6 Hz), 7.10(2H, d, J=9.0 Hz), 9.71(1H, s) Preparation 42 20 4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5 yl]phenol white powder MS (ESI+) : m/z 298 (M+H)+ 200MHz 1HNMR (DMSO-d6, d) : 3.84 (6H, s), 6.05(1H, s), 6.73(2H, 25 d, J=8.6 Hz), 6.85(1H, d, J=8.8 Hz), 7.05(2H, d, J=8.6 Hz), 7.59 (IH, dd, J=8.8,2.7 Hz), 7. 98 (1H, d, J=2.7 Hz), 9. 77 (1H, s) Preparation 43 30 4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5 yl] phenol white powder 299 WO 2004/050632 PCT/JP2003/014489 MS (ESI+) : m/z 312 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.33(3H, t, J=7.0 Hz), 3.84(3H, s), 4.18(2H, q, J=7.0 Hz), 6.03(1H, s), 6.73(2H, d, J=8.6 Hz), 6.84 (1H, d, J=8.7 Hz), 7.05 (2H, d, J=8.6 Hz), 7 .57 (iH, 5 dd, J=2.6,8.7 Hz), 7.97(1H, d, J=2.6 Hz), 9.76(1H, s) Preparation 44 4-[l-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H pyrazol-5-yllphenol 10 MASS (ESI+): m/z = 371.2 (M+Na). 1HNMR ( 400MHz, CDCl3): 2.15 ( 3H, s), 3.78 ( 3H, s), 6.79 ( 2H, d, J= 8.9Hz ), 6.8 ( 2H, d, J = 8.6Hz ), 7.01 ( 2H, d, J = 8.6Hz ), 7.13 ( 2H, d, J = 8.9Hz ). 15 Preparation 45 4-[3-cyclopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol 5-yl]phenol white powder MS(ESI+) : m/z 308 (M+H) 20 1HNMR ( 200MHz, CDC13) 0.76 - 0.85 ( 2H, m), 0.93 - 1.06 ( 2H, m), 1.97 - 2.08 ( 1H, m), 3.91 ( 3H, s), 6.08 ( 1H, s), 6.15 ( 1H, s), 6.68 - 6.76 ( 3H, m), 7.04 ( 2H, d, J = 8.6Hz ), 7.56 ( 1H, dd, J = 2.7 ,6.2Hz), 8.02 ( 1H, d, J = 2.7Hz 25 Preparation 46 4-[3-(cyclopentyloxy)-1-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl]phenol white powder 30 MS (ESI+) : m/z 352 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.09 - 2.41 ( 8H, m), 3.84 ( 3H, s), 4.92 - 5 ( IH, m), 6.01 ( 1H, s), 6.73 ( 2H, d, J= 8.6Hz ), 300 WO 2004/050632 PCT/JP2003/014489 6.84 ( 1H, d, J = 8.8Hz ), 7.05 (2H, d, J = 8.6Hz ), 7.57 1H, dd, J = 2.7 ,8.8Hz), 7.97 ( 1H, d, J = 2.7Hz ), 9.76 1H, brs) 5 Preparation 47 4-[1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H pyrazol-5-yl]phenol white powder MS (ESI+) : m/z 365 (M+H) 10 1HNMR ( 200MHz, DMSOd6): 3.76 ( 3H, s), 4.8 ( 1H, d, J 9Hz ), 4.89 ( 1H, d, J = 9Hz ), 6.15 ( 1H, s), 6.71 ( 2H, d, J 8.6Hz ), 6.93 ( 2H, d, J = 8.9Hz ), 7.03 ( 2H, d, J = 8.6Hz ), 7.14 ( 2H, d, J = 8.9Hz ), 9.74 ( 1H, brs) 15 Preparation 48 4-[3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-1H pyrazol-5-ylphenol white powder MS (ESI+) : m/z 347 (M+H) 20 1HNMR ( 200MHz, DMSOd6): 3.76 ( 3H, s), 4.43 ( 2H, dt, J =3.5 ,14.9Hz), 6.08 ( 1H, s), 6.40 ( 1H, tt, J= 3.5, 54.6Hz), 6.71 ( 2H, d, J= 8.6Hz ), 6.92 ( 2H, d, J= 9.0Hz), 7.02 ( 2H, d, J = 8.6Hz ), 7.14 ( 2H, d, J = 9.0Hz 25 Preparation 49 4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy) 1H-pyrazol-5-yl]phenol white powder MS (ESI+) : m/z 366 (M+H) 30 1HNMR ( 200MHz, CDCl3): 3.92 ( 3H, s), 4.61 ( 1H, d, J = 8.5Hz ), 4.69 ( 1H, d, J = 8.5Hz ), 5.39 ( 1H, brs), 5.97 1H, s), 6.72 (1H, d, J= 8.9Hz ), 6.76 ( 2H, d, J= 8.5Hz ), 301 WO 2004/050632 PCT/JP2003/014489 7.09 ( 2H, d, J= 8.5Hz ), 7.51 ( 1H, dd, J = 2.7 ,8.9Hz), 8.01 ( 1H, d, J = 2.7Hz Preparation 50 5 4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl phenol white powder MS (ESI+) : m/z 348 (M+H) 1HNMR ( 200MHz, CDC13): 3.92 ( 3H, s), 4.46 ( 2H, dt, J = 10 4.2 ,13.5Hz), 5.42 ( 1H, brs), 5.93 ( 1H, s), 6.16 ( 1H, tt, J= 4.2, 55.4Hz ), 6.72 ( 1H, d, J= 8.7Hz ), 6.76 ( 2H, d, J = 8.6Hz ), 7.09 ( 2H, d, J = 8.6Hz ), 7.51 ( IH, dd, J = 2.7 ,8.7Hz), 8.01 ( 1H, d, J = 2.7Hz 15 Preparation 51 4-[1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-5-yllphenol white powder MS (ESI+) : m/z 281 (M+H) 200MHz 1H NMR (DMSO-d6, d) : 2. 00 (3H, s) , 3.74 (3H, s) , 6.74 (2H, 20 d, J=8.5 Hz), 6.88(2H, d, J=9.0 Hz), 6.96(2H, d, J=8.5 Hz), 7.09(2H, d, J=9.0 Hz), 7.53(1H, s), 9.66(1H, s) Preparation 52 4-[1-(6-methoxy-3-pyridinyl)-4-methyl-1H-pyrazol-5 25 yl]phenol white powder MS (ESI+) : m/z 282 (M+H) 1HNMR (200MHz, DMSOd6): 2.01 ( 3H, s), 3.83 ( 3H, s), 6.75 - 6.85 ( 3H, m), 7.01 ( 2H, d, J= 8.6Hz ), 7.53 ( 1H, dd, 30 J = 2.7 ,8.8Hz), 7.6 ( 1H, s), 7.96 ( 1H, d, J = 2.7Hz ), 9.73 ( 1H, brs) 302 WO 2004/050632 PCT/JP2003/014489 Preparation 53 To a solution of 4'-benzyloxypropiophenone (6.0g) in THF (120ml) at -60 'C was added 38ml of 1N lithium bis(trimethylsilyl)amide (LiHMDS), and the mixture was 5 stirred at under -60'C for 45mins. 1-(Trifluoroacetyl) imidazole (3.4ml) was added and the mixture was stiired at -60'C for 1 hour and at 00C for 30 min. The raction mixture was quenched with 0. 5N HCl, the mixture was poured into EtOAc and water, and the EtOAc layer was separated, washed with 10 brine, died over MgSO4, and concentrated to give 1-[4-(benzyloxy)phenyl]-4,4,4-trifluoro-2-methyl 1,3-butanedione. MASS (ESI+): m/z = 359.2 (m+Na). 1HNMR (400MHz, CDC13): 1.36 ( 1H, d, J= 7.2Hz ), 1.52 ( 2H, 15 d, J= 7Hz ), 5.16 ( 2H, s), 7.02 - 7.08 ( 2H, m), 7.37 7.44 ( 5H, m), 7.92 - 7.98 ( 2H, m). Preparation 54 Toa mixtureof4-(methylthio)aniline (6.

3 g) andconc.HCl 20 (45ml) was added dropwise NaNO2 (3.6g) in water (18ml) under ice-coling. After stirring for 30 min., SnClH2O (28.6g) in conc.HCl (24ml) was added under ice cooling over 1 hour. After stirring for 1 hour, filtrate, washed with conc.HCl and water, and dried to give 14.1g of 25 [4-(methylthio)phenyl]hydrazine hydrochloride as a solid. MASS (ESI+): m/z = 139.3 (M-NH2+1). 1HNMR ( 400MHz, DMSOd6): 2.42 ( 3H, s), 3.75 ( 2H, b.s), 6.97 ( 2H, d, J= 8.7Hz ), 7.24 ( 2H, d, J= 8.7Hz ), 10.24 ( 1H, b.s). 30 Preparation 55 Amixture of 4-hydroxypropiophenone (20g), benzyl chloride 303 WO 2004/050632 PCT/JP2003/014489 (16.1ml), K2CO3 (12.9g) and KI (2.21g) in EtOH (80ml) and H20 (1ml) was stirred under reflux condition for 4 hours. The reaction mixture was cooled and filtered. Appeared crystal was dissovled with EtOAc and water. Organic layer 5 was separated and washed with water and brine, dried over MgSO4 and filtered. Filtrate was evaporated under reduced pressure to give 30.Og (94%) of 1-[4-(benzyloxy)phenyl]-l-propanone as a crystal. MASS (ESI+): m/z = 263.2 (M+Na). 10 1HNMR ( 400MHz, CDCl3): 1.21 ( 3H, t, J= 7.3Hz ), 2.95 ( 2H, q, J= 7.3Hz ), 5.13 ( 2H, s), 7 ( 2H, d, J= 8.9Hz ), 7.34 - 7.45 ( 5H, m), 7.95 ( 2H, d, J = 8.9Hz ). Preparation 56 15 1M NaOH (4.8ml) was added to a solution of 4-benzyloxybenzaldehyde (5g) and cyclopropyl methyl ketone (3.96g) in EtOH (24ml) and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with H20 and EtOH. The mixture was stirred at ambient 20 temperature for 20minutes. Pale yellow crystals were collected and washed with H20 and 50% aqueous EtOH to give (2E)-3-[4-(benzyloxy)phenyl]-l-cyclopropyl-2-propen-l one (6.29g). Pale yellow crystals 25 MS (ESI+) : m/z 301 (M+Na) 1HNMR ( 200MHz, CDCl3): 0.9 - 1.00 ( 2H, m), 1.11 - 1.19 ( 2H, m), 2.16 - 2.29 ( 1H, m), 5.11 ( 2H, s), 6.77 ( 1H, d, J= 16.1Hz ), 6.99 ( 2H, d, J= 8.8Hz ), 7.32 - 7.46 C 4H, m), 7.52 ( 2H, d, J = 8.8Hz ), 7.58 ( 2H, d, J = 16.1Hz 30 Preparation 57 (2E)-3-[4-(Benzyloxy)phenyl]-l-cyclopropyl-2-propen-l 304 WO 2004/050632 PCT/JP2003/014489 one (6.25g) was suspendedin EtOH (67.5ml), acetone (22.5ml). To this mixture was added hydrogen peroxide 30% aqueous solution (4.5ml), and 3M NaOH (4.5ml), and the mixture was stirred at ambient temperature for 1day. The mixture was 5 diluted with H20. White precipitates were collected and washed with H20, and air dried to give { (2R,3S)-3-[4 (benzyloxy)phenyl]-2-oxiranyl}(cyclopropyl)methanone (6.27g). powder 10 MS (ESI+) : m/z 317 (M+Na) 1HNMR ( 200MHz, DMSOd6): 0.96 - 1.07 ( 2H, m), 1.12 - 1.19 ( 2H, m), 2.11 - 2.22 ( 1H, m), 3.59 ( 1H, d, J = 1.8Hz ), 4.04 ( 1H, d, J 1.8Hz ), 5.08 ( 2H, s), 6.97 ( 2H, d, J = 8.8Hz ), 7.23 ( 2H, d, J= 8.8Hz ), 7.35 - 7.43 ( 5H, m) 15 Preparation 58 To a solution of 4-[3-methoxy-1-(4-methoxyphenyl) 1H-pyrazol-5- yl]phenol (501mg) in CH2C12 (5ml) was added trifluoromethanesulfonic anhydride (300pl) and 20 diisopropylethylamine (324pl) under ice-bath cooling. The mixture was stirred at same temperature for 2hours. Additional trifluoromethanesulfonic anhydride (57pl) and diisopropylethylamine (147p1) were added and stirring at same temperature was continued for hour. The mixture was 25 washed with 1M HCl, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluted with AcOEt / n-hexane = 20% to give 30 4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl] phenyl trifluoromethanesulfonate (712.3mg) as an oil. MS (ESI+) : m/z 429 (M+H) 305 WO 2004/050632 PCT/JP2003/014489 1HNMR ( 200MHz, CDCl3): 3.81 ( 3H, s), 3.98 ( 3H, s), 5.97 ( lH, s), 6.85 ( 2H, d, J = 9.0Hz ), 7.11 - 7.32 ( 6H, m) The following compound(s) was (were) obtained in a similar 5 manner to that of Preparation 58. Preparation 59 4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl] phenyl trifluoromethanesulfonate 10 oil MS ESI+) : m/z 457 (M+H) 1HNMR ( 200MHz, CDC13): 1.40 ( 6H, d, J= 6.1Hz ), 3.81 ( 3H, s), 4.89 ( 1H, m), 5.94 ( 1H, s), 6.84 ( 2H, d, J= 9.0Hz ), 7.14 ( 2H, d, J = 9.0Hz ), 7.20 - 7.32 ( 4H, m) 15 Preparation 60 4-[3-chloro-1-(4-methoxyphenyl)-lH-pyrazol-5-yl] phenyl trifluoromethanesulfonate oil 20 MS (ESI+) : m/z 433 (M+H) 1HNMR ( 200MHz, CDCl3): 3.82 ( 3H, s), 6.46 ( 1H, s), 6.86 ( 2H, d, J= 9.0Hz), 7.17 ( 2H, d, J= 9.0Hz ), 7.23 - 7.32 ( 4H, m) 25 Preparation 61 A mixture of 4-[3-methoxy-1-(4-methoxyphenyl)-lH pyrazol-5-yl]phenyl trifluoromethanesulfonate (679mg), zinc cyanide (279mg), and tetrakis(triphenylphosphine) palladium(0) (183mg) in DMF (4ml) was stirred at 85'C for 30 5hours. The reaction mixture was cooled to ambient temperature and AcOEt and H20 were added. Unsoluble matter was filtered off through a celite pad. The filtrate was 306 WO 2004/050632 PCT/JP2003/014489 partitioned, and the organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / 5 n-hexane = 20%. The pure fractions were collected and concentrated in vacuo to give 4-[3-methoxy-l-(4-methoxy phenyl)-1H-pyrazol-5-yl]benzonitrile (326mg) as a powder. mp.112-113'C MS (ESI+) m/z 306 (M+H), 328 (M+Na) 10 IR (KBr) 2929, 2227, 1568, 1552, 1541, 1518cm-1 1HNMR ( 200MHz, CDC13): 3.81 ( 3H, s), 3.98 ( 3H, s), 6.01 ( 1H, s), 6.85 ( 2H, d, J= 8.9Hz ), 7.15 ( 2H, d, J= 8.9Hz ), 7.30 ( 2H, d, J =8.5Hz ), 7.57 ( 2H, d, J = 8.5Hz) 15 The following compound(s) was (were) obtained in a similar manner to that of Preparation 61. Preparation 62 4-[3-isopropoxy-l-(4-methoxyphenyl)-lH-pyrazol-5-yl] 20 benzonitrile mp.96-97DC MS (EST+) : m/z 334 (M+H), 356 (M+Na) 1HNMR ( 200MHz, CDC13): 1.40 ( 6H, d, J= 6.1Hz ), 3.81 ( 3H, s), 4.89 ( 1H, m), 5.98 ( 1H, s), 6.84 ( 2H, d, J= 9.0Hz ), 25 7.14 ( 2H, d, J = 9.0Hz ), 7.30 ( 2H, d, J = 8.6Hz), 7.56 ( 2H, d, J = 8.6Hz Preparation 63 4-[l-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy) 30 1H-pyrazol-5-yl]benzonitrile oil MS (ESI+) : m/z 375 (M+H) 307 WO 2004/050632 PCT/JP2003/014489 1HNMR ( 200MHz, CDC13): 3.94 ( 3H, s), 4.62 ( 1H, d, J = 8.4Hz), 4.71 ( 1H, d, J= 8.4Hz ), 6.12 ( 1H, s), 6.76 ( 1H, d, J 8.7Hz ), 7.33 ( 2H, d, J = 8.4Hz ), 7.5 ( 1H, dd, J = 2.7 ,8.7Hz), 7.62 ( 2H, d, J 8.4Hz ), 7.97 ( 1H, d, 5 J = 2.7Hz ) Preparation 64 4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl] benzonitrile 10 powder MS (ESI+) : m/z 310 (M+H), 332 (M+Na) 1HNMR ( 200MHz, CDC13): 3.83 ( 3H, s), 6.50 ( 1H, s), 6.87 ( 2H, d, J= 9.0Hz ), 7.16 ( 2H, d, J= 9.0Hz ), 7.30 ( 2H, d, J = 8.5Hz ), 7.60 ( 2H, d, J = 8.5Hz) 15 Preparation 65 4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl] benzonitrile powder 20 MS (ESI+) : m/z 311 (M+H), 333 (M+Na) 1HNMR ( 200MHz, CDC13): 3.94 ( 3H, s), 6.53 ( 1H, s), 6.78 ( 1H, d, J = 8.9Hz ), 7.33 ( 2H, d, J = 8.4Hz ), 7.54 ( 1H, dd, J= 2.7 ,8.9Hz), 7.64 ( 2H, d, J = 8.4Hz ), 7.99 ( 1H, d, J = 2.7Hz 25 Preparation 66 A solution of trifluoromethanesulfonic anhydride (207pl) in CH2C12 (1ml) was added to a solution of 4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy) 30 1H-pyrazol-5-yllphenol (300mg) and pyridine (1 99 pl) in CH2Cl2 (3ml) inder ice-bath cooling. The mixture was stirred at same temperature for hour. The reaction was quenched 308 WO 2004/050632 PCT/JP2003/014489 by adding saturated aqueous ammonium chloride solution (5ml) The mixture was partitioned between AcOEt and 1M HC1. The mixture was washed with saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution, 5 dried over magnesium sulfate, and concentrated in vacuo to give 4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro ethoxy)-1H-pyrazol-5-yl]phenyl trifluoromethane sulfonate (439mg) as an oil. MS (ESI+) : m/z 498 (M+H) 10 lHNMR ( 200MHz, CDCl3): 3.94 ( 3H, s), 4.62 ( 1H, d, J 8.4Hz), 4.71 ( 1H, d, J= 8.4Hz ), 6.08 ( 1H, s), 6.74 ( 1H, d, J 8.7Hz ), 7.22 - 7.38 ( 4H, m), 7.47 ( 1H, dd, J = 2.7 ,8.7Hz), 8.01 ( 1H, d, J = 2.7Hz ) 15 The following compound(s) was (were) obtained in a similar manner to that of Preparation 66. Preparation 67 4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl] 20 phenyl trifluoromethanesulfonate oil MS (ESI+) : m/z 434 (M+H) 1HNMR ( 200MHz, CDCl3): 3.94 ( 3H, s), 6.49 ( 1H, s), 6.76 ( 1H, d, J = 8.9Hz ), 7.23 - 7.34 ( 4H, in), 7.52 ( 1H, dd, 25 J = 2.8 ,8.9Hz), 8.02 ( 1H, d, J = 2.8Hz Preparation 68 A solution of 4-[3-chloro-1-(4-methoxyphenyl)-1H pyrazol-5-yllphenyl benzyl ether (2.79g) and thioanisole 30 (3. 56g) in trifluoroacetic acid (25ml) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo. The residue was recrystallizedfromAcOEt (15ml) andn-hexane 309 WO 2004/050632 PCT/JP2003/014489 (12ml) togivrlstcropofFR28211 7 (1.48g) . Themotherliqour was washed with H20, saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column 5 chromatography eluted with AcOEt / n-hexane = 30%. The pure fractions were collected and concentrated in vacuo. The residual crystals were collected and washed with IPE to give 2nd crop of 4-[3-chloro-l-(4-methoxyphenyl)-lH pyrazol-5-yl]phenol(457.2mg) white powder 10 Mass (ESI+) : m/z 301 (M+H) 200MHz 1HNMR (DMSO-d6, d) : 3.78 (3H, s) , 6.62 (lH, s) , 6.71 (2H, d, J=8.7 Hz) , 6. 96 (2H, d, J=9.0 Hz) , 7.03 (2H, d, J=8.7 Hz) , 7.19(2H, d, J=9.0 Hz), 9.80(1H, s) 15 The following compound (s) was (were) obtained in a similar manner to that of Preparation 68. Preparation 69 4-[1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazol-5-yl] 20 phenol powder MS (ESI+) : m/z 313 (M+H) 1HNMR ( 200MHz, DMSOd6): 2.50 ( 3H, s), 3.77 ( 3H, s), 6.49 ( 1H, s), 6.70 ( 2H, d, J= 8.6Hz), 6.94 ( 2H, d, J= 9.0Hz ), 25 7.02 ( 2H, d, J = 8.6Hz ), 7.16 ( 2H, d, J = 9.0Hz ), 9.71 ( H, brs) The following compound(s) was (were) obtained in a similar manner to that of Example 596. 30 Preparation 70 4-[1-[4-(methylthio)phenyl]-3-(trifluoromethyl)-lH 310 WO 2004/050632 PCT/JP2003/014489 pyrazol-5-yl]phenol MASS (ESI+): m/z = 373.1 (M+Na). 1HNMR ( 400MHz, CDCl3): 2.49 ( 3H, s), 5.13 ( 1H, b.s), 6.67 ( 1H, s) , 6.79 ( 2H, d, J 8.7Hz ) 7.1 ( 2H, d, J = 8.7Hz 5 7.2 ( 2H, d, J = 9.1Hz ), 7.23 ( 2H, d, J = 9.1Hz ). Preparation 71 4-{3-(difluoromethyl)-1-[4-(methylthio)phenyl]-1H pyrazol-5-yl}phenol 10 MASS (EST+) m/z = 355.1 (M+Na) 1HNMR ( 400MHz, CDCl3): 2.49 ( 3H, s), 5.17 ( 1H, b.s), 6.65 ( 1H, s) , 6.76 ( 1H, t, J= 55Hz ), 6.78 ( 2H, d, J= 8.7Hz ) 7.1 ( 2H, d, J = 8.7Hz ), 7.2 ( 4H, s). 15 Preparation 72 4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H pyrazol-5-yl]benzonitrile MASS (EST+): m/z = 345.1, 367.1 (m+H, m+Na). 1HNMR ( 400MHz, CDC13) : 3.96 ( 3H, s) , 6.8 ( 1H, d, J= 8.8Hz ) 20 6.85 ( 1H, s), 7.36 ( 2H, d, J = 8.4Hz ), 7.57 ( 1H, dd, J = 2.7 ,8.8Hz), 7.66 ( 2H, d, J = 8.4Hz ), 8.04 ( 1H, d, J = 2.7Hz ). Preparation 73 25 4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl]benzonitrile MASS (ESI+): m/z = 327.1 (m+1) 1HNMR ( 400MHz, CDC13): 3.95 ( 3H, s), 6.77 ( 1H, t, J = 54.8Hz ), 6.79 ( 1H, d, J = 8.8Hz ), 6.82 ( 1H, s), 7.36 30 ( 2H, d, J = 8.4Hz ), 7.54 ( 1H, dd, J = 2.8 ,8.8Hz), 7.65 2H, d, J = 8.4Hz ), 8.04 ( 1H, d, J = 2.8Hz ). 311 WO 2004/050632 PCT/JP2003/014489 Example 415 4M HCl in dioxane (3ml) was added to a solution of tert-butyl (2-{4-[3-(1-hydroxy-1-methylethyl)-1 (6-methoxy-3-pyridinyl)-1H-py'razol-5-yl]phenoxylethyl) 5 carbamate (236mg) in CH2Cl2 (3ml) . The reaction mixture was stirred at ambient temperature for 3hours. 2-Propanol (2ml) was added to dissolve unsoluble oil, and stirred at ambient temperature for 4hours. The mixture was concentrated in vacuo. The residue was suspended in CH2C12 (3ml). 10 Methanesulfonyl chloride (127mg) was added and then Et3N was added to adjust pH of the rection mixture to neutral. After stirring for hour, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The mixture was extracted with ethyl 15 acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 50% AcOEt / n-hexane 20 to give N-(2-{4-[3-isopropenyl-l-(6-methoxy-3 pyridinyl)-1H-pyrazol-5-yl phenoxy}ethyl)methane sulfonamide (118mg) as an oil. 1H NMR (CDCl3) 5 2.20(3H, s), 3.03(3H, s), 3.51-3.60(2H, m), 3.93(3H, s), 4.07-4.13(2H, m), 4.77 (1H, t, J=6.0 Hz), 25 5.15(1H, brs), 5.60(1H, brs), 6.59(1H, s), 6.73(1H, d, J=8.9 Hz), 6.83(2H, d, J=8.8 Hz), 7.17(2H, d, J=8.8 Hz), 7.55(1H, dd, J=2.6,8.8 Hz), 8.09(1H, d, J=2.6 Hz) Example 416 30 A mixture of 10% Pd-C 50% wet (20mg) and N-(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-lH pyrazol-5-ylIphenoxy}ethyl)methanesulfonamide (118mg) in 312 WO 2004/050632 PCT/JP2003/014489 THF (iml) and MeOH (Iml) was hydrogenated under H2 latm at ambient temperature for lday.The catalyst was removed by filtration.The filtrate and combined washings were concentrated in vacuo. The residue was purified by 5 preparative thin layer silica gel chromatography developed by AcOEt/n-hexane= 70%. The seaparated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residue was recrystallized from AcOEt-IPE to give N-(2-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H 10 pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide (68.6mg) as white powder. white powder mp. 96-97'C IR (KBr) : 3269, 2970, 1612, 1512cm-l 15 MS (ESI+) : m/z 431 (M+H) 1H NMR (DMSO-d6) 5 1.27(6H, d, J=6.9 Hz), 2.88-2.99(1H, m), 2.92(3H, s), 3.92-3.35(2H, m), 3.85(3H, s), 3.99-4.06(2H, m), 6.46(1H, s), 6.88 (1H, d, J=8.7 Hz), 6.94(2H, d, J=8.8 Hz), 7.17(2H, d, J=8.8 Hz), 7.28(lH, s), 7.60(lH, dd, 20 J=2.7,8.7 Hz), 8.02(1H, d, J=2.7 Hz) The following compound(s) was (were) obtained in a similar manner to that of Example 416. 25 Example 417 tert-butyl {4-[3-isopropyl-1-(4-methoxyphenyl)-lH pyrazol-5-yllbenzyl}carbamate oil MS (ESI+) : m/z 422 (M+H) 30 1HNMR ( 200MHz, ): 1.34 ( 6H, d, J = 7.0Hz ), 1.46 ( 9H, s), 3.08 ( 1H, m), 3.80 ( 3H, s), 4.30 ( 2H, d, J=5.9Hz ), 4.81 ( 1H, brs), 6.31 ( 1H, s), 6.83( 2H, d, J = 9.0Hz ), 313 WO 2004/050632 PCT/JP2003/014489 7.15 - 7.26 ( 6H, m) Example 418 tert-butyl {4-[3-isopropyl-1-(6-methoxy-3-pyridinyl) 5 1H-pyrazol-5-y1]benzyl}carbamate oil MS (ESI+) : m/z 423 (M+H) 1HNMR ( 200MHz, CDCl3) 1.34 ( 6H, d, J = 7Hz ), 1.46 ( 9H, s), 3.07 ( 1R, in), 3.92 ( 3H, s), 4.30 ( 2H, d, J= 6.0Hz ), 10 4.84 ( 1H, brs), 6.33 ( 1H, s), 6.72 ( 1H, d, J = 8.8Hz ), 7.15 - 7.26 ( 4H, m), 7.56 ( 1H, dd, J = 2.7 ,8.8Hz) , 8.04 ( 1H, d, J 2.7Hz Example 419 15 A 4M solution of HCl in dioxane (2ml) was added to a solution of ter-butyl (2-{4-[3-isopropenyl-1-(6-methoxy-3 pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)carbamate (269.7mg) in CH2C12 (2ml) . The reaction mixture was stirred at ambient temperature for 2hours, then, was concentrated 20 in vacuo to give (2-{4-[3-isopropenyl-1-(6-methoxy-3 pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)amine dihydrochloride (259mg) as an amorphous powder. MS (ESI+) : m/z 351 (M+H) 1H NMR (DMSO-d6) 5 2.10(3H, s), 3.15-3.23(2H, m), 3.86(3H, 25 s), 4.16-4.24(2Hm), 5.15(1H, brs), 5.63(1H, brs), 6.85(1H, s), 6.86-7.00(3H, m), 7.18-7.25(2H, m), 7.66(lH, dd, J=2.8,8.7 Hz), 8.06(1K, d, J=2.8 Hz), 8.24(2H, brs) The following compound(s) was (were) obtained in a similar 30 manner to that of Example 419. Example 420 314 WO 2004/050632 PCT/JP2003/014489 (2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl] phenoxy}ethyl) amine hydrochloride white powder Mass (ESI+) : 340 (M+H)+ 5 200MHz 1H NMR (DMSO-d6, d) : 3.16-3.23(2H, m), 3.76(3H, s), 3. 84 (3H, s) , 4.14-4.20 (2H, m) , 6.06 (1H, s) , 6. 93 (2H, d, J=8. 9 Hz), 6. 94 (2H, d, J=8 .7 Hz), 7. 14 (2H, d,, J=8.9 Hz), 7.17 (2H, d, J=8.7 Hz), 8.16(2H, brs) 10 Example 421 (2-{4-[3-ethoxy-l-(4-methoxyphenyl)-lH-pyrazol-5-yl] phenoxylethyl)amine hydrochloride white powder Mass (ESI+) : 354 (M+H)+ 15 200MHz 1H NMR (DMSO-d6, d) : 1.33(3H, t, J=7.0 Hz), 3.14-3.23(2H, m), 3.76(3H, s), 4.12-4.23(4H, in), 6.04(1H, s), 6.92(2H, d, J=9.0 Hz), 6.94 (2H, d, J=8.8 Hz), 7.12(2H, d, J=9.0 Hz), 7.16(2H, d, J=8.8 Hz), 8.24(2H, brs) 20 Example 422 (2-{4-[3-isobutoxy-l-(4-methoxyphenyl)-1H-pyrazol-5 ylphenoxy}ethyl)amine hydrochloride amorphous Mass (ESI+) : 382 (M+H)+ 25 200MHz 1H NMR (DMSO-d6, d) : 0.97 (6H, d, J=6.7 Hz), 2.03(1H, m), 3.14-3.23(2H, m), 3.76(3H, s), 3.90(2H, d, J=6.6 Hz), 4.14-4.20 (2H, m) , 6.06 (1H, s), 6.92(2H, d, J=9.0 Hz) , 6.94 (2H, d, J=8.8 Hz), 7.08-7.19(4H, m), 8.23(2H, brs) 30 Example 423 (2-{4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-lH pyrazol-5-yl]phenoxy}ethyl)amine hydrochloride 315 WO 2004/050632 PCT/JP2003/014489 amorphous Mass (ESI+) : 384 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.15-3.23(2H, m), 3.31 (3H, s), 3.62-3.67(2H, m), 3.75(3H, s), 4.14-4.27 (4H, m), 6.06(1H, 5 s), 6.92(2H, d, J=8.9 Hz), 6.95 (2H, d, J=8.8 Hz), 7.13(2H, d, J=8.9 Hz), 7.17(2H, d, J=8.8 Hz), 8.20(2H, brs) Example 424 (2-{4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1H 10 pyrazol-5-yl]phenoxy}ethyl)amine hydrochloride amorphous Mass (ESI+) : 398 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.13(3H, t, J=7.0 Hz), 3.15-3.24 (2H, m), 3.50 (2H, q, J=7.0 Hz), 3.66-3.71(2H, m), 15 3.76 (3H, s) , 4 13-4. 27 (4H, m) , 6. 07 (1H, s) , 6. 93 (2H, d, J=8. 9 Hz), 6.95(2H, d, J=8.7 Hz), 7.13 (2H, d, J=8.9 Hz), 7.17 (2H, d, J=8.7 Hz), 8.13(2H, brs) Example 425 20 (2-{4-[3-methoxy-l-(6-methoxy-3-pyridinyl)-1H-pyrazol 5-yl]phenoxy}ethyl)amine dihydrochloride amorphous MS (ESI+) : m/z 341 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.16-3.23(2H, m), 3.84(3H, s), 25 3.85 (3H, s) , 4.16-4.21 (2H, m) , 6.12 (1H, s) , 6.86 (1H, d, J=8.7 Hz), 6.98 (2H, d, J=8.7 Hz), 7.21(2H, d, J=8.7 Hz), 7.62 (1H, dd, J=2.5,8.7 Hz), 7.99(1H, d, J=2.5 Hz), 8.24(2H, brs) Example 426 30 (2-{4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-lH-pyrazol-5 yl]phenoxy}ethyl)amine dihydrochloride amorphous 316 WO 2004/050632 PCT/JP2003/014489 MS (EST+) : m/z 355 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.33(3H, t, J=7.0 Hz), 3.15-3.24(2H, m), 3.84(3H, s), 4.13-4.24(2H, m), 4.19(2H, q, J=7.0 Hz), 6.10(1H, s), 6.86(1H, d, J=8.9 Hz), 6.98(2H, 5 d, J=8.8 Hz), 7.21(2H, d, J=8.8 Hz), 7.60(1H, dd, J=2.7,8.9 Hz), 7.98(1H, d, J=2.7 Hz), 8.19(2H, brs) Example 427 (2-{4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoro 10 methyl)-1H-pyrazol-5-yl]phenoxy}ethyl)amine hydrochloride MASS (EST+): m/z = 392.2 (M+H). 1HNMR (400MHz, DMSOd6): 2.09 ( 3H, s), 3.1 - 3.3 ( 2H, m), 3.36 ( 2H, b.s), 3.57 (3H, s), 4.20 ( 2H, t, J 5Hz ), 15 6.94 ( 2H, d, J = 8.9Hz ), 7.01 ( 2H, d, J = 8.8Hz ), 7.2 ( 2H, d, J = 8.9Hz ), 7.21 ( 2H, d, J = 8.8Hz ), 8.29 (2H, br.s). Example 428 20 (2-{4-[1-[4-(methylthio)phenyl]-3-(trifluoromethyl)-lH pyrazol-5-yl]phenoxy}ethyl)amine hydrochloride MASS (ESI+): m/z = 394.1 (M(Free)+1, HCl salt). 1HNMR ( 200MHz, DMSOd6): 2.5 ( 3H, s), 3.15 - 3.25 ( 2H, m), 4.22 ( 2H, t, J = 5Hz ), 7 ( 2H, d, J = 8.7Hz ), 7.1 25 ( 1H, s) , 7.26 ( 2H, d, J= 8.7Hz ), 7.27 ( 2H, d, J = 9.8Hz 7.33 ( 2H, d, J = 9.8Hz ), 8.35 ( 2H, b.s). Example 429 [2-(4-{3-(difluoromethyl)-1-[4-(methylthio)phenyl]-1H 30 pyrazol-5-yl}phenoxy)ethyl]amine hydrochloride MASS (EST-): m/z = 410.0 (M-1). 1HNMR ( 400MHz, DMSOd6): 2.49 ( 3H, s), 3.2 ( 2H, t, J = 317 WO 2004/050632 PCT/JP2003/014489 5Hz ), 4.19 ( 2H, t, J = 5Hz ), 6.87 ( 1H, s), 6.99 ( 1H, d, J = 8.7Hz ), 7.09 ( 1H, t, J = 53.5Hz ), 7.24 ( 4H, d, J = 9.6Hz ), 7.3 ( 2H, d, J = 8.7Hz ), 8.17 ( 2H, b.s). 5 Example 430 (2-{4-[3-cyclopropyl-l-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl]phenoxylethyl)amine dihydrochloride amorphous powder MS (ESI+) : m/z 351 (M+H) 10 1HNMR ( 200MHz, DMSOd6): 0.70- 0.78 ( 2H, m), 0.86 - 1.02 ( 2H, m), 1.88 - 1.99 ( 1H, m), 3.10 - 3.20 ( 2H, m), 3.85 ( 3H, s), 4.15 - 4.21 ( 2H, m), 6.31 ( 1H, s), 6.86 ( 1H, d, J = 8.9Hz ), 6.96 ( 2H, d, J = 8.8Hz ), 7.17 ( 2H, d, J= 8.8Hz ), 7.60 ( 1H, dd, J = 2.7 ,8.9Hz), 8.00 ( 1H, d, 15 J = 2.7Hz ), 8.24 ( 2H, brs) Example 431 (2-{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl) 1H-pyrazol-5-yllphenoxy}ethyl)amine hydrochloride 20 amorphous powder MS (ESI+) : m/z 421 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.43 - 1.72 ( 6H, m), 3.14 - 3.24 ( 2H, m), 3.52 - 3.70 ( 2H, m), 3.77 - 3.95 ( 2H, m), 3.78 ( 3H, s), 4.15 - 4.20 ( 2H, m), 6.79 ( 1H, s), 6.96 ( 2H, 25 d, J = 8.8Hz ), 6.99 ( 2H, d, J = 8.9Hz ), 7.21 ( 2H, d, J = 8.8Hz ), 7.24 ( 2H, d, J = 8.9Hz ), 8.14 ( 2H, brs) Example 432 (2-14-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl 30 carbonyl)-1H-pyrazol-5-ylphenoxyethyl)amine dihydrochloride amorphous powder 318 WO 2004/050632 PCT/JP2003/014489 MS (ESI+) : m/z 422 (M+H) 1HNMR ( 200MHz, CDCl3): 1.42 - 1.75 ( 6H, m), 3.14 - 3.24 ( 2H, m), 3.52 - 3.70 ( 2H, m), 3.73 - 3.94 ( 2H, m), 3.87 ( 3H, s), 4.16 - 4.22 ( 2H, m), 6.83 ( 1H, s), 6.91 ( 1H, 5 d, J = 8.9Hz ), 6.99 ( 2H, d, J = 8.8Hz ), 7.25 ( 2H, d, J = 8.8Hz ), 7.69 ( 1H, dd, J= 2.7 ,8.9Hz), 8.14 ( 1H, d, J = 2.7Hz ), 8.21 ( 2H, brs) Example 433 10 5-[4-(2-aminoethoxy)phenyl]-N-ethyl-1-(6-methoxy-3 pyridinyl)-N-methyl-1H-pyrazole-3-carboxamide dihydrochloride amorphous powder Mass (ESI+) : m/z 396 (M+H) 15 1HNMR ( 200MHz, DMSOd6): 1.09 - 1.23 ( 3H, m), 2.98, 3.29 ( 3H, s), 3.13 - 3.25 ( 2H, m), 3.43 - 3.78 ( 4H, m), 3.87 ( 3H, s), 4.16- 4.22 ( 2H, m), 6.84, 6.86 ( 1H, s), 6.91 ( 1H, d, J= 8.7Hz ), 7 .00( 2H, d, J= 8.7Hz ), 7.25 ( 2H, d, J = 8.7Hz ), 7.61 - 7.74 ( 1H, m), 8.13 - 8.20 ( 3H, m) 20 Example 434 (2-{4-[3-(cyclopentyloxy)-1-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl]phenoxylethyl)amine dihydrochloride amorphous powder 25 MS (ESI+) :m/z 395 (M+H) 1HNMR ( 400MHz, DMSOd6): 1.57 - 1.91 ( 8H, m), 3.16 - 3.21 2H, m), 3.84 ( 3H, s), 4.17 - 4.21 ( 2H, m), 4.95 - 5 ( 1H, m), 6.08 ( 1H, s), 6.85 ( 1H, d, J = 8.8Hz ), 6.98 ( 2H, d, J = 8.8Hz ), 7.2 ( 2H, d, J = 8.8Hz ), 7.59 ( 1H, dd, 30 J = 2.8 ,8.8Hz), 7.98 C 1H, d, J = 2.8Hz ), 8.24 ( 2H, brs) Example 435 319 WO 2004/050632 PCT/JP2003/014489 (2-{4-[1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy) 1H-pyrazol-5-yl]phenoxy}ethyl)amine hydrochloride oil MS (ESI+) : m/z 408 (M+H) 5 1HNMR ( 200MHz, DMSOd6): 3.13 - 3.24 ( 2H, m), 3.76 ( 3H, s), 4.15 - 4.21 ( 2H, m), 4.82 ( 1H, d, J = 9.0Hz ), 4.91 ( 1H, d, J= 9.0Hz ), 6.23 ( 1H, s), 6.92- 6.99 ( 4H, m), 7.13 - 7.21 ( 4H, m), 8.20 ( 2H, brs) 10 Example 436 (2-{4-[3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-lH pyrazol-5-yl]phenoxyJethyl)amine hydrochloride amorphous powder MS (ESI+) : m/z 390 (M+H) 15 1HNMR ( 200MHz, DMSOd6): 3.13- 3.23 ( 2H, m), 3.76 ( 3H, s), 4.14 - 4.20 ( 2H, m), 4.44 (2H, dt, J= 3.5 ,14.9Hz), 6.16 ( 1H, s), 6.41 ( 1H, tt, J= 3.5, 54.6Hz ), 6.94 ( 2H, d, J = 8.9Hz ), 6.95 ( 2H, d, J = 8.9Hz ), 7.16 ( 2H, d, J = 8.9Hz ), 7.18 ( 2H, d, J = 8.9Hz ), 8.17 ( 2H, brs) 20 Example 437 (2-{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro ethoxy)-1H-pyrazol-5-yl]phenoxylethyl)amine dihydrochloride 25 amorphous powder MS (ESI+) : m/z 409 (M+H) 1HNMR ( 200MHz, DMSOd6): 3.16 - 3.21 ( 2H, m), 3.85 ( 3H, s), 4.16 - 4.22 ( 2H, m), 4.83 ( 1H, d, J = 9.0Hz ), 4.92 1H, d, J= 9.OHz ), 6.29 ( 1H, s), 6.88 ( 1H, d, J= 8.8Hz ), 30 6.99 ( 2H, d, J = 8.8Hz ), 7.22 ( 2H, d, J = 8.8Hz ), 7.63 ( 1H, dd, J = 2.7 ,8.8Hz), 8.03 ( 1H, d, J = 2.7Hz ), 8.19 ( 2H, brs) 320 WO 2004/050632 PCT/JP2003/014489 Example 438 (2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3 pyridinyl)-1H-pyrazol-5-yl]phenoxylethyl)amine 5 dihydrochloride powder MS (ESI+) : m/z 391 (M+H) 1HNMR ( 200MHz, DMSOd6): 3.15 -3.24 ( 2H, m), 3.85 ( 3H, s), 4.16 - 4.22 ( 2H, m), 4.46 ( 2H, dt, J= 3.5 ,14.9Hz), 10 6.22 ( 1H, s), 6.42 ( 1H, tt, J= 3.5, 54.5Hz ), 6.87 ( 1H, d, J 8.9Hz ), 6.99 ( 2H, d, J = 8.7Hz ), 7.22 ( 2H, d, J 8.7Hz ), 7.62 ( 1H, dd, J = 2.7 ,8.9Hz), 8.02 ( 1H, d, J = 2.7Hz ), 8.20 ( 2H, brs) 15 Example 439 {4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H pyrazol-5-yilbenzyl}amine hydrochloride amorphous powder MS (ESI+) : m/z 391 (M+H) 20 1HNMR ( 200MHz, DMSOd6): 1.43-1.74 ( 6H, m), 3.51 - 3.72 ( 2H, m), 3.77 - 3.93 ( 2H, m), 3.79 ( 3H, s), 3.97 - 4.06 ( 2H, m), 6.90 ( 1H, s), 6.99 ( 2H, d, J = 8.9Hz ), 7.26 ( 2H, d, J = 8.9Hz ), 7.30 ( 2H, d, J = 8.2Hz ), 7.46 ( 2H, d, J = 8.2Hz ), 8.38 ( 2H, brs) 25 Example 440 5-[4-(aminomethyl)phenyl]-N-ethyl-i-(4-methoxyphenyl) N-methyl-1H-pyrazole-3-carboxamide hydrochloride powder 30 MS (ESI+) : m/z 365 (M+H) 1HNMR ( 200MHz, DMSOd 6): 1.09 - 1.22 ( 3H, m), 2.98, 3.29 3H, s), 3.35 - 3.80 ( 2H, m), 3.79 ( 3H, s), 3.97 - 4.08 321 WO 2004/050632 PCT/JP2003/014489 ( 2H, m), 6.91, 6.93 ( 1H, s), 6.99 ( 2H, d, J = 8.9Hz ), 7.26 ( 2H, d, J = 8.9Hz ), 7.30 ( 2H, d, J= 8.3Hz ), 7.46 2H, d, J 8.3Hz ), 8.37 ( 2H, brs) 5 Example 441 {4-[3-isopropyl-1-(4-methoxyphenyl)-lH-pyrazol-5-yl] benzyl amine hydrochloride oil MS (ESI+) : m/z 322 (M+H) 10 1HNMR ( 200MHz, DMSOd6): 1.27 ( 6H, d, J = 6.8Hz ), 2.96 ( 1H, m), 3.77 ( 3H, s), 3.95 - 4.03 ( 2H, m), 6.51 ( 1H, s), 6.94 ( 2H, d, J = 8.9Hz ), 7.17 ( 2H, d, J = 8.9Hz ), 7.25 ( 2H, d, J = 8.2Hz ), 7.45 ( 2H, d, J= 8.2Hz ), 8.45 ( 2H, brs) 15 Example 442 1-[5-[4-(aminomethyl)phenyl]-1-(4-methoxyphenyl)-1H pyrazol-3-yl]-2-methyl-1-propanone hydrochloride amorphous powder 20 MS (ESI+) : m/z 350 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.16 ( 6H, d, J = 6.9Hz ), 3.68 ( 1H, m), 3.80 ( 3H, s), 4.01 ( 2H, s), 7.01 ( 2H, d, J = 8.9Hz ), 7.10 11H, s), 7.26 - 7.34 ( 4H, m), 7.46 ( 2H, d, J = 8.2Hz ), 8.33 ( 2H, brs) 25 Example 443 {4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl carbonyl)-1H-pyrazol-5-yl]benzylamine dihydrochloride oil 30 MS (ESI+) : m/z 392 (M+H) 1HNMR ( 200MHz, DMSO-d6): 1.45 - 1.73 ( 6H, m), 3.53 - 3.70 2H, m), 3.70 - 3.98 ( 2H, m), 3.98 - 4.08 ( 2H, m), 6.92 322 WO 2004/050632 PCT/JP2003/014489 1H, d, J = 8.8Hz ), 6.93 ( 1H, s), 7.32 - 7.55 ( 4H, m), 7.74 ( 1H, dd, J = 2.7 ,8.8Hz), 8.15 ( 1H, d, J = 2.7Hz ), 8.38 ( 2H, brs) 5 Example 444 5-[4-(aminomethyl)phenyl]-N-ethyl-i-(6-methoxy-3 pyridinyl)-N-methyl-1H-pyrazole-3-carboxamide dihydrochloride oil 10 MS (ESI+) : m/z 366 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.09 - 1.23 ( 3H, m), 2.98, 3.29 3H, s), 3.43 - 3.77 ( 2H, m), 3.88 ( 3H, s), 3.97 - 4.06 2H, m), 6.89 - 6.96 ( 2H, m), 7.32 - 7.80 ( 5H, m), 8.14 - 8.16 ( 1H, m), 8.52 ( 2H, brs) 15 Example 445 {4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5 yl]benzyllamine dihydrochloride amorphous powder 20 MS (EST+) : m/z 323 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.28 ( 6H, d, J = 6.9Hz ), 2.86 - 3.05 ( 1H, m), 3.85 ( 3H, s), 3.96 - 4.06 ( 2H, m), 6.57 1H, s), 6.88 ( 1H, d, J = 8.8Hz ), 7.26 - 7.53 ( 4H, m), 7.66 ( 1H, dd, J = 2.7 ,8.8Hz), 8.02 ( 1H, d, J = 2.7Hz ), 25 8.48 ( 2H, brs) Example 446 1-[5-[4-(aminomethyl)phenyl]-1-(6-methoxy-3-pyridinyl) 1H-pyrazol-3-yl]-2-methyl-l-propanone dihydrochloride 30 oil MS (ESI+) : m/z 351 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.17 ( 6H, d, J = 6.8Hz ), 3.68 323 WO 2004/050632 PCT/JP2003/014489 ( 1H, m), 3.89 ( 3H, s), 3.98 - 4.06 ( 2H, m), 6.95 ( 1H, d, J 8.8Hz ), 7.13 ( 1H, s), 7.36 ( 2H, d, J = 8.2Hz ), 7.51 ( 2H, d, J = 8.2Hz ), 7.80 ( 1H, dd, J = 2.7 ,8.8Hz), 8.19 ( 1H, d, J = 2.7Hz ), 8.43 ( 2H, brs) 5 Example 447 (2-{4-[l-(4-methoxyphenyl)-4-methyl-1H-pyrazol-5-yll phenoxy}ethyl)amine hydrochloride powder 10 MS (ESI+) : m/z 324 (M+H) 200MHz 1H NMR (DMSO-d6, d) : 2.02 (3H, s), 3.17-3.26(2H, m), 3.74 (3H, s), 4.13-4.19 (2H, m), 6.89 (2H, d, J=9.0 Hz), 6.98 (2H, d, J=8.7 Hz), 7.10(2H, d, J=8.9 Hz), 7.13(2H, d, J=8.7 Hz), 7.57(1H, s), 8.05(2H, brs) 15 Example 448 (2-{4-[1-(6-methoxy-3-pyridinyl)-4-methyl-lH-pyrazol-5 yl]phenoxy}ethyl)amine dihydrochloride oil 20 MS(ESI+) : m/z 325 (M+H) 1HNMR ( 200MHz, DMSOd6): 2.03 ( 3H, s), 3.16 - 3.24 ( 2H, m), 3.83 ( 3H, s), 4.18 - 4.24 ( 2H, m), 6.84 ( 1H, d, J = 8.7Hz ) , 7.01 ( 2H, d, J= 8.8Hz ), 7.17 ( 2H, d, J 8.8Hz ), 7.56 ( 1H, dd, J = 2.7 ,8.7Hz), 7.64 ( 1H, s), 7.98 ( 1H, 25 d, J 2.7Hz ), 8.28 ( 2H, brs) Example 449 (2-{4-[1-(4-methoxyphenyl)-3-(methylthio)-lH-pyrazol-5 yl]phenoxy}ethyl)amine hydrocbloride 30 amorphous powder MS (ESI+) : m/z 356 (M+H) 1HNMR ( 200MHz, DMSOd6): 2.52 ( 3H, s), 3.14 - 3.23 ( 2H, 324 WO 2004/050632 PCT/JP2003/014489 m), 3.77 ( 3H, s), 4.15 - 4.21 ( 2H, m), 6.57 ( 1H, s), 6.95 ( 4H, d, J= 8.9Hz ), 7.17 ( 4H, d, J= 8.9Hz ), 8.22 ( 2H, brs) 5 The following compound(s) was (were) obtained in a similar manner to that of Example 428. Example 450 5-[4-(aminomethyl)phenyl]-1-(4-methoxyphenyl)-1H 10 pyrazole-3-carbonitrile hydrochloride MASS (ESI+): m/z = 304.2 (M+1) . Example 451 To a solution of (2-{4-[3-isopropenyl-l-(6-methoxy 15 3-pyridinyl)-lH-pyrazol-5-yllphenoxy}ethyl)amine dihydrochloride (126.4mg) and Et3N (125pl) in CH2Cl2 (2ml) was added methanesulfonyl chloride ( 3 4

.

7 pl) under ice bath cooling. The mixture was stirred at ambient temperature for hour. Additional methanesulfonyl chloride (6. 9pl) and Et3N 20 ( 4 1.6pl) were added and the reaction mixture was stirred at ambient temperature for 30minutes. The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and 1M HC. The aqueous layer was reextracted with AcOEt. The combined organic layers were washed with 25 saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, andconcentratedinvacuo. The residue waspurified by preparative thin layer silica gel chromatography developed by AcOEt/n-hexane= 70%. The seaparated silica 30 gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residue was crystallized from AcOEt-IPE to give N-(2-{4-[3-isopropenyl-l-(6-methoxy 325 WO 2004/050632 PCT/JP2003/014489 3-pyridinyl)-lH-pyrazol-5-yllphenoxylethyl)methane sulfonamide (48.0mg) as white powder. mp. 96-99 0 C IR (KBr) 3205, 3140, 1612, 1502cm-1 5 MS (ESI+) m/z 429 (M+H) 1H NMR (CDCl3) 6 2.20(3H, s), 3.03(3H, s), 3.51-3.60(2H, m)), 3.93(3H, s), 4.07-4.13(2H, m), 4.25(1H, t, J=5.8 Hz), 5.15(1H, brs), 5.60(1H, brs), 6.59(1H, s), 6.73(1H, d, J=8.9 Hz), 6.83 (2H, d, J=8.8 Hz), 7. 17 (2H, d, J=8.8 Hz), 7.55 (1H, 10 dd, J=2.6,8.8 Hz), 8.09(1H, d, J=2.6 Hz) The following compound(s) was(were) obtained in a similar manner to that of Example 451. 15 Example 452 N-(2-{4-[3-{[(dimethylamino)carbonyl]amino}-1-(4 methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methane sulfonamide powder : mp. 166-167oC 20 IR (KBr) : 3309, 3188, 3182, 3174, 1657, 1651, 1643, 1568, 1514cm-1 Mass (ESI+) : 474 (M+H)+ 200MHz 1H NMR (CDCl3, d) : 3.02(3H, s), 3.04(6H, s), 3.49-3.57 (2H, m), 3.81(3H, s), 4.07 (2H, t, J=5.0 Hz), 4.84 (1H, 25 t, J=5.5 Hz), 6.78 (2H, d, J=8.9 Hz), 6.85(2H, d, J=9.0 Hz), 6.85(1H, s), 7.05(1H, s), 7.15(2H, d, J=9.0 Hz), 7.18 (2H, d, J=8.9 Hz) Example 453 30 N-(2-{4-[3-[[(dimethylamino)carbonyl](methyl)amino]-1 (4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl) methanesulfonamide 326 WO 2004/050632 PCT/JP2003/014489 amorphous IR (neat) :1658, 1649, 1641, 1631, 1620, 1612, 1518, 1502cm-1 Mass (ESI+) : 488 (M+H)+ 200MHz 1HNMR (DMSO-d6, d) : 2.79(6H, s) , 2.94 (3H, s) , 3.12 (3H, 5 s), 3.30-3.34 (2H, m), 3.76(3H, s), 4.02(2H, t, J=5.4 Hz), 6.26(1H, s), 6.92 (2H, d, J=8.7 Hz), 6.94 (2H, d, J=8.9 Hz), 7.16(2H, d, J=8.7 Hz), 7.16(2H, d, J=8.9 Hz), 7.29(1H, s) Example 454 10 N-(2-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol 5-yl phenoxylethyl)methanesulfonamide white powder : mp. 112-114'C IR (KBr) : 3280, 1612cm-1 Mass (ESI+) : 423 (M+H)+ 15 200MHz 1H NMR (DMSO-d6, d) : 2.94 (3H, s), 3.29-3.34(2H, m), 3.87 (3H, s), 4.03(2H, t, J=5.4 Hz), 6.75(1H, s), 6.89(1H, d, J=8.8 Hz), 6.96(2H, d, J=8.7 Hz), 7.20(2H, d, J=8.7 Hz), 7.29 (1H, brs), 7.67 (1H, dd, J=2.7,8.8 Hz) , 8.11(1H, d, J=2.7 Hz) 20 Example 455 N-(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5 yl]phenoxylethyl)methanesulfonamide mp. 103-104 0 C 25 IR (KBr) : 3271, 1612, 1579, 1560, 1520, 1514cm-1 Mass (ESI+) : 418 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.94(3H, s), 3.28-3.33(2H, m), 3.76(3H, s), 3.83(3H, s), 3.98-4.05(2H, m), 6.05(1H, s), 6.88-6.96(4H, m), 7.09-7.17(4H, m), 7.27(1H, s) 30 Example 456 N-(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5 327 WO 2004/050632 PCT/JP2003/014489 yl]phenoxylethyl)ethanesulfonamide white powder : mp. 117.8-118.0 0 C IR (KBr) : 3269, 1612, 1552, 1520cm-1 Mass (ESI+) : 432 (M+H)+ 5 200MHz 1H NMR (DMSO-d6, d) : 1.18 (3H, t, J=7.3 Hz), 3.04(2H, q, J=7.3 Hz), 3.26-3.34(2H, m), 3.75(3H, s), 3.83(3H, s), 3.96-4.03(2H,m), 6.05(1H, s), 6.91(2H, d, J=8.9Hz), 6.92(2H, d, J=9.0 Hz), 7.09-7.17(4H, m), 7.32(1H, brs) 10 Example 457 N-(2-{4-[3-ethoxy-l-(4-methoxyphenyl)-1H-pyrazol-5-yll phenoxylethyl)methanesulfonamide white powder : mp. 146-147 0 C IR (KBr) : 3130, 1612, 1518cm-1 15 Mass (ESI+) : 432 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.33(3H, t, J=7.0 Hz), 2.94(3H, s), 3.27-3.36(2H,m), 3.75(3H, s), 3.98-4.05(2H,m), 4.17(2H, q, J=7.0 Hz), 6.03(1H, s), 6.91(2H, d, J=8.8 Hz), 6.92(2H, d, J=9.0 Hz), 7.12(2H, d, J=9.0 Hz), 7.14 (2H, d, J=8.8 Hz), 20 7.29(1H, t, J=5.8 Hz) Example 458 N-(2-{4-[3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazol-5 yl]phenoxy}ethyl)methanesulfonamide 25 white powder : mp. 164.3-165.2 0 C IR (KBr) : 3140, 2952, 2933, 2870, 1614, 1518cm-1 Mass (ESI+) : 460 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 0.97 (6H, d, J=6.8 Hz), 2.03(1H, m), 2.94(3H, s), 3.27-3.36(2H, m), 3.75(3H, s), 3.90(2H, 30 d, J=6.6 Hz), 3.99-4.05(2H, m), 6.05(1H, s), 6.88-6.96(4H, m), 7.12(2H, d, J=9.0 Hz), 7.14 (2H, d, J=8.8 Hz), 7.28(1H, t, J=5.8 Hz) 328 WO 2004/050632 PCT/JP2003/014489 Example 459 N-(2-{4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-1H pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide 5 white powder : mp. 94.5-94.7'C IR (KBr) : 3319, 2933, 2891, 1612, 1520cm-1 Mass (ESI+) : 462 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.94 (3H, s), 3.29-3.35(2H, m), 3.30(3H, s), 3.62-3.67(2H, m), 3.75(3H, s), 3.98-4.05(2H, 10 m), 4.22-4.27(2H, m), 6.05(1H, s), 6.89-6.95(4H, m), 7.10-7.17(4H, m), 7.28(1H, s) Example 460 N-(2-{4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1H 15 pyrazol-5-yl]phenoxylethyl)methanesulfonamide white powder : mp. 116.3-116.4 0 C IR (KBr) : 3141, 2873, 1612, 1518cm-1 Mass (ESI+) : 476 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.13(3H, t, J=7.0 Hz), 2.94(3H, 20 s), 3.28-3.40(2H, m), 3.49(2H, q, J=7.0 Hz), 3.66-3.71(2H, m), 3.75(3H, s), 3.98-4.05(2H,m), 4.21-4.26(2H,m), 6.06(1H, s), 6.89-6.95(4H, m), 7.09-7.17(4H, m), 7.29(1H, brs) Example 461 25 N-(2-{4-[3-methoxy-l-(6-methoxy-3-pyridinyl)-lH pyrazol-5-yllphenoxy}ethyl)methanesulfonamide mp. 116-117.5 0 C IR (KBr) 3126, 1614, 1520, 1500cm-1 MS (ESI+) m/z 419 (M+H)+ 30 200MHz 1H NMR (DMSO-d6, d) : 2.94 (3H, s), 3.28-3.36(2H, m), 3.85(3H, s) , 4.00-4.06(2H, m), 6.11(1H, s) , 6.85(1H, d, J=8.9 Hz), 6.94 (2H, d, J=8.8 Hz), 7.18 (2H, d, J=8.8 Hz), 7.29(1H, 329 WO 2004/050632 PCT/JP2003/014489 s), 7.60(1H, dd, J=2.6,8.9 Hz), 8.00(1H, d, J=2.6 Hz) Example 462

N-(

2 -{4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol 5 5 -yl]phenoxylethyl)methanesulfonamide white powder : mp. 122.0-122.6 0 C IR (KBr) 3242, 1614, 1518, 1502cm-1 MS (ESI+) m/z 433 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.33(3H, t, J=7.0 Hz), 2.94(3H, 10 s), 3.29-3.35(2H, m), 3.84(3H, s), 4.00-4.06(2H,m), 4.19(2H, q, J=7.0 Hz), 6.10(1H, s), 6.85(1H, d, J=8.8 Hz), 6.94 (2H, d, J=8.7 Hz), 7.18 (2H, d, J=8.7 Hz), 7.29(1H, brs) 7.59(1H, dd, J=2.7,8.8 Hz), 7.99(1H, d, J=2.7 Hz) 15 Example 463 N-(2-44-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoro methyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methane sulfonamide MASS (ESI+): m/z = 492.1 (M+Na). 20 1HNMR ( 400MHz, CDC13): 2.15 ( 3H, s), 3.03 ( 3H, s), 3.53 - 3.57 ( 2H, m), 3.79 ( 3H, s), 4.11 ( 2H, t, J 5.0Hz ), 4.78 ( 1H, t, J = 6.0Hz ), 6.81 ( 2H, d, J = 9.0Hz ) 6.86 ( 2H, d, J= 8.8Hz), 7.08 25 ( 2H, d, J = 8.8Hz ), 7.13 ( 2H, d, J = 9.0Hz Example 464 N-[2-(4-{3-(difluoromethyl)-1-[4-(methylthio)phenyl] 30 1H-pyrazol-5-yl}phenoxy)ethyl]methanesulfonamide mp: 122.7-122.8'C . MASS (ESI+): m/z = 476.1 (M+Na). 330 WO 2004/050632 PCT/JP2003/014489 1HNMR ( 400MHz, CDC13): 2.49 ( 3H, s), 3.03 ( 3H, s), 3.55 ( 2H, dt, J= 4.9 ,6Hz), 4.1 ( 2H, t, J = 4.9Hz ), 4.8 1H, t, J= 6Hz), 6.66 ( 1H, s), 6.76 ( 1H, t, J= 55Hz ), 6.83 ( 2H, d, J= 8.8Hz ), 7.16 ( 2H, d, J = 8.8Hz ), 7.22 5 ( 4H, s). Example 465 N-{4-[I-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H pyrazol-5-yl]benzyl}methanesulfonamide 10 Crystal. mp: 125-126'C MASS (ESI+): 449.0 (M+Na). 1HNMR ( 400MHz, CDC13): 2.91 ( 3H, s), 3.94 ( 3H, s), 4.34 ( 2H, d, J = 6.2Hz ), 4.74 ( 1H, t, J = 6.2Hz ), 6.74 ( lH, s), 6.77 ( 1H, d, J= 8.8Hz ), 7.24 ( 2H, d, J= 8.3Hz ), 15 7.35 ( 2H, d, J= 8.3Hz ), 7.58 ( 1H, dd, J = 2.7 ,8.8Hz), 8.03 ( 1H, d, J = 2.7Hz ). Example 466 N-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-lH 20 pyrazol-5-yllbenzyl}methanesulfonamide mp: 125.7-126.1 0 C MASS (ESI+): m/z = 431.0 (M+Na). 1HNMR ( 400MHz, CDC13): 2.92 ( 3H, s), 3.94 ( 3H, s), 4.33 C 2H, d, J= 6.1Hz ), 4.73 ( 1H, b.s), 6.74 ( 1H, s), 25 6.77 ( 1H, t, J = 55Hz ), 7.24 ( 2H, d, J = 8.8Hz ), 7.25 (1H, d, J =7.9Hz ),7.34 (2H, d, J =7.9Hz), 7.55 ( 1H, dd, J= 2.3 ,8.8Hz), 8.03 ( 1H, d, J = 2.3Hz Example 467 30 N-(2-{4-[3-cyclopropyl-l-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide mp. 95-97 0 C 331 WO 2004/050632 PCT/JP2003/014489 MS (ESI+) : m/z 429 (M+H) 1HNMR ( 200MHz, ): 0.70 -0.78 ( 2H, in), 0.87 - 0.98 ( 2H, m), 1.87 - 1.99 ( 1H, m), 2.94 ( 3H, s), 3.20 - 3.52 ( 2H, m), 3.85 ( 3H, s), 3.99 - 4.05 ( 2H, m), 6.30 ( 1H, s), 6.85 5 ( 1H, d, J = 8.8Hz ), 6.93 ( 2H, d, J 8.7Hz ), 7.15 ( 2H, d, J= 8.7Hz ), 7.27 (1H, brs), 7.59 ( 1H, dd, J 2.7 ,8.8Hz), 8.00 ( 1H, d, J = 2.7Hz Example 468 10 N-(2-{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl) 1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide mp.149.1-150.3 C Mass (ESI+) : 499 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.43 - 1.74 ( 6H, m), 2.94 ( 3H, 15 s), 3.25 -3.39 ( 2H, m), 3.52 - 3.70 ( 2H, m), 3.77- 3.92 ( 2H, m), 3.78 ( 3H, s), 3.99 - 4.06 ( 2H, m), 6.78 ( 1H, s), 6.93 ( 2H, d, J = 8.9Hz ), 6.98 ( 2H, d, J = 8.9Hz ), 7.18 ( 2H, d, J = 8.9Hz ), 7.23 ( 2H, d, J = 8.9Hz ), 7.27 ( 1H, brs) 20 Example 469 N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl carbonyl)-1H-pyrazol-5-yllphenoxylethyl)methane sulfonamide 25 mp.158.8-159.1 0 C Mass (ESI+) : m/z 500 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.43 - 1.74 ( 6H, m), 2.94 ( 3H, s), 3.22 - 3.40 ( 2H, m), 3.52 - 3.69 C 2H, m), 3.75 - 3.91 ( 2H, m), 3.87 ( 3H, s), 4.00 - 4.07 ( 2H, m), 6.82 ( 1H, 30 s), 6.90 ( 1H, d, J = 8.8Hz ), 6.96 ( 2H, d, J = 8.8Hz ), 7.22 ( 2H, d, J= 8.8Hz ), 7.28 ( 1H, brs), 7.68 ( 1H, dd, J = 2.7 ,8.8Hz), 8.14 ( 1H, d, J = 2.7Hz 332 WO 2004/050632 PCT/JP2003/014489 Example 470 N-ethyl-i-(4-methoxyphenyl)-N-methyl-5-(4-{2-[(methyl sulfonyl)amino]ethoxy}phenyl)-1H-pyrazole-3-carboxamide 5 mp.106.0-106.3 0 C Mass (ESI+) : m/z 473 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.08 - 1.22 ( 3H, m), 2.94 ( 3H, s), 2.97, 3.29 ( 3H, s), 3.28 - 3.35 ( 2H, m), 3.42 - 3.53, 3.67 - 3.79 ( 2H, m), 3.78 ( 3H, s), 3.99 - 4.06 ( 2H, m), 10 6.79, 6.81 ( 1H, s), 6.93 ( 2H, d, J= 8.9Hz ), 6.98 ( 2H, d, J = 9Hz ), 7.15 - 7.26 ( 4H, m), 7.28 ( 1H, brs) Example 471 N-ethyl-1-(6-methoxy-3-pyridinyl)-N-methyl-5-(4-{2 15 [(methylsulfonyl)amino]ethoxy}phenyl)-1H-pyrazole-3 carboxamide mp.110-111 0C Mass (ESI+) : m/z 474 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.09 - 1.23 ( 3H, m), 2.94 ( 3H, 20 s), 2.98, 3.28 ( 3H, s), 3.28 - 3.36 ( 2H, m), 3.42 - 3.55, 3.66 - 3.78 ( 2H, m), 3.87 ( 3H, s), 4.01 - 4.07 ( 2H, m), 6.83, 6.85 ( 1H, s), 6.90 ( 1H, d, J = 9.0Hz ), 6.96 ( 2H, d, J= 8.7Hz ), 7.22 ( 2H, d, J= 8.7Hz ), 7.28 ( 1H, brs), 7.61 - 7.75 ( 1H, m), 8.14 - 8.16 ( 1H, m) 25 Example 472 N-(2-{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl]phenoxylethyl)methanesulfonamide mp. 155.6-155.8-C 30 MS (ESI+) : m/z 459 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.16 ( 6H, d, J = 6.9Hz ), 2.94 3H, s), 3.25 - 3.40 ( 2H, m), 3.68 ( 1H, m), 3.88 ( 3H, 333 WO 2004/050632 PCT/JP2003/014489 s), 4.01 - 4.07 ( 2H, m), 6.93 ( 1H, d, J = 8.7Hz ), 6.96 ( 2H, d, J= 8.7Hz ), 7.02 ( 1H, s), 7.23 ( 2H, d, J= 8.7Hz ), 7.28 ( 1H, brs), 7.74 ( 1H, dd, J= 2.7 ,8.7Hz), 8.18 ( 1H, d, J 2.7Hz 5 Example 473 N-(2-{4-[3-(cyclopentyloxy)-1-(6-methoxy-3-pyridinyl) 1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide oil 10 MS (ESI+) : m/z 473 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.51 - 2.00 ( 8H, m), 2.94 ( 3H, s), 3.24 - 3.39 ( 2H, m), 3.84 ( 3H, s), 4 - 4.06 ( 2H, m), 4.98 ( 1H, m), 6.07 ( 1H, s), 6.84 ( 1H, d, J = 8.8Hz ), 6.94 ( 2H, d, J = 8.8Hz ), 7.18 ( 2H, d, J = 8.8Hz ), 7.28 15 ( 1H, brs), 7.58 ( 1H, dd, J = 2.7 ,8.8Hz), 7.99 ( 1H, d, J = 2.7Hz ) Example 474 N-(2-{4-[1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy) 20 1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide mp.131.3-131.4 C MS (ESI+) : m/z 486 (M+H) 1HNMR ( 200MHz, DMSOd6) : 2.94 ( 3H, s), 3.25 - 3.39 ( 2H, m), 3.76 ( 3H, s), 3.99 - 4.05 ( 2H, m), 4.81 ( 1H, d, J 25 = 9.0Hz ), 4.90 ( 1H, d, J = 9.0Hz ), 6.22 ( 1H, s), 6.90 - 6.98 ( 4H, m), 7.11 - 7.18 ( 4H, m), 7.28 ( 1H, brs) Example 475 N-(2-{4-[3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-1H 30 pyrazol-5-ylJphenoxylethyl)methanesulfonamide mp. 145.0-145.1'C MS (ESI+) : m/z 468 (M+H) 334 WO 2004/050632 PCT/JP2003/014489 1HNMR ( 200MHz, DMSOd6): 2.93 ( 3H, s), 3.28 - 3.34 ( 2H, m), 3.76 ( 3H, s), 3.99 - 4.05 ( 2 H, m), 4.44 ( 2H, dt, J = 3.5 ,14.9Hz) , 6.15 ( 1H, s), 6.41 ( 1H, tt, J = 3.5, 54.6Hz ), 6.92 ( 2H, d, J = 9.0Hz ), 6.93 ( 2H, d, J = 9.0Hz ), 7.11 5 - 7.18 ( 4H, m), 7.27 ( 1H, brs) Example 476 N-(2-14-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro ethoxy)-1H-pyrazol-5-yllphenoxyIethyl)methane 10 sulfonamide oil MS (ESI+) : m/z 487 (M+H) 1HNMR ( 200MHz, DMSOd6): 2.94 ( 3H, s), 3.29 - 3.35 ( 2H, m), 3.85 ( 3H, s), 4.00 - 4.06 ( 2H, m), 4.83 ( 1H, d, J 15 = 9.0Hz ), 4.92 ( 1H, d, J= 9.0Hz ), 6.28 ( 1H, s), 6.87 1H, d, J= 8.8Hz ), 6.95 ( 2H, d, J= 8.8Hz ), 7.19 ( 2H, d, J= 8.8Hz ), 7.28 (1H, brs), 7.61 ( 1H, dd, J= 2.7 ,8.9Hz), 8.03, ( 1H, d, J = 2.7Hz 20 Example 477 N-(2-{4-[3-(2,2-difluoroethoxy)-l-(6-methoxy-3 pyridinyl)-lH-pyrazol-5-yllphenoxy}ethyl)methane sulfonamide solid 25 MS (ESI+) : m/z 469 (M+H) 1HNMR ( 200MHz, CDCl3): 3.03 ( 3H, s), 3.51 - 3.60 ( 2H, m), 3.92 ( 3H, s), 4.07 - 4.13 ( 2H, m), 4.46 ( 2H, dt, J =4.2 ,13.4Hz), 4.76 ( 1H, t, J= 6Hz), 5.95 ( 1H, s), 6.17 1H, tt, J = 4.2, 55.4Hz ) , 6.72 ( 1H, d, J = 8.8Hz ) , 6.83 30 ( 2H, d, J= 8.8Hz ), 7.15 ( 2H, d, J = 8.8Hz ), 7.49 ( 1H, dd, J = 2.8 ,8.8Hz), 8.01 ( 1H, d, J = 2.8Hz 335 WO 2004/050632 PCT/JP2003/014489 Example 478

N-(

2

-{

4

-[

3 -chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl] phenoxy}ethyl)- 2 -hydroxyethanesulfonamide mp.139.1-139.4 0 C 5 MS (ESI+) : m/z 452 (M+H) 1HNMR ( 200MHz, DMSOd6): 3.18 - 3.35 ( 4H, m), 3.69 - 3.77 ( 2H, m), 3.78 ( 3H, s), 3.97 - 4.04 ( 2H, m), 4.90 ( 1H, t, J = 5.6Hz ), 6.69 ( 1H, s), 6.90 - 7.01 ( 4H, m), 7.14 - 7.26 ( 5H, m) 10 Example 479 N-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl) 1H-pyrazol-5-yl]phenoxylethyl)methanesulfonamide oil 15 Mass (ESI+) : m/z 439 (M+H) 1HNMR ( 200MHz, CDCl3): 3.03 ( 3H, s), 3.51 - 3.60 ( 2H, m), 3.94 ( 3H, s), 4.08 - 4.14 ( 2H, m), 4.75 ( 1H, t, J = 5.6Hz ), 6.68 ( 1H, s), 6.75 ( 1H, d, J = 8.9Hz ), 6.76 1H, t, J = 55Hz ), 6.85 ( 2H, d, J = 8.8Hz ), 7.17 ( 2H, 20 d, J= 8.8Hz ), 7.53 ( 1H, dd, J= 2.7 ,8.9Hz), 8.08 ( 1H, d, J = 2.7Hz Example 480 N-{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-lH 25 pyrazol-5-yl]benzyl}methanesulfonamide mp.179.3-179.6 0 C MS (ESI+) : m/z 469 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.42 - 1.72 ( 6H, m), 2.85 ( 3H, s), 3.52 - 3.69 ( 2H, m), 3.75 - 3.92 ( 2H, m), 3.78 ( 3H, 30 s), 4.15 ( 2H, s), 6.85 ( 1H, s), 6.98 ( 2H, d, J= 9Hz ), 7.21 - 7.35 ( 6H, m), 7.58 ( 1H, brs) 336 WO 2004/050632 PCT/JP2003/014489 Example 481 N-ethyl-1-(4-methoxyphenyl)-N-methyl-5-(4-{[(methyl sulfonyl)amino]methyl}phenyl)-1H-pyrazole-3-carboxamide mp.149.8-150.8 C 5 MS (EST+) : m/z 443 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.09 - 1.21 ( 3H, m), 2.86 ( 3H,, s), 2.98, 3.29 ( 3H, s), 3.40 - 3.78 ( 2H, m), 3.78 ( 3H, s), 4.13 - 4.17 ( 2H, m), 6.86, 6.88 ( 1H, s), 6.98 ( 2H, d, J = 9Hz ), 7.21 - 7.35 ( 6H, m), 7.58 ( 1H, brs) 10 Example 482

N-{

4

-[

3 -isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl] benzyl}methanesulfonamide mp.130.9-131.0 C 15 MS (ESI+) : m/z 400 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.27 ( 6H, d, J = 6.9Hz ), 2.84 ( 3H, s), 2.96 ( 1H, m), 3.76 ( 3H, s), 4.14 ( 2H, s), 6.47 ( 1H, s), 6.93 ( 2H, d, J= 8.9Hz ), 7.11 - 7.21 ( 4H, m), 7.30 ( 2H, d, J = 8.2Hz ), 7.56 ( 1H, brs) 20 Example 483

N-{

4 -[3-isobutyryl-1-(4-methoxyphenyl)-lH-pyrazol-5 yl]benzyl}methanesulfonamide mp.155.8-155.9OC 25 MS (ESI+) : m/z 428 (M+H) 1HNMR ( 200MHz, ): 1.16 ( 6H, d, J = 6.9Hz ), 2.86 C 3H, s), 3.68 ( 1H, m), 3.79 ( 3H, s), 4.15 ( 2H, s), 7.00 ( 2H, d, J = 8.9Hz ), 7.06 ( 1H, s), 7.22 - 7.35 ( 6H, m), 7.58 ( 1H, s) 30 Example 484 N-{4-[l-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl 337 WO 2004/050632 PCT/JP2003/014489 carbonyl)-1H-pyrazol-5-yllbenzyl}methanesulfonamide mp.182.6-182.9 0 C MS (ESI+) : m/z 470 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.42 - 1.72 ( 6H, m), 2.86 ( 31H, 5 s), 3.53 - 3.69 ( 2H, m), 3.75 - 3.9 ( 2H, m), 3.87 ( 3H, s), 4.16 ( 2H, s), 6.89 ( 1H, s), 6.90 ( 1H, d, J= 8.8Hz ), 7.28 ( 2H, d, J 8.4Hz ), 7.36 ( 2H, d, J = 8.4Hz ), 7.59 1H, s), 7.70 ( 1H, dd, J= 2.7 ,8.8Hz), 8.14 ( 1H, d, J = 2.7Hz 10 Example 485 N-ethyl-1-(6-methoxy-3-pyridinyl)-N-methyl-5-(4 {[(methylsulfonyl)aminolmethyl}phenyl)-1H-pyrazole-3 carboxamide 15 white powder MS (ESI+) : m/z 444 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.09 - 1.23 ( 3H, m), 2.86 ( 3H, s), 2.98, 3.29 ( 3H, s), 3.49, 3.72 ( 2H, q, J = 7.1Hz ), 3.87 ( 3H, s), 4.16 ( 2H, s), 6.88 - 6.93 ( 2H, m), 7.28 20 ( 2H, d, J= 8.3Hz), 7.36 ( 2H, d, J= 8.3Hz ), 7-56 ( 1H, brs), 7.65 - 7.74 ( iH, m), 8.13 - 8.14 ( 1H, m) Example 486 N-{4-[3-isopropyl-l-(6-methoxy-3-pyridinyl)-1H-pyrazol 25 5-yl]benzyl}methanesulfonamide oil MS (ESI+) m/z 401 (M+H) 1HNMR ( 200MHz, CDC13): 1.34 ( 6H, d, J= 6.9Hz), 2.86 ( 3H, s), 3.03 ( 1H, m), 3.90 ( 3H, s), 4.28 ( 2H, d, J= 6.1Hz ), 30 5.19 ( 1H, t, J = 6.1Hz ), 6.34 ( 1H, s), 6.72 ( 1H, d, J = 8.8Hz ) , 7.21 ( 2H, d, J= 8.2Hz ), 7.29 ( 2H, d, J= 8.2Hz ) 7.56 ( 1H, dd, J = 2.7 ,8.8Hz), 7.98 ( 1H, d, J = 2.7Hz 338 WO 2004/050632 PCT/JP2003/014489 Example 487 N-{4-[3-isobutyryl-l-(6-methoxy-3-pyridinyl)-lH pyrazol-5-yl]benzyl}methanesulfonamide 5 mp.160.8-161.2 0 C MS (ESI+) : m/z 429 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.16 ( 6H, d, J = 6.8Hz ), 2.86 3H, s), 3.68 ( 1H, m), 3.88 ( 3H, s), 4.16 ( 2H, d, J = 5.5Hz ), 6.93 ( 1H, d, J 8.8Hz ), 7.09 ( 1H, s), 7-29 10 ( 2H, d, J = 8.3Hz ) , 7.36 ( 2H, d, J = 8.3Hz ), 7.59 ( 1H, t, J= 5.5Hz ), 7.76 ( 1H, dd, J= 2.8 ,8.8Hz), 8.18 ( 1H, d, J = 2.7Hz Example 488 15 N-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5 yl]benzyl}methanesulfonamide mp.94.0-94.3 0 C MS (ESI+) : m/z 388 (M+H) 1HNMR ( 200MHz, DMSOd6): 2.85 ( 3H, s), 3.76 ( 3H, s), 3.84 20 ( 3H, s), 4.14 ( 2H, s), 6.12 ( 1H, s), 6.92 ( 2H, d, J = 8.9Hz ), 7.14 ( 2H, d, J= 8.9Hz ), 7.20 ( 2H, d, J = 8.2Hz ), 7.30 ( 2H, d, J = 8.2Hz ), 7.57 ( 1H, s) Example 489 25 N-{4-[3-isopropoxy-l-(4-methoxyphenyl)-1H-pyrazol-5 yllbenzyllmethanesulfonamide amorphous MS (ESI+) : m/z 416 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.32 ( 6H, d, J = 6.1Hz ), 2.85 30 ( 3H, s), 3.75 ( 3H, s), 4.14 ( 2H, s), 4.77 ( 1H, m), 6.07 ( 1H, s), 6.91 ( 2H, d, J= 8.9Hz), 7.13 ( 2H, d, J= 8.9Hz ), 7.19 ( 2H, d, J = 8.2Hz ), 7.30 ( 2H, d, J= 8.2Hz ), 7.57 339 WO 2004/050632 PCT/JP2003/014489 1H, brs) Example 490 N-{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro 5 ethoxy)-1H-pyrazol-5-yl]benzyl}methanesulfonamide mp.130-131 0 C Mass (ESI+) : 457 (M+H) 1HNMR ( 200MHz, CDCl3): 2.92 ( 3H, s), 3.93 ( 3H, s), 4.33 ( 2H, d, J= 6.0Hz ), 4.54 - 4.71 ( 1H, m), 4.62 ( 1H, d, 10 J = 8.4Hz ), 4.70 ( 1H, d, J = 8.4Hz ), 6.04 ( 1H, s) , 6.73 ( 1H, d, J= 8.8Hz ), 7.22 ( 2H, d, J= 8.3Hz ), 7.33 ( 2H, d, J = 8.3Hz ), 7.52 ( 1H, dd, J = 2.7 ,8.8Hz), 7.95 ( 1H, d, J = 2.7Hz 15 Example 491 N-{4-[3-chloro-1-(4-methoxyphenyl)-lH-pyrazol-5 yl]benzyl}methanesulfonamide mp.68.3-69.3 C Mass (ESI+) : 392 (M+H) 20 1HNMR ( 200MHz, DMSOd6): 2.85 ( 3H, s), 3.77 ( 3H, s), 4.14 2H, s), 6.76 ( 1H, s), 6.96 ( 2H, d, J = 8.9Hz ), 7.17 - 7.24 ( 4H, m), 7.32 ( 2H, d, J = 8.2Hz ), 7.58 ( 1H, s) Example 492 25 N-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5 yl]benzyl}methanesulfonamide oil Mass (ESI+) : 393 (M+H) 1HNMR ( 200MHz, DMSOd6): 2.86 ( 3H, s), 3.86 ( 3H, s), 4.16 30 ( 2H, s), 6.82 ( 1H, s), 6.89 ( 1H, d, J = 8.8Hz ), 7.26 ( 2H, d, J= 8.3Hz ) , 7.35 ( 2H, d, J = 8.3Hz ) , 7.59 ( 1H, brs), 7.69 (1H, dd, J= 2.7 ,8.8Hz), 8.1 (11H, d, J= 2.7Hz 340 WO 2004/050632 PCT/JP2003/014489 Example 493 N- (2-{4- [1- (4-methoxyphenyl) -3- (methylthio) -lH-pyrazol 5-ylphenoxy)ethyl)methanesulfonamide 5 mp. 165.0-166.0 0 C MS (ESI+) : m/z 434 (M+H) 1HNMR (200MHz, DMSOd6): 2.51 ( 3H, s), 2.94 ( 3H, s), 3.27 -3.36 ( 2H, m), 3.77 ( 3H, s), 3.99 - 4.05 ( 2H, m), 6.56 1H, s), 6.92 ( 2H, d, J= 8.8Hz ), 6.95 ( 2H, d, J= 8.9Hz ), 10 7.15 ( 2H, d, J = 8.8Hz ), 7.17 ( 2H, d, J = 8.9Hz ), 7.27 1H, t, J = 5.8Hz Example 494 N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl) 15 1H-pyrazol-5-ylphenyl}ethyl)benzenesulfonamide amorphous powder Mass (ESI+) : 503 (M+H)+ 200MHzlHNMR (DMSO-d6, d) :2.64-2.72(2H, m), 2.91-3.02(2H, m), 3.88 (3H, s), 6.91(1H, d, J=9.0 Hz), 7.03-7.21(5H, m), 20 7.56-7.80(7H, in), 8.18(lH, d, J=2.6 Hz) Example 495 N-methoxy-1-(4-methoxyphenyl)-N-methyl-5-(4-{2 [(methylsulfonyl)amino]ethyl}phenyl)-lH-pyrazole- 3 25 carboxamide oil Mass (ESI+) : m/z 459 (M+H) 1HNMR ( 200MHz, CDCl3): 2.84 - 2.91 ( 2H, m), 2.87 ( 3H, s), 3.35 - 3.46 ( 2H, m), 3.51 ( 3H, s), 3.83 ( 3H, s), 3.85 30 ( 3H, s) , 4.26 ( 1H, t, J = 6.2Hz ), 6.86 ( 2H, d, J= 9.0Hz ) 6.97 ( 1H, s), 7.12 - 7.29 ( 6H, m) 341 WO 2004/050632 PCT/JP2003/014489 Example 496 N-methoxy-1- (6-methoxy-3-pyridinyl) -N-methyl-5- (4-{2 [(methylsulfonyl)amino]ethyl}phenyl)-lH-pyrazole- 3 carboxamide 5 oil Mass (ESI+) : m/z 460 (M+H) 1HNMR ( 200MHz, CDCl3): 2.80 -2.93 ( 2H, m), 2.88 ( 3H, s), 3.36 - 3.47 ( 2H, m), 3.50 ( 3H, s), 3.85 ( 3H, s), 3.94 ( 3H, s), 4.28 ( 1H, t, J= 6.2Hz ), 6.75 ( 1H, d, J= 8.8Hz ), 10 6.98 (1H, s), 7.20 ( 4H, s), 7.56 (1H, dd, J= 2.7 ,8.8Hz), 8.10 ( iH, d, J = 2.7Hz Example 497 Trimethylsilyl isocyanate (73.

8 pl) was addded to a solution 15 of (2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H pyr'azol-5-yllphenoxy} ethyl) amine dihydrochloride (115.4mg) and Et3N (114pl) and the mixture was stirred at ambient temperature for 1.5 hours. The mixture was concentrated invacuo andthe residuewas partitionedbetween 20 AcOEt and 1M HCl. The aqueous layer was reextracted with AcOEt. The combined organic layers were washedwith saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo. The residue was purified by 25 preparative thin layer silica gel chromatography developed by 10% MeOH/CHCl3. The seaparated silica gel was extracted with 10% MeOH/CHC13 and the solvent was evaporated in vacuo. The residue was crystallized from AcOEt-IPE to give N-(2-{4-[3-isopropenyl-l-(6-methoxy-3-pyridinyl)-1H 30 pyrazol-5-yl]phenoxy}ethyl)urea (40.1mg) as a white powder. white powder : mp. 94-98'C 342 WO 2004/050632 PCT/JP2003/014489 IR (KBr) : 3435, 3388, 3344, 3333, 1657, 1631, 1610, 1577, 1572, 1562, 1552, 1502cm-i 1HNMR (DMSO-d6) 5 2.10(3H, s), 3.28-3.27(2H, m), 3.86(3H, s), 3.91-3.97(2H, m), 5.15(1H, brs), 5.53(2H, s), 5.62(1H, 5 brs), 6.16(1H, t, J=5.5 Hz), 6.84(1H, s), 6.88(1H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 7.19(2H, d, J=8.8 Hz), 7.64 (1H, dd, J=2.7,8.8 Hz), 8.07(1H, d, J=2.7 Hz) The following compound(s) was (were) obtained in a similar io manner to that of Example 497. Example 498 N-(2-{4-[3-methoxy-l-(4-methoxyphenyl)-1H-pyrazol-5 yl]phenoxylethyl)urea 15 mp. 108-111 0 C IR (KBr) : 3388, 3342, 1657, 1631, 1612, 1593, 1577, 1562, 1522cm-1 Mass (ESI+) : 383 (M+H)+ 200MHz 1H NMR (CDC13, d) : 3.54-3.62(2H, m), 3.79(3H, s), 20 3 .96 (3H, s) , 3. 98-4.04 (2H, m) , 4.44 (2H, s), 5.03 (1H, t, J=5.5 Hz), 5.88 (1H, s), 6.78(2H, d, J=8.8 Hz), 6.82(2H, d, J=8.9 Hz), 7.12(2H, d, J=8.8 Hz), 7.16(2H, d, J=8.9 Hz) Example 499 25 N-(2-{4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5 yl]phenoxy}ethyl)urea white powder : mp. 154.2-154.4 0 C IR (KBr) : 3398, 3332, 1658, 1631, 1612, 1566, 1518cm-1 Mass (ESI+) : 397 (M+H)+ 30 200MHz 1H NMR (DMSO-d6, d) : 1.33(3H, t, J=7.0 Hz), 3.27-3.34(2H, m), 3.75(3H, s), 3.89-3.96(2H, m), 4.17(2H, q, J=7.0 Hz), 5.53(2H, s), 6.03(1H, s), 6.15(1H, t, J=5.6 343 WO 2004/050632 PCT/JP2003/014489 Hz), 6.90(2H, d, J=8.9 Hz), 6.92(2H, d, J=9.0 Hz), 7.10-7.15(4H, m) Example 500 5 Imidazole (680mg) and t-butyldimethylsilyl chloride (903mg) was added successively to a solution of ethyl 5-[4-{2-(hydroxy)ethoxy}phenyl]-1-(4-methoxyphenyl) lH-pyrazole-3-carboxylate (1.91g) in DMF (15ml) under cooling in an ice bath. After stirring at ambient temperature 10 for 2hours, the mixture was partitioned between AcOEt and H20. The oreganic layer was washed with H20, saturated aqueous sodium chloride solution, dried over MgSO4, concentrated in vacuo. The residual crystals were collected and washed with n-hexane to give ethyl 15 5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy) phenyl]-1-(4-methoxyphenyl)-lH-pyrazole-3-carboxylate (2.34g). powder mp. 86-87 0 C 20 MS (ESI+) : m/z 497 (M+H) 1H NMR (CDCl3) 5 0.09(6H, s), 0.90(9H, s), 1.42(3H, t, J=7.1 Hz), 3.82(3H, s), 3.94-3.97(2H, m), 4.01-4.04(2H, m), 4.44 (2H,' q, J=7.1 Hz), 6.83(2H, d, J=8.7 Hz), 6.85 (2H, d, J=8.9 Hz), 6.96(1H, s), 7.11(2H, d, J=8.7 Hz), 7.24 (2H, d, 25 J=8.9 Hz) Example 501 A solution of ethyl 5- [4- (2-{ [tert-butyl (dimethyl) silyl] oxy}ethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazole-3 30 carboxylate (0.3g) in THF (3ml) was added dropwise to a 1M solution of methylmagnesium bromide (3ml) at ambient temperature. The reaction mixture was stirred at ambient 344 WO 2004/050632 PCT/JP2003/014489 temperature for hour, then was poured into a mixture of crushed ice and saturated aqueous ammonium chloride solution. The mixture was extracted with AcOEt. The oreganic layer was washed with saturated aqueous sodium bicarbonate 5 solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give 2-[5-[4-(2-{[tert-butyl(dimethyl)silylloxy} ethoxy)phenyll-1-(4-methoxyphenyl)-1H-pyrazol-3-yl)-2 propanol (0.27g) as an oil. 10 oil MS (ESI+) : m/z 483 (M+H) 1H NMR (CDCl3) 5 0.09(6H, s), 0.90(9H, s), 1.65(6H, s), 3.81(3H, s), 3.94-3.97(2H, m), 4.01-4.04(2H, m), 6.35(1H, s), 6.82 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.9 Hz), 7.12 (2H, 15 d, J=8.8 Hz), 7.21(2H, d, J=8.9 Hz) The following compound(s) was(were) obtained in a similar manner to that of Example 501. 20 Example 502 N-(2-14-[3-(1-hydroxy-1-methylethyl)-1-(4-methoxy phenyl)-1H-pyrazol-5-yllphenoxy}ethyl)urea white powder : mp. 147-152'C IR (KBr) : 3333, 3271, 2976, 1676, 1664, 1658, 1612, 1547, 25 1537, 1516, 1502cm-l MS (ESI+) : m/z 411 (M+H) 1H NMR (DMSO-d6) 5 1.48 (6H, s), 3.22-3.40(2H, m), 3.76(3H, s), 3.90-3.96(2H, m), 4.98(1H, s), 5.52(2H, s), 6.14(1H, t, J=5.6 Hz), 6.49(1H, s), 6.90 (2H, d, J=8.7 Hz), 6.94 (2H, 30 d, J=8.8 Hz), 7.12(2H, d, J=8.7 Hz), 7.15 (2H, d, J=8.8 Hz) Example 503 345 WO 2004/050632 PCT/JP2003/014489 tert-butyl {4-[3-(l-hydroxy-1-methylethyl)-1 (4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}carbamate powder MS (ESI+) : m/z 438 (M+H) 5 1HNMR ( 200MHz, DMSOd6): 1.39 ( 9H, s), 1.49 ( 6H, s), 3.76 3H, s), 4.11 ( 2H, d, J = 6.1Hz ), 5.01 ( 1H, s), 6.54 1H, s) , 6.94 ( 2H, d, J= 8.9Hz ) , 7.15 ( 2H, d, J= 8.9Hz 7.17 ( 4H, brs), 7.4 ( 1H, t, J = 6.1Hz 10 Example 504 tert-butyl {4-[3-(1-hydroxy-1-methylethyl)-1 (6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl} carbamate powder 15 MS (ESI+) : m/z 439 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.39 ( 9H, s), 1.49 ( 6H, s), 3.85 ( 3H, s), 4.12 ( 2H, d, J = 6.1Hz ), 5.05 ( 1H, s), 6.59 ( 1H, s), 6.86 ( 1H, d, J 8.8Hz ), 7.20 ( 4H, s), 7.40 ( 1H, t, J 6.1Hz ), 7.62 ( 1H, dd, J = 2.7 ,8.8Hz), 8.00 20 ( 1H, d, J 2.7Hz Example 505 A solution of 2-[5-[4-(2-{[tert-butyl(dimethyl)silyl] oxylethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3 25 yl]-2-propanol (180mg) in DMF (2ml) was added dropwise to a suspension of sodium hydride 60% dispersion in mineral oil (17mg) in DMF (1ml) under cooling in an ice bath. After minutes, iodemethane (63.5mg) was added and the reaction mixture was stirred at same temperature for lhour and at 30 ambient temperature for lhour. Additional iodomethane was added until all startingmaterial was consumed. The reaction was quenched by adding saturated ammonium chloride. The 346 WO 2004/050632 PCT/JP2003/014489 mixture was extracted with ethyl acetate. The organic layer was washed with H20 and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column 5 chromatography eluted with AcOEt / n-hexane, which polarity was gradually changed from 20% to 80%, to give 5-[4-(2-{ [tert-butyl (dimethyl)silyl]oxylethoxy) phenyll 3-(1-methoxy-l-methylethyl)-1-(4-methoxyphenyl)-lH pyrazole (32.2mg) as an oil. 10 Mass (ESI+) : 497 (M+H) lH NMR (CDCl3) 5 0.09(6H, s), 0.90(9H, s), 1.58(3H, s), 1.63(3H, s), 3.22(3H, s), 3.81(3H, s), 3.93-4.04(4H, m), 6.42 (1H, s), 6.82 (2H, d, J=8.8 Hz), 6.84 (2H, d, J=9.0 Hz), 7.13(2H, d, J=8.8 Hz), 7.22(2H, d, J=9.0 Hz) 15 Example 506 A 1M solution of tetra-n-butylammonium fluoride in THF (0.24ml) was added to a solution of 5-[4-(2-{ [tert-butyl (dimethyl)silyl]oxy}ethoxy)phenyl]-3-(l-methoxy-l 20 methylethyl)-l-(4-methoxyphenyl)-1H-pyrazole (98mg) in THF(2ml) under ice bath cooling. The reaction mixture was stirred at same temperature for hour. The mixture was partitioned between ethyl acetate and H20. The organic layer was washed with saturated aqueous sodium chloride solution, 25 dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by 50% AcOEt / n-hexane. The seaparated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give 30 2-{4-[3-(1-methoxy-l-methylethyl)-1-(4-methoxyphenyl) 1H-pyrazol-5-yl]phenoxy}ethanol (66mg) as an oil. IR (neat) : 3423, 3398, 3371, 2976, 2935, 1647, 1612, 1566, 347 WO 2004/050632 PCT/JP2003/014489 1549, 1512cm-1 MS (ESI-+) : m/z 383 (M+H) 1H NMR (CDC13) 6 1.60(3H, s), 1.63(3H, s), 2.03(1H, t, J=6.1 Hz), 3.22(3H, s), 3.81(3H, s), 3.91-4.00(2H, m), 5 4.05-4.10(2H,m), 6.43(lH, s), 6.83(2H,d,J=8.9Hz), 6.84(2H, d, J=8.9 Hz), 7.15(2H, d, J=8.9 Hz), 7.21(2H, d, J=8.9 Hz) Example 507 A 4M solution of HCl in dioxane (2ml) was added to a solution 10 of ethyl 5-(4-{2-[(tert-butoxycarbonyl)amino]ethoxyl phenyl)-1-(4- methoxyphenyl)-lH-pyrazole-3-carboxylate (300mg) in CH2Cl2 (3ml) under coolingin an ice bath. After stirring at ambient temperature for hour, the reaction mixturewas concentrated invacuo. The residue was dissolved 15 in CH2Cl2 (3ml), Et3N (189mg) and trimethylsilylisocyanate (108mg) were added, and the mixture was stirred at ambient temperature overnight. The stirring was continued for more 4hours, adding more trimethylsilyl isocyanate and Et3N to consume all starting material. The mixture was concentrated 20 in vacuo and the residue was partitioned between ethyl acetate and IM HCl. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residual crystals 25 were suspended in hot ethyl acetate, cooled with stirring, collected and washed with ethyl acetate to give ethyl 5-(4-{2-[(aminocarbonyl)amino]ethoxylphenyl)-1-(4 methoxyphenyl)-lH-pyrazole-3-carboxylate (217mg) as a white powder. 30 MS (ESI+) : m/z 425 (M+H) 1H NMR (DMSO-d6) 5 1.31(3H, t, J=7.1Hz), 3.27-3.36(2H, m), 3.79 (3H, s), 3.90-3. 96 (2H, m) , 4.32 (2H, q, J=7.I Hz), 5.52 (2H, 348 WO 2004/050632 PCT/JP2003/014489 s), 6.14 (lH, t, J=5.7 Hz), 6.92(2H, d, J=8.8 Hz), 6.99(2H, d, J=8.8 Hz), 7.01(1H, s), 7.17(2H, d, J=8.8 Hz), 7.25(2H, d, J=8 .8 Hz) 5 Example 508 1M NaOH (5ml) was added to a solution of ethyl 5-(4-{2-[(aminocarbonyl)amino]ethoxylphenyl)-l-(4 methoxyphenyl)-1H-pyrazole-3-carboxylate (1.75g) in THF (15ml) and MeOH (10ml). The reaction mixture was stirred 10 at ambient temperature and concentrated in vacuo. The residue was dissolved in H20 and acidified by IM HCl. white precipitates were collected and washed successively with H20 and IPE to give 5-(4-{2-[(aminocarbonyl)amino] ethoxylphenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3 15 carboxylic acid (1.58g) as a white powder. MS (ESI+) : m/z 397 (M+H) 1H NMR (DMSO-d6) 5 3.15-3.55(2H, m), 3.90-3.97(2H, m), 5. 52 (2H, s) , 6.14 (1H, t, J=5.7 Hz) , 6.89-7. 03 (5H, m) , 7.17 (2H, d, J=8.8 Hz), 7.24(2H, d, J=8.9 Hz) 20 The following compound(s) was (were) obtained in a similar manner to that of Example 508. Example 509 25 5-(4-{[(tert-butoxycarbonyl)aminomethyl}phenyl)-l-(4 methoxyphenyl)-lH-pyrazole-3-carboxylic acid white powder MS (ESI+) : m/z 424(M+H) 1HNMR ( 200MHz, DMSOd6): 1.38 ( 9H, s), 3.79 ( 3H, s), 4.11 30 ( 2H, d, J= 6.1Hz ), 6.99 ( 2H, d, J= 8.9Hz ), 7.01 ( 1H, s), 7.20 ( 4H, brs), 7.25 ( 2H, d, J = 8.9Hz ), 7.41 ( 1H, t, J = 6.1Hz ), 12.92 ( 1H, brs 349 WO 2004/050632 PCT/JP2003/014489 Example 510 5-(4-{[(tert-butoxycarbonyl)aminolmethyl}phenyl)-l-(6 methoxy-3-pyridinyl)-1H-pyrazole-3-carboxylic acid 5 powder MS (ESI+) : m/z 425 (M+H) 1HNMR ( 200MHz, CDCl3): 1.46 ( 9H, s), 3.95 ( 3H, s), 4.33 2H, d, J= 5.9Hz ), 4.9 (1H, brs), 6.76 (1H, d, J= 8.8Hz ), 7.07 ( 1H, s), 7.19 ( 2H, d, J = 8.4Hz ), 7.27 ( 2H, d, J 10 = 8.4Hz ), 7.58 ( 1H, dd, J = 2.7 ,8.8Hz), 8.11 ( 1H, d, J = 2.7Hz ) Example 511 A mixture of 5-(4-{2-[(aminocarbonyl)amino]ethoxyl 15 phenyl) -1- (4-methoxyphenyl) -lH-pyrazole-3-carboxylic acid (1.56g), diphenylphosphoryl azide (1.62g), and Et3N (597mg) in t-butanol (5ml) was refluxed for 3hours. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and H20. The combined 20 organic layer was washed twice with 1M HCl. and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was purified by silica gel column chromatography eluted with ethyl acetate 25 to give tert-butyl [5-(4-{2-[(aminocarbonyl)amino] ethoxylphenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3 yl]carbamate (519mg) as an amorphous powder. MS (ESI+) : m/z 468 (M+H) 1HNMR (DMSO-d6) 5 1.46(9H, s), 3.27-3.36(2H, m), 3.76(3H, 30 s), 3.90-3.96(2H, m), 5.52 (2H, s), 6.15(1H, t, J=5.6 Hz), 6.55(1H, s), 6.90(2H, d, J=8.9 Hz), 6.93(2H, d, J=8.9 Hz), 7.13(4H, d, J=8.9 Hz), 9.74(1H, s) 350 WO 2004/050632 PCT/JP2003/014489 Example 512 A 4M solution of HCl in dioxane (3ml) was added to a solution of tert-butyl [5-(4-{2-[(aminocarbonyl)amino]ethoxy} 5 phenyl)-1-(4-methoxyphenyl)-lH-pyrazol-3-yl]carbamate (478mg) in CH2Cl2 (3ml) . The reaction mixture was stirred at ambient temperature for hours and concentrated in vacuo. The residue was partitioned between CHCl3 and saturated aqueous sodium bicarbonate solution. The aq layer was 10 reextrated with CHCl3. The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with CHCl3:MeOH:28% aqueous NH40H=10:1:0.1 to give N-(2-{4-[3-amino-l-(4-methoxyphenyl)-lH-pyrazol-5 15 yl]phenoxy}ethyl)urea (244.6mg) as an amorphous powder. MS (ESI+) : m/z 368 (M+H) IR (neat) : 3400, 3388, 3342, 3330, 1658, 1651, 1643, 1612, 1579, 1562, 1554, 1520cm-1 1H NMR (DMSO-d6) 5 3.27-3.37(2H, m), 3.73(3H, s), 20 3.89-3.95(2H, m), 4.83(2H, s), 5.52(2H, s), 5.73(lH, s), 6.15(1H, t, J=5.5 Hz), 6.85-6.92(4H, m), 7.03-7.12(4H, m) Example 513 37% aqueous solution of formaldehyde (0.23ml) and sodium 25 cyanoborohydride (53mg) were added to a solution of N-(2-{4-[3-amino-i-(4-methoxyphenyl)-1H-pyrazol-5-yll phenoxy}ethyl)urea (103.1mg) in MeOH (2ml). The reaction mixture was stirred at ambient temperature for 3hours. 37% aqueous solution of formaldehyde (0.23ml) and sodium 30 cyanoborohydride (53mg) were added to the mixture and the reaction mixture was stirred at ambient temperature for 4days. The mixture was concentrated in vacuo, and the residue was 351 WO 2004/050632 PCT/JP2003/014489 partitioned between ethyl acetate and H20. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica 5 gel chromatography developed by CHC13 : MeOH : 28%aqueous NH40H= 100:10:1. The seaparated silica gel was extracted with same solvent and the solvent was evaporated in vacuo to give N-(2-{4-[3-(dimethylamino)-1-(4-methoxyphenyl) 1H-pyrazol-5-yllphenoxylethyl)urea (59.9mg) as an 10 amorphous powder. MS (ESI+) .: m/z 396 (M+H) 1H NMR (DMSO-d6) 6 2.81(6H, s), 3.27-3.36(2H, i), 3.74(3H, s), 3.89-3.96(2H, m), 5.52(2H, s), 5.78(lH, s), 6.15(lH, t, J=5.7 Hz), 6.87-6.92(4H, m), 7.05-7.15(4H, m) 15 Example 514 Toasolutionof4-[3-(dimethylamino)-1-(4-methoxyphenyl) 1H-pyrazol-5-yllphenol (98.7mg) in DMF (2ml) was added sodium hydride 60% dispersion in mineral oil (15.3mg). The 20 mixture was stirred at ambient temperature for hour. To the reaction mixture was added (2-bromoethoxy)-tert butyldimethylsilane (153mg) in DMF (1ml) dropwise and the mixture was stirred at ambient temperature overnight. The mixture was poured into ice water, extracted with AcOEt, 25 washed with H20 and saturated aqueous sodium chloride solution. The aqueous layer was reextracted with AcOEt. The combined organic layers were dried over magnesium sulfate, and concentrated invacuo. The residue was dissolved in EtOH (2ml) . To this solution was added concentrated hydrochloric 30 acid (100pl) and the mixture was stirred at ambient temperature for 3hours. Themixture was concentrated invacuo, and the residue was partitioned between AcOEt and saturated 352 WO 2004/050632 PCT/JP2003/014489 aqueous sodium bicarbonate solution, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography 5 developed by AcOEt / n-hexane = 60%. The residual crystals were collected and washed with IPE to give 2-{4-[3-(dimethylamino)-1-(4-methoxyphenyl)-lH-pyrazol 5-yllphenoxy}ethanol (97mg) as a white powder. mp. 120-122'C 10 IR (KBr) : 3292, 2924, 1612, 1577, 1562, 1531, 1514cm-1 Mass (ESI+) : 354 (M+H) + 200MHz 1H NMR (DMSO-d6, d) : 2.81(6H, s), 3.66-3.72(2H, m), 3.74(3H, s), 3.94-4.00(2H, m), 4.86(1H, br), 6.02(1H, s), 6.86-6. 94 (4H, m) , 7.10 (2H, d, J=8.9 Hz), 7. 12 (2H, d, J=8.7 15 Hz) The following compound(s) was (were) obtained in a similar manner to that of Example 514. 20 Example 515 N-[5-[4-(2-hydroxyethoxy)phenyll-1-(4-methoxyphenyl) 1H-pyrazol-3-yl]-N,N',N'-trimethylurea oil IR (neat) : 3410, 2931, 1658, 1649, 1641, 1631, 1612, 1518, 25 1502cm-1 Mass (ESI+) : 411 (M+H)+ 200MHz 1H NMR (CDC13, d) : 2.08 (1H, t, J=5.9 Hz), 2.89(6H, s), 3.33 (3H, s), 3.81(3H, s), 3.92-4.00 (2H, m) , 4.05-4. 10 (2H, m) , 6. 15 (1H, s) , 6.84 (4H, d, J=9. 1 Hz) , 7. 14 (2H, d, J=9. 1 30 Hz), 7.19(2H, d, J=9.1 Hz) Example 516 353 WO 2004/050632 PCT/JP2003/014489 2-{4-[3-ethoxy-1-(4-methoxyphenyl)-lH-pyrazol-5-yll phenoxylethanol white powder : mp. 67.7-69.2'C IR (ATR) : 3363, 2993, 2956, 2925, 2837, 1610, 1577, 1552, 5 1508cm-i Mass (ESI+) : 355 (M+H)+ 200MHz 1H NMR (CDCl3, d) : 1.42 (3H, t, J=7.1 Hz), 2.01(1H, t, J=6.0 Hz), 3.79(3H, s), 3.92-4.00(2H, m), 4.04-4.10(2H, m), 4.29(2H, q, J=7.1 Hz), 5.87(1H, s), 6.77-6.85(4H, m), 10 7.14(2H, d, J=8.8 Hz), 7.17(2H, d, J=8.9 Hz) Example 517 2-{4-[3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl] phenoxy}ethanol 15 oil Mass (ESI+) : m/z 383 (M+H)+ 200MHz 1H NMR (CDCl3, d) : 1.03(6H, d, J=6.8 Hz), 2.02(lH, t, J=6.1 Hz), 2.11(1H, m), 3.79(3H, s), 3.91-4.09(4H, m), 3.99(2H, d, J=6.8 Hz), 5.88(1H, s), 6.77-6.86(4H, m), 20 7.09-7.21(4H, m) Example 518 2-{4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-lH pyrazol-5-yllphenoxylethanol 25 oil Mass (ESI+) : 385 (M+H)+ IR (neat) : 3400, 3390, 3369, 2935, 1612, 1517cm-1 200MHz 1H NMR (DMSO-d6, d) : 3.31(3H, s), 3.62-3.73(4H, m), 3.75(3H, s), 3.94-3.99(2H, m), 4.22-4.27(2H, m), 4.85(1H, 30 t, J=5.5 Hz), 6.04 (1H, s), 6.89(2H, d, J=8.8 Hz), 6.92 (2H, d, J=8.9 Hz), 7.08-7.15(4H, m) 354 WO 2004/050632 PCT/JP2003/014489 Example 519 2-{4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1H pyrazol-5-yl]phenoxylethanol oil 5 IR(neat) : 2972, 2933, 2873, 1612, 1554, 1518, 1510cm-1 Mass (ESI+) : 399 (M+H)+ 200MHz 1H NMR (CDC13, d) : 1.25(3H, t, J=7.0 Hz), 2.04(1H, t, J=6.1 Hz), 3.61(2H, q, J=7.0 Hz), 3.78-3.83(2H, m), 3.79(3H, s), 3.93-4.00(2H, m), 4.04-4.07(2H, m), 10 4.38-4.44 (2H, m), 5.92 (1H, s) , 6.82(4H, d, J=8.8 Hz) , 7.13(2H, d, J=8.8 Hz), 7.16(2H, d, J=8.8 Hz) Example 520 2-{[5-[4-(2-hydroxyethoxy)phenyl]-1-(4-methoxyphenyl) 15 1H-pyrazol-3-ylloxy}-N,N-dimethylacetamide white powder : mp. 106.6-107.1 0 C IR (KBr) 3321, 2939, 1658, 1643, 1608, 1518cm-i MS (ESI+) m/z 412 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.84(3H, s), 2.97 (3H, s), 20 3.65-3.73(2H, m), 3.75(3H, s), 3.94-4.00(2H, m), 4.87(1H, t, J=5.1 Hz), 4.87(2H, s), 6.07(1H, s), 6.90(2H, d, J=8.8 Hz), 6. 92 (2H, d, J=9.0 Hz), 7. 11(2H, d, J=9.0 Hz), 7. 12 (2H, d, J=8.8 Hz) 25 Example 521 2-{4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5 yl]phenoxylethanol white powder : mp.92.2-92.5 0 C IR (KBr) 3325, 1614, 1525, 1504cm-1 30 MS (ESI+) m/z 342 (M+H)+ 200MHz 1HNMR (CDC13, d) : 2.01(1H, t, J=6.1Hz), 3.92-4.10 (4H, m), 3.92(3H, s), 3.97(3H, s), 5.91(1H, s), 6.70(1H, d, J=8.5 355 WO 2004/050632 PCT/JP2003/014489 Hz), 6.85(2H, d, J=8.8 Hz), 7.15(2H, d, J=8.8 Hz), 7.52(1H, dd, J=2.5,8.5 Hz), 8.04(1H, d, J=2.5 Hz) Example 522 5 2-{4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5 yllphenoxy)ethanol white powder : mp. 81-82 C IR (KBr) : 3303, 3298, 1612, 1516cm-1 Mass (sample ID cox022145) (ESI+) : 356 (M+H)+ 10 200MHz 1H NMR (DMSO-d6, d) : 1.33(3H, t, J=7.0 Hz), 3.65-3.74(2H, m), 3.84(3H, s), 3.95-4.01(2H, m), 4.19(2H, q, J=7.0 Hz), 4.87 (lH, t, J=5. 4 Hz), 6.09(lH, s), 6.85(1H, d, J=8.8 Hz), 6.93(2H, d, J=8.8 Hz), 7.16(2H, d, J=8.8 Hz), 7.58(lH, d, J=2.6,8.8 Hz), 7.99(1H, d, J=2.6 Hz) 15 Example 523 To a solution of 5- (hydroxyl) phenyl-l- (4-methoxyphenyl) 4-methyl-3-(trifluoromethyl)-1H-pyrazole (5.0g) and 2-bromoethoxy-tert-butyldimethylsilane (6.87g) in DMF 20 (100ml) was added portionwise NaH (919mg, 50% in oil) at room temperature. The reacion mixture was stirred overnight. The reaction mixture was quenched with water. Aqueouslayer was extracted twice with EtOAc. Combined organic layerwaswashed twice withwater, andbrine. Dried, 25 filteredand evaporated under reducedpressure to give 5.29g (73%) of 5-[4-(2-{[tert-butyl(dimethyl)silylloxy) ethoxy)phenyl]-1-(4-methoxyphenyl)-4-methyl-3 (trifluoromethyl)-1H-pyrazole. MASS (ESI+): m/z = 507.1 (M+1), 529.0 (M+Na). 30 1HNMR ( 400MHz, CDC13): .07 ( 3H, s), .09 ( 3H, s), .9 ( 9H, s), 2.15 ( 3H, s), 3.78 ( 3H, s), 3.62 - 4.13 ( 4H, m), 6.79 2H, d, J = 8.5Hz ), 6.88 ( 2H, d, J= 8.7Hz ), 7.05 ( 2H, 356 WO 2004/050632 PCT/JP2003/014489 d, J = 8.7Hz ), 7.13 ( 2H, d, J = 8.5Hz ). Example 524 2-{4-[1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H 5 pyrazol-5-yl]phenoxy}ethanol mp 50.7-51.7 0 C Mass (ESI+) : 409 (M+H)+ 1HNMR ( 200MHz, CDCl3): 1.99 ( 1H, t, J= 6.OHz ), 3.80 ( 3H, s), 3.92 - 4.00 ( 2H, m), 4.05 - 4.10 ( 2H, m), 4.62 ( 1H, 10 d, J = 8.5Hz ), 4.70 ( 1H, d, J = 8.5Hz ), 5.95 ( 1H, s), 6.79 - 6.92 ( 4H, m), 7.07 - 7.18 ( 4H, m) Example 525 2-{4-[3-(2,2-difluoroethoxy)-l-(4-methoxyphenyl)-1H 15 pyrazol-5-yl]phenoxy}ethanol oil Mass (ESI+) : 391 (M+H) 1HNMR ( 200MHz, CDC13): 1.99 ( 1H, t, J= 6.1Hz ), 3.80 ( 3H, s), 3.92 - 4.00 ( 2H, m), 4.05 - 4.09 ( 2H, m), 4.47 ( 2H, 20 dt, J = 4.2 ,13.5Hz), 5.92 ( 1H, s), 6.17 ( 1H, tt, J = 4.2,55.5Hz ), 6.79 - 6.87 ( 4H, m), 7.09 - 7.20 ( 4H, m) Example 526 2-{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro 25 ethoxy)-1H-pyrazol-5-yl]phenoxy}ethanol mp. 91.2-91.3'C Mass (sample ID cox031168) (ESI+) : 410 (M+H)+ 1HNMR ( 200MHz, CDCl3): 1.99 ( 1H, t, J= 6.1Hz ), 3.91 ( 3H, s), 3.92 - 4.01 ( 2H, m), 4.06 - 4.11 ( 2H, m), 4.61 C 1H, 30 d, J = 8.4Hz ), 4.70 ( 1H, d, J = 8.4Hz ), 5.98 ( 1H, s), 6.71 ( 1H, d, J = 8.8Hz ), 6.86 ( 2H, d, J= 8.8Hz ), 7.14 2H, d, J = 8.8Hz ), 7.40 ( 1H, dd, J = 2.7 ,8.8Hz), 8.02 357 WO 2004/050632 PCT/JP2003/014489 1H, d, J = 2.7Hz Example 527 2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl) 5 1H-pyrazol-5-yl]phenoxylethanol oil Mass (ESI+) : 392 (M+H) 1HNMR ( 200MHz, CDCl3): 3.92 ( 3H, s), 3.93 - 4.00 ( 2H, m), 4.06 - 4.11 ( 2H, m), 4.46 ( 2H, dt, J = 4.2 ,13.2Hz), 10 5.94 ( 1H, s), 6.17 ( 1H, tt, J= 4.2, 55.5Hz ), 6.71 ( 1H, d, J = 9.0Hz ), 6.86 ( 2H, d, J = 8.9Hz ), 7.14 ( 2H, d, J = 8.9Hz ), 7.48 ( 1H, dd, J = 2.7 , 9.0Hz), 8.02 ( 1H, d, J = 2.7Hz 15 Example 528 Carbonyldiimidazole (1.26g) was added to a solution of 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-amino-1H pyrazole (2.4g) in 1-methyl-2-pyrrolidinone (22ml) . After stirring at ambient temperature for 2hour, 2M solution of 20 dimethylamine in THF (7.4ml) was added and th emixture was stirred ambient temperature for 2hour. The reaction mixture was partitioned between ethyl acetate and H20. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated 25 in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / n-hexane =80% to give N'-[5-[4-(benzyloxy)phenyl]-l-(4-methoxyphenyl)-1H pyrazol-3-yl]-N,N-dimethylurea (2.35g) as amorphous powder. 30 Mass (ESI+) : 443 (M+H)+ 200MHz1HNMR (DMSO-d6, d) :2.91(6H, s), 3.76(3H, s), 5.09(2H, s), 6.63(lH, s), 6.93(2H, d, J=9.0 Hz), 6.98 (2H, d, J=9.0 358 WO 2004/050632 PCT/JP2003/014489 Hz), 7.14(2H, d, J=9.0 Hz), 7.15(2H, d, J=9.0 Hz), 7.34-7.44(5H, m), 9.02(1H, s) Example 529 5 A mixture of N'-[5-[4-(hydroxy)pheny]-1-(4 methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea (121. 9mg), 2- (tert-butyl- dimethylsilyloxy) ethyl bromide (166mg), and K2CO3 (95.6mg) in DMF (1.5ml) was stirred at 75'C for 7hours. 2 -(tert-butyldimethylsilyloxy)ethyl 10 bromide (83mg) and KI (57.4mg) was added to the reaction mixture, and the mixture was stirred at 75 0 C overnight. The mixture was allowed to cool to ambient temperature, and was partitioned between ethyl acetate andH20. The aqueous layer was reextracted with ethyl acetate. The combined organic 15 layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by 5% MeOH / CHCl3. The seaparated silica gel was extracted with 10% MeCH/CHCl3 and 20 the solvent was evaporated in vacuo to give N'-[5-[4-(2-hydroxyethoxy)phenyl]-1-(4-methoxyphenyl) 1H-pyrazol-3-yl] -N, N-dimethylurea (115mg) as an amorphous powder. 84.3mg of amorphous powder was crystallized from AcOEt-IPE to give N'-[5-[4-(2-hydroxyethoxy)phenyl] 25 1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea (79.5mg) as a white powder. mp. 167.4-167.6 0 C IR (KBr) : 3317, 1670, 1612, 1587, 1572, 1510cm-1 Mass (ESI+) : 397 (M+H)+ 30 200MHz 1H NMR (DMSO-d6, d) : 2.91(6H, s), 3.65-3.74(2H, m), 3

.

7 6

(

3 H, s), 3. 94-4.00 (2mH, m), 4.87 (H, t, J=5.5 Hz), 6.62.(1H, s), 6.90(2H, d, J=8.7 Hz), 6.93(2H, d, J=8.9 Hz), 7.12(2H, 359 WO 2004/050632 PCT/JP2003/014489 d, J=8.7 Hz), 7.15(2H, d, J=8.9 Hz), 9.02(1H, s) Example 530 Diethylazodicarboxylate 308mg was added to a solution of 5 N'-[5-[4-(hydroxy)-phenyl]-l-(4-methoxyphenyl)-lH pyrazol-3-yl]-N,N-dimethylurea 415mg, tert-butyl N- (2-hydroxyethyl) carbamate 380mg, and triphenylphosphine 463mg in THF 5ml. After stirring at ambient temperature for overnight, the reaction mixture was concentrated in vacuo. 10 To a solution of the residue in CH2C12 5ml, was added 4M aolution of HCl in dioxane 5ml. After stirring at ambient temperature for 1.5hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between AcOEt and 1M HCl. The aqueous layer was reextracted with 15 AcOEt and concentrated in vacuo. The remained H20 was evaporated azeotropically with toluene to give N'-[5-[4-(2-aminoethoxy)phenyl]-l-(4-methoxyphenyl)-1H pyrazol-3-yl]-N,N-dimethylurea hydrochloride 580mg as an amorphous powder. 20 Mass (ESI+) : 396 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.91(6H, s), 3.15-3.24 (2H, m), 3.76(3H, s), 4.14-4.21 (2H, m) , 6.64 (1H, s) , 6. 94 (2H, d, J=8. 9 Hz), 6.95 (2H, d, J=8.7 Hz), 7.15(2H, d, J=8.9 Hz), 7.17 (2H, d, J=8.7 Hz), 8.20(2H, brs), 9.04(lH, s) 25 The following compound(s) was (were) obtained in a similar manner to that of Example 530. Example 531 30 N-[5-[4-(2-aminoethoxy)phenyll-l-(4-methoxyphenyl)-lH pyrazol-3-yl]-N,N',N'-trimethylurea hydrochloride amorphous 360 WO 2004/050632 PCT/JP2003/014489 Mass (ESI+) : 410(M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.79(6H, s), 3.13(3H, s), 3 .14-3.24 (2H, m) , 3.80 (3H, s) , 4.15-4.20 (2H, m) , 6.27 (1H, s), 6.94 (2H, d, J=8.6 Hz), 6.94 (2H, d, J=8.9 Hz), 7.16(2H, 5 d, J=8.9 Hz), 7.19(2H, d, J=8.6 Hz), 8.24(2H, brs) Example 532 2-{[5-[4-(2-aminoethoxy)phenyll-1-(4-methoxyphenyl)-lH pyrazol-3-yl]oxy}-N,N-dimethylacetamide hydrochloride 10 amorphous MS (ESI+) : m/z 411 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.84(3H, s), 2.97(3H, s), 3.14-3.24(2H, m), 3.76(3H, s), 4.14-4.20(2H, m), 4.88(2H, s), 6.09(lH, s), 6.93(2H, d, J=9.0 Hz), 6.95(2H, d, J=8.8 15 Hz), 7.07-7.29(4H, m), 8.21(2H, brs) Example 533 A solution of potassium cyanate (64.9mg) in H20 (0.5ml) was added to a solution of N'-[5-[4-(2-aminoethoxy)phenyl] 20 1-(4-methoxy-phenyl)-lH-pyrazol-3-yl]-N,N-dimethylurea hydrochloride (172.8mg) and sodium acetate (65.6mg) in a mixture of DMF (1.5ml) and H20 (0.5ml) . The reactionmixture was stirred at ambient temperature overnight. The mixture was diluted with H20, partitioned between AcOEt and H20. 25 The aqueous layer was reextracted with AcOEt. saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was purified by preparative thin layer silica gel chromatography developed by 10% MeOH / CHCl3. The seaparated silica gel 30 was extracted with 10% MeOH / CHCl3 and the solvent was evaporated in vacuo. The residue was crystallized from AcOEt-IPE to give N'-[5-(4-{2-[(aminocarbonyl) 361 WO 2004/050632 PCT/JP2003/014489 amino]ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3 yl]-N,N-dimethylurea

(

8 7.Omg) as a powder. mp. 193-196'C IR (KBr) : 3437, 3421, 1660, 1649, 1620, 1612, 1581, 1562, 5 1554, 1529, 1512cm-1 Mass (ESI+) : 439 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.91(6H, s), 3.27-3.34(2H, m), 3.76(3H, s), 3.93(2H, t, J=5.5 Hz), 5.53(2H, s), 6.16(1H, t, J=5.7 Hz), 6.62(1H, s), 6.91 (2H, d, J=8.7 Hz), 6.93(2H, 10 d, J=8. 9 Hz), 7.13 (2H, d, J=8.7 Hz), 7.15 (2H, d, J=8.9 Hz) , 9.02(1H, s) The following compound (s) was (were) obtained in a similar manner to that of Example 533. 15 Example 534 N-[5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-1-(4 methoxyphenyl)-1H-pyrazol-3-yl]-N,N',N'-trimethylurea powder mp. 158.6-159.0'C 20 IR (KBr) 3433, 3369, 1687, 1658, 1643, 1612, 1514, 1500cm-i Mass (ESI+) : 453 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 2.79(6H, s), 3.12(3H, s), 3.27-3.34 (2H, m) , 3.76(3H, s), 3. 93 (2H, t, J=5.5Hz), 5. 53 (2H, s), 6.15(1H, t, J=5.6 Hz), 6.25(1H, s), 6.91(2H, d, J=8.7 25 Hz), 6.94(2H, d, J=8.9 Hz), 7.15(2H, d, J=8.7 Hz), 7.15(2H, d, J=8.9 Hz) Example 535 N-(2-{4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-1H 30 pyrazol-5-yl]phenoxy}ethyl)urea white powder : mp. 131-132'C IR (KBr) : 3435, 3429, 3388, 3350, 1658, 1612, 1562, 1554, 362 WO 2004/050632 PCT/JP2003/014489 1518cm-1 Mass (sample ID cox022116) (ESI+) : 427 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.28-3.38 (2H, m), 3.30(3H, s), 3.62-3.68(21H, m), 3.75(3H, s), 3.89-3.96(21H, m), 5 4.21-4.27 (2H, m), 5.53 (2H, s), 6.05(1IH, s), 6.15(1H, t, J=5.7 Hz), 6.91(2H, d, J=8.9 Hz), 6.92(2H, d, J=9.0 Hz), 7.10-7.15(4H, m) Example 536 10 N-(2-{4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1H pyrazol-5-yl]phenoxy}ethyl)urea white powder : mp. 124.1-124.2 0 C IR (KBr) : 3388, 3379, 3340, 1657, 1643, 1612, 1562, 1554, 1518cm-1 15 Mass (ESI+) : 441 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.13(3H, t, J=7.0 Hz), 3.27-3.36(2H, m), 3.49(2H, q, J=7.OHz), 3.66-3.71(2H, m), 3.75(3H, s), 3.89-3.96(2H, m), 4.21-4.26(2H, m), 5.53(2H, s), 6.06(1H, s), 6.15(1H, t, J=5.7 Hz), 6.91(2H, d, J=8.8 20 Hz), 6.92(2H, d, J=9.0 Hz), 7.10-7.15(4H, m) Example 537 2-{[5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-1 (4-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-N,N-dimethyl 25 acetamide white powder : mp.223-227 0 C IR (KBr) : 3402, 3332, 3201, 3194, 2925, 1664, 1612, 1518, 1502cm-1 MS (ESI+) : m/z 454 (M+H)+ 30 200MHz 1H NMR (DMSO-d6, d) : 2.84(3H, s), 2.97(3H, s), 3.27-3.35(2H, m), 3.75(3H, s), 3

.

8 9 -3.96(2H, m), 4.87(2H, s), 5.53(2H, s), 6.07 (1H, s), 6.15(1H, t, J=5.5 Hz), 6.91(2H, 363 WO 2004/050632 PCT/JP2003/014489 d, J=8.9 Hz), 6.93(2H, d, J=9.0 Hz), 7.11 (2H, d, J=9.0 Hz), 7.13(2H, d, J=8.9 Hz) Example 538 5 N-(2-{4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl]phenoxylethyl)urea white powder : mp. 192.6-192.7'C IR (KBr) : 3390, 3352, 3311, 3305, 1657, 1610, 1583, 1568, 1525, 1502cm-1 10 MS (ESI+) : m/z 384 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.27-3.36(2H, m), 3.34(3H, s), 3.85(3H, s), 3.91-3.97(2H, m), 5.53(2H, s), 6.11(1H, s), *6.15(1H, t, J=5.7 Hz), 6.85(lH, d, J=8.7 Hz), 6.94(2H, d, J=8.8 Hz), 7.17(2H, d, J=8.8 Hz), 7.59(1H, dd, J=2.6,8.7 15 Hz), 8.00(1H, d, J=2.6 Hz) Example 539 N-(2-{4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-lH-pyrazol 5-yl]phenoxylethyl)urea 20 white powder : mp. 133-138'C IR (KBr) : 3350, 1657, 1643, 1612, 1579, 1562, 1554, 1518, 1500cm-1; MS (ESI+) : m/z 398 (M+H)4 200MHz IH NMR (DMSO-d6, d) : 1.33(3H, t, J=7.0 Hz), 3.28-3.35(2H, m), 3.84(3H, s), 3.91-3.97(2H, m), 4.19(2H, 25 q, J=7.0 Hz), 5.53(2H, s), 6.09(1H, s), 6.16(1H, t, J=5.6 Hz), 6.85(1H, d, J=8.8 Hz), 6.94(2H, d, J=8.8 Hz), 7.17 (2H, d, J=8.8 Hz), 7.58 (1H, dd, J=2.7,8.8 Hz), 8.00 (1H, d, J=2.7 Hz) 30 Example 540 N-(2-{4-[3-cyclopropyl-l-(6-methoxy-3-pyridinyl)-lH pyrazol-5-yl]phenoxy}ethyl)urea 364 WO 2004/050632 PCT/JP2003/014489 mp. 94-96 C MS (ESI+) : m/z 394 (M+H) 1HNMR ( 200MHz, DMSOd6): 0.72 - 0.78 ( 2H, m), 0.87 - 0.95 ( 2H, m), 1.87 - 2.01 ( 1H, m), 3.23 - 3.42 ( 2H, n), 3.85 5 ( 3H, s), 3.90 - 3.97 ( 2H, m), 5.52 ( 2H, s), 6.12 ( 1H, t, J 5.6Hz ), 6.30 ( 1H, s), 6.85 ( 1H, d, J = 8.8Hz ), 6.92 ( 2H, d, J = 8.7Hz ), 7.13 ( 2H, d, J = 8.7Hz ), 7.58 1H, dd, J = 2.7 ,8.8Hz), 8.01 ( 1H, d, J = 2.7Hz 10 Example 541 N-(2-{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl) 1H-pyrazol-5-yl]phenoxylethyl)urea mp.152.0-152.2 C Mass (ESI+) : 464 (M+H) 15 1HNMR ( 200MHz, DMSOd6): 1.42- 1.73 ( 6H, m), 3.27 - 3.36 2H, m), 3.53 - 3.67 ( 2H, m), 3.73 - 3.96 ( 2H, m), 3.78 3H, s), 3.90 - 3.97 ( 2H, m), 5.51 ( 2H, s), 6.14 ( 1H, t, J = 5.7Hz ), 6.77 ( 1H, s), 6.92 ( 2H, d, J = 8.8Hz ), 6.98 ( 2H, d, J = 9,0Hz ), 7.17 ( 2H, d, J= 8.8Hz), 7.23 20 ( 2H, d, J = 9.0Hz Example 542 N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl carbonyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea 25 mp.164-167 0 C Mass (ESI+) : 465 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.42 -1.73 ( 6H, m), 3.22 - 3.40 ( 2H, m), 3.52 - 3.70 ( 2H, m), 3.75 - 3.95 ( 2H, m), 3.87 ( 3H, s), 3.92 - 3.98 ( 2H, m), 5.52 ( 2H, s), 6.15 ( 1H, 30 t, J = 5.6Hz ), 6.81 ( 1H, s), 6.90 ( 1H, d, J = 8.9Hz ), 6.95 ( 2H, d, J = 8.8Hz ), 7.21 ( 2H, d, J = 8.8Hz ), 7.67 1H, dd, J = 2.7 ,8.9Hz), 8.14 ( 1H, d, J = 2.7Hz 365 WO 2004/050632 PCT/JP2003/014489 Example 543 5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-N-ethyl-1 (6-methoxy-3-pyridinyl)-N-methyl-1H-pyrazole-3 5 carboxamide mp.146.3-146.7*C MS (ESI+) : m/z 439 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.09 - 1.23 ( 3H, m), 2.98, 3.28 ( 3H, s), 3.28 - 3.37 ( 2H, m), 3.40 - 3.53, 3.63 - 3.77 10 ( 2H, m), 3.87 ( 3H, s), 3.92 - 3.98 ( 2H, m), 5.52 ( 2H, s), 6.15 ( 1H, t, J = 5.5Hz ), 6.82, 6.85 ( 1H, s), 6.90 ( 1H, d, J= 9.0Hz ), 6.95 ( 2H, d, J= 8.7Hz ), 7.21 ( 2H, d, J = 8.7Hz ), 7.60 - 7.73 ( 1H, m), 8.14 - 8.16 ( 1H, m) 15 Example 544 N-(2-{4-[l-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy) 1H-pyrazol-5-yl]phenoxy}ethyl)urea mp.130-132 C MS (ESI+) : m/z 451 (M+H) 20 1HNMR ( 200MHz, DMSOd6): 3.27 -3.33 ( 2H, m), 3.76 ( 3H, s), 3.90 - 3.96 ( 2H, m), 4.81 ( 1H, d, J = 9.0Hz ), 4.90 ( 1H, d, J= 9.0Hz ), 5.52 ( 2H, s), 6.14 ( 1H, t, J= 5.6Hz ), 6.21 ( 1H, s), 6.89 - 6.98 ( 4H, m), 7.12 - 7.18 ( 4H, m) 25 Example 545 N-(2-{4-[3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-1H pyrazol-5-yl]phenoxylethyl)urea mp. 138.6-139.1'C MS (ESI+) : m/z 432 (M+H) 30 1HNMR ( 200MHz, DMSOd6): 3.27 -3.36 ( 2H, m), 3.76 ( 3H, s), 3.90 - 3.96 ( 2H, m), 4.44 ( 2H, dt, J = 3.5 ,14.9Hz), 5.52 ( 2H, s), 6.11 - 6.17 ( 1H, m), 6.15 ( 1H, s), 6.41 366 WO 2004/050632 PCT/JP2003/014489 1H, tt, J= 3.5, 54.6Hz ), 6.91 ( 2H, d, J= 8.9Hz), 6.93 2H, d, J= 8.9Hz ), 7.14 ( 2H, d, J= 8.9Hz ), 7.15 ( 2H, d, J = 8.9Hz 5 Example 546 N-(2-{ -[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro ethoxy)-1H-pyrazol-5-yllphenoxylethyl)urea mp. 134.8-134.9'C MS (ESI+) : m/z 452 (M+H) 10 1HNMR ( 200MHz, ) 3.24 - 3.39 ( 2H, m), 3.85 ( 3H, s), 3.91 - 3.98 ( 2H, m), 4.83 ( 1H, d, J = 9Hz ), 4.92 ( 1H, d, J =9Hz), 5.52 ( 2H, s), 6.15 ( 1H, t, J= 5.6Hz ), 6.27 ( 1H, s), 6.87 ( 1H, d, J = 8.8Hz ), 6.95 ( 2H, d, J = 8.8Hz ), 7.18 ( 2H, d, J= 8.8Hz ), 7.61 ( 1H, dd, J = 2.7 ,8.8Hz), 15 8.04 ( 1H, d, J =2.7Hz Example 547 N-(2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3 pyridinyl)-lH-pyrazol-5-yl]phenoxylethyl)urea 20 mp.146.9-147.3 0 C MS (ESI+) : m/z 434 (M+H) 1HNMR ( 200MHz, DMS~d6): 3.23 - 3.40 ( 2H, m), 3.85 ( 3H, s), 3.91 - 3.97 ( 2H, m), 4.45 ( 2H, dt, J = 3.5 ,14.9Hz), 5.52 ( 2H, s), 6.15 ( 1H, t, J= 5.7Hz ), 6.21 ( 1H, s), 25 6.42 ( 1H, tt, J= 3.5, 54.6Hz ), 6.86 ( 1H, d, J= 8.8Hz ), 6.94 ( 2H, d, J= 8.8Hz), 6.94 ( 2H, d, J = 8.8Hz), 7.60 ( 1H, dd, J = 2.8 ,8.8Hz), 8.03 ( 1H, d, J = 2.8Hz Example 548 30 5-(4-{[(aminocarbonyl)amino]methyl}phenyl)-N-ethyl-1 (4-methoxyphenyl)-N-methyl-1H-pyrazole-3-carboxamide mp. 184 .7-185.1 0 C 367 WO 2004/050632 PCT/JP2003/014489 MS (ESI+) : m/z 408 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.09 - 1.22 ( 3H, m), 2.98, 3.29 ( 3H, s), 3.41 - 3.78 ( 2H, m), 3.78 ( 3H, s), 4.16 ( 2H, d, J= 6.0Hz ), 5.54 ( 2H, s), 6.44 ( 1H, t, J= 6Hz ), 6.84, 5 6.86 ( 1H, s), 6.99 ( 2H, d, J = 8.9Hz ), 7.2 - 7.27 ( 6H, m) Example 549 N-{4-[3-isopropyl-1-(4-methoxyphenyl)-lH-pyrazol-5 10 yl]benzyl}urea amorphous powder MS (EST+) : m/z 365 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.27 ( 6H, d, J = 7.0Hz ), 2.95 1H, m), 3.76 ( 3H, s), 4.15 ( 2H, d, J = 6.0Hz ), 5.53 15 ( 2H, s), 6.42 ( 1H, t, J = 6.0Hz ), 6.44 ( 1H, s), 6.93 (2H, d, J = 8.9Hz ), 7.11 - 7.22 (6H,m) Example 550 N-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl 20 carbonyl)-1H-pyrazol-5-yl]benzyl}urea mp.178.9-178.9-C MS (EST+) : m/z 435 (M+H) 1HNMR ( 400MHz, DMSOd6): 1.47 - 1.70 ( 6H, m), 3.55 -3.66 ( 2H, m), 3.78 - 3.89 ( 2H, m), 3.87 ( 3H, s), 4.17 ( 2H, 25 d, J 6.0Hz ), 5.55 ( 2H, s), 6.45 ( 1H, t, J 6.0Hz ), 6.86 ( 1H, s), 6.91 ( 1H, d, J = 8.8Hz ), 7.24 ( 4H, s), 7.70 ( 1H, dd, J = 2.7 ,8.8Hz), 8.14 ( 1H, d, J = 2.7Hz Example 551 30 5-(4-{[(aminocarbonyl)amino]methyl}phenyl)-N-ethyl-1 (6-methoxy-3-pyridinyl)-N-methyl-1H-pyrazole-3 carboxamide 368 WO 2004/050632 PCT/JP2003/014489 mp.172.6-172.8 0 C MS (ESI+) : m/z 409 (M+H) 1HNMR ( 400MHz, DMSOd6): 1.13 , 1.19 ( 3H, t, J = 7.0Hz 2.98, 3.29 ( 3H, s), 3.48, 3.72 ( 2H, q, J= 7.0Hz ), 3.87 5 ( 3H, s), 4.18 ( 2H, d, J = 6.0Hz ), 5.55 ( 2H, s), 4.45 ( 1H, t, J = 6.0Hz ), 6.87- 6.93 ( 2H, m), 7.24 ( 4H, s), 7.67 - 7.73 ( 1H, m), 8.14 - 8.16 ( 1H, m) Example 552 10 N-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol 5-yl]benzyl}urea mp.139-144 C MS (ESI+) : m/z 366 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.27 ( 6H, d, J = 7.0Hz ), 2.97 15 ( 1H, m), 3.85 ( 3H, s), 4.17 ( 2H, d, J = 6.0Hz ), 5.53 ( 2H, s), 6.43 ( 1H, t, J = 6.0Hz ), 6.5 0( 1H, s), 6.86 ( 1H, d, J = 8.8Hz ), 7.15 -7.26 ( 4H, m), 7.62 ( 1H, dd, J = 2.8 ,8.8Hz), 8.02 ( 1H, d, J 2.7Hz 20 Example 553 N-{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yllbenzyl}urea mp.157.0-157.3*C MS (ESI+) : m/z 394 (M+H) 25 1HNMR ( 200MHz, DMSOd6): 1.16 ( 6H, d, J = 6.8Hz ), 3.68 ( 1H, m), 3.88 ( 3H, s), 4.17 ( 2H, d, J = 6.0Hz ), 5.54 ( 2H, s), 6.45 ( 1H, t, J= 6.0Hz ), 6.93 ( 1H, d, J= 8.8Hz ), 7.06 ( 1H, s), 7.25 ( 4H, s), 7.76 ( 1H, dd, J= 2.7 ,8.8Hz), 8.18 ( 1H, d, J = 2.7Hz 30 Example 554 N-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5 369 WO 2004/050632 PCT/JP2003/014489 yllbenzyl}urea mp.206.0-260.9 0 C MS (ESI+) : m/z 353 (M+H) 1HNMR ( 200MHz, DMSOd6): 3.76 ( 3H, s), 3.84 ( 3H, s), 4.15 5 ( 2H, d, J 6.0Hz ), 5.53 ( 2H, s), 6.09 ( 1H, s), 6.42 ( 1H, t, J= 6.0Hz), 6.93 ( 2H, d, J = 9Hz), 7.12 - 7.23 ( 6H, m) Example 555 10 N-{ 4 -[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5 yl]benzyl}urea solid MS (EST+) : m/z 381 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.31 ( 6H, d, J = 6.1Hz ), 3.76 15 ( 3H, s), 4.15 ( 2H, d, J = 6.0Hz ), 4.76 ( 1H, m), 5.53 ( 2H, s), 6.04 ( 1H, s), 6.43 ( 1H, t, J = 6.0Hz ), 6.92 ( 2H, d, J = 8.9Hz ), 7.10 - 7.22 ( 6H, m) Example 556 20 N-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl] benzyl urea mp.125.5-126.2 0 C Mass (ESI+) : 357 (M+H) 1HNMR ( 200MHz, DMSOd6): 3.78 ( 3H, s), 4.15 ( 2H, d, J = 25 6.1Hz), 5.54 ( 2H, s), 6.43 ( 1H, t, J= 6.lHz ), 6.73 ( 1H, s), 6.97 ( 2H, d, J = 8.9Hz ), 7.14 - 7.24 (6H, m) Example 557

N-{

4

-[

3 -chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5 30 yl]benzyllurea mp. 111-115 C Mass (EST+) : 358 (M+H) 370 WO 2004/050632 PCT/JP2003/014489 1HNMR ( 200MHz, DMSOd6): 3.87 ( 3H, s), 4.17 ( 2H, d, J = 6.0Hz ), 5.54 ( 2H, s), 6.44 ( 1H, t, J= 6.0Hz), 6.79 ( 1H, s), 6.89 ( 1H, d, J= .8Hz ), 7.23 ( 4H, s), 7.69 ( 1H, dd, J = 2.7 ,8.8Hz), 8.11 ( 1H, d, J = 2.7Hz 5 Example 558 N-(2-{4-[1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-5-yl] phenoxylethyl)urea amorphous powder 10 MS (ESI+) : m/z 367 (M+H) 1HNMR ( 400MHz, DMSOd6): 2.02 ( 3H, s), 3.32 - 3.36 ( 2H, m), 3.74 ( 3H, s), 3.92 -3.96 ( 2H, m), 5.51 ( 2H, s), 6.15 ( 1H, t, J = 5.6Hz ), 6.89 ( 2H, d, J = 8.9Hz ), 6.94 ( 2H, d, J = 8.8Hz ), 7.08 ( 2H, d, J = 8.8Hz ), 7.09 ( 2H, d, 15 J = 8.9Hz ), 7.55 ( 1H, s) Example 559 N-(2-{4-[1-(6-methoxy-3-pyridinyl)-4-methyl-1H-pyrazol 5-yllphenoxy}ethyl)urea 20 powder MS (EST+) : m/z 368 (M+H) 1HNMR ( 400MHz, DMSOd6): 2.03 ( 3H, s), 3.31 - 3.36 ( 2H, m), 3.83 ( 3H, s), 3.94 -3.98 ( 2H, m), 5.51 ( 2H, s), 6.15 ( 1H, t, J= 5.6Hz ), 6.82 ( 1H, d, J = 8.8Hz ), 6.97 ( 2H, 25 d, J = 8.8Hz ), 7.13 (2H, d, J = 8.8Hz ), 7.53( 1H, dd, J = 2.7 ,8.8Hz), 7.62 ( 1H, s), 7.98 ( 1H, d, J = 2.7Hz Example 560 N-(2-{4-[1-(4-methoxyphenyl)-3-(methylthio)-lH-pyrazol 30 5-yllphenoxylethyl)urea mp. 141.2-142.2 0 C MS (ESI+) : m/z 399 (M+H) 371 WO 2004/050632 PCT/JP2003/014489 1HNMR ( 200MHz, DMSOd6): 2.50 ( 3H, s), 3.27 - 3.36 ( 2H, m), 3.77 ( 3H, s), 3.90 - 3.96 ( 2H, m), 5.52 ( 2H, s), 6.14 ( 1H, t, J= 5.6Hz ), 6.56 (IH, s), 6.91 ( 2H, d, J= 8.8Hz ), 6.95 ( 2H, d, J = 8.8Hz ), 7.14 ( 2H, d, J = 8.8Hz ), 7.17 5 ( 2H, d, J = 8.8Hz Example 561 N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl) 1H-pyrazol-5-yl]phenyl}ethyl)urea 10 mp.205-206 0 C MS (ESI+) : m/z 406 (M+H) 1HNMR ( 200MHz, DMSOd6): 2.64 -2.72 ( 2H, m), 3.13 - 3.24 ( 2H, m), 3.88 ( 3H, s), 5.42 (2H, s), 5.95 ( 1H, t, J = 5.6Hz ), 6.92 ( 1H, d, J= 8.9Hz ), 7.17 ( 1H, s), 7.24 ( 4H, 15 s), 7.75 ( 1H, dd, J= 2.8 ,8.9Hz), 8.19 ( 1H, d, J= 2.8Hz Example 562 5-(4-{2-[(aminocarbonyl)amino]ethyl}phenyl)-N-methoxy 1-(4-methoxyphenyl)-N-methyl-lH-pyrazole-3-carboxamide 20 oil MS (ESI+) : m/z 243 (M+H) 1HNMR ( 200MHz, CDC13): 2.75 - 2.82 ( 2H, m), 3.34 - 3.45 2H, m), 3.51 ( 3H, s), 3.82 ( 3H, s), 3.83 ( 3H, s), 4.46 2H, s), 4.92 (1H, t, J= 5.5Hz ), 6.84 ( 2H, d, J= 9.OHz ), 25 6.92 ( 1H, s), 7.11 ( 4H, s), 7.15 ( 2H, d, J = 9.0Hz Example 563 5-(4-{2-[(aminocarbonyl)amino]ethyl}phenyl)-N-methoxy 1-(6-methoxy-3-pyridinyl)-N-methyl-1H-pyrazole-3 30 carboxamide oil MS (ESI+) : m/z 425 (M+H) 372 WO 2004/050632 PCT/JP2003/014489 1HNMR ( 200MHz, CDCl3): 2.78 - 2.86 ( 2H, m), 3.39 -3.49 2H, m), 3.49 ( 3H, s), 3.85 ( 3H, s), 3.94 ( 3H, s), 4.39 2H, s), 4.70 (1H, t, J= 5.8Hz ), 6.75 (1H, d, J= 8.9Hz ), 6.80 (H, s),7.12-7.23 (4H,m),7.56 (1H, dd, J=2.7,8.9Hz), 5 8.05 ( 1H, d, J = 2.7Hz Example 564 Sodiumhydride 60%dispersioninmineraloil 93.1mgwasadded in one portion to a solution of N-[5-[4-(benzyloxy)phenyl] 10 1-(4-methoxyphenyl)-lH-pyrazol-3-yl]-N',N'-dimethylurea 1. 43g in DMF 10ml under i'ce bath cooling. The reactionmixture was stirred at ambient temperature for hour. MeI 688mg was added the reactionmixture was stirred at ambient temperature overnight. Themixture was partitionedbetween ethyl acetate 15 and H20. The organic layer was washedwith saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt-n-hexane=75%, 80% to give N-[5-[4-(benzyloxy)phenyl]-1-(4-methoxy 20 phenyl)-1H-pyrazol-3-yl]-N,N',N'-trimethylurea 1.45g as an oil. Mass (ESI+) : 457 (M+H)+ 200MHzlHNMR (DMSO-d6, d) :2.79(6H, s), 3.12(3H, s), 3.77(3H, s), 5.09(2H, s), 6.25(1H, s), 6.91-7.00(4H,m), 7.14-7.19(4H, 25 in), 7.32-7.46(5H, m) Example 565 A mixture of N-(2-{4-[3-amino-l-(4-methoxyphenyl) 1H-pyrazol-5- yl]phenoxy}ethyl)urea 111mg, lithium 30 chloride 64mg, and copper(II) chloride 81.2mg in acetonitrile 2ml was stirred at ambient temperature for minutes. To this mixture was added isoamyl nitrite 62.3mg, 373 WO 2004/050632 PCT/JP2003/014489 and the mixture was stirred at ambient temperature for 3hours. The mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with saturated aqueous ammonium chloride 5 solution, H20, and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by MeOH / CHCl3 = 10%. The seaparated silica gel was extracted with 10% MeOH/CHCl3 10 and the solvent was evaporated in vacuo. The residu was crystallized from AcOEt / IPE to give N-(2-{4-[3-chloro-l (4-methoxyphenyl)-liH- pyrazol-5-yl]phenoxy}ethyl)urea 31.1mg as a white powder. mp. 140-142'C 15 Mass (ESI+) : 386 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 3.27-3.34(2H, m), 3.77 (3H, s), 3.93(2H, t, J=5.5 Hz), 5.52 (2H, s), 6.15(1H, t, J=5.7 Hz), 6.68 (1H, s), 6.92 (2H, d, J=9.0 Hz), 6.97(2H, d, J=9.0 Hz), 7.15(2H, d, J=9.0 Hz), 7.20(2H, d, J=9.0 Hz) 20 Example 566 Diethyl azodicarboxylate (0.17ml) was added dropwise to a suspension of 3-methoxy-l-(4-methoxyphenyl)-5-(4 hydroxyphenyl)-lH-pyrazole (215.6mg), tert-butyl 25 N-(2-hydroxyethyl)carbamate (352mg), and triphenylphosphine (286mg) in THF (3ml) . The mixture was stirred at ambient temperature for 7hours. Triphenylphosphine (19.1mg) and diethyl azodicarboxylate (11.5pl) were added and the mixture stirred at ambient 30 temperature overnight. Themixturewas concentratedinvacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=30% to give tert-butyl 374 WO 2004/050632 PCT/JP2003/014489 (2-{4-[3-methoxy-l-(4-methoxyphenyl)-1H-pyrazol-5 yl]phenoxy}ethyl)carbamate (319mg) as an oil. Mass (ESI+) : 440 (M+H)+ 5 200MHz 1H NMR (CDCl3, d) : 1.45(9H, s), 3.47-3.56(2H, m), 3.80 (3H, s), 3.96-4.03 (2H, m), 3.97 (3H, s), 4.96(1H, brs), 5.87 (1H, s), 6.79(2H, d, J=8.8 Hz), 6.82(2H, d, J=8.9 Hz), 7.09-7.20(4H, m) 10 The following compound(s) was (were) obtained in a similar manner to that of Example 566. Example 567 tert-butyl (2-{4-[3-isobutoxy-1-(4-methoxyphenyl) 15 1H-pyrazol-5-yl]phenoxylethyl)carbamate white powder Mass (ESI+) : 482 (M+H)+ 200MHz 1H NMR (CDC13, d) : 1.03(6H, d, J=6.7 Hz), 1.45(9H, s), 2.11 (1H, m) , 3.48-3.57 (2H, m) , 3.79(3H, s), 3.97-4.03(2H, 20 m), 4.97(lH, br), 5.88(1H, s), 6.79(2H, d, J=8.7 Hz), 6.82(2H, d, J=8.9 Hz), 7.09-7.19(4H, m) Example 568 tert-butyl (2-{4-[3-(2-methoxyethoxy)-l-(4-methoxy 25 phenyl)-1H-pyrazol-5-yl]phenoxylethyl)carbamate solid Mass (ESI+) : 484 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.37(9H, s), 3.22-3.32(2H, m), 3.31(3H, s), 3.62-3.67 (2H, m), 3.75(3H, s), 3.91-3.97(2H, 30 m), 4.21-4.27(2H, m), 6.04(lH, s), 6.86-6.99(5H, m), 7.10-7.15(4H, m) 375 WO 2004/050632 PCT/JP2003/014489 Example 569 tert-butyl ( 2

-{

4 -[3-(2-ethoxyethoxy)-1-(4-methoxy phenyl)-lH-pyrazol-5-yl]phenoxy}ethyl)carbamate oil 5 Mass (ESI+) : 498 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.09-1.21(3H, overlapping), 1.37(9H, s), 3.25-3.34(2H, m), 3.66-3.71(2H, m), 3.75(3H, s), 3.90-4.15(4H, m), 4.21-4.26(2H, m), 6.06(1H, s), 6.86-6.96(4H, m), 7.01(1H, m), 7.12(4H, d, J=8.9 H2), 10 Example 570 tert-butyl ( 2 -{4-[3-methoxy-l-(6-methoxy-3-pyridinyl) -1H-pyrazol-5-ylJphenoxy}ethyl)carbamate powder 15 MS (EST+) : m/z 441 (M+H)+ 200MHz 1H NMR (CDC13, d) 1.45(9H, s), 3.48-3.57(2H, m), 3.92(3H, s), 3.97(3H, s), 3

.

9 8

-

4 .03(2H, m) , 4.99(1H, br), 5.90(1H, s), 6.70 (1H, d, J=8.5 Hz), 6.82 (2H, d, J=8.9 Hz), 7. 14 (2H, d, J=8.9 Hz), 7.52 (1H, dd, J=2.5, 8.5 Hz), 8.03 (1H, 20 d, J=2.5 Hz) Example 571 tert-butyl ( 2

-{

4 -[3-ethoxy-1-(6-methoxy-3-pyridinyl) 1H-pyrazol-5-yl]phenoxylethyl)carbamate 25 white powder MS (ESI+) : m/z 455 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) :1.33(3H, t, J=7.0 Hz), 1.37(9H, s), 3

.

2 2

-

3 .33( 2 H,m), 3.84(3H, s), 3.92-3.98(2Hm), 4.19(2H, q), 6.08((lH, s), 6.85(1H, d, J=8.8 Hz), 6.92(2H, d, J=8.8 30 Hz), 7.02(1H, t, J=5.5 Hz), 7.16(2H, d, J=8.8 Hz), 7.58(1H, dd, J=2.7,8.8 Hz), 7.99(1H, d, J=2.7 Hz) 376 WO 2004/050632 PCT/JP2003/014489 Example 572 tert-butyl [ 2

-(

4 -{3-(difluoromethyl) -l-[4- (methyl thio) phenyl] -lH-pyrazol-5-yl}phenoxy) ethyl] carbamate MASS (ESI+): m/z = 498.2 (M+Na). 5 1HNMR ( 400MHz, CDC13): 1.45 ( 9H, s), 2.49 ( 3H, s), 3.54 ( 2H, q, J = 5.1Hz ), 4.02 ( 2H, t, J = 5.1Hz ), 4.98 ( lH, b-s), 6.66 ( 1H, s), 6.76 ( 1H, t, J= 55.1Hz), 6.84 ( 2H, d, J = 8.8Hz ), 7.15 ( 2H, d, J = 8.8Hz ), 7.2 ( 4H, s). 10 Example 573 tert-butyl (2-{4-[3-cyclopropyl-l-(6-methoxy-3 pyridinyl) -1H-pyrazol-5-yl]phenoxy} ethyl) carbamate oil MS ESI+) : m/z 451 (M+H) 15 1HNMR ( 200MHz, CDCl3): 0.77 - 0.86 ( 2H, m), 0.93- 1.04 ( 2H, m), 1.45 ( 9H, s), 1.96 - 2.09 ( 1H, m), 3.48 - 3.57 ( 2H, m), 3.92 ( 3H, s), 3.97 - 4.03 ( 2H, m), 4.97 ( 1H, brs), 6.10 ( 1H, s), 6.71 ( 1H, d, J = 8.8Hz ), 6.81 ( 2H, d, J = 8.8Hz ), 7.11 ( 2H, d, J = 8.8Hz ), 7.53 ( 1H, dd, 20 J = 2.7 ,8.8Hz), 8.03 ( 1H, d, J = 2.7Hz Example 574 tert-butyl (2-{4-[3-(cyclopentyloxy)-1-(6-methoxy-3 pyridinyl)-lH-pyrazol-5-yl]phenoxy}ethyl)carbamate 25 oil MS (ESI+) : m/z 494 (M+H) 1HNMR ( 200MHz, CDCl3): 1.45 ( 9H, s), 1.5 -1.99 ( 8H, m), 3.48 - 3.57 ( 2H, m), 3.91 ( 3H, s), 3.98 - 4.04 ( 2H, m), 4.92 -5.05 ( 2H, m), 5.88 (1H, s), 6.69 (1 H, d, J= 8.9Hz ), 30 6.82 ( 2H, d, J = 8.8Hz), 7.14 ( 2H, d, J = 8.8Hz ), 7.52 1H, dd, J = 2.7 ,8.9Hz), 8.02 ( 1H, d, J = 2.7Hz 377 WO 2004/050632 PCT/JP2003/014489 Example 575 tert-butyl ( 2 -{4-[1-(4-methoxyphenyl)-3-(2,2,2-tri fluoroethoxy)-1H-pyrazol-5-yl]phenoxy}ethyl)carbamate oil 5 MS (ESI+) : m/z 508 (M+H) 1HNMR ( 200MHz, CDCl3): 1.45 ( 9H, s), 3.48 - 3.57 ( 2H, m), 3.81 ( 3H, s), 3.97 - 4.03 ( 2H, m), 4.62 ( 1H, d, J 8.5Hz ), 4.70 ( 1H, d, J= 8.5Hz ), 4.95 ( 1H, brs), 5.95 1H, s), 6.77 - 6.86 ( 4H, m), 7.08 - 7.18 ( 4H, m) 10 Example 576 tert-butyl ( 2

-{

4

-[

3

-(

2 ,2-difluoroethoxy)-1-(4-methoxy phenyl)-lH-pyrazol-5-yl]phenoxy}ethyl)carbamate oil 15 MS (ESI+) : m/z 490 (M+H) 1HNMR ( 200MHz, CDCl3): 1.45 ( 9H, s), 3.48 - 3.57 ( 2H, m), 3.80 ( 3H, s), 3.97 - 4.03 ( 2H, m), 4.46 ( 2H, dt, J = 4.3 ,13.4Hz), 4.96 ( 1H, brs), 5.91 ( 1H, s), 6.17 ( 1H, tt, J = 4.3, 55.5Hz ), 6.77 - 6.88 ( 4H, m), 7.09 - 7.18 20 ( 4H, m) Example 577 tert-butyl (2-{4-[l-(6-methoxy-3-pyridinyl)-3-(2,2,2 trifluoroethoxy)-1H-pyrazol-5-yllphenoxylethyl) 25 carbamate oil MS (ESI+) : m/z 509 (M+H) 1HNMR ( 200MHz, CDCl3): 1.45 ( 9H, s), 3.48 - 3.57 ( 2H, m), 3.92 ( 3H, s), 3.98 - 4.04 ( 2H, m), 4.61 ( 1H, d, J 30 = 8.4Hz ), 4.70 ( 1H, d, J= 8.4Hz ), 4.96 ( 1H, brs), 5.97 1H, s), 6.71 ( 1H, d, J= 8.8Hz ), 6.83 ( 2H, d, J= 8.8Hz ), 7.13 ( 2H, d, J = 8.8Hz ), 7.48 ( 1H, dd, J = 2.7 ,8.8Hz), 378 WO 2004/050632 PCT/JP2003/014489 8.02 ( IH, d, J = 2.7Hz Example 578 tert-butyl (2-{4-[3-(2,2-difluoroethoxy)-1-(6 5 methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl) carbamate solid MS (ESI+) : m/z 513 (M+Na) 1HNMR ( 200MHz, CDC13): 1.45 ( 9H, s), 3.48 - 3.57 (2H, m), 10 3.92 ( 3H, s), 3.98 - 4.04 ( 2H, m), 4.46 ( 2H, dt, J = 4.2 ,13.4Hz), 4.96 (1H, brs), 5.94 ( 1H, s), 6.16 ( 1H, tt, J = 4.2, 55.5Hz ), 6.71 ( 1H, d, J = 8.8Hz ), 6.83 ( 2H, d, J = 8.9Hz ), 7.13 ( 2H, d, J = 8.9Hz ), 7.48 ( 1H, dd, J = 2.7 ,8.8Hz), 8.02 ( 1H, d, J = 2.7Hz 15 Example 579 tert-butyl (2-{4-[1-(4-methoxyphenyl)-4-methyl-1H pyrazol-5-yllphenoxylethyl)carbamate oil 20 MS (ESI+) : m/z 424 (M+H) 200MHz 1H NMR (DMSO-d6, d) : 1.37(9H, s), 2.01(3H, s), 3.23-3.33(2H, m), 3.74(3H, s), 3.92-3.98(2H, m), 6.86-6.95(4H, m), 7.05-7.12(4H, m), 7.55(1H, s) 25 Example 580 tert-butyl (2-14-[1-(6-methoxy-3-pyridinyl)-4-methyl 1H-pyrazol-5-yl]phenoxy}ethyl)carbamate oil MS (ESI+) : m/z 425 (M+H) 30 1HNMR ( 400MHz, CDC13): 1.42 ( 9H, s), 2.09 ( 3H, s), 3.52 - 3.57 ( 2H, m), 3.91 ( 3H, s), 4.01 - 4.04 ( 2H, m), 4.98 1H, brs), 6.68 ( 1H, d, J = 8.8Hz ), 6.87 ( 2H, d, J = 379 WO 2004/050632 PCT/JP2003/014489 8.8Hz), 7.08 ( 2H, d, J=8.8Hz ), 7.48 ( 1H, dd, J=2.7 ,8.8Hz), 7.58 ( 1H, s), 8.00 ( 1H, d, J = 2.7Hz Example 581 5 tert-butyl (2-{4-[1-(4-methoxyphenyl)-3-(methylthio) 1H-pyrazol-5-ylphenoxy)ethyl)carbamate oil Mass (ESI+) : m/z 456 (M+H) 1HNMR ( 200MHz, CDCl3): 1.45 ( 9H, s), 2.58 ( 3H, s), 3.48 10 - 3.57 ( 2H, m), 3.81 ( 3H, s), 3.97 - 4.03 ( 2H, m), 4.96 1H, m), 6.36 ( 1H, s), 6.77 - 6.86 ( 4H, m), 7.12 ( 2H, d, J = 8.9Hz ), 7.2 ( 2H, d, J = 9.0Hz Example 582 15 To a solution of (2-{4-[3-methoxy-1-(4-methoxyphenyl) 1H-pyrazol-5-yl]phenoxy}ethyl)amine hydrochloride (150mg) and triethylamine (121mg) in CH2Cl2 (3ml) was added trifluoromethanesulfonic anhydride (113mg). The mixture was stirred at ambient temperature for 2hours. Additional 20 triethylamine (92mg) was added and stirring at ambient temperature was continued for 4hours. The mixture was concentrated in vacuo. The residue was partitioned between AcOEt and 1M HCl. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous 25 sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / n-hexane = 50% to give 1,1,1-trifluoro-N-(2-{4-[3-methoxy-1-(4 methoxy-phenyl)-lH-pyrazol-5-yllphenoxy}ethyl)methane 30 sulfonamide (109mg) as an oil. IR (neat) : 2960, 1612, 1522cm-1 Mass (ESI+) : 472 (M+H)+ 380 WO 2004/050632 PCT/JP2003/014489 200MHz 1H NMR (CDC13, d) : 3.60-3.73(2H, m), 3.80(3H, s), 3

.

9 7

(

3 H, s), 4.06-4.12(2H, m), 5.45(1H, brs), 5.89(1H, s), 6.70-6.87(4H, m), 7.15(2H, d, J=8.9 Hz), 7.17(2H, d, J=9.0 Hz) 5 Example 583 To a suspension of 5-[4-(benzyloxy)phenyl]-3-hydroxy-1 (4-methoxyphenyl) -lH-pyrazole 2. Og and K2CO3 2. 23g in DMSO 20ml was added diethylsulfate 1.24g. After stirring at 10 ambient temperature for 2hours, the reaction was quenched by adding 28% aqueous ammonium hydroxide solution and ice. The mixture was partitioned between AcOEt and H20. The organic layer was washed with H20 and saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and 15 concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / n-hexane = 40% and the solvent was evaporated in vacuo. The reisual solid was recrystallized from IPE to give 5-[4-(benzyloxy)phenyl]-3-ethoxy-1-(4-methoxy-phenyl) 20 1H-pyrazole 1.44g as a powder. Mass (ESI+) : 401(M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.32(3H, t, J=7.0 Hz), 3.76(3H, s), 4 .17 ( 2 H, q, J=7.0 Hz), 5.08 (2H, s), 6.03(1H, s), 6.92(2H, d, J=9.0 Hz), 6.97(2H, d, J=8.8 Hz), 7.09-7.16(4H, m), 25 7.32-7.46(5H, m) The following compound(s) was (were) obtained in a similar manner to that of Example 583. 30 Example 584 5-{5-[4-(benzyloxy)phenyl]-3-ethoxy-1H-pyrazol-1-yl}-2 methoxypyridine 381 WO 2004/050632 PCT/JP2003/014489 oil; MS (ESI+) : m/z 402 (M-+H)+ 200MHz 1H NMR (CDC13, d) : 1.43(3H, t, J=7.1 Hz), 3.92(3H, s), 4.28 (2H, q, J=7.1 Hz), 5.05(2H, s), 5.90 (1H, s), 6.70 (1H, d, J=8.7 Hz), 6.91 (2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 Hz), 5 7.35-7.43'(5H, m), 7.51 (1H, dd, J=2.6,8.7 Hz), 8.04(1H, d, J=2.6 Hz) Example 585 To a solution of 4-[3-ethoxy-l-(4-methoxyphenyl)-1H 10 pyrazol-5-yl]phenol (515.5mg) in DMF (5ml) was addedsodium hydride 60% dispersion in mineral oil (79.7mg) at 3*C. The mixture was stirred at ambient temperature for 40minutes. To the rection mixture was added a solution of tert-butyl (2-bromoethyl)carbamate(558mg) in DMF (2ml) . The mixture 15 was stirred at at 60'C for 24hours. The reaction mixture was poured into ice water and was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was crystallized from 20 AcOEt, collected and washed with IPE to give 1st crop of tert-butyl (2-{4-[3-ethoxy-1-(4-methoxyphenyl)-lH pyrazol-5-yl]phenoxy}ethyl)carbamate (344mg) as a white powder. The mother ligour was concentrated in vacuo and purified by silica gel column chromatography eluted with 25 AcOEt / CHCl3 = 10% to give 2nd crop of tert-butyl (2-{4-[3-ethoxy-l-(4-methoxyphenyl)-1H-pyrazol-5 yl]phenoxy}ethyl)carbamate (218mg ) as a powder. Mass (ESI+) : 454 (M+H)+ 200MHz 1H NMR (CDCl3, d) : 1.42(3H, t, J=7.1 Hz), 1.45(9H, 30 s), 3.48-3.57(2H, m), 3.80(3H, s), 3.97-4.03(2H, m), 4.29(2H, q, J=7.1 Hz), 5.87 (1H, s), 6.79(2H, d, J=9.0 Hz), 6.82 (2H, d, J=8.9 Hz), 7.00-7.19(4H, m) 382 WO 2004/050632 PCT/JP2003/014489 Example 586 A suspension of 5-[4-(benzyloxy)phenyll-3-hydroxy 1-(4-methoxyphenyl)-lH-pyrazole (1.5g), 1-bromo-2 5 methylpropane (2.76g) and anhydrous potassium carbonate (1.67g) in DMF (10ml) was added stirred at 100"C for hour. The mixture was poured into ice water and extracted with AcOEt. The organic layer was washed with H20, saturated aqueous sodium chloride solution, dried over magnesium. 10 sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / n-hexane =30% to give 5-[4-(benzyloxy)phenyl]-3 isobutoxy-1-(4-methoxyphenyl)-lH-pyrazole (1.64g) as a solid. 15 powder Mass (ESI+) : 429 (M+H)+ 200MHz 1H NMR (CDCl3, d) : 1.03(6H, d, J=6.6 Hz), 2.11(1H, m), 3.80 (3H, s) , 3.99 (2H, d, J=6.6 Hz), 5.04 (2H, s), 5.88 (1H, s), 6.82(2H, d, J=9.0 Hz), 6.88(2H, d, J=8.8 Hz), 20 7.11-7.20(4H, m), 7.35-7.43(5H, m) The following compound(s) was (were) obtained in a similar manner to that of Example 586. 25 Example 587 5-[4-(benzyloxy)phenyl]-3-(2-methoxyethoxy)-1-(4 methoxyphenyl)-1H-pyrazole powder Mass (ESI+) : 431 (M+H)+ 30 200MHz 1H NMR (CDCl3, d) : 3.46(3H, s), 3.73-3.80(2H, m), 3.79(3H, s), 4.39-4.44(2H, m), 5.04(2H, s), 5.91(1H, s), 6.83 (2H, d, J=8.9 Hz), 6.87 (2H, d, J=9.0 Hz), 7. 10-7.20 (4H, 383 WO 2004/050632 PCT/JP2003/014489 m), 7.34-7.42(5H, m) Example 588 5-[4-(benzyloxy)phenyl]-3-(2-ethoxyethoxy)-1-(4 5 methoxyphenyl)-lH-pyrazole oil Mass (ESI+) : 445 (M+H)+ 400Mfz 1H NMR (CDCl3, d) : 1.25(3H, t, J=7.0 Hz), 3.61(2H, q, J=7.0 Hz), 3.79-3.82(2H, m), 3.80(3H, s), 4.39-4.42(2H, 10 m), 5.04(2H, s), 5.91(1H, s), 6.82(2H, d, J=8.9 Hz), 6.88 (2H, d, J=8.7 Hz), 7.12 (2H, d, J=8.7 Hz), 7.17 (2H, d, J=8.9 Hz), 7.36-7.41(5H, m) Example 589 15 2-{[5-[4-(benzyloxy)phenyl]-l-(4-methoxyphenyl)-lH pyrazol-3-ylloxy}-N,N-dimethylacetamide powder Mass (ESI+) : 458 (M+H)+ 200MHz 1HNMR (DMSO-d6, d) :2.84 (3H, s) , 2.97(3H, s) , 3.76(3H, 20 s), 4.87(2H, s), 5.09(2H, s), 6.08 (1H, s), 6.92(2H, d, J=9.0 Hz), 6.98 (2H, d, J=8.8 Hz), 7.09-7.17(4H, m), 7.34-7.43(5H, m) Example 590 25 5-[5-[4-(benzyloxy)phenyl]-3-(cyclopentyloxy)-lH pyrazol-1-yl]-2-methoxypyridine solid MS (ESI+) : m/z 442 (M+H) 1HNMR ( 200MHz, CDCl3): 1.52 - 1.98 ( 8H, m), 3.92 ( 3H, 30 s), 4.98 - 5.05 ( 1H, m), 5.05 ( 2H, s), 5.88 ( 1H, s), 6.69 ( 1H, d, J= 8.7Hz ), 6.91 ( 2H, d, J= 8.8Hz ), 7.15 ( 2H, d, J = 8.8Hz ), 7.35 - 7.43 ( 5H, m), 7.52 (1H, dd, J= 384 WO 2004/050632 PCT/JP2003/014489 2.7 ,8.7Hz), 8.04 ( 1H, d, J = 2.7Hz Example 591 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-(2,2,2 5 trifluoroethoxy)-lH-pyrazole oil MS (ESI+) : m/z 455 (M+H) 1HNMR ( 200MHz, DMSOd6): 3.76 ( 3H, s), 4.81 ( 1H, d, J = 9.0Hz ), 4.90 ( I , d, J= 9.0Hz ), 5.09 ( 2H, s), 6.21 ( 1H, 10 s), 6.91 - 7.01 ( 4H, m), 7.13- 7.19 ( 4H, m), 7.34 - 7.46 5H, m) Example 592 5-[4-(benzyloxy)phenyl]-3-(2,2-difluoroethoxy)-1-(4 15 methoxyphenyl)-lH-pyrazole oil MS (ESI+) : m/z 437 (M+H) 1HNMR ( 200MHz, CDCl3): 3.80 ( 3H, s), 4.46 ( 2H, dt, J 4.2 ,13.5Hz), 5.04 ( 2H, s), 5.91 ( 1H, s), 6.17 ( 1H, tt, 20 J = 4.2, 55.5Hz ), 6.81 - 6.91 ( 4H, m), 7.10 - 7.19 ( 4H, m), 7.34 - 7.43 ( 5H, m) Example 593 5-[5-[4-(benzyloxy)phenyl]-3-(2,2,2-trifluoroethoxy) 25 1H-pyrazol-1-yl]-2-methoxypyridine oil Mass (ESI+) : 456 (M+H) 1HNMR 200MHz, CDCl3): 3.93 ( 3H, s), 4.61 ( 1H, d, J = 8.4Hz ), 4.69 ( 1H, d, J= 8.4Hz ), 5.05 ( 2H, s), 5.97 ( 1H, 30 s), 6.71 ( 1H, d, J= 9Hz ), 6.91 ( 2H, d, J= 8.9Hz ), 7.14 ( 2H, d, J = 8.9Hz ), 7.36 - 7.43 ( 5H, m), 7.48 ( 1H, dd, J = 2.7 ,9Hz), 8.04 ( 1H, d, J = 2.7Hz 385 WO 2004/050632 PCT/JP2003/014489 Example 594 5-[5-[4-(benzyloxy)phenyl]-3-(2,2-difluoroethoxy)-lH pyrazol-1-yl]-2-methoxypyridine 5 oil MS (ESI+) : m/z 438 (M+H) 1HNMR ( 200MHz, CDCl3): 3.93 ( 3H, s), 4.46 ( 2H, dt, J 4.2 ,13.3Hz), 5.05 ( 2H, s), 5.94 ( 1H, s), 6.16 ( 1H, tt, J = 4.2, 55.4Hz ), 6.71 ( 1H, d, J = 8.8Hz ), 6.91 ( 2H, 10 d, J = 8.8Hz ), 7.14 ( 2H, d, J = 8.8Hz ), 7.35 - 7.43 ( 5H, m), 7.48 ( 1H, dd, J= 2.8 ,8.8Hz), 8.04 ( 1H, d, J= 2.8Hz Example 595 A suspension of 5-{5-[4-(benzyloxy)phenyll-3-hydroxy-lH 15 pyrazol-1-yl)-2-methoxypyridine (800mg), dimethyl carbonate (0.9ml) and potassium carbonate (888mg) in DMF (8ml) was stirredat 120 0 C for hours. Themixture waspoured into ice water and extracted with AcOEt. The organic layer was washed with H20, saturated aqueous sodium chloride 20 solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / n-hexane =30% to give 5-{5-[4-(benzyloxy)phenyl]-3-methoxy-lH-pyrazol-1-yl} 2-methoxy-pyridine (1.069g) as a solid. 25 powder MS (ESI+) : m/z 388 (M+H)+ 200MHz1HNMR (CDCl3, d) : 3.92(3H, s), 3.97 (3H, s), 5.05(2H, s) , 5. 90 (1H, s) , 6. 71 (1H, d, J=8.7 Hz) , 6. 91 (2H, d, J=8. 9 Hz), 7.14 (2H, d, J=8.9 Hz), 7.35-7.43 (5H, m) , 7.52 (1H, dd, 30 J=2.6,8.7 Hz), 8.05(lH, d, J=2.6 Hz) Example 596 386 WO 2004/050632 PCT/JP2003/014489 A solution of 4,4,4-trifluoro-l-[4-(2-hydroxy ethyl)phenyl]- 1,3-butanedione (670mg) and (4-nitrophenyl)hydrazine hydrochloride (439mg) in AcOH (5ml) and H20 (0.5ml) was stirred at ambient temperature 5 overnight. The mixture was cocncentrated in vacuo, and the residue was partitioned between AcOEt and 1M HCl. The oreganic layerwaswashedwith 1MHCl fortwo times, saturated aqueous sodium bicarbonate solution for three times, and saturated aqueous sodium chloride solution, dried over 10 magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt / n-hexane = 10% and 15% to give 2-{4-[1-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol 5-yl]phenyl}ethyl acetate (501mg) as an oil. 15 MS (ESI+) : m/z 420(M+H)+ , 442(M+Na)+ 200MHz 1H NMR (DMSO-d6, d) : 1.96(3H, s), 2.91(2H, t, J=6.8 Hz), 4.22(2H, t, J=6.8 Hz), 7.22-7.37(5H, m), 7.61(2H, d, J=9.0 Hz), 8.30(2H, d, J=9.0 Hz) 20 The following compound(s) was (were) obtained in a similar manner to that of Example 596. Example 597 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-4-methyl-3 25 (trifluoromethyl)-1H-pyrazole MASS (ESI+): m/z = 439.1 (M+1), 461.2 (M+Na). 1HNMR ( 400MHz, CDCl3): 2.15 ( 3H, s), 3.79 ( 3H, s), 5.06 ( 2H, s), 6.8 ( 2H, d, J= 8.9Hz ), 6.95 ( 2H, d, J= 8.7Hz ), 7.07 ( 2H, d, J = 8.7Hz ), 7.14 ( 2H, d, J = 8. 9Hz ), 7.342 30 - 7.44 ( 5H, m). Example 598 387 WO 2004/050632 PCT/JP2003/014489 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl]phenyl}ethyl acetate MASS (ESI+): m/z = 346.1 (M-Ac+2), 388.1 (M+1). 1HNMR ( 400MHz, CDCl3): 2.04 ( 3H, s), 2.94 ( 2H, t, J = 5 7Hz ), 3.94 ( 3H, s), 4.28 ( 2H, t, J = 7Hz ), 6.72 ( IH, s), 6.77 ( 1H, t, J = 55Hz ), 6.75 ( 1H, d, J = 8.8Hz ), 7.17 ( 2H, d, J = 8.5Hz ), 7.22 ( 2H, d, J= 8.5Hz ), 7.54 ( 1H, dd, J = 3.9 ,8.8Hz), 8.08 ( 1H, d, J = 3.9Hz ). 10 Example 599 To a solution of ammonium chloride 58.8mg in H20 0.5ml was added iron powder 368mg and EtOH 2ml. The reaction mixture was warmed in oil bath, and a solution of 2-{4-[1-(4-nitrophenyl)-3-(trifluoromethyl)-lH-pyrazol 15 5-yllphenyl}ethyl acetate 460.7mg in EtOH 3ml was added. After being refluxed for 3hours, the reaction mixture was cooled to ambient temperature and unsoluble matter was removedbyfiltration. Thefiltratewasconcentratedinvacuo. The residuewas dissolved inAcOEt, andwashedwith saturated 20 aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from IPE to give 2-{4-[1-(4-aminophenyl)-3-(trifluoro methyl)-1H-pyrazol-5-ylIphenyl}ethyl acetate 182.3mg as a 25 powder. MS (ESI+) : m/z 390 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) : 1.96(3H, s), 2.87 (2H, t, J=6.8 Hz), 4.20 (2H, t, J=6.8 Hz), 5.46(2H, s), 6.54 (2H, d, J=8.7 Hz), 6.95(2H, d, J=8.7 Hz), 7.07 (1H, s), 7.18-7.28 (4H, m) 30 Example 600 A mixture of 2-{4-[1-(4-aminophenyl)-3-(trifluoro 388 WO 2004/050632 PCT/JP2003/014489 methyl) -1H-pyrazol-5-yljphenyl}ethyl acetate 165.6mg and 2,5-dimethoxytetrahydrofuran 112mg in AcOH 3ml was stirred at 50'C for 3hours. 2,5-Dimethoxytetrahydrofuran 0.22ml was added and the mixture was stirred at 50'C for 2hours. The 5 mixture was partitioned between ethyl acetate and H20. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer 10 silica gel chromatography developed by AcOEt / n-hexane = 20%. The seaparated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give 2-{4-[1-[4-(1H-pyrrol-1-yl)phenyl]-3-(trifluoromethyl) 1H-pyrazol-5-yl]phenyl}ethyl acetate 136.1mg as an oil. 15 MS (ESI+) : m/z 440 (M+H)+ 200MHz 1H NMR (DMSO-d6, d) 1.95 (3H, s), 2.88 (2H, t, J=6.8 Hz), 4.20(2H, t, J=6.8 Hz), 6.29(2H, t, J=2.0 Hz), 7.18 (1H, s), 7.23-7.32(4H, m), 7.39-7.47(4H, m), 7.69(2H, d, J=8.8 Hz) 20 Example 601 IM NaOH (436pl) was added to a solution of 2-{4-[l-[4-(lH-pyrrol-1-yl)phenyl]-3-(trifluoromethyl) 1H-pyrazol-5-yllphenyl}ethyl acetate (128mg) in THF 25 (1.5ml) andMeOH (0.3ml) under ice bath cooling. Themixture was stirred at 0 0 C-ambient temperature for 2hours. The mixture was neutralized with 1M HCl ( 436 pl), and was partitioned between AcOEt and H20. The organic layer was washed with saturated aqueous sodium chloride solution, 30 dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by AcOEt / n-hexane = 50%. The 389 WO 2004/050632 PCT/JP2003/014489 seaparated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give 2-{4-[1-[4-(lH-pyrrol-1-yl)phenyl]-3-(trifluoromethyl) 1H-pyrazol-5-yl]phenyl}ethanol (96.5mg) as an amorphous 5 powder. IR (KBr) 3404, 2924, 2883, 1612, 1522cm-1 MS (ESI+) m/z 398 (M+H)+ 200MHzlHNMR (DMSO-d6, d) :2.67-2.75(2H, m), 3.55-3.65(2H, m)), 4.64 (1H, t, J=5.1 Hz), 6.30 (2H, t, J=2.0 Hz), 7.16(1H, 10 s), 7.19-7.28(4H, m), 7.40-7.48 (4H, m), 7.70(2H, d, J=8.9 Hz) Example 602 A mixture of 10% Pd-C 50% wet (100mg) and ethyl 15 5-(4-cyanophenyl)-l-(4-methoxyphenyl)-1H-pyrazole-3 carboxylate (lg) in THF (10ml), MeCH (5ml), and 1M HCl (2. 9ml) was hydrogenatedunder H2 latmat ambient temperature for 6.5hours. The catalyst was filtered off through a celite pad andthepadwas washedwithMeOH. The filtrate and combined 20 washings were concentrated in vacuo. The residue was dissolved in EtOH and concentrated in vacuo. The residue was crystallized from AcOEt to give ethyl 5-[4-(aminomethyl)phenyl]-1-(4-methoxyphenyl)-1H pyrazole-3-carboxylate hydrochloride (984mg) as a powder. 25 MS (ESI+) : m/z 352 (M+H)+ 1HNMR (DMSO-d6) 51.32 (3H, t, J=7.lHz), 3.80 (3H, s), 4.01(2H, s), 4.33(2H, q, J=7.1 Hz), 7.00(2H, d, J=9.0 Hz), 7.14(1H, s), 7.28 (2H, d, J=9.0 Hz), 7.31 (2H, d, J=8.3 Hz), 7.47 (2H, d, J=8.3 Hz), 8.30(2H, brs) 30 The following compound(s) was (were) obtained in a similar manner to that of Example 602. 390 WO 2004/050632 PCT/JP2003/014489 Example 603 ethyl 5-[4-(aminomethyl)phenyl]-l-(6-methoxy-3 pyridinyl)-1H-pyrazole-3-carboxylate dihydrochloride 5 powder MS (ESI+) : m/z 353 (M+H) lHNMR ( 200MHz, DMSOd6): 1.32 ( 3H, t, J = 7.1Hz ), 3.88 ( 3H, s), 3.97 - 4.06 ( 2H, m), 4.34 ( 2H, q, J 7.1Hz ), 6.94 ( 1H, d, J= 8.7Hz ), 7.17 ( 1H, s), 7.35 ( 2H, d, J 10 = 8.2Hz ), 7.51 ( 2H, d, J = 8.2Hz ), 7.78 ( 1H, dd, J = 2.7 ,8.7Hz), 8.15 ( 1H, d, J = 2.7Hz ), 8.47 ( 2H, brs) Example 604 {4-[3-methoxy-1-(4-methoxyphenyl)-lH-pyrazol-5-yl] 15 benzyl}amine hydrochloride oil MS (ESI+) : m/z 310 (M+H) 1HNMR (200MHz, DMSOd6): 3.76 ( 3H, s), 3.85 ( 3H, s), 3.91 - 4.26 ( 2H, m), 6.16 ( 1H, s), 6.93 ( 2H, d, J = 8.9Hz ), 20 7.16 ( 2H, d, J = 8.9Hz ), 7.26 ( 2H, d, J = 8.2Hz), 7.45 2H, d, J = 8.2Hz ), 8.41 ( 2H, brs) Example 605 {4-[3-isopropoxy-1-(4-methoxyphenyl)-lH-pyrazol-5 25 yl]benzyl}amine hydrochloride powder MS (ESI+) : m/z 338 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.32 ( 6H, d, J = 6.2Hz ), 3.76 ( 3H, s), 4.00 ( 2H, s), 4.77 ( 1H, m), 6.11 ( 1H, s), 6.93 30 ( 2H, d, J = 8.9Hz), 7.15 ( 2H, d, J = 8.9Hz), 7.25 ( 2H, d, J = 8.2Hz ), 7.44 ( 2H, d, J = 8.2Hz ), 8.31 ( 2H, brs) 391 WO 2004/050632 PCT/JP2003/014489 Example 606 Et3N (326mg) and thena solution of di-tert-butyldicarbonate (594mg) in CH2Cl2 (3ml) was added successively to a suspension of ethyl 5-[4-(aminomethyl)phenyl1-l-(4 5 methoxyphenyl)-1H-pyrazole-3-carboxylate hydrochloride (960mg) in CH2Cl2 (9ml). After stirring at ambient temperature for hour, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and 1M HCl. The organic layer was washed with saturated 10 aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from AcOEt / n-hexane to give ethyl 5-(4-{[(tert-butoxy carbonyl)aminolmethyllphenyl)-1-(4-methoxyphenyl)-lH 15 pyrazole-3-carboxylate (1.045g) as a powder. MS (ESI+) : m/z 452 (M+H)+ 1HNMR (DMSO-d6) 51.31 (3H, t, J=7.1 Hz), 1.38 (9H, s), 3.79 (3H, s), 4.11(2H, d, J=6.2 Hz), 4.32(2H, q, J=7.1 Hz), 6.99(2H, d, J=8.9 Hz), 7.07(1H, s), 7.20(4H, s), 7.26(2H, d, J=8.9 20 Hz), 7.40(1H, t, J=6.2 Hz) The following compound(s) was (were) obtained in a similar manner to that of Example 606. 25 Example 607 ethyl 5-(4-{[(tert-butoxycarbonyl)amino]methyl}phenyl) 1-(6-methoxy-3-pyridinyl)-lH-pyrazole-3-carboxylate powder Mass (ESI+) : m/z 453 (M+H) 30 1HNMR ( 200MHz, DMSOd6): 1.32 ( 3H, t, J = 7.1Hz ), 1.38 9H, s), 3.88 ( 3H, s), 4.12 ( 2H, d, J = 6.1Hz ), 4.33 2H, q, J = 7.1Hz ), 6.92 ( 1H, d, J = 8.9Hz ), 7.10 ( 1H, 392 WO 2004/050632 PCT/JP2003/014489 s), 7.19 - 7.28 ( 4H, m), 7.41 ( 1H, t, J = 6.0Hz ), 7.74 1H, dd, J = 2.7 ,8.9Hz), 8.14 ( 1H, d, J = 2.7Hz Example 608 5 A mixture of ethyl 5-(4-{[(tert-butoxycarbonyl)aminol methyl}phenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3 carboxylate (500mg) and sodium methoxide (239mg) in formamide 5ml was stirred at 70'C for 2hours. The mixture was cooled to ambient temperature and partitioned between 10 AcOEt and brine. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give tert-butyl {4-[3-(aminocarbonyl)-1-(4-methoxyphenyl)-lH-pyrazol 5-yl]benzyl}carbamate (512mg) as an oil. 15 MS (ES1+) : m/z 423 (M+H)+ 1H NMR (DMSO-d6) 5 1.38 (9H, s), 3.78(3H, s), 4.11(2H, d, J=6.1Hz), 6.93 (1H, s), 6.98 (2H, d, J=8.9Hz), 7.19-7.43 (8H, m), 7.64(1H, brs) 20 Example 609 Phosphorous oxychloride (0.22ml) was added to DMF (2ml) under ice bath cooling. To this solution was added a solution of tert-butyl {4-[3-(aminocarbonyl)-1-(4-methoxyphenyl) 1H-pyrazol-5-yl]benzyl}carbamate (499mg) in DMF (3ml) 25 dropwise. The reactionmixture was stirred at 4'C for hour. Phosphorous oxychloride (0. 15ml) was added and the reaction mixture was stirred at 4 0 C for hour. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The 30 organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by 393 WO 2004/050632 PCT/JP2003/014489 preparative thin layer silica gel chromatography developed by AcOEt/n-hexane=40%. The seaparated silica gel was extractedwith 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give tert-butyl {4-[3-cyano-1-(4-methoxy 5 phenyl)-lH-pyrazol-5-yl]benzylcarbamate (136mg) asanoil. MS (ESI+) : m/z 427 (M+Na)+ , (ESI-) : m/z 403 (M-H)+ 200MHz1HNMR (CDCl3, d) :1.46(9H, s), 3.83(3H, s), 4.32(2H, d, J=5.9 Hz), 4.75(1H, br), 6.83(1H, s), 6.87(2H, d, J=9.0 Hz), 7.11-7.26(6H, m) 10 Example 610 To a solution of 5-[4-(2-{[tert-butyl(dimethyl) silylloxy}ethoxy)phenyl)-1-(4-methoxyphenyl)-4-methyl 3-(trifluoromethyl)-1H-pyrazole (5.2g) inEtOH (200ml) was 15 added conc.HCl (20ml) at room temperature. After stirring for 2 hrs, the reactionmixture was partitioned between EtOAc and water. Organic layer was separated andwashed with water, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (Hex/EtOAc=2: 1 -1: 1) to give 20 2.05g (51%) of 2-{4-[1-(4-methoxyphenyl)-4-methyl-3 (trifluoromethyl)-1H-pyrazol-5-yl]phenoxyjethanol as a crystal. MASS (ESI+): e/z = 415.1 (M+Na). 1HNMR ( 400MHz, CDCl3): 2.15 ( 3H, s), 1.99 ( 1H, t, J 25 6.2Hz ), 2.15 ( 3H, s), 3.95 - 4.00 ( 2H, m), 4.08 - 4.10 ( 2H, m), 6.80 ( 2H, d, J= 9Hz ), 6.90 ( 2H, d, J = 8.8Hz), 7.08 ( 2H, d, J = 8.8Hz ), 7.13 ( 2H, d, J = 9Hz ). Example 611 30 To solution of 4-[1-[4-(methylthio)phenyl]-3-(tri fluoromethyl)-1H-pyrazol-5yllphenol (5.0g) in DMF(20ml) was added NaH(0.75g) over 25min under ice cooling 394 WO 2004/050632 PCT/JP2003/014489 (5~20 C) (gas), stir at 3'C for 10min. tert-Butyl N-(2-bromoethyl)carbamate (4.48g) in DMF(5ml) was added to the mixture over 10min stir at 60 0 C(bath 70 0 C) for 6h and allowed to stand for overnight. 5 The mixture was poured into water (50ml) and.EtOAc (30ml), seperation and extracted with EtOAc(10ml) . The organic layer was washed with water(25 x 3) and brine (25ml), dried MgSO4, evaporated. The residue was column chromatographed on silica gel (75ml, 15v/w, AcOEt/Hex(2:1-1:1) and 10 evaporated to give 7.0g of tert-butyl (2-{4-[1-[4- (methyl thio)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl] phenoxy}ethyl)carbamate as an oil. MASS (ESI+): m/z = 516.1 (M+Na). 1HNMR ( 400MHz, CDC13): 1.45 ( 9H, s), 2.49 ( 3H, s), 3.49 15 - 3.58 ( 2H, m), 4.02 ( 2H, t, J= 10.2Hz ), 4.97 ( 1H, b.s), 6.68 ( 1H, s), 6.84 ( 2H, d, J = 17.5Hz ), 7.14 ( 2H, d, J = 17.5Hz ), 7.21 ( 4H, s). The following compound(s) was (were) obtained in a similar 20 manner to that of Example 611. Example 612 tert-butyl (2-{4-[l-(4-methoxyphenyl)-4-methyl-3 (trifluoromethyl)-1H-pyrazol-5-yllphenoxylethyl) 25 carbamate MASS (ESI+): m/z = 514.2 (M+Na). 1HNMR (400MHz, CDCl3): 1.45 ( 9H, s), 2.15 ( 3H, s), 3.52 3.56 ( 2H, m), 3.79 ( 3H, s), 4.02 ( 2H, t, J = 5.1Hz ), 4.99 ( 1H, b.s), 6.80 ( 2H, d, J = 9.0Hz ), 6.87 ( 2H, d, 30 J = 8.8Hz ), 7.07 ( 2H, d, J = 8.8Hz ), 7.13 ( H, d, J 9.0Hz ). 395 WO 2004/050632 PCT/JP2003/014489 Example 613 To a suspension of (2-{4-[l-[4-(methylthio)phenyl]-3 (trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)amine hydrochloride (7.5g) in H20 (150ml) and EtOH (75ml) was added 5 NaOCN (2.27g) at room temperature. pH was ajusted to 6.3 with 1NHCl . The mixture was stirred for 5 hours under the conditionofpH6.0-7.0. Thereactionmixturewasextracted with EtOAc and washed with dil. NaCl (twice), dried over MgSO4, filtered and evaporated. The residue was column 10 chromatographedonsilicagel (CH2Cl2/MeOH) andevaporated. The residue was crytalizedfromIPE/EtOH. Recrystalized from EtOH/H20 (50ml-50ml Final) and dried to give 4.10g (54%) of N-(2-{4-[l-[4-(methylthio)phenyl]-3-(trifluoro methyl)-1H-pyrazol-5-yllphenoxy}ethyl)urea. 15 MASS (ESI+): m/z = 459.1 (m+Na) 1HNMR ( 400MHz, DMSOd6): 2.05 ( 3H, s), 3.33 ( 2H, q, J= 5.6Hz ), 3.95 ( 2H, t, J = 5.6Hz ), 5.54 ( 2H, b.s), 6.16 ( 1H, t, J= 5.6Hz ), 6.96 ( 2H, d, J= 8.8Hz ), 7.09 ( 1H, s), 7.22 ( 2H, d, J = 8.6Hz ), 7.27 ( 2H, d, J = 8.7Hz ), 20 7.32 ( 2H, d, J = 8.7Hz ). HORIBA FT-IR for Windows Ver. 4.08 (cm-1):3399.89, 3197.40, 1650.77, 1614.13, 1554.34, 1475.28, 1459.85,1442.49, 1232.29, 1160.94, 1126.22, 1087.66, 1049.09, 970.019, 827.312. 25 The following compound(s) was(were) obtained in a similar manner to that of Example 61-3. Example 614 30 N-(2-{4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoro methyl)-1H-pyrazol-5-yl]phenoxylethyl)urea mp: 150.5-151.1'C 396 WO 2004/050632 PCT/JP2003/014489 MASS (ESI+): m/z = 457.2 (m+Na). 1HNMR ( 400MHz, CDC13): 2.15 ( 3H, s), 3.6 ( 2H, dt, J = 5 ,5.4Hz), 3.78 ( 3H, s), 4.04 ( 2H, t, J= 5Hz ), 4.5 ( 2H, b.s), 5.08 ( 1H, t, J = 5.4Hz ), 6.8 ( 2H, d, J = 9Hz ), 5 6.86 ( 2H, d, J = 8.8Hz ), 7.07 ( 2H, d, J= 8.8Hz.), 7.13 ( 2H, d, J = 9Hz ). Example 615 N-[2-(4-{3-(difluoromethyl)-1-[4-(methylthio)phenyll 10 1H-pyrazol-5-yl phenoxy)ethyl]urea mp: 184.3-184.7'C MASS (ESI+): m/z = 441.1 (M+Na). 1HNMR ( 400MHz, DMSOd6): 2.5 ( 3H, s), 3.33 ( 2H, dt, J= 5.6 ,6.3Hz), 3.95 ( 2H, t, J= 5.6Hz ), 5.53 ( 2H, b.s), 15 6.15 ( 1H, t, J = 6.3Hz ), 6.85 ( 1H, s), 6.95 ( 2H, d, J = 8.7Hz), 7.09( 1H, t, J= 54.lHz ), 7.2 ( 2H, d, J= 8.7Hz ), 7.23 ( 2H, d, J = 8.7Hz ), 7.3 ( 2H, d, J = 8.7Hz ). Example 616 20 N-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl) 1H-pyrazol-5-yl]phenyllethyl)urea mp: 194-196 'C MASS (ESI+): m/z = 410.2 (M+Na) 1HNMR ( 400MHz, DMSOd6): 2.68 ( 2H, t, J = 7.3Hz ), 3.19 25 ( 2H, dt, J = 5.6 ,7.3Hz), 3.88 ( 3H, s), 5.42 ( 2H, b.s), 5.95 ( 1H, t, J = 5.6Hz ), 6.91 ( IH, d, J = 8.8Hz ), 6.93 1H, s), 7.11 ( 1H, t, J = 54.4Hz ), 7.23 ( 4H, s), 7.7 1H, dd, J = 2.8 ,8.8Hz), 8.15 ( 1H, d, J = 2.8Hz ). 30 Example 617 N-{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H pyrazol 397 WO 2004/050632 PCT/JP2003/014489 5-yl]benzyl urea Crystal. mp: 147-149 0 C MASS (ESI+): m/z = 414.1 (M+Na). 1HNMR ( 400MHz, CDC13): 3.93 ( 3H, s), 4.37 ( 2H, d, J 5 6Hz ), 4.52 ( 2H, b.s), 5.08 ( 1H, t, J = 6Hz ), 6.73 ( 1H, s), 6.77 ( 1H, d, J = 8.8Hz ), 7.18 ( 2H, d, J = 8.3Hz ), 7.27 ( 2H, d, J= 8.3Hz ), 7.59 ( 1H, dd, J = 2.7 ,8.8Hz), 8.03 ( 1H, d, J = 2.7Hz ). 10 Example 618 N-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H pyrazol-5-yl]benzyl urea MASS (ESI+): m/z = 396.1 (m+Na). 1HNMR ( 400MHz, DMSOd6): 3.87 ( 3H, s), 4.17 ( 2H, d, J = 15 6Hz ), 5.55 ( 2H, b.s), 6.45 ( 1H, t, J = 6Hz ), 6.91 ( 1H, d, J= 8.8Hz ), 6.94 ( 1H, s), 7.11 ( 1H, t, J = 53.2Hz ), 7.27 ( 4H, s), 7.71 ( 1H, dd, J = 2.7 ,8.8Hz), 8.14 ( 1H, d, J 2.7Hz 20 Example 619 A mixture of N-(2-{4-[1-[4-(methylthio)phenyl]-3-(tri fluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea (250mg) and mCPBA (326mg) in CH2C12 (10ml)was stirred for 18 hrs. sat. NaHCO3 and CH2Cl2 was added. Aqueou layer 25 was separated and extracted. The combined organic layer was washed with sat. NaHCO3 (twice), dried and evaporated to give 207mg (79.9%) of crude product. The crude product was columnchromatographedbypreparativeTLCtogive207mg (80%) of N-(2-{4-[1-[4-(methylsulfinyl)phenyl]-3 30 (trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea as an amorphous. MASS (ESI+): 475.1 (m+Na). 398 WO 2004/050632 PCT/JP2003/014489 1HNMR ( 400MHz, DMSOd6): 2.79 ( 3H, s), 3.3 - 3.34 ( 2H, m), 3.95 ( 2H, t, J= 5.6Hz ), 5.53 ( 2H, b.s), 6.15 ( 1H, t, J 5.6Hz ), 6.97 ( 2H, d, J = 8.8Hz ), 7.16 ( 1H, s), 7.23 ( 2H, d, J = 8.8Hz ), 7.55 ( 2H, d, J = 8.6Hz ), 7.77 5 ( 2H, d, J = 8.6Hz ). Example 620 A mixture of N-(2-14-[1-[4-(methylthio)phenyl]-3-(tri fluoromethyl)-lH-pyrazol-5-yl]phenoxylethyl)urea 10 (250mg) and mCPBA (326mg) in CH2C12 (10ml)was stirred for 18 hrs. sat. NaHCO3 and CH2Cl2 was added. Aqueou layer was separated and extracted. The combined organic layer was washed with sat. NaHCO3 (twice), dried and evaporated to give 207mg (79.9%) of crude product. The crude product was 15 column chromatographed by preparative TLC to give 116mg (43%) of N-(2-{4-[1-[4-(methylsulfonyl)phenyl]-3 (trifluoromethyl)-lH-pyrazol-5-yl]phenoxy}ethyl)urea as a amorphous. MASS (ESI+): m/z = 491.0 (m+Na). 20 1HNMR ( 400MHz, DMSOd6): 3.28 ( 3H, s), 3.28 - 3.34 ( 2H, m), 3.96 ( 2H, t, J= 5.4Hz ), 5.54 ( 2H, b.s), 6.16 ( 1H, t, J = 5.4Hz ), 6.99 ( 2H, d, J = 8.4Hz ), 7.18 ( 1H, s), 7.25 ( 2H, d, J= 8.4Hz), 7.61 ( 2H, d, J= 8.4Hz ), 8.01 ( 2H, d, J = 8.4Hz ). 25 Example 621 To a solution of 2-{4-[3-(difluoromethyl)-1-(6-methoxy 3-pyridinyl)-lH-pyrazol-5-yl]phenyl}ethyl acetate (10g) in THF (120ml) and MeOH (30ml) was added 1NNaOH (60ml) at 30 room temperature. The reaction mixture was stirred at the same temperature for 4 hrs, and then neutralized with 1NHCl (60ml), evaporated, and extracted twice with EtOAc. The 399 WO 2004/050632 PCT/JP2003/014489 organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated to give crude product. The residue was column chromatographed on silica gel and crystalized from IPE and filtered to give 3.Og of 5 2-{4-[3-(difluoromethyl)-l-(6-methoxy-3-pyridinyl)-lH pyrazol-5-yl]phenyl)ethanol. The filtrate was evaporated and filtered to give 4.65g of second crystal. MASS (ESI+): m/z = 368.2 (M+Na). 1HNMR ( 400MHz, CDCl3): 1.49 ( 1H, t, J= 5.8Hz ), 2.87 ( 2H, 10 t, J = 6.5Hz ), 3.88 ( 2H, dt, J = 5.8 ,6.5Hz), 6.71 ( 1H, s), 6.76 ( 1H, t, J = 55Hz ), 6.75 ( IH, d, J = 8.8Hz ), 7.17 ( 2H, d, J= 8.4Hz ), 7.21 ( 2H, d, J= 8.4Hz ), 7.55 ( 1H, dd, J = 2.8 ,8.8Hz), 8.08 ( 1H, d, J = 2.8Hz ). 15 Example 622 To a solution of 2-{4-[3-(difluoromethyl)-1-(6-methoxy 3-pyridinyl)-lH-pyrazol-5-yl]phenyl}ethanol (7.4g) and Et3N(4.5ml) in CH2Cl2 (75ml) was added MsCl (2.5ml) under ice-cooling. After stirring for 1 hour, the reaction 20 mixture was quenched with water, separated. The aqueous layer was extracted with CH2Cl2 and combined organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 10. 5g (quant) of 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl) 25 1H-pyrazol-5-yl]phenyl}ethyl methanesulfonate as an oil. MASS (ESI+): m/z = 446.1 (M+Na). 1HNMR ( 400MHz, CDCl3) 2.9 ( 3H, s) , 3.06 ( 2H, t, J= 6.8Hz ) 3.94 ( 3H, s), 4.42 ( 2H, t, J = 6.8Hz ), 6.73 C 1H, s), 6.76 ( 1H, d, J = 8.8Hz ), 6.77 ( 1H, t, J = 55Hz ), 7.19 30 ( 2H, d, J = 8.6Hz ), 7.23 ( 2H, d, J= 8.6Hz ), 7.55 ( 1H, dd, J = 2.6 ,8.8Hz), 8.04 ( 1H, d, J = 2.6Hz ). 400 WO 2004/050632 PCT/JP2003/014489 Example 623 A mixture of 2-{4-[3-(difluoromethyl)--(6-methoxy-3 pyridinyl)-1H-pyrazol-5-yl]phenyl}ethyl methanesulf onat e (7. 4g) and Ph (CO) 2NK ( 3. 88 g ) in DMF (50ml) 5 was stirred at 60 0 C for 8 hours. Added water. The organic layer was extracted twice with EtOAc. Aqueous layer was washed with water (twice) and brine, dried over MgSO4, filtered, and evaporatedunder reducedpressure. Theresidue was triturated with IPE, filtered and dried to give 7.65g 10 of 2-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3 pyridinyl)-1H-pyrazol-5-yl]phenyl}ethyl)-1H-isoindole 1,3(2H)-dione as a solid. MASS (ESI+): 475.2 (M+1), 497.2 (M+Na). 1HNMR ( 400MHz,- CDC13): 3 ( 2H, t, J= 7.6Hz ), 3.92 ( 2H, 15 t, J = 7.6Hz ), 3.95 ( 3H, s), 6.7 ( 1H, s), 6.73 ( 11H, d, J = 8.8Hz ), 6.76 ( 1H, t, J = 55Hz ), 7.14 ( 2H, d, J = 8.1Hz) ,7.22 (2H, d, J=8.1Hz), 7.46 ( 1H, dd, J=2.7 ,8.8Hz), 7.71 - 7.73 ( 2H, m), 7.83 - 7.85 ( 2H, m), 8.1 ( 1H, d, J = 2.7Hz ). 20 Example 624 Amixture of 2-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3 pyridinyl)-1H-pyrazol-5-yl]phenyl}ethyl)-lH-isoindole 1,3(2H)-dion (5.0g) and NH2NH2 (2.8ml) in CH3CN (50ml) 25 was stirred at 600C for 8 hours. The reaction mixture was filtered. Filtrate was evaporated under reduced pressure. 4N HCl/Dioxane and then IPE was added. The product was triturated, filtered and died under reduced pressure to give 3.94g (90%) of (2-{4-[3-(difluoromethyl)-1-(6-methoxy 30 3-pyridinyl)-1H-pyrazol-5-yl]phenyllethyl)amine dihydrochloride as a solid. MASS (ESI+): m/z = 345.2 (M(free)+1). 401 WO 2004/050632 PCT/JP2003/014489 1HNMR ( 400MHz, DMSOd6): 2.9 - 2.95 ( 2H, m), 3.01- 3.06 ( 2H, m), 3.88 ( 3H, s), 6.92 ( 1H, d, J = 8.8Hz ), 6.95 (1H, s) , 7.13 ( 1H, t, J 56.1Hz ), 7.27 ( 2H, d, J= 8.4Hz ), 7.3 ( 2H, d, J = 8.4Hz ), 7.72 ( 1H, dd, J = 2.8 ,8.8Hz), 5 8.15 ( 1H, d, J = 2.8Hz ). The following compound(s) was (were) obtained in a similar manner to that of Example 602. 10 Example 625 {4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H pyrazol-5-yl]benzyl}amine dihydrochloride MASS (ESI+): m/z = 332.2 (M-NH2), 349.1 (M+H). 1HNMR ( 400MHz, DMSOd6): 3.88 ( 3H, s), 6.94 ( 1H, d, J = 15 9.6Hz ), 7.25 ( 1H, s), 7.37 ( 2H, d, J= 8Hz ), 7.53 ( 2H, d, J = 8Hz ), 7.8 ( 1H, dd, J = 2.9 ,9.6Hz), 8.45 ( 1H, d, J = 2.8Hz ). Example 626 20 {4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-lH pyrazol-5-yl]-benzyl}amine hydrochloride MASS (ESI+): m/z = 314.2 (M-NH2), 331.1 (M+1). 1HNMR ( 400MHz, DMSOd6): 3.88 ( 3H, s), 6.93 ( 1H, d, J = 8.8Hz), 7.00 ( 1H, s), 7.14 ( 1H, t, J= 54Hz ), 7.35 ( 2H, 25 d, J = 8.2Hz ), 7.53 ( 2H, d, J = 8.2Hz ), 7.75 ( 1H, dd, J = 2.7 ,8.8Hz), 8.15 ( 1H, d, J = 2.7Hz ). Example 627 To a solution of 5-hydrazino-2-methoxypyridine 30 dihydrochloride (4.78g) andEt3N (7.01g) inEtOH (50ml) was added {(2R,3S)-3-[4-(benzyloxy)phenyll-2-oxiranyl} (cyclopropyl)methanone (5.10g) and refluxed for 9hours. 402 WO 2004/050632 PCT/JP2003/014489 THs mixture was concentrated in vacuo. To the residue were added AcOEt and lMHCl, and unsoluble matter was filtered off through a celit pad. The filtrate was partitioned, and the organic lauer was washed with saturated aqueous sodium 5 bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in CH2C12 (50ml). To this solution were added Et3N (5.26g) and methanesulfonyl chloride (2.98g) successively under ice-bath cooling. The mixture was stirred at ambient 10 temperature for 2hours. The mixture was washed with 1M HCl, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 15 AcOEt/n-hexane=20% togive5-{5-[4-(benzyloxy)phenyl]- 3 cyclopropyl-lH-pyrazol-1-yl}-2-methoxypyridine (4.20g) as a solid. MS (ESI+) : m/z 398 (M+H) 1HNMR ( 200MHz, DMSOd6): 0.69 - 0.78 ( 2H, m), 0.87 - 0.97 20 ( 2H, m), 1.89 - 1.99 ( 1H, m), 3.85 ( 3H, s), 5.09 ( 2H, s), 6.30 ( 1H, s), 6.85 ( 1H, d, J = 8.8Hz ), 6.99 ( 2H, d, J= 8.8Hz ), 7.15 ( 2H, d, J= 8.8Hz), 7.34 - 7.46 ( 5H, m), 7.60 ( 1H, dd, J= 2.7 ,8.8Hz), 8.01 ( 1H, d, J= 2.7Hz 25 Example 628 To a mixture of tert-butyl (2-{4-[l-(4-methoxyphenyl)-3 carboxy-1H-pyrazol-5-yl]phenoxy)ethyl)carbamate (313.9mg), piperidine (88.4mg), and1-hydroxybenzotriazole (140mg) in DMF 3ml was added water soluble carbodiimide 30 hydrochloride (199mg) under ice-bath cooling. The mixture was stirred at ambient temperature overnight, then was partitioned between AcOEt and H20. The organic layer was 403 WO 2004/050632 PCT/JP2003/014489 separated, washed with IM HCl, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column 5 chromatography eluted withAcOEt / n-hexane = 70%. The residu was crystallized from IPE to give tert-butyl 2-{4-[1-(4-methoxyphenyl)-3-(l-piperidinyl-carbonyl) 1H-pyrazol-5-yllphenoxy}ethyl)carbamate (332.5mg) as a white powder. 10 MS (ESI+) : m/z 521 (M+H) 1HNMR ( 200MHz, CDCl3): 1.45 ( 9H, s), 1.53 - 1.79 ( 6H, m), 3.48 - 3.57 ( 2H, m), 3.67 - 3.81 ( 2H, m), 3.82 ( 3H, s), 3.88 - 4.02 ( 2H, m), 3.98 - 4.04 ( 2H, m), 4.96 ( 1H, brs), 6.77 ( 1H, s), 6.81 ( 2H, d, J= 8.8Hz ), 6.86 ( 2H, 15 d, J = 9.0Hz ), 7.15 ( 2H, d, J = 8.8Hz ), 7.21 ( 2H, d, J = 9.0Hz ) The following compound(s) was (were) obtained in a similar manner to that of Example 628. 20 Example 629 tert-butyl (2-{4-[1-(6-methoxy-3-pyridinyl)-3 (1-piperidinylcarbonyl)-lH-pyrazol-5-yl]phenoxy}ethyl) carbamate 25 powder MS (ESI+) : m/z 522 (M+H) 1HNMR ( 200MHz, CDCl3): 1.45 ( 9H, s), 1.54 - 1.78 ( 6H, m), 3.49 -3.57 ( 2H, m), 3.69- 3.82 ( 2H, m), 3.86 - 3.99 ( 2H, m), 3.94 ( 3H, s), 3.99 - 4.05 ( 2H, m), 4.96 ( 1H, 30 s), 6.73 ( 1H, d, J 8.8Hz ), 6.79 ( 1H, s), 6.84 ( 2H, d, J = 8.8Hz ), 7.16 ( 2H, d, J = 8.8Hz ), 7.50 ( 1H, dd, J = 2.7 ,8.8Hz), 8.12 ( 1H, d, J = 2.7Hz 404 WO 2004/050632 PCT/JP2003/014489 Example 630 tert-butyl (2-{4-[3-{[ethyl(methyl)amiino]carbonyl} 1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy} 5 ethyl)carbamate powder Mass (ESI+) : m/z 496 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.08 - 1.22 ( 3H, m), 1.37 ( 9H, s), 2.98, 3.29 ( 3H, s), 3.23 - 3.32 ( 2H, m), 3.42 - 3.53, 10 3.63 - 3.75 ( 2H, m), 3.87 ( 3H, s), 3.93- 4.00 ( 2H, m), 6.82, 6.84 ( 1H, s), 6.87 - 7.00 ( 4H, m), 7.21 ( 2H, d, J = 8.6Hz ), 7.61 - 7.72 ( 1H, m), 8.13 - 8.15 ( 1H, m) Example 631 15 2-{4-[1-(4-methoxyphenyl)-3-(l-piperidinylcarbonyl)-lH pyrazol-5-yl]phenoxy}ethanol mp.121.9-123.8 0 C Mass (ESI+) : m/z 422 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.42 - 1.74 ( 6H, m), 3.53 - 3.70 20 ( 2H, m), 3.65 - 3.73 ( 2H, m), 3.70 - 3.92 ( 2H, m), 3.78 ( 3H, s), 3.95 - 4.00 ( 2H, m), 4.86 ( 1H, t, J 5.4Hz ), 6.77 ( 1H, s), 6.91 ( 2H, d, J = 8.8Hz ), 6.98 ( 2H, d, J = 8.9Hz ), 7.16 ( 2H, d, J= 8.8Hz ), 7.23 ( 2H, d, J= 8.9Hz 25 Example 632 2-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl carbonyl)-1H-pyrazol-5-yl]phenoxy}ethanol mp.123.4-124.0 C Mass (ESI+) : m/z 423 (M+H) 30 1HNMR ( 200MHz, DMSOd6): 1.45 - 1.74 ( 6H, m), 3.50 - 3.69 ( 2H, n), 3.65 - 3.74 ( 2H, m), 3.71 - 3.90 ( 2H, m), 3.87 (3H, s), 3.96 - 4.02 ( 2H, m), 4.86 ( 1H, t, J = 5.4Hz ), 405 WO 2004/050632 PCT/JP2003/014489 6.81 ( 1H, s), 6.90 ( 1H, d, J = 8.7Hz ), 6.94 ( 2H, d, J = 8.6Hz ), 7.20 ( 2H, d, J = 8.6Hz ), 7.68 ( 1H, dd, J = 2.7 ,8.7Hz), 8.14 ( 1H, d, J = 2.7Hz 5 Example 633 tert-butyl {4-[l-(4-methoxyphenyl)-3-(1-piperidinyl carbonyl)-lH-pyrazol-5-yl]benzyl}carbamate amorphous powderr MS (ESI+) : m/z 491 (M+H) 10 1HNMR (200MHz, CDCl3): 1.46 ( 9H, s), 1.55 - 1.8 ( 6H, m), 3.68 - 3.82 ( 2H, m), 3.82 ( 3H, s), 3.97 - 4.00 ( 2H, m), 4.31 ( 2H, d, J= 6.0Hz ), 4.84 ( 1H, brs), 6.82 ( IH, s), 6.86 ( 2H, d, J = 9Hz ), 7.15 - 7.25 ( 6H, m) 15 Example 634 tert-butyl {4-[3-{[ethyl(methyl)amino]carbonyl}-1 (4-methoxyphenyl)-1H-pyrazol-5-yljbenzyl}carbamate amorphous powder MS (ESI+) : m/z 465 (M+H) 20 1HNMR ( 200MHz, CDC13): 1.20 - 1.31 ( 3H, m), 1.46 ( 9H, s), 3.11, 3.40 ( 3H, s), 3.61, 3.85 ( 2H, q, J = 7.1Hz ), 3.82 ( 3H, s), 4.31 ( 2H, d, J= 5.8Hz ), 4.86 ( 1H, brs), 6.81 - 6.90 ( 3H, m), 7.16 - 7.25 ( 6H, m) 25 Example 635 tert-butyl {4-[3-{[methoxy(methyl)amino]carbonyl} 1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}carbamate solid MS (ESI+) : m/z 467 (M+H) 30 1HNMR ( 200MHz, CDCl3): 1.46 ( 9H, s), 3.51 ( 3H, s), 3.82 ( 3H, s), 3.85 ( 3H, s), 4.31 ( 2H, d, J = 5.9Hz ), 4.87 ( 1H, brs), 6.86 ( 2H, d, J = 9.0Hz ), 6.96 ( 1H, s), 7.15 406 WO 2004/050632 PCT/JP2003/014489 - 7.26 ( 6H, m) Example 636 tert-butyl 5 {4-[l-(6-methoxy-3-pyridinyl)-3-(l-piperidinyl carbonyl)-lH-pyrazol-5-yl]benzyl}carbamate oil MS (ESI+) : m/z 492 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.39 ( 9H, s), 1.46 - 1.75 ( 6H, 10 m), 3.52 - 3.69 ( 2H, m), 3.75 - 3.93 ( 2H, m), 3.87 ( 3H, s), 4.13 ( 2H, d, J = 6.1Hz ), 6.86 ( 1H, s), 6.90 ( 1H, d, J= 8.9Hz ), 7.19 - 7.28 ( 4H, m), 7.41 ( 1H, t, J 6.1Hz ), 7.70 ( 1H, dd, J = 2.7 ,8.9Hz), 8.13 ( 1H, d, J = 2.7Hz 15 Example 637 tert-butyl {4-[3-{[ethyl(methyl)amino]carbonyl}-l (6-methoxy-3-pyridinyl)-1H-pyrazol-5-yllbenzyl} carbamate oil 20 MS (ESI+) : m/z 466 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.09 - 1.22 ( 3H, m), 1.39 ( 9H, s), 2.98,3.28 (3H, s), 3.73 - 3.77 ( 2H, m), 3.87 ( 3H, s), 4.13 ( 2H, d, J 6.0Hz ), 6.87 - 6.93 ( 2H, m), 7.18 - 7.30 ( 4H, m) , 7.41 ( 1H, t, J = 6.0Hz ), 7.65 - 7.74 ( 1H, 25 m), 8.14 ( 1H, d, J = 2.6Hz Example 638 tert-butyl {4-[3-{[methoxy(methyl)amino]carbonyl}-1-(6 methoxy-3-pyridinyl)-lH-pyrazol-5-yl]benzyl}carbamate 30 powder MS (ESI+) : m/z 468 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.39 ( 9H, s), 3.37 ( 3H, s), 3.77 407 WO 2004/050632 PCT/JP2003/014489 ( 3H, s), 3.87 ( 3H, s), 4.13 ( 2H, d, J = 6.1Hz ), 6.91 ( 1H, d, J = 8.8Hz ), 6.97 ( 1H, s), 7.25 ( 4H, s), 7.42 ( 1H, t, J = 6.1Hz ), 7.71 ( 1H, dd, J = 2.7 ,8.8Hz), 8.15 ( 1H, d, J = 2.7Hz 5 Example 639 5-[4-(2-hydroxyethyl)phenyll-N-methoxy-1-(4-methoxy phenyl)-N-methyl-1H-pyrazole-3-carboxamide oil 10 MS (ESI+) : m/z 382 (M+H) 1HNMR ( 200MHz, CDC13): 1.44 ( 1H, t, J = 5.8Hz ), 2.83 2.90 ( 2H, m), 3.51 ( 3H, s), 3.82 ( 3H, s), 3.85 ( 3H, s), 3.84 -3.89 ( 2H, m), 6.86 ( 2H, d, J= 9.0Hz ), 6.96 ( 1H, s), 7.13 - 7.26 ( 6H, m) 15 Example 640 5-[4-(2-hydroxyethyl)phenyl]-N-methoxy-1-(6-methoxy-3 pyridinyl)-N-methyl-1H-pyrazole-3-carboxamide oil 20 Mass (ESI+) : m/z 383 (M+H) 1HNMR ( 200MHz, CDCl3): 2.84 - 2.91 ( 2H, m), 3.51 ( 3H, s), 3.85 ( 3H, s), 3.81 -3.92 ( 2H, m), 3.95 ( 3H, s), 6.74 ( 1H, d, J = 8.6Hz ), 6.97 ( 1H, s), 7.20 ( 4H, s), 7.55 ( 1H, dd, J = 2.8 ,8.6Hz), 8.13 ( 1H, d, J = 2.8Hz 25 Example 641 To a solution of tert-butyl{4-[3-(1-hydroxy-1-methyl ethyl)-l-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl} carbamate (1.lg) and Et3N (1.02g) was addedmethanesulfonyl 30 chloride (576mg). The mixture was stirred at ambient temperature overnight. The mixture was concentrated in vacuo. The residue was partitioned between AcOEt and IM HCl. The 408 WO 2004/050632 PCT/JP2003/014489 organic layer was separated, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica 5 gel column chromatography eluted with AcOEt / n-hexane = 25%. The pure fraction was collected and concentrated in vacuo to give tert-butyl {4-[3-isopropenyl-l-(4 methoxyphenyl)-1H-pyrazol-5-ylIbenzyl}carbamate (857mg) as a solid. 10 MS (ESI+) : m/z 420 (M+H) 1HNMR ( 200MHz, ): 1.46 ( 9H, s), 2.21( 3H, s), 3.81 ( 3H, s), 4.30 ( 2H, d, J= 5.9Hz ), 4.84 ( 1H, brs), 5.13 ( 1H, brs) , 5.60 ( 1H, brs), 6.60 ( 1H, s) , 6.84 ( 2H, d, J= 8.9Hz ) 7.18 - 7.26 ( 6H, m) 15 The following compound(s) was (were) obtained in a similar manner to that of Example 641. Example 642 20 tert-butyl {4-[3-isopropenyl-l-(6-methoxy-3-pyridinyl) 1H-pyrazol-5-yl]benzyl carbamate oil MS (ESI+) : m/z 421 (M+H) 1HNMR ( 200MHz, DMSOd6): 1.39 ( 9H, s), 2.10 ( 3H, s), 3.86 25 ( 3H, s), 4.12 ( 2H, d, J= 6.2Hz ), 5.15 ( 1H, brs), 5.63 1H, brs), 6.88 ( 1H, s), 6.88 ( 1H, d, J= 8.8Hz ), 7.22 4H, s), 7.40 ( 1H, t, J = 6.2Hz ), 7.67 ( 1H, dd, J 2.7 ,8.8Hz), 8.06 ( 1H, d, J = 2.7Hz 30 Example 643 A0.76MsolutionofisopropylmagnesiumbromideinTHF (8.5ml) was added dropwise to a solution of tert-butyl 409 WO 2004/050632 PCT/JP2003/014489 {4-[3-{[methoxy(methyl)amino]carbonyl}-l-(4-methoxy phenyl)-1H-pyrazol-5-yl]benzyl}carbamate (lg) in THF (10ml) at 10-15'C. The mixture was stirred at ambient temperature for 4hours. The reaction mixture was poured into 5 a mixture of 1M HCl and ice. The mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica 10 gel column chromatography eluted with AcOEt / n-hexane = 20%, 25%, then 10% MeOH/CHCl3. The combined pure fraction was concentrated in vacuo to give tert-butyl {4-[3-isobutyryl-l-(4-methoxyphenyl)-1H-pyrazol-5 yl]benzyl}carbamate (318mg) as an amorphous powder. 15 MS (ESI+) : m/z 450 (M+H) 1HNMR ( 200MHz, CDCl3): 1.25 ( 6H, d, J= 6.8Hz), 1.46 ( 9H, s), 3.72 - 3.87 ( 1H, m), 3.83 ( 3H, s), 4.31 ( 2H, d, J = 5.9Hz ), 4.75 - 4.93 ( 1H, m), 6.88 ( 2H, d, J = 9Hz ), 6.98 ( 1H, s), 7.14 - 7.27 ( 6H, m) 20 The following compound(s) was (were) obtained in a similar manner to that of Example 643. Example 644 25 tert-butyl {4-[3-isobutyryl-l-(6-methoxy-3-pyridinyl) 1H-pyrazol-5-yllbenzyl carbamate oil MS (ESI+) : m/z 451 (M-H) 1HNMR ( 200MHz, DMSOd6): 1.16 ( 6H, d, J = 6.8Hz ), 1.38 30 ( 9H, s), 3.68 ( 1H, m), 3.88 ( 3H, s), 4.13 ( 2H, d, J 6.1Hz ), 6.92 ( 1H, d, J = 8.8Hz ), 7.07 ( 1H, s), 7.19 7.29 ( 4H, m), 7.41 ( 1H, t, J = 6.lHz ), 7.75 ( 1H, dd, 410 WO 2004/050632 PCT/JP2003/014489 J = 2.7 ,8.8Hz), 8.17 ( 1H, d, J = 2.7Hz Example 645 To a solution of 4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2 5 trifluoroethoxy)-lH-pyrazol-5-yl]benzonitrile (197mg) in THF (2ml) was added lithium aluminum hydride (30mg) under ice-bath cooling. Themixture was stirred at same temperature for hour and then at ambient temperature for 2hours. The reaction was quenched by adding 5% aqueous solution of 10 potassium sodium tartaric acid (ca.0.5ml). The mixture was diluted with AcOEt, dried over MgSO4, and filtered through a celite pad. The filtrate was concentrated in vacuo to give {4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro ethoxy)-1H-pyrazol-5-yllbenzyl}amine (200mg) as an oil. 15 MS ((ESI+) : m/z 379 (M+H) 1HNMR ( 200MHz, DMSOd6): 3.75 ( 2H, s), 3.85 ( 3H, s), 4.84 ( 1H, d, J = 9Hz ), 4.93 ( 1H, d, J = 9Hz ), 6.32 ( 1H, s), 6.87 ( 1H, d, J= 8.9Hz ), 7.19 ( 2H, d, J= 8.2Hz ), 7.33 ( 2H, d, J = 8.2Hz ), 7.64 ( 1H, dd, J = 2.7 ,8.9Hz), 8.03 20 ( 1H, d, J= 2.7Hz) The following compound(s) was (were) obtained in a similar manner to that of Example 645. 25 Example 646 1-{4-[3-chloro-l-(4-methoxyphenyl)-lH-pyrazol-5-yl] phenyl methanamine oil MS : (ESI+) : m/z 314 (M+H) 30 1HNMR ( 200MHz, DMSOd6): 3.69 ( 2H, s), 3.78 ( 3H, s), 6.72 ( 1H, s), 6.96 ( 2H, d, J= 9Hz), 7.16 ( 2H, d, J= 8.2Hz), 7.22 ( 2H, d, J = 9Hz ), 7.3 ( 2H, d, J = 8.2Hz 411 WO 2004/050632 PCT/JP2003/014489 Example 647 l-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5 yl]phenyl}methanamine 5 powder MS (ESI+) : m/z 315 (M+H) 1HNMR ( 200MHz, DMSOd6): 3.70 ( 2H, s), 3.86 ( 3H, s), 6.78 ( 1H, s), 6.89 ( IH, d, J= 8.7Hz ), 7.20 ( 2H, d, J= 8.3Hz ), 7.33 ( 2H, d, J= 8.3Hz ), 7.69 ( 1H, dd, J = 2.7 ,8.7Hz), 10 8.10 ( 1H, d, J =2.7Hz Example 648 A mixture of 5-[4-(benzyloxy)phenyl]-3-amino-l-(4 methoxyphenyl)-1H-pyrazole (4.Og), lithium chloride 15 (2.28g), and copper(II) chloride (2.90g) in acetonitrile (50ml) was stirred at ambient temperature for minutes. To this mixture was added isoamyl nitrite (2. 52g), and the mixture was stirred at ambient temperature for 1.5hours. To the reaction mixture was added a mixture of ethyl acetate 20 and saturated aqueous ammonium chloride solution. The mixture was stirred at ambient temperature for a while, and partitioned. The aqueous layer was reextracted with ethyl acetate. The combined organic layers were washed with saturated aqueous ammonium chloride solution and saturated 25 aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 20% AcOEt / n-hexane. The pure fractions were collected and concentrated in vacuo to give 5-[4-(benzyloxy)phenyl 30 3-chloro-1-(4-methoxyphenyl)-lH-pyrazole (2.81g) as a solid. MS ESI+) : m/z 391 (M+H) 412 WO 2004/050632 PCT/JP2003/014489 1HNMR (200MHz, CDCl3): 3.81 ( 3H, s), 5.05 ( 2H, s), 6.35 ( 1H, s), 6.84 ( 2H, d, J= 9Hz ), 6.89 ( 2H, d, J= 8.9Hz ), 7.12 ( 2H, d, J = 8.9Hz ), 7.19 ( 2H, d, J = 9Hz ), 7.34 - 7.43 ( 5H, m) 5 Example 649 A solution of 4-benzyloxypropiophenone (5g) in N,N-dimethylformamide dimethyl acetal (20ml) was refluxed for 24hours. The mixture was concentrated in vacuo. The 10 residue was dissolved in toluene and concentrated in vacuo. This was repeated one more time. The residue was dissolved inEtOH. To this solution was added 4-methoxyphenylhydrazine hydrochloride (3.63g), and the mixture was refluxed for 3hours. The reaction mixture was cooled to ambient 15 temperature and partitioned between AcOEt and 1MHCl. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column 20 chromatography eluted with AcOEt / n-hexane = 30% to give 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-4-methyl IH-pyrazole (5.31g) as a powder. MS (ESI+) : m/z 371(M+H) 200MHz1HNMR (CDCl3, d) :2.10 (3H, s), 3.79(3H, s), 5.06(2H, 25 s), 6.80(2H, d, J=8.9 Hz), 6.94 (2H, d, J=8.8 Hz), 7.09(2H, d, J=8.8 Hz), 7.14(2H, d, J=8.9 Hz), 7.31-7.48(5H, m), 7.55(2H, s) The following compound(s) was (were) obtained in a similar 30 manner to that of Example 649. Example 650 413 WO 2004/050632 PCT/JP2003/014489 5-{5-[4-(benzyloxy)phenyll-4-methyl-lH-pyrazol-1-yl}-2 methoxypyridine powder MS (ESI+) : m/z 372 (M+H) 5 200MHz 1H NMR (CDCl3, d) : 2.10 (3H, s), 3.91(3H, s), 5.06(2H, s), 6.68 (lH, d, J=8.8 Hz), 6.96(2H, d, J=8.7 Hz), 7.09(2H, d, J=8.7 Hz), 7.36-7.52(6H, m), 7.59(lH, s), 8.02(1H, d, J=2.7 Hz) 10 Example 651 A solution of t-butyl nitrite (1.14ml) in CHC13 (3ml) was added dropwise to a solution of 5-[4- (benzyloxy)phenyl] -1 (4-methoxyphenyl)-3-amino-lH-pyrazole (1.5g) and dimethyldisulfide (1.15ml) in CHCl3 (10ml) . After all of 15 t-butyl nitrite solution was added, the tempearature of reaction mixture began to rise and reached to reflux. After the reflux ceased, the mixture was stirred at ambient temperature for Ihour. The mixture was concentrated in vacuo and the residue was purified by silica gel column 20 chromatography eluted with AcOEt / n-hexane = 25% to give 5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3 (methylthio)-lH-pyrazole (635.2mg) as an oil. Mass (ESI+) : m/z 403 (M+H) 1HNMR ( 200MHz, CDCl3): 2.58 ( 3H, s), 3.81 ( 3H, s), 5.04 25 ( 2H, s), 6.36 ( 1H, s), 6.81 - 6.91 ( 4H, m), 7.13 ( 2H, d, J = 8.7Hz ), 7.20( 2H, d, J = 9Hz ), 7.34 - 7.43 ( 5H, m) Example 652 30 A mixture of 3-cyano-l-(4-methoxyphenyl)-5-[4 (aminometyl)phenyl]-lH-pyrazole (90mg) , trimethylsilylisocyanate (152mg) and Et3N (0.18ml) in 414 WO 2004/050632 PCT/JP2003/014489 CH2C12 (5ml) was stirred at room temperature. After stirring for 5 hours (checked by TLC), water and CHCl3 was added. The organic layer was separated. Aqueous layer was extracted with EtOAc. The combined organic layer was 5 washed with water and brine. Dried over MgSO4, filtered and evaporated under reduced pressure to give 48mg (52%) of N-{4-[3-cyano-l-(4-methoxyphenyl)-lH-pyrazol 5-yllbenzyl}urea. MASS (ESI+): m/z = 370.1 (M+Na). 10 1HNMR (200MHz, CDCl3) 3.83 ( H, s), 4.38 ( 2H, d, J= 6Hz), 4.42 ( 2H, b.s), 4.902 - ( 1H, m), 6.82 ( 1H, s), 6.87 ( 2H, d, J = 9Hz ), 7.15 ( 2H, d, J = 8.3Hz ), 7.19 ( 2H, d, J = 9Hz ), 7.26 ( 2H, d, J = 8.3Hz ). 15 Example 653 To amixture of (2-{4-[3-methoxy-l-(4-methoxyphenyl)-1H pyrazol-5-yllphenoxy}ethyl)amine hydrochloride (150mg) in CHCl3 (2ml) and saturated aqueous sodium bicarbonate solution (lml) was added thiophosgene (68.8mg) under 20 ice-bath cooling. The mixture was stirred at ambient temperature for 5hours. To the mixture was added 28% aqueous ammonium hydroxide (Iml) and the mixture was stirred at ambient temperature overnight. To the mixture were added 28% aqueous ammonium hydroxide (1ml) and MeOH (lml) and the 25 mixture was stirred at r.t. for 7hours. The reactionmixture was partitioned between AcOEt and H20. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. 30 The residue was crystallized from ACOEt-IPE. The obtained powder was recrystallized from AcOEt-n-hexane to give N-(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5 415 WO 2004/050632 PCT/JP2003/014489 yl]phenoxy}ethyl)thiourea (116mg) as a powder. mp. 141.6-142.3'C MS (ESI+) : m/z 399 (M+H) 1HNMR ( 200MHz, DMSOd6): 3.61 - 3.89 ( 2H, m), 3.75 ( 3H, 5 s), 3.83 ( 3H, s), 3.98 -4.12 ( 2H, m), 6.04 ( 1H, s), 6.92 ( 4H, d, J = 8.9Hz ), 7.09 ( 2H, brs), 7.13 ( 4H, d, J = 8.9Hz ), 7.77 ( 1H, t, J = 5.2Hz Example 654 10 A solution of methanesulfonyl chloride (328mg) in CH2C12 (2ml) was added to a solution of 5-[4-(2-hydroxyethyl) phenyl]-N-methoxy-l-(4-methoxyphenyl)-N-methyl-lH pyrazole-3-carboxamide (840mg) and Et3N (334mg) in CH2C12 (10ml) under ice bath cooling. The mixture was stirred at 15 sametemperature for hour. The mixture was diluted with CHCl3 and washedwith 1MHCl, saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography 20 eluted with AcOEt / n-hexane = 80%, 90%. The pure fractions were collected and concentrated in vacuo to give 2-{4-[3-{[methoxy(methyl)amino]carbonyl}-1-(4-methoxyph enyl)-lH-pyrazol-5-yl]phenyl}ethyl methanesulfonate (1.01g) as an oil. 25 Mass (ESI+) : m/z 460 (M+H) 1HNMR ( 200MHz, CDCl3): 2.89 ( 3H, s), 3.05 ( 2H, t, J 6.8Hz ), 3.51 ( 3H, s), 3.83 ( 3H, s), 3.85 ( 3H, s), 4.41 ( 2H, t, J = 6.88Hz ), 6.86 ( 2H, d, J = 9.0Hz ), 6.97 ( 1H, s), 7.18 - 7.26 ( 6H, m) 30 The following compound(s) was (were) obtained in a similar manner to that of Example 654. 416 WO 2004/050632 PCT/JP2003/014489 Example 655 2-{4-[3-{[methoxy(methyl)amino]carbonyl)-1-(6-methoxy 3-pyridinyl)-1H-pyrazol-5-yl]phenyllethyl 5 methanesulfonate oil Mass (ESI+) : m/z 461 (M+H) 1HNMR ( 200MHz, CDCl3): 2.91 ( 3H, s), 3.06 ( 2H, t, J 6.8Hz ), 3.50 ( 3H, s), 3.85 ( 3H, s), 3.94 ( 3H, s), 4.43 10 ( 2H, t, J= 6.8Hz ), 6.74 ( 1H, d, J = 8.8Hz), 6.99 ( 1H, s), 7.32 ( 4H, s), 7.55 ( 1H, dd, J= 2.7 ,8.8Hz), 8.09 ( IH, d, J = 2.7Hz Example 656 15 Amixture of2-{4-[3-{ [methoxy(methyl)amino]-carbonyl}-1 (4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}ethyl methanesulfonate (1.02g), 15-crown-5 (489mg), sodium azide (722mg) in hexamethylphosphoric triamide (6ml) was stirred at 550C for lhour. The mixture was poured into ice 20 water, and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in MeOH (6ml) . To this solution was added a solution of 6M HCl (0.37ml) in MeOH 25 (2ml) and 10% palladium on carbon (50%wet) (200mg). The mixturewashydrogenatedunderH2 latmat ambient temperature for 2hours. The catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 5-[4-(2-aminoethyl)phenyl]-N-methoxy-1-(4-methoxy 30 phenyl)-N-methyl-1H-pyrazole-3-carboxamide hydrochloride (0.93g) as an oil. Mass (ESI+) : m/z 381 (M+H) 417 WO 2004/050632 PCT/JP2003/014489 1HNMR ( 200MHz, DMSOd6): 2.79 - 3.16 ( 4H, m), 3.38 ( 3H, s), 3.77 ( 3H, s), 3.79 ( 3H, s), 6.95 ( 1H, s), 6.99 ( 2H, d, J = 9.0Hz ), 7.15 - 7.36 ( 6H, m), 8.00 ( 2H, brs) 5 The following compound (s) was (were) obtained in a similar manner to that of Example 656. Example 657 5-[4-(2-aminoethyl)phenyl]-N-methoxy-1-(6-methoxy-3 10 pyridinyl)-N-methyl-1H-pyrazole-3-carboxamide hydrochloride oil Mass (ESI+) : m/z 382 (M+H) 1HNMR ( 200MHz, DMSOd6): 2.80 - 3.15 ( 4H, m), 3.38 ( 3H, 15 s), 3.77 ( 3H, s), 3.88 ( 3H, s), 6.92 (1H, d, J= 8.8Hz ), 6.98 (1H, s), 7.22-7.36 ( 4H, m) , 7.72 ( 1H, dd, J=2.7 ,8.8Hz), 8.02 ( 2H, brs), 8.17. ( 1H, d, J = 2.7Hz Example 658 20 To a 0.76M solution of isopropylmagnesium bromide in THF (2.Oml) was added a solution of 5-(4-{2-[(aminocarbonyl) amino]ethyliphenyl)-N-methoxy-l-(4-methoxyphenyl)-N methyl-lH-pyrazole-3-carboxamide (130mg) in THF (2ml) dropwise at at 4*C. The mixture was stirred at ambient 25 temperature overnight. Additional 0.76M solution of isopropylmagnesium bromide in THF (2. Oml) was added and the mixture was stirred at 50 0 C for hours. The reactionmixture was cooled to ambient temperature and was quenched by adding saturated aqueous ammonium chloride solution. The mixture 30 was extracted with AcOEt. The oreganic layer was washed with IM HCl, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over 418 WO 2004/050632 PCT/JP2003/014489 magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by MeOH/CHC3 10%. The seaparated silica gel was extracted with 10% MeOH/CHCl3 and the solvent 5 was evaporated in vacuo to give N- (2-{4- [3-isobutyryl-l- (4 methoxyphenyl)-lH-pyrazol-5-yllphenyllethyl)urea (30mg) as amorphous powder. MS (ESI+) : m/z 407 (M+H) 1HNMR ( 200MHz, CDCl3): 1.25 ( 6H, d, J = 6.8Hz ) , 2.77 10 2.85 ( 2H, m), 3.37 - 3.48 ( 2H, m), 3.72 - 3.87 ( 1H, m), 3.83 ( 3H, s), 4.32 ( 2H, s), 4.57 ( IH, t, J = 4.9Hz ), 6.89 ( 2H, d, J = 8.9Hz ), 6.96 ( 1H, s), 7.14 ( 4H, s), 7.24 ( 2H, d, J = 8.9Hz 15 The following compound(s) was (were) obtained in a similar manner to that of Example 658. Example 659 N-(2-{4-[3-isobutyryl-l-(4-methoxyphenyl)-lH-pyrazol-5 20 yl]phenyl}ethyl)methanesulfonamide oil MS (ESI+) : m/z 442 1HNMR ( 200MHz, CDCl3): 1.26 ( 6H, d, J= 6.9Hz ), 2.84 2.91 ( 2H, m), 2.87 C 3H, s), 3.35 - 3.46 ( 2H, m), 3.73 25 - 3.87 ( 1H, m), 3.84 ( 3H, s), 4.21 ( 1H, t, J = 6.1Hz ), 6.89 ( 2H, d, J= 9.0Hz ), 6.99 ( 1I, s), 7.13 - 7.29 ( 6H, M) Example 660 30 N-(2-{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-lH pyrazol-5-yl phenyl}ethyl)urea oil 419 WO 2004/050632 PCT/JP2003/014489 MS (EST+) : m/z 408 (M+H) 1HNMR ( 200MHz, CDC13): 1.26 ( 6H, d, J = 6.9Hz ), 2.79 2.87 ( 2H, m), 3.39 - 3.50 ( 2H, m), 3.77 - ( 1H, m), 3.95 3H, s), 4.35 ( 2H, s), 4.57 ( 1H, t, J = 5.4Hz ), 6.78 5 ( 1H, d, J = 8.9Hz ), 6.98 ( 1H, s), 7.17 ( 4H, s), 7.60 1H, dd, J = 2.7 ,8.9Hz), 8.07 ( 1H, d, J = 2.7Hz Example 661 N-(2-{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-lH 10 pyrazol-5-yljphenyl}ethyl)methanesulfonamide oil MS (ESI+) : m/z 443 (M+H) 1HNMR ( 200MHz, CDC13): 1.26 ( 6H, d, J = 6.8Hz ), 2.85 2.93 ( 2H, m), 2.88 ( 3H, s), 3.36 - 3.47 ( 2H, m), 3.77 15 ( 3H, m), 3.95 ( 3H, s), 4.24 ( 1H, t, J 6.2Hz ), 6.78 ( 1H, d, J = 8.8Hz ), 7.00 ( 1H, s), 7.19 ( 4H, s), 7.57 ( IH, dd, J = 2.7 ,8.8Hz), 8.11 ( 1H, d, J = 2.7Hz Example 662 20 To a solution of cyclopropylmagnesium bromide, which was prepared from cyclopropyl bromide (257mg) and magnesium (57mg) in THF (lml) as usual method, was added a solution of 5-(4-{2-[(aminocarbonyl)-amino]ethyl}phenyl)-N- methoxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole 25 3-carboxamide (90mg) in THF (3ml) dropwise at ambient temperature. The mixture was stirred at 50'C for Shours. The reaction mixture was cooled to ambient temperature and was quenched by adding saturated aqueous armnonium chloride solution. The mixture was extracted with AcOEt. The oreganic 30 layer was washed with 1M HC1, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated 420 WO 2004/050632 PCT/JP2003/014489 in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by MeOH/CHC3 10%. The seaparated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give 5 N-( 2

-{

4 -[3-(cyclopropylcarbonyl)-l-(4-methoxyphenyl) 1H-pyrazol-5-yl]phenyl}ethyl)urea (23mg) as a powder. Mass (ESI+) : m/z 405 (M+H) 1HNMR ( 200MHz, CDCl3): 0.99 - 1.09 ( 2H, m), 1.22 - 1.30 ( 2H, m), 2.77 - 2.84 ( 2H, m), 3.13 ( 1H, m), 3.37 - 3.48 10 ( 2H, m), 3.84 ( 3H, s), 4.33 ( 2H, s), 4.59 ( 1H, t, J = 5.4Hz ), 6.89 ( 2H, d, J= 8.9Hz ), 6.96 ( 1H, s), 7.14 ( 4H, s), 7.26 ( 2H, d, J = 8.9Hz ) The following compound(s) was (were) obtained in a similar 15 manner to that of Example 662. Example 663 N-(2-{4-[3-(cyclopropylcarbonyl)-1-(4-methoxyphenyl) 1H-pyrazol-5-yl]phenyl}ethyl)methanesulfonamide 20 oil MS (ESI+) : m/z 440 (M+H 1HNMR ( 200MHz, CDCl3): 0.99 - 1.09 ( 2H, m), 1.22 - 1.31 .( 2H, m), 2.80 - 2.91 ( 2H, m), 2.87 ( 3H, s), 3.14 ( 1H, m), 3.35 - 3.46 ( 2H, m), 3.84 ( 1H, s), 4.22 ( 1H, t, J 25 5.7Hz ), 6.90 ( 2H, d, J = 9.0Hz ), 6.99 ( 1H, s), 7.12 4H, s), 7.27 ( 2H, d, J = 9.0Hz Example 664 N-(2-{4-[3-(cyclopropylcarbonyl)-1-(6-methoxy-3 30 pyridinyl)-1H-pyrazol-5-yl]phenyl}ethyl)methane sulfonamide oil 421 WO 2004/050632 PCT/JP2003/014489 Mass (EST+) : m/z 441 (M+H) 1HNMR ( 200MHz, CDC13): 1.03 - 1.11 ( 2H, m), 1.24 - 1.32 ( 2H, m), 2.85 - 2.93 ( 2H, m), 2.88 ( 3H, s), 3.11 ( 1H, m), 3.36 - 3.47 ( 2H, m), 3.96 ( 3H, s), 4.22 ( 1H, t, J 5 = 6.0Hz ), 6.78 ( 1H, d,. J 8.9Hz ), 7.00( 1H, s), 7.20 4H, s), 7.60 ( 1H, dd, J = 2.7 ,8.9Hz), 8.13 ( 1H, d, J 2.7Hz 10 422

Claims (12)

1. A compound of the formula (I): R 4 -Z-(X)m NI R2 N R3 Y () 5 wherein R 1 is hydrogen or lower alkyl; R2 is lower alkyl optionally substituted with halogen, hydroxy, lower alkoxyimino or lower alkoxy; lower alkenyl; cycloalkyl; cyano; lower alkanoyl; cycloalkylcarbonyl; 10 N,N-di(lower)alkylcarbamoyl; carbamoyl; N-lower alkoxy-N-lower alkylcarbamoyl; amino; di(lower)alkylamino; lower alkoxycarbonylamino; N,N-di(lower)alkylcarbamoylamino; 15 N-(N,N-di(lower)alkylcarbamoyl)-N-lower alkylamino; halogen; hydroxy; carboxy; lower alkoxycarbonyl; aroyl; heterocycliccarbonyl; heterocyclic group; lower alkylsulfonyl; lower alkoxy optionally substituted with lower 20 alkoxy, NN-di(lower)alkylcarbamoyl or halogen; cycloalkyloxy; lower alkylthio; or lower alkylsufinyl; R 3 is lower alkyl optionally substitutedwith amino, carbamoylamino or lower alkylsulfonylamino; 25 halogen; cyano; hydroxy; lower alkanoyloxy; lower alkylenedioxy; lower alkoxy optionally 423 WO 2004/050632 PCT/JP2003/014489 substituted with aryl, hydroxy, cyano, amino, lower alkoxycarbonylamino, lower alkylsulfonylamino or carbamoylamino; nitro; amino; hetrocyclic group; lower 5 alkylthio; lower alkylsulfinyl; or lower alkylsufonyl; R 4 is hydrogen; cyano; amino optionally substituted with phthaloyl or lower alkyl; aryl; heterocyclic group; lower alkoxy; hydroxy; 10 lower alkylsulfonyloxy; lower alkanoyloxy; lower alkyl substituted with tritylamino and lower alkoxycarbonyl, amino and lower alkoxycarbonyl, amino and carboxy, amino and carbamoyl, or amino and hydroxy; N-lower 15 alkoxycarbonyl-N-lower alkylamino; lower alkanoyl optionally substituted with halogen; carboxy; lower alkylsulfonyl; sulfo; lower alkylsilyloxy; lower alkoxycarbonyl; sulfamoyl optionally 20 substituted with lower alkyl; carbamoyl optionally substituted with lower alkyl; lower alkylthio; lower alkylsulfinyl; carbamoyloxy; thioureido; or a group of the formula: 25 R 5 -G-J in which G is -CO- or -SO 2 -; J is -N(R 6 ) _ (wherein R 6 is hydrogen or lower alkyl); and R 5 is amino optionally substituted with 30 lower alkoxycarbonyl or lower alkyl; lower alkyl optionally substituted with hydroxy, lower 424 WO 2004/050632 PCT/JP2003/014489 alkoxycarbonylamino, lower alkanoyloxy, amino or halogen; lower alkoxy; hydrogen; heterocyclic group; or aryl; 5 X is 0, S, SO or SO 2 ; Y is CH or N; Z is lower alkylene or lower alkenylene; and m is 0 or 1; provided that when R 4 is hydrogen; 10 then R 3 is lower alkyl substituted with amino, carbamoylamino or lower alkylsulfonylamino; or lower alkoxy substituted with aryl, hydroxy, cyano, amino, lower alkoxycarbonylamino, 15 lower alkylsulfonylamino or carbamoylamino; or salts thereof.

2. The compound of Claim 1, wherein 20 RI is hydrogen; R 2 is lower alkyl optionally substituted with halogen, hydroxy, lower alkyoxyimino or lower alkoxy; cycloalkyl; halogen; lower alkoxy optionally substituted with halogen; or lower alkylthio; 25 R 3 is lower alkoxy optionally substituted with aryl, hydroxy, cyano, amino, lower alkoxyxcarbonylamino, lower alkylsulfonylamino or carbamoylamino; R4 is a group of the formula: 30 R 5 -G-J in which R 5 , G and J are each as defined in claim 1; 425 WO 2004/050632 PCT/JP2003/014489 X is 0 or S; and Z is lower alkylene.

3. The compound of Claim 2, wherein 5 R 2 is lower alkyl optionally substituted with halogen; cycloalkyl; halogen; or lower alkoxy optionally substituted with halogen; R 3 is lower alkoxy; R 4 is a group of the formula: 10 R 5 -G-J in which G is -CO- or -SO 2 -, J is -NH- and R5 is amino or lower alkyl; and X is 0. 15

4. The compound of Claim 3, which is N-(2-{4-[3-chloro-l-(4-methoxyphenyl)-lH-pyrazol-5-yl] phenoxylethyl)urea, N-{4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-lH 20 pyrazol-5-yllbenzyl methanesulfonamide, N-{4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1H pyrazol-5-yl]benzyl}urea, N- (2-{ 4- [3- (difluoromethyl) -l- (4-methoxyphenyl) -lH pyrazol-5-yl]phenoxy}ethyl)urea, 25 N-(2-{4-[l-(4-methoxyphenyl)-3-(trifluoromethyl)-1H pyrazol-5-yl]phenoxylethyl)urea, N-(2-{4-[3-(difluoromethyl)-l-(6-methoxy-3-pyridinyl) 1H-pyrazol-5-yl]phenoxylethyl)urea, N-(2-{4-[3-cyclopropyl-l-(4-methoxyphenyl)-1H-pyrazol 30 5-yl]phenoxy}ethyl)urea, N-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl) 1H-pyrazol-5-yl]phenoxy}ethyl)urea, 426 WO 2004/050632 PCT/JP2003/014489 N-(2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-lH pyrazol-5-yl]phenoxy}ethyl)acetamide, or N-(2-{4-[3-(2,2-difluoroethoxy)-l-(6-methoxy-3 pyridinyl)-lH-pyrazol-5-yl]phenoxy}ethyl)urea. 5

5. A process of preparing a compound of the formula: R 4 -Z-(X)m 'NN R 3 Y N(IR wherein R1 is hydrogen or lower alkyl; R2 is lower alkyl optionally substituted with 10 halogen, hydroxy, lower alkoxyimino or lower alkoxy; lower alkenyl; cycloalkyl; cyano; lower alkanoyl; cycloalkylcarbonyl; N,N-di(lower)alkylcarbamoyl; carbamoyl; N-lower alkoxy-N-lower alkylcarbamoyl; amino; 15 di(lower)alkylamino; lower alkoxycarbonylamino; N,N-di(lower)alkylcarbamoylamino; N-(N,N-di(lower)alkylcarbamoyl)-N-lower alkylamino; halogen; hydroxy; carboxy; lower 20 alkoxycarbonyl; aroyl; heterocycliccarbonyl; heterocyclic group; lower alkylsulfonyl; lower alkoxy optionally substituted with lower alkoxy, N,N-di(lower)alkylcarbamoyl or halogen; cycloalkyloxy; lower alkylthio; or 25 lower alkylsufinyl; R 3 is lower alkyl optionally substituted with amino, carbamoylamino or lower alkylsulfonylamino; 427 WO 2004/050632 PCT/JP2003/014489 halogen; cyano; hydroxy; lower alkanoyloxy; lower alkylenedioxy; lower alkoxy optionally substituted with aryl, hydroxy, cyano, amino, lower alkoxycarbonylamino, lower 5 alkylsulfonylamino or carbamoylamino; nitro; amino; hetrocyclic group; lower alkylthio; lower alkylsulfinyl; or lower alkylsufonyl; R 4 is hydrogen; cyano; amino optionally substituted 10 with phthaloyl or lower alkyl; aryl; heterocyclic group; lower alkoxy; hydroxy; lower alkylsulfonyloxy; lower alkanoyloxy; lower alkyl substituted with tritylamino and lower alkoxycarbonyl, amino and lower 15 alkoxycarbonyl, amino and carboxy, amino and carbamoyl, or amino and hydroxy; N-lower alkoxycarbonyl-N-lower alkylamino; lower alkanoyl optionally substituted with halogen; carboxy; lower alkylsulfonyl; 20 sulfo; lower alkylsilyloxy; lower alkoxycarbonyl; sulfamoyl optionally substituted with lower alkyl; carbamoyl optionally substituted with lower alkyl; lower alkylthio; lower alkylsulfinyl; 25 carbamoyloxy; thioureido; or a group of the formula: R 5 -G-J in which G is -CO- or -SO 2 -; J is -N(R 6 )_ 30 (wherein R 6 is hydrogen or lower alkyl); and R 5 is amino optionally substituted with lower alkoxycarbonyl or lower 428 WO 2004/050632 PCT/JP2003/014489 alkyl; lower alkyl optionally substituted with hydroxy, lower alkoxycarbonylamino, lower alkanoyloxy, amino or halogen; 5 lower alkoxy; hydrogen; heterocyclic group; or aryl; X is 0, S, SO or SO 2 ; Y is CH or N; Z is lower alkylene or lower alkenylene; and 10 m is 0 or 1; provided that when R 4 is hydrogen; then R 3 is lower alkyl substituted with amino, carbamoylamino or lower alkylsulfonylamino; or lower alkoxy 15 substituted with aryl, hydroxy, cyano, amino, lower alkoxycarbonylamino, lower alkylsulfonylamino or carbamoylamino; or salts thereof, 20 which comprises, 1) reacting a compound of the formula: NHNH 2 R3 Y T(IT) or its salt with a compound of the formula: R4--(X)m R1 25 O(II) 429 WO 2004/050632 PCT/JP2003/014489 or its salt in the acidic condition to provide a compound of the formula: R 4 -Z-(X)m R2 N~N 1 2 3 4 5 R , R , R3 , R4, X, Y, Z and m are each as defined above, or 2) reacting a compound of the formula: H-Xa N N R 2 R 3 y (IV) 10 or its salt with a compound (V) of the formula: R 4 -Z-Q (y) or its salt to provide a compound of the formula: R 4 -Z-Xa N N R2 15 R 3 y (Ib) or its salt, in the above formulas: R', R 2, R3, R4, Y and Z are each as defined above, 430 WO 2004/050632 PCT/JP2003/014489 Xa is 0 or S, and Q is hydroxy or an acid residue.

6. A pharmaceutical composition comprising the compound 5 of Claim 1, as an active ingredient, in association with a pharmaceutically non-toxic carrier or excipient.

7. A compound of Claim 1 for use as a medicament 10

8. A method for treatment and/or prevention of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases, analgesic, thrombosis, cancer or neurodegerative diseases which comprises administering an effective amount of the compound 15 of Claim 1 to human beings or animals.

9. Use of the compound of Claim 1 for the manufacture of a medicament for treatment and/or prevention of inflammatory conditions, various pains, collagen diseases, 20 autoimmune diseases, various immunity diseases, analgesic, thrombosis, cancer or neurodegerative diseases in human beings or animals.

10. The analgesic agent comprising the compound of Claim 25 1, which is usable for treating and/or preventing pains caused by or associated with acute or chronic inflammations without causing gastrointestinal disorders.

11. The analgesic agent of Claim 10, which is usable for 30 treating or preventing pains caused by or associated with rheumatoid arthritis, osteoarthritis, lumbar rheumatism, rheumatoid spondylitis, gouty arthritis, or juvenile 431 WO 2004/050632 PCT/JP2003/014489 arthritis; lumbago; cervico-omo-brachial syndrome; scapulohumeral periarthritis; pain and tumescence after operation or injury without causing gastrointestinal disorders. 5

12. A commercial package comprising the pharmaceutical composition containing the compound (I) identified in Claim 1 and a written matter associated therewith, wherein the written matter states that the compound (I) can or should 10 be used for preventing or treating inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases, analgesic, thrombosis, cancer or neurodegerative diseases. 432