CA2186947A1 - Oxime derivative and bactericide containing the same as active ingredients - Google Patents

Abstract

A compound represented by general formula (I) or a salt thereof, a process for producing the same, an intermediate for the production thereof, and a bactericide containing the same as the active ingredient wherein R1 represents optionally substituted aryl, optionally substituted heterocycle, mono- or disubstituted methyleneamino, optionally substituted (substituted imino)methyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, substituted carbonyl or substituted sulfonyl; R2 represents alkyl, alkenyl, alkynyl or cycloalkyl; R3 represents optionally substituted heterocycle; R4 represents hydrogen, alkyl, alkoxy, halogen, nitro, cyano or haloalkyl; M represents oxygen, S(O)i (i being 0, 1 or 2), NR16 (R16 being hydrogen, alkyl or acyl) or a single bond; n represents 0 or 1, provided n represents 1 when R3 represents imidazol-1-yl or 1H-1, 2, 4triazol-1-yl; and the symbol represents the E form, Z form or a mixture thereof.

Description

::

DEMANDES OU 8R~Vt 1 ~ VOLUMINEUX

I A ~ ~TE PARl IE DE CETTE DEMANDE OU CE BREVET
C~MPP~END PLUS D'UN TOME. - . -.

CEC1 EST LE TOME t DE 2 NO~E: .Pou~ les tomes additionels, veui~lez c~macler le Bureau canadien desbrevets ~ ~ 8~ qLt7 JUMBO APPLICATIONSIPATENTS

THIS SECTION OF TI~E APPLICATIONIPATENT CONTAINS MORE
THA~ ONE VOI UME

THlS IS VO~UME L ~ 2 NOTE: F~r additianal valumes please c~3ntacl the Canadian Patent ~ffice - _ _ 21 86947 DESCRIPTION

OXIME DERIVATIVE AND BACTERICIDE
CONTAINING THE SAME AS ACTIVE INGREDIENT
s TECHNICAL FIELD
The present invention relates to an oxime derivative, particularly a heterocyclic compound substituted with a- (O-substituted oxyimino)-2-substituted benzyl, a process for producing it, intermediates therefor, and a bactericide (fungicide) containing it as an active ingredient.

BACKGROUND ART
Compounds containing a- (O-substituted oxyimino)-benzyl known so far include benzohydroxymoylazole derivatives having insecticidal activity (JP-A 1-308260, JP-A 5-1046, WO92/09581, JP-A 5-331011, JP-A 5-331012, JP-A 6-41086), oxime derivatives having insecticidal activity (JP-A 3-68559), l-azolyl-substituted oxime ethers having fungicidal activity (JP-A 60-87269), etc.
The present invention is to provide a compound having more potent fungicidal activity, higher utility, etc., than the known compounds as well as low toxicity.

DISCLOSURE OF INVENTION

21 86q47 The present inventors have intensively studied to achieve the above object. As a result, it has been found that a heterocyclic compound substituted with a-(o-substituted oxyimino)-2-substituted benzyl has potent fungicidal activity. After further studies, the present invention has been completed.
The present invention provides:
1. A compound of the formula (I):

M~ R1 (CH2)n R4 ~N`~R2 I

wherein Rl is optionally substituted aryl, an optionally substituted heterocyclic group, mono or disubstituted methyleneamino, optionally substituted (substituted imino)methyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, substituted carbonyl or substituted sulfonyli R2 is alkyl, alkenyl, alkynyl or cycloalkyl; R3 is an optionally substituted heterocyclic group; Rg is hydrogen, alkyl, alkoxy, halogen, nitro, cyano or halogenated alkyl; M is an oxygen atom, S(O)i (in which i is 0, 1 or 2), NRl6 (in which R16 is hydrogen, alkyl or acyl) or a single bond; n is 0 or 1, provided that, when R3 is imidazol-1-yl or lH-1,2,4-triazol-1-yl, n is 1; and - indicates an E- or Z-isomer or a mixture thereof; or a salt thereofi 2. A compound according to the above item 1, wherein the optionally substituted heterocyclic group represented by R1 is pyridyl, pyrimidinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyridazinyl, pyrrolyl, pyrazolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, quinolyl, indolyl, benzisothiazolyl, benzisoxazolyl or pyrazinyl, each of which is unsubstituted or substituted, or a salt thereofi 3. A compound according to the above item 1, wherein R1 is phenyl or a heterocyclic group, each of which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, lower alkyl, halogenated lower alkyl, lower alkoxy, lower alkylthio, phenyl, phenoxy and nitro, or a salt thereofi 4. A compound according to the above item 1, wherein R1 is phenyl; phenyl substituted with halogen and/or lower alkyli or pyridyl substituted with halogen and/or halogenated lower alkyl; or a salt thereof:

5. A compound according to the above item 1, wherein R1 is phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-_ _ 21 86947 chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 4-chloro-2-methylphenyl, 2-chloropyridin-3-yl, 3,5-dichloro-pyridin-2-yl, 5-trifluoromethylpyridin-2-yl, 5-trifluoromethyl-3-chloropyridin-2-yl or 3-trifluoromethyl-5-chloropyridin-2-yl, or a salt thereof;

6. A compound according to the above item 1, wherein Rl is a group of the formula (a):

(a) wherein R9 and Rl are the same or different and are hydrogen, optionally substituted alkyl, acyl, alkylthio, alkylsulfinyl alkylsulfonyl, optionally substituted amino, cycloalkyl, optionally substituted aryl or an optionally substituted heterocyclic group, or R9 and Rl are linked together to form a monocyclic or polycyclic ring which may contain a heteroatom, or a salt thereof;

7. A compound according to the above item 1, wherein R9 and Rl are the same or different and are hydrogen, alkyl, haloalkyl, alkoxyalkyl, alkylcarbonyl, optionally substituted phenyl, optionally substituted naphthyl or an optionally substituted heterocyclic group, or R9 and Rl are linked together to form a cyclopentane or cyclohexane ring which may form a condensed ring with another ring, or a salt thereofi 8. A compound according to the above item 1, wherein R9 is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted hydroxyl, alkylthio, optionally substituted amino, nitro, phenyl and cyano, or a salt thereofi 9. A compound according to the above item 1, wherein R9 is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of chlorine, methyl, trifluoromethyl and methoxy, or a salt thereof;

10. A compound according to the above item 1, wherein R9 is morpholino, pyridyl, pyridazinyl, pyrazolyl, pyrimidinyl, furyl, thienyl, oxazolyl, isoxazolyl, benzothiazolyl, quinolyl, quinazolinyl or pyrazinyl, each of which is unsubstituted or substituted, or a salt thereof 11. A compound according to the above item 1, wherein R10 is hydrogen or alkyl, or a salt thereofi 12. A compound according to the above item 1, wherein R10 is hydrogen, methyl or ethyl, or a salt thereof 13. A compound according to the above item 1, wherein R2 is alkyl or alkenyl, or a salt thereofi 14. A compound according to the above item 1, wherein R2 is methyl, ethyl or allyl, or a salt thereof;

15. A compound according to the above item 1, wherein R3 is isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, furyl, thienyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiazolinyl, isoxazolinyl, imidazolinyl, oxazolinyl or thiazolidinyl, each of which is unsubstituted or substituted, or a salt thereof 16. A compound according to the above item 1, wherein R3 is imidazolyl; imidazolyl substituted with lower alkyl; imidazolinyl; triazolyl; imidazolinyl substituted with lower alkyl; isoxazolyl; isoxazolyl substituted with lower alkyli oxadiazolyl; oxadiazolyl substituted with lower alkyl;
isoxazolinyl; isoxazolinyl substituted with lower alkyl;
oxazolinyl; pyrazolyl; pyrazolyl substituted with lower alkyl; thiazolinyl; furyl; tetrazolyl substituted with lower alkyl; oxazolyl; isothiazolyl substituted with lower alkyl;
thiazolidinyl; or thiazolidinyl substituted with lower alkyl;
or a salt thereof;

17. A compound according to the above item 1, wherein R3 is imidazol-1-yl, imidazol-2-yl, 1-methylimidazol-2-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methyl-imidazol-1-yl, 2-imidazolin-2-yl, lH-1,2,4-triazol-1-yl, 1-methyl-2-imidazolin-2-yl, isoxazol-3-yl, 3-methylisoxazol-5-yl, 5-methylisoxazol-3-yl, 5-methyl-1,2,4-oxadiazol-3-yl, 3-21 86~47 ethyl-1,2,4-oxadiazol-5-yl, 2-isoxazolin-3-yl, 2-oxazolin-2-yl, 3-methyl-2-isoxazolin-5-yl, pyrazol-1-yl, 1-methylpyrazol-5-yl, 2-thiazolin-2-yl, 2-furyl, 3-methylisothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 2-methyltetrazol-5-yl, oxazol-5-yl, isoxazol-5-yl, thiazolidin-2-yl or 3-methylthiazolidin-2-yl, or a salt thereof;

18. A compound according to the above item 1, wherein Rg is hydrogen, or a salt thereof;

19. A compound according to the above item 1, wherein M is an oxygen atom, or a salt thereof;

20. A fungicidal composition comprising a compound according to any one of the above items 1 to 19 or a salt thereof as an active ingredient;

21. A process for producing a compound of the formula (I):

M
(CH2)n R4 ~ N~rR2 I

wherein each symbol is as defined in the above item 1, which comprises reacting the compound of the formula (V):

~_ (CH2)n R4 ~N ~ R2 A
V

wherein A is halogen and the other symbols are as defined in the above item 1, with a compound of the formula (X):

R3-H (X) wherein R3 is an optionally substituted heterocyclic group;

22. A process according to the above item 21, wherein R3 is pyrrolyl, imidazolyl, pyrazolyl or triazolyl, each of which is unsubstituted or substituted 23. A compound of the formula (V):

I

~ (CH2)n R4~N,~.R2 AV
wherein A is halogen and the other symbols are as defined in the above item 1, or a salt thereof;

24. A compound according to the above item 23, wherein M is an oxygen atom, or a salt thereof;

25. A compound of the formula (XIV):

l R1 R4 ~HO)n XIV
wherein each symbol is as defined in the above item 1, provided that, when M is an oxygen atom and R3 is isoxazol-4-yl, n is 1, or a salt thereof;

26. A compound according to the above item 25, wherein M is an oxygen atom, or a salt thereof; and 27. A compound of the formula (XLVIII):
I P

,~,(CH2)n R4 ~ o XLVm wherein P is a protective group of a hydroxyl group, and the other symbols are as defined in the above item 1, or a salt thereof.
The term "lower" used herein means having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, unless otherwise indicated.

21 86q47 The aryl of the optionally substituted aryl represented by R1 includes aryl having 6 to 14 carbon atoms such as phenyl, naphthyl, etc.
The optionally substituted heterocyclic group represented by R1 includes unsubstituted or substituted heterocyclic groups. Examples of the heterocyclic group include 5- to 7-membered heterocyclic groups containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen in the ring, such as pyridyl (e.g., pyridin-2-yl, pyridin-3-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl), benzoxazolyl (e.g., benzoxazol-2-yl), benzothiazolyl (e.g., benzothiazol-2-yl), benzimidazolyl, isoxazolyl (e.g., isoxazol-3-yl, isoxazol-5-yl), isothiazolyl, thiadiazolyl [e.g., 1,3,4-thiadiazolyl (e.g., 1,3,4-thiadiazol-2-yl), 1,2,4-thiadiazolyl, etc.], pyridazinyl, pyrrolyl, pyrazolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl (e.g., 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, etc.), triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, etc.), quinolyl (e.g., quinolin-2-yl), indolyl, benzisothiazolyl, benz-isoxazolyl, pyrazinyl (e.g., pyrazin-2-yl), etc. The heterocyclic group may form a condensed cyclic group with a carbocycle or another heterocycle. The heterocycle has a bond to M at any possible position in the ring.
The substituent of the substituted aryl and substituted heterocyclic group represented by Rl includes, for example, lower alkyl (e.g., methyl, ethyl, propyl, butyl, etc.), lower alkenyl (e.g., vinyl, allyl, crotyl, etc.), lower alkynyl (e.g., ethynyl, propargyl, butynyl, etc.), cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl, etc.), cycloalkenyl (e.g., cyclopentenyl, cyclohexenyl, etc.), lower alkanoyl (e.g., acetyl, propionyl, isobutyryl, etc.), lower alkylsilyl (e.g., methylsilyl, ethylsilyl, propylsilyl, butylsilyl, etc.), halogenated lower alkyl (e.g., trifluoromethyl, trichloromethyl, chloromethyl, 2-bromoethyl, 1,2-dichloropropyl, etc.), di(lower)alkylamino (e.g., dimethylamino, diethylamino, etc.), phenyl, phenyl(lower)alkyl (e.g., benzyl, phenethyl, etc.), phenyl(lower)alkenyl (e.g., styryl, cinnamyl, etc.), furyl(lower)alkyl (e.g., 3-furylmethyl, 2-furylethyl, etc.), furyl(lower)alkenyl (e.g., 3-furylvinyl, 2-furylallyl, etc.), halogen (e.g., fluorine, chlorine, bromine, iodine), nitro, cyano, lower alkylthio (e.g., methylthio, ethylthio, propylthio, etc.), -ORll [wherein Rll is hydrogen, lower alkyl group (e.g., methyl, ethyl, propyl, etc.), lower alkenyl (e.g., vinyl, allyl, crotyl, etc.), lower alkynyl (e.g., ethynyl, 2-propynyl, 3-butynyl, etc.), lower alkanoyl (e.g., acetyl, propionyl, butyryl, etc.), phenyl, lower alkoxyphenyl (e.g., 3-methoxyphenyl, 4-ethoxyphenyl, etc.), nitrophenyl (e.g., 3-nitrophenyl, 4-nitrophenyl, etc.), phenyl(lower)alkyl (e.g., benzyl, phenethyl, phenylpropyl, etc.), cyanophenyl(lower)alkyl (e.g., 3-cyanophenylmethyl, 4-cyanophenylethyl, etc.), benzoyl, tetrahydropyranyl, pyridyl, trifluoromethylpyridyl, pyrimidinyl, benzothiazolyl, quinolyl, benzoyl(lower)alkyl (e.g., benzoylmethyl, benzoyl-ethyl, etc.), benzensulfonyl, or lower alkylbenzenesulfonyl (e.g., toluenesulfonyl, etc.)], -CH2-Z-R12 [wherein Z is -O-, -S- or -NR13- (in which R13 is hydrogen or lower alkyl), R12 is phenyl, halophenyl (e.g., 2-chlorophenyl, 4-fluorophenyl, etc.), lower alkoxyphenyl (e.g., 2-methoxyphenyl, 4-ethoxyphenyl, etc.), pyridyl, or pyrimidinyl], etc. In particular, halogen, lower alkyl, halogenated lower alkyl, lower alkoxy, lower alkylthio, phenyl, phenoxy and nitro are preferred. More preferred are halogen and lower alkyl. The substituent may be at any possible position in the ring. The number of the substituent(s) is 1 to S, preferably 1 to 4, more preferably 1 to 3. The substituents may be the same or different.
R1 is preferably phenyl or a heterocyclic group each of which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, lower alkyl, halogenated lower alkyl, lower alkoxy, lower alkylthio, phenyl, phenoxy and nitro. Preferred examples of R1 include phenyl, phenyl substituted with halogen (preferably chlorine) and/or lower alkyl (preferably methyl) (e.g., 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 4-chloro-2-methylphenyl, etc.), pyridyl substituted with halogen (preferably chlorine) and/or halogenated lower alkyl (preferably trifluoromethyl) (e.g., 2-chloropyridin-3-yl, 3,5-dichloropyridin-2-yl, 5-trifluoromethylpyridin-2-yl, 5-trifluoromethyl-3-chloropyridin-2-yl, 3-trifluoromethyl-5-chloropyridin-2-yl, etc.), etc.
Mono or disubstituted methyleneamino is also preferred for Rl. The mono or disubstituted methyleneamino is represented, for example, by the above formula (a). The alkyl of the optionally substituted alkyl represented by R9 or Rl in the formula (a) includes, for example, alkyl having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc. In particular, methyl or ethyl is preferred. Examples of the substituted alkyl include haloalkyl containing as the substituent at least one halogen (e.g., fluorine, chlorine, bromine, iodine, preferably fluorine)(e.g., difluoromethyl, trifluoromethyl, chloromethyl, 2-bromoethyl, 2,3-dichloropropyl, etc.);
alkoxyalkyl containing as the substituent alkoxy having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms (e.g., methoxy, ethoxy, propoxy, butoxy, etc.)(e.g., methoxymethyl, ethoxymethyl, methoxyethyl, etc.)i etc. In particular, trifluoromethyl is preferred for the haloalkyl, and methoxymethyl is preferred for the alkoxyalkyl.
The acyl represented by R9 or R10 includes, for example, alkylcarbonyl, arylcarbonyl, etc. Examples of the alkylcarbonyl includes C16 alkylcarbonyl, preferably C14 alkylcarbonyl, such as acetyl, trifluoroacetyl, propionyl, butyryl, etc. Examples of the arylcarbonyl include C614 arylcarbonyl such as benzoyl, naphthoyl, etc.
The alkyl of the alkylthio, alkylsulfinyl and alkylsulfonyl represented by R9 or R10 includes the above alkyl of the optionally substituted alkyl represented by R9 or R1o The optionally substituted amino represented by R9 R10 includes, for example, amino, amino mono or disubstituted with alkyl having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms (e.g., monomethylamino, dimethylamino, monoethylamino, etc.), amino monosubstituted with formyl, amino monosubstituted with alkylcarbonyl having 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms (e.g., methylcarbonyl-amino, etc.), etc.
The cylcloalkyl represented by R9 or R10 includes cycloaklyl having 3 to 7 carbon atoms, preferably 5 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

The optionally substituted aryl represented by R9 or Rl includes, for example, C6 l4 aryl such as phenyl, naphthyl (e.g., l-naphthyl, etc.), fluorenyl, etc. In particular, phenyl is preferred. The aryl may be substituted at any possible position in the group. The number of the substituent(s) is 1 to 3. Examples the substituent include halogen, optionally substituted alkyl, optionally substituted hydroxyl, alkylthio, optionally substituted amino, nitro, phenyl, cyano, etc.
Examples of the halogen as the substituent of the optionally substituted aryl represented by R9 or Rl~ include fluorine, chlorine, bromine, and iodine.
Examples of the optionally substituted alkyl as the substituent of the optionally substituted aryl represented by R9 or Rl include the optionally substituted alkyl represented by Rl described hereinafter. Of them, alkyl or haloalkyl, in particular methyl or trifluoromethyl, is preferred.
Examples of the optionally substituted hydroxyl as the substituent of the optionally substituted aryl represented by R9 or Rl include hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, aryloxy, etc. The alkoxy includes, for example, alkoxy having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, etc. In particular, methoxy is preferred.

-The alkenyloxy includes, for example, alkenyloxy having 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, such as vinyloxy, allyloxy, crotyloxy, etc. In particular, allyloxy is preferred. The alkynyloxy includes, for example, alkynyloxy having 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, such as ethynyloxy, propargyloxy, butynyloxy, etc. In particular, propargyloxy is preferred. The haloalkoxy includes alkoxy described above which is substituted with at least one halogen (e.g., fluorine, chlorine, bromine iodine) such as difluoromethoxy, trifluoromethoxy, chloromethoxy, etc. In particular, difluoromethoxy is preferred. The aryloxy includes, aryloxy having 6 to 12 carbon atoms, preferably 6 to 8 carbon atoms, such as phenoxy, naphthoxy, etc.
Examples of the alkylthio as the substituent of the optionally substituted aryl represented by R9 or R10 include alkylthio having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 to 2 carbon atoms, such as methylthio, ethylthio, propylthio, butylthio, etc. In particular, methylthio is preferred.
Examples of the optionally substituted amino as the substituent of the optionally substituted aryl represented by R9 or R10 include amino, amino mono or disubstituted with alkyl having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms (e.g., monomethylamino, dimethylamino, monoethylamino, etc.), etc.
The optionally substituted heterocyclic group represented by R9 or R10 includes, for example, heterocyclic groups containing 1 to 4, preferably 1 to 2 heteroatoms (e.g., oxygen, nitrogen, sulfur, etc.) in the ring. At any possible position in the ring, the heterocyclic group contains the bond to the methylene carbon atom in the formula (a). Examples of the heterocyclic group include morpholinyl, pyridyl, pyridazinyl, pyrazolyl, pyrimidinyl, furyl, thienyl, oxazolyl, isoxazolyl, benzothiazolyl, quinolyl, quinazolinyl, pyrazinyl, etc. In particular, morpholinyl (e.g., morpholino, etc.), furyl (e.g., 2-furyl, etc.), thienyl (e.g., 2-thienyl, etc.), pyridyl (e.g., 2-pyridyl, etc.), pyrazinyl (e.g., 2-pyrazinyl, etc.), or pyrimidinyl (e.g., 2-pyrimidinyl, etc.) is preferred. The heterocyclic group is unsubstituted or substituted. Examples of the substituent include the above substituents of the optionally substituted aryl represented by R9 or R10.
The monocyclic or polycyclic ring which may contain a heteroatom and is formed by R9 and R10 is a 4 to 8 membered ring which is formed by R9 and R10 together with the carbon atom to which R9 and Rl are attached and which may contain at least one heteroatom (e.g., oxygen, nitrogen, sulfur, etc.). The ring may form a condensed ring with -another ring. Examples of the monocyclic or polycyclic ring include cyclopentane, cyclohexane, indan, 1,2,3,4-tetrahydro-naphthalene, 5,6,7,8-tetrahydroquinoline, 4,5,6,7-tetrahydrobenzo[b]furan, etc. At any possible position in the ring, the monocyclic or polycyclic ring contains the bivalent bond to the methyleneamino nitrogen atom.
R9 is preferably phenyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen (preferably chlorine), optionally 10 substituted alkyl [e.g., alkyl (preferably in particular methyl), haloalkyl (preferably trifluoromethyl), alkoxyalkyl, etc.], optionally substituted hydroxyl [e.g., hydroxyl, alkoxy (preferably methoxy), alkenyloxy, alkynyloxy, haloalkoxy, aryloxy, etc.], alkylthio, optionally substituted 15 amino, nitro, phenyl and cyano; or morpholino, pyridyl, pyridazinyl, pyrazolyl, pyrimidinyl, furyl, thienyl, oxazolyl, isoxazolyl, benzothiazolyl, quinolyl, quinazolinyl or pyrazinyl, each of which is unsubstituted or substituted.
R1O is preferably hydrogen or alkyl (preferably 20 methyl or ethyl).
The optionally substituted (substituted imino)methyl represented by Rl is represented, for example, by the formula (b):

21 ~6947 (b) wherein R14 and R15 have the same meanings as the above R10 and R9, respectively.
The optionally substituted alkyl represented by includes, for example, alkyl having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc. In particular, methyl and ethyl are preferred. The substituted alkyl includes, for example, haloalkyl containing as the substituent at least one halogen atom (e.g., fluorine, chlorine, bromine, iodine, preferably fluorine)(e.g., difluoromethyl, trifluoromethyl, chloromethyl, 2-bromoethyl, 2,3-dichloropropyl, etc.); alkoxyalkyl groups containing as the substituent alkoxy having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms (e.g., methoxy, ethoxy, propoxy, butoxy, etc.)(e.g., methoxymethyl ethoxymethyl, methoxyethyl, etc.), etc. In particular, trifluoromethyl is preferred for the haloalkyl, and methoxymethyl is preferred for the alkoxyalkyl.
The optionally substituted alkenyl represented by R1 includes, for example, alkenyl having 2 to 8 carbon atoms, preferably 3 to 6 carbon atoms, such as allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, hexadienyl, etc. In particular, allyl is preferred. When the alkenyl is substituted, the substituent is, for example, halogen (e.g., fluorine, chlorine, bromine, iodine, preferably fluorine), alkoxy having 1 to 8, preferably 1 to 4 carbon atoms (e.g., methoxy, ethoxy, propoxy, butoxy, etc.), etc.
The alkynyl represented by R1 includes, for example, alkynyl having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, such as propargyl, ethynyl, butynyl, etc.
When the alkynyl is substituted, the substituent is, for example, halogen (e.g., fluorine, chlorine, bromine, iodine, preferably fluorine), alkoxy having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms (e.g., methoxy, ethoxy, propoxy, butoxy, etc.), etc.
The substituted carbonyl represented by includes, for example, (optionally substituted alkyl)carbonyl, (optionally substituted aryl)carbonyl, (optionally substituted heterocyclic group)carbonyl, etc.
The substituted sulfonyl represented by includes, for example, (optionally substituted alkyl)sulfonyl, (optionally substituted aryl)sulfonyl, (optionally substituted heterocyclic group)sulfonyl, etc.

The optionally substituted alkyl, optionally substituted aryl and optionally substituted heterocyclic group in the substituted carbonyl or substituted sulfonyl include those represented by R1 described above.
The alkyl represented by R2 includes, for example, alkyl having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl propyl, isopropyl, butyl, isobutyl, t-butyl, etc. In particular, methyl or ethyl is preferred.
The alkenyl represented by R2 includes, for example, alkenyl having 2 to 8 carbon atoms, preferably 3 to 6 carbon atoms, such as allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, hexadienyl, etc. In particular, allyl is preferred.
The alkynyl represented by R2 includes, for example, alkynyl having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, such as propargyl, ethynyl, butynyl, etc.
The cycloalkyl represented by R2 includes, for example, cycloalkyl having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclopentyl cyclohexyl, etc.
R2 is preferably alkyl or alkenyl. In particular, methyl, ethyl and allyl are preferred.
The optionally substituted heterocyclic group represented by R3 includes unsubstituted or substituted heterocyclic groups. The heterocyclic group is a 5 to 7 membered heterocyclic group containing in the ring 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen.
Examples of the heterocyclic group include isoxazolyl (e.g., isoxazol-3-yl, isoxazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-5-yl), thiazolyl (e.g., thiazol-2-yl), isothiazolyl (e.g., isothiazol-5-yl), thiadiazolyl [e.g., 1,3,4-thiadiazolyl (e.g., 1,3,4-thiadiazol-2-yl), 1,2,4-thiadiazolyl, etc.], pyrrolyl, pyrazolyl (e.g., pyrazol-1-yl, pyrazol-5-yl), furyl (e.g., 2-furyl), thienyl (e.g., 2-thienyl), imidazolyl (e.g., imidazol-1-yl, imidazol-2-yl), triazolyl [e.g., 1,2,4-triazolyl (e.g., lH-1,2,4-triazol-1-yl, 4H-1,2,4-triazol-4-yl, 1,2,4-triazol-5-yl), etc.], tetrazolyl (e.g., lH-tetrazol-5-yl, 2H-tetrazol-5-yl), oxadiazolyl [e.g., 1,3,4-oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), 1,2,4-oxadiazolyl (e.g., 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl), etc.], thiazolinyl (e.g., 2-thiazolin-2-yl), isoxazolinyl (e.g., 2-isoxazolin-3-yl), imidazolinyl (e.g., 2-imidazolin-2-yl), oxazolinyl (e.g., 2-oxazolin-2-yl), thiazolidinyl, etc. The heterocyclic group may form a condensed ring with a carbocycle or another heterocycle. At any possible position, the heterocyclic group contains a bond to the oxime carbon atom in the formula (I).
Examples of the substituent of the substituted heterocyclic group represented by R3 include the above substituents of the substituted heterocyclic group represented by R1. In particular, halogenated lower alkyl or lower alkyl is preferred.
R3 is preferably imidazolyl (e.g., imidazol-1-yl, imidazol-2-yl, etc.), imidazolinyl (e.g., 2-imidazolin-2-yl, etc.), triazolyl (e.g., lH-1,2,4-triazol-1-yl, etc.), isoxazolyl (e.g., isoxazol-3-yl, isoxazol-5-yl, etc.), oxazolyl (e.g., oxazol-2-yl, etc.), tetrazolyl (e.g., lH-tetrazol-5-yl, etc.), oxadiazolyl (e.g., 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, etc.), isoxazolinyl (e.g., 2-isoxazolin-3-yl, 2-isoxazolin-5-yl, etc.), oxazolinyl (e.g., 2-oxazolin-2-yl, etc.), pyrazolyl (e.g., pyrazol-1-yl, pyrazol-5-yl, etc.), thiazolinyl (e.g., 2-thiazolin-2-yl, etc.), furyl (2-furyl, etc.), isothiazolyl (e.g., isothiazol-5-yl, etc.), thiazolidinyl (e.g., thiazolidin-2-yl, etc.), etc., each of which is unsubstituted or substituted.
R3 is more preferably imidazolyl (e.g., imidazol-1-yl, imidazol-2-yl, etc.); imidazolyl substituted with lower alkyl (preferably methyl) (e.g., 1-methylimidazol-2-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, etc.); imidazolinyl (e.g., 2-imidazolin-2-yl, etc.);
triazolyl (e.g., lH-1,2,4-triazol-1-yl, etc.); imidazolinyl substituted with lower alkyl (preferably methyl) (e.g., 1-methyl-2-imidazolin-2-yl, etc.)i isoxazolyl (e.g., isoxazol-3-yl, isoxazol-5-yl, etc.); isoxazolyl substituted with lower alkyl (preferably methyl) (e.g., 3-methylisoxazol-5-yl, 5-methylisoxazol-3-yl, etc.); oxadiazolyl (e.g., 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, etc.)i oxadiazolyl substituted with lower alkyl (preferably methyl or ethyl) (e.g., 5-methyl-1,2,4-oxadiazol-3-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 3-ethyl-1,2,4-oxadiazol-5-yl, etc.)i isoxazolinyl (e.g., 2-isoxazolin-3-yl, etc.); isoxazolinyl substituted with lower alkyl (preferably methyl) (e.g., 3-methyl-2-isoxazolin-5-yl, etc.); oxazolinyl (e.g., 2-oxazolin-2-yl, etc.); pyrazolyl (e.g., pyrazol-1-yl, etc.);
pyrazolyl substituted with lower alkyl (preferably methyl) (e.g., 1-methylpyrazol-5-yl, etc.); thiazolinyl (e.g., 2-thiazolin-2-yl, etc.); furyl (e.g., 2-furyl, etc.);
tetrazolyl substituted with lower alkyl (preferably methyl) (e.g., 2-methyltetrazol-5-yl, etc.); isothiazolyl substituted with lower alkyl (preferably methyl) (e.g., 3-methylisothiazol-5-yl, etc.); thiazolidinyl (e.g., thiazolidin-2-yl, etc.); thiazolidinyl substituted with lower alkyl (e.g., 3-methylthizolidin-2-yl, etc.), etc.
The alkyl represented by R4 includes the above alkyl represented by R2.
The alkoxy represented by Rq includes, for example, alkoxy having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, etc.

The halogen represented by R4 includes, for example, fluorine, chlorine, bromine, and iodine.
The halogenated alkyl represented by R4 includes the above alkyl represented by R2 which is substituted with at least one halogen (e.g., fluorine, chlorine, bromine, iodine), such as trifluoromethyl, etc.
R4 is preferably hydrogen.
The alkyl and acyl represented by Rl6 include the above alkyl and acyl represented by R9 or Rl, respectively.
M is preferably an oxygen atom, sulfur atom or NRl6, more preferably an oxygen atom.
When R3 is imidazol-l-yl or 1,2,4-triazol-1-yl, n is 1.
The compound of the present invention has two kinds of isomers: E and Z isomers. The present invention includes these isomers and mixtures of the isomers in any mixing ratios. This is herein indicated by the wave line (~) in the formulas.
In addition, the compound of the present invention includes its hydrochloric acid salt, sulfuric acid salt, nitric acid salt, oxalic acid salt and p-toluenesulfonic acid salt.
Specific examples of the compound of the formula (I) of the present invention include compounds described in Examples hereinafter. Particularly preferred are the compounds of the formula (I) wherein Rl is phenyl, R2 is methyl, R3 iS imidazol-l-yl, R4 is hydrogen, and n is 1 (Compound No. 1: Compound Nos.
correspond to those in Examples hereinafter);
Rl is 4-chlorophenyl, R2 is methyl, R3 is imidazol- -l-yl, R4 iS hydrogen, and n is 1 (Compound No. 7);
Rl is 2-methylphenyl, R2 is methyl, R3 is imidazol-l-yl, R4 iS hydrogen, and n is 1 (Compound No. 13);
Rl is 4-methylphenyl, R2 is methyl, R3 iS imidazol-l-yl, R4 iS hydrogen, and n is 1 (Compound No. 15);
Rl is 2-ethylphenyl, R2 is methyl, R3 is imidazol-l-yl, R4 iS hydrogen, and n is 1 (Compound No. 16);
Rl is 2,5-dimethylphenyl, R2 is methyl, R3 is imidazol-l-yl, R4 iS hydrogen, and n is 1 (Compound No. 39) Rl is phenyl, R2 is ethyl, R3 iS imidazol-l-yl, R4 is hydrogen, and n is 1 (Compound No. 61);
Rl is phenyl, R2 is allyl, R3 iS imidazol-l-yl, R4 is hydrogen, and n is 1 (Compound No. 81);
Rl is 2,5-dimethylphenyl, R2 is methyl, R3 iS 1-methylimidazol-2-yl, R4 is hydrogen, and n is 1 (Compound No.
136);
Rl is 4-chloro-2-methylphenyl, R2 is methyl, R3 iS
l-methylimidazol-2-yl, R4 is hydrogen, and n is 1 (Compound No. 141);

`- 2186947 Rl is 2,5-dimethylphenyl, R2 is methyl, R3 is isoxazol-3-yl, R4 is hydrogen, and n is 1 (Compound No. 336);
Rl is 5-trifluoromethylpyridin-2-yl, R2 is methyl, R3 is isoxazol-3-yl, R4 is hydrogen, and n is 1 (Compound No.
387);
Rl is 5-trifluoromethyl-3-chloropyridin-2-yl, R2 is methyl, R3 is isoxazol-3-yl, R4 is hydrogen, and n is (Compound No. 390);
Rl is 2,5-dimethylphenyl, R2 is methyl, R3 is 5-methylisoxazol-3-yl, R4 is hydrogen, and n is 1 (Compound No.
436);
Rl is 2,5-dimethylphenyl, R2 is methyl, R3 is 3-methylisoxazol-5-yl, R4 is hydrogen, and n is 1 (Compound No.
636);
Rl is 5-trifluoromethyl-3-chloropyridin-2-yl, R2 is methyl, R3 is 3-methylisoxazol-5-yl, R4 is hydrogen, and n is 1 (Compound No. 690);
Rl is 2-methylphenyl, R2 is methyl, R3 is 1, 3,4-oxadiazol-2-yl, R4 is hydrogen, and n is 1 (Compound No.
712);
Rl is 2,5-dimethylphenyl, R2 is methyl, R3 is 1,3,4-oxadiazol-2-yl, R4 is hydrogen, and n is 1 (Compound No. 736);

Rl is 4-chloro-2-methylphenyl, R2 is methyl, R3 is 1,3,4-oxadiazol-2-yl, R4 is hydrogen, and n is 1 (Compound No. 741);
Rl is 4-chlorophenyl, R2 is methyl, R3 iS 1, 2,4-oxadiazol-3-yl, R4 is hydrogen, and n is 1 (Compound No.
807);
Rl is 2-methylphenyl, R2 is methyl, R3 iS 1, 2,4-oxadiazol-3-yl, R4 is hydrogen, and n is 1 (Compound No.
812);
Rl is 2,5-dimethylphenyl, R2 is methyl, R3 is 1,2,4-oxadiazol-3-yl, R4 iS hydrogen, and n is 1 (Compound No. 836);
Rl is 2-methylphenyl, R2 is methyl, R3 iS 5-methyl-1,2,4-oxadiazol-3-yl, R4 iS hydrogen, and n is 1 (Compound No. 912);
Rl is 2,5-dimethylphenyl, R2 is methyl, R3 iS 5-methyl-1,2,4-oxadiazol-3-yl, R4 iS hydrogen, and n is 1 (Compound No. 936);
Rl is 2,5-dimethylphenyl, R2 is methyl, R3 iS 1-methyl-2-imidazolin-2-yl, R4 iS hydrogen, and n is (Compound No. 1136);
Rl is 4-chlorophenyl, R2 is methyl, R3 iS 1, 2,4-oxadiazol-5-yl, R4 iS hydrogen, and n is 1 (Compound No.
1584);

Rl is 2,5-dimethylphenyl, R2 is methyl, R3 is 2-methyl-2H-tetrazol-5-yl, R4 iS hydrogen, and n is 1 (Compound No. 2036)i - Rl is 3,5-dichloropyridin-2-yl, R2 is methyl, R3 is isoxazol-3-yl, R4 is hydrogen, and n is 1 (Compound No.
2276)i Rl is 5-chloro-3-trifluoromethylpyridin-2-yl, R2 is methyl, R3 iS isoxazol-3-yl, R4 iS hydrogen, and n is 1 (Compound No. 2306);
Rl is a group represented by the formula (a), R9 is 4-chlorophenyl, Rl is methyl, R2 is methyl, R3 is isoxazol-3-yl, R4 iS hydrogen, and n is 1 (Compound No. 2387);
Rl is a group of by the formula (a), R9 is 3-trifluoromethylphenyl, Rl is methyl, R2 is methyl, R3 is isoxazol-3-yl, R4 is hydrogen, and n is 1 (Compound No.
2399)i Rl is a group of the formula (a), R9 is 3,4-dichlorophenyl, Rl is methyl, R2 is methyl, R3 is isoxazol-3-yl, R4 is hydrogen, and n is 1 (Compound No. 2408);
Rl is a group represented by the formula (a), R9 is 4-chlorophenyl, Rl is methyl, R2 is methyl, R3 is 3-methylisoxazol-5-yl, R4 is hydrogen, and n is 1 (Compound No.
2507)i Rl is a group of the formula (a), R9 is 3-trifluoromethylphenyl, Rl is methyl, R2 is methyl, R3 is thiazolidin-2-yl, R4 is hydrogen, and n is 1 (Compound No.
2799); or Rl is a group of the formula (a), R9 is 3-trifluoromethylphenyl, Rl is methyl, R2 is methyl, R3 is 3-methylthiazolidin-2-yl, R4 is hydrogen, and n is 1 (Compound No. 2839).
The compound (I) (i.e., the compound of the formula (I); hereinafter the compounds of other formulas are sometimes abbreviated likewise) can be prepared, for example, according to the following synthetic routes.
[Route 1]
(Scheme 1) R1 l R1 R~ + R20NH2 ~ R4~fHo)n A m NHOR2 IIa IV

wherein A is halogen (e.g., chlorine, bromine, iodine, etc.), and the other symbols are as defined above.
The compound of the formula (IV) can be prepared by reacting the compound (IIa) with the compound (III) or a salt thereof (e.g., hydrochloric acid salt, sulfuric acid salt) in the presence of a base in the absence of a solvent or in an appropriate solvent (alone or as a mixture).

-In this reaction, the amount of the compound (III) to be used is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound tIIa).
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, étc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), amines (e.g., pyridine, triethylamine, etc.), etc. The amount of 10 the base to be used is 1 equivalent or more, preferably 1 to 3 equivalents.
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), 15 halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran (THF), dioxane, etc.), water, mixtures thereof, etc.
The reaction temperature is -30C to 150C, preferably -10C to 100C. The reaction time varies with the 20 kind of compound, and is 0.5 to 48 hours.
The compound (IV) thus obtained can be used in the next step as the crude product or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).

The acid halide (IIa) used as the starting material in this reaction can be prepared according to JP-A
5-331124, for example, by halogenating the corresponding carboxylic acid with a thionyl halide (e.g., thionyl chloride, etc.), phosphoryl halide (e.g., phosphoryl chloride, etc.), phosgene, etc.
[Route 1 (continued)]
(Scheme 2) MR1 Halogenating l R1 R4~H2)n agent ~ R4~HN)~R2 lV V

wherein each symbol is as defined above.
The compound of the formula (V) can be prepared by reacting the above compound (IV) with a halogenating agent in the absence of a solvent or in an appropriate solvent (alone or as a mixture).
Examples of the halogenating agent to be used include thionyl halides (e.g., thionyl chloride, thionyl bromide, etc.), phosphoryl halides (e.g., phosphoryl chloride, phosphoryl bromide, etc.), phosphorus halides (e.g., phosphorus pentachloride, phosphorus trichloride, phosphorus pentabromide, phosphorus tribromide, etc.), - 21 8694~ --phosgene, oxalyl halides (e.g., oxalyl chloride, etc.), triphenylphosphine / carbon tetrachloride, triphenylphosphine / carbon tetrabromide, etc. The amount of the halogenating agent to be used is 1 equivalent or more, preferably 1 to 4 equivalents.
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), nitriles (e.g., acetonitrile, etc.), mixed solvents thereof, etc.
The reaction temperature is -30C to 150C, preferably -10C to 120C. The reaction time varies with the kind of compound, and is 0.1 to 48 hours.
The compound (V) thus obtained can be used in the next step as the crude product or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 1 (continued)]
(Scheme 3) R ~ + R2ONH2 , R4 ~ o Vl m wherein each symbol is as defined above.
The compound of the formula (VII) can be prepared by reacting the compound (VI) with the compound (III~ or a salt thereof (e.g., hydrochloric acid salt, sulfuric acid salt) in the presence of a base in the absence of a solvent or in an appropriate solvent (alone or as a mixture).
The amount of the compound (III) to be used in this reaction is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound (VI).
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), amines (e.g., pyridine, triethylamine, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 3 equivalents.
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, etc.), water, mixed solvents thereof, etc.

` -The reaction temperature is -30C to 150C, preferably -10C to 100C. The reaction time varies with the kind of compound, and is 0.5 to 48 hours.
The compound (VII) thus obtained can be used in the next step as the reaction mixture or the crude product or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
The compound (VI) used as the starting material in this reaction can be prepared according to Takahashi et al.
10 Tetrahedron Letters 22 (28), 2651-2654 (1981), for example, by halogenating the corresponding phthalide with triphenyl-phosphine dichloride, etc.
[Route 1 (continued)]
(Scheme 4) Halogenating A
R4 ~ agent ~ R4 ~ N~OR2 VII vm wherein each symbol is as defined above.
The compound of the formula (VIII) can be prepared by reacting the compound (VII) with a halogenating agent in the absence of a solvent or in an appropriate solvent (alone or as a mixture).

Examples of the halogenating agent to be used include thionyl halides (e.g., thionyl chloride, thionyl bromide, etc.), phosphoryl halides (e.g., phosphoryl chloride, phosphoryl bromide, etc.), phosphorus halides (e.g., phosphorus pentachloride, phosphorus trichloride, etc.), phosgene, and oxalyl halides (e.g., oxalyl chloride, etc.). The amount of the halogenating agent to be used is 1 equivalent or more, preferably 1 to 2 equivalents.
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), mixed solvents thereof, etc.
The reaction temperature is -30C to 150C, preferably -10C to 120C. The reaction time varies with the kind of compound, and is 0.1 to 48 hours.
The compound (VIII) thus obtained can be used in the next step as the crude product or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 1 (continued)]
(Scheme 5) R4~ ",oR2 + R1--MH ~ R4~N~R2 A lX A
vm Va wherein each symbol is as defined above.
The compound of the formula (Va) can be prepared by reacting the compound (VIII) with the compound (IX) in the presence of a base in the absence of a solvent or in an appropriate solvent (alone or as a mixture).
The amount of the compound (IX) to be used in this reaction is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound (VIII).
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 3 equivalents.
Examples of the solvent to be used include N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, etc.), ketones (e.g., acetone, methyl`ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), water, mixed solvents thereof, etc.
The reaction temperature is -30C to 150C, preferably -10C to 100C. The reaction time varies with the kind of compound, and is 0.5 to 120 hours.
The compound (Va) thus obtained can be used in the next step as the reaction mixture or the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 1 (continued)]
(Scheme 6) 1 l ~_(CH2)n ~ (CH2)n R4~fN,~OR2 + R3--H ~ R4--~N~.OR2 V X

wherein each symbol is as defined above, and, in this reaction, R3 is preferably pyrrolyl (e.g., pyrrol-1-yl, etc.), imidazolyl (e.g., imidazol-1-yl, etc.), pyrazolyl (e.g., pyrazol-1-yl, etc.) or triazolyl (e.g., lH-1,2,4-triazol-1-yl, etc.).

The compound of the formula (I) of the present invention can be prepared by reacting the compound (V) with the compound (X) in the presence or absence of a base in the absence of a solvent or in an appropriate solvent (alone or as a mixture).
The amount of the compound (X) to be used in this reaction is 1 equivalent or more, preferably 1 to 5 equivalents, based on the compound (V).
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal hydrides (e.g., sodium hydride, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), amines (e.g., pyridine, triethylamine, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 5 equivalents.
Examples of the solvent to be used include N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), water, mixed solvents thereof, etc.
The reaction temperature is -30C to 170C, preferably -10C to 140C. The reaction time varies with the kind of compound, and is 0.5 to 80 hours.
If necessary, the desired compound (I) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 2]
(Scheme 7) MR

R4~z Xll ( X~l ) ~HO)n R
Xl XIV

wherein Z is lithium or magnesium halide (e.g., -MgBr, -MgI, etc.), L is halogen (e.g., chlorine, bromine, iodine, etc.), alkoxy (e.g., lower alkoxy such as methoxy, ethoxy, propoxy, etc.), imidazol-1-yl or N-methyl-N-methoxyamino, R3 is an optionally substituted heterocyclic group, and the other symbols are as defined above.
The compound of the formula (XIV) can be prepared by reacting the compound (XI) with the compound (XII) or (XIII) in an appropriate solvent (alone or as a mixture).

~`

The amount of the compound (XII) or (XIII) to be used in this reaction is 1 equivalent or more, preferably 1 to 3 equivalents, based on the compound (XI).
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., THF, diethyl ether, dioxane, etc.), triethylamine, mixed solvents thereof, etc.
The reaction temperature is -100C to 100C, preferably -80C to 40C. The reaction time varies with the kind of compound, and is 0.5 to 80 hours.
The compound (XIV) thus obtained can be used in the next step as the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
The compound (XI) used as the starting material in this reaction can be prepared according to JP-A 3-246268 or JP-A 5-97768, for example, by reacting a compound corresponding to the compound (XI) wherein the moiety z is halogen with butyl lithium or magnesium.
[Route 2 (continued)]
(Scheme 8) 2 i 86947 MR1 l R1 ~,(CH2)n ~,,(CH2)n R4~ + R3--Z ~ R4 1[ XV R3 ~V

wherein each symbol is as defined above.
The compound of the formula (XIV) can be prepared by reacting the compound (II) with the compound (xV) in an appropriate solvent (alone or as a mixture).
The amount of the compound (xV) to be used in this reaction is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound (II).
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., THF, diethyl ether, dioxane, etc.), triethylamine, mixed solvents thereof, etc.
The reaction temperature is -100C to 100C, preferably -80C to 40C. The reaction time varies with the kind of compound, and is 0. 5 to 80 hours.
The compound (XIV) thus obtained can be used in the next step as the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).

-21 86~47 The compound (XV) can be prepared by reference to A. R. Katritzky, Handbook of Heterocyclic Chemistry, 360-361 (1985), for example, by lithiating the corresponding heterocyclic compound with butyl lithium, etc., or by reacting the corresponding halogenated heterocyclic compound with magnesium.
[Route 2 (continued)]
(Scheme 9) MRl MR1 10R4~ + R20NH2 ~ R4~N)nOR2 ~V I

wherein each symbol is as defined above.
The compound of the formula (I) of the present invention can be prepared by reacting the compound (XIV) with the compound (III) or a salt thereof (e.g., hydrochloric acid salt, sulfuric acid salt) in an appropriate solvent (alone or as a mixture).
The amount of the compound (III) to be used in this reaction is 1 equivalent or more, preferably 1 to 4 equivalents, based on the compound (XIV).
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), alcohols (e.g., methanol, ethanol, propanol, etc.), water, mixed solvents thereof, etc.
The reaction temperature is 0C to 160C, preferably 60C to 130C. The reactlon time varies with the kind of compound, and is 0.5 to 90 hours.
If necessary, the desired compound (I) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 2 (continued)]
(Scheme 10) R1 l R1 ~ (CH2)n ~,(CH2)n R4 - ~ + HONH2 ' R4 --N~O H
R3 . R3 XIV XVI

wherein each symbol is as defined above.
The compound of the formula (XVI) can be prepared by reacting the compound (XIV) with hydroxylamine or a salt thereof (e.g., hydrochloric acid salt, sulfuric acid salt) in an appropriate solvent (alone or as a mixture).
The amount of the hydroxylamine or a salt thereof to be used in this reaction is 1 equivalent or more, preferably 1 to 4 equivalents, based on the compound (XIV).

Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), alcohols (e.g., methanol, ethanol, propanol, etc.), water, mixed solvents thereof, etc.
The reaction temperature is 0C to 160C, preferably 60C to 130C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
The compound (XVI) thus obtained can be used in the next step as the reaction mixture or the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 2 (continued)]
(Scheme 11) MR1 l R1 R4 {~N"O H + R2_y ~ R4 ~HN)rr R2 XVI I
wherein Y is halogen (e.g., chlorine, bromine, iodine, etc.), alkylsulfonyloxy (e.g., lower alkylsulfonyloxy such as methylsulfonyloxy, ethylsulfonyloxy, etc.) or alkoxysulfonyloxy (e.g., lower alkoxysulfonyloxy such as methoxysulfonyloxy, ethoxysulfonyloxy, etc.), and the other symbols are as defined above.
The compound of the formula (I) of the present invention can be prepared by reacting the compound (XVI) with the compound (XVII) in the presence of a base in an appropriate solvent (alone or as a mixture).
The amount of the compound (XVII) to be used in this reaction is 1 equivalent, preferably 1 to 2 equivalents, based on the compound (XVI).
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 2 equivalents.
Examples of the solvent to be used include N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), water, mixed solvents thereof, etc.

- ` -The reaction temperature is -30C to 150C, preferably -10C to 100C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
If necessary, the desired compound (I) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 3]
(Scheme 12) ~(CH2)n R5 ~_(CH2)n R4~N.~R2 +(MeO)2C--N(Me)2 R ~N,."OR2 CONH2 CON-CN(Me)2 XVIII XIX XX Rs wherein R5 is hydrogen or alkyl (e.g., lower alkyl such as methyl, ethyl, propyl, etc.), and the other symbols are as defined above.
The compound of the formula (XX) can be prepared by reacting the compound (XVIII) with the compound (XIX) in the absence of a solvent or in an appropriate solvent (alone or as a mixture), for example, by reference to Y. Lin et al., J. Org. Chem., 44, 4160 (1979).
The amount of the compound (XIX) to be used in this reaction is 1 equivalent or more, preferably 1 to 5 equivalents, based on the compound (XVIII).

Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., THF, diethyl ether, dioxane, etc.), mixed solvents thereof, etc.
The reaction temperature is 0C to 180C, preferably 20C to 120C. The reaction time varies with the kind of compound, and is 0.5 to 80 hours.
The compound (XX) thus obtained can be used in the next step as the reaction mixture or the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
The compound (XVIII) used as the starting material in this reaction can be prepared, for example, according to JP-A 3-246268 or JP-A 5-97768, for example, by reacting the corresponding carboxylic acid ester with ammonia or by subjecting the corresponding ~-ketoamide to oximation.

[Route 3 (continued)]
(Scheme 13) R1 l R1 ~ (C H2)n ~ "(C H2)n R4~NrrR + R6NHNH2 -,, R4~N~r~oR2 5CON_CIN(Me)2 X~ R6--NN
~g R5 N ~ R5 wherein R6 is hydrogen or alkyl (e.g., lower alkyl such as methyl, ethyl, propyl, etc.), and the other symbols are as 10defined above.
The compound of the formula (Ia) of the present invention can be prepared by reacting the compound (XX) with the compound (XXI) in the presence of an acid in the absence of a solvent or in an appropriate solvent (alone or as a mixture) by reference to Y. Lin et al., J. Org. Chem., 44, 4160 (1979).
The amount of the compound (XXI) to be used in this reaction is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound (XX).
Examples of the acid to be used include aliphatic carboxylic acids (e.g., acetic acid, etc.). The amount of the acid to be used is 1 equivalent or more, preferably 5 to 50 equivalents, based on the compound (XX).
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., THF, dioxane, etc.), mixed solvents thereof, etc.
The reaction temperature is 0C to 180C, preferably 20C to 120C. The reaction time varies with the kind of compound, and is 0.5 to 80 hours.
If necessary, the desired compound (Ia) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 4]
(Scheme 14) R1 Ml R1 ~_(CH2)n ~ (CH2)n R4~N~R + HONH2R4 ~Nr,OR2 CON-CN(Me)2 CON-CNHOH

X~
wherein each symbol is as defined above.
The compound of the formula (XXII) can be prepared by reacting the compound (Xx) with hydroxylamine in the presence of an acid in the absence of a solvent or in an appropriate solvent (alone or as a mixture) by reference to Y. Lin et al., J. Org. Chem., 44, 4160 (1979).

The amount of the hydroxylamine to be used in this reaction is 1 equivalent or more, preferably 1 to 3 equivalents, based on the compound (XX).
Examples of the acid to be used include aliphatic carboxylic acids (e.g., acetic acid, etc.). The amount of the acid to be used is 1 equivalent or more, preferably 5 to 50 equivalents, based on the compound (XX).
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., THF, dioxane, etc.), water, mixed solvents thereof, etc.
The reaction temperature is -10C to 120C, preferably 0C to 80C. The reaction time varies with the kind of compound, and is 0.1 to 40 hours.
The compound (XXII) thus obtained can be used in the next step as the reaction mixture or the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 4 (continued)]
(Scheme 15) ` - --l R1 l R1 R4~N)nOR2 ACid R4~HN)nOR2 CON CINHOH o N

XXII N=~R5 wherein each symbol is as defined above.
The compound of the formula (Ib) of the present invention can be prepared by subjecting the compound (XXII) to ring closure reaction in the presence of an acid in the absence of a solvent or in an appropriate solvent (alone or as a mixture) by reference to Y. Lin et al., J. Org. Chem., 44, 4160 (1979).
Examples of the acid to be used include aliphatic carboxylic acids (e.g., acetic acid, etc.). The amount of the acid to be used is 1 equivalent or more, preferably 5 to 50 equivalents, based on the compound (XXII).
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., THF, dioxane, etc.), mixed solvents thereof, etc.

The reaction temperature is 20C to 180C, preferably 50C to 140C. The reaction time varies with the kind of compound, and is 0.5 to 80 hours.
If necessary, the desired compound (Ib) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 5]
(Scheme 16) MR

R4~ ,~oR2 +Rs~ OH Base R ~ N).~R2 COCI ~
XXIII XX~V N=~R5 wherein each symbol is as defined above.
The compound of the formula (Ib) of the present invention can be prepared by reacting the compound (XXIII) with the compound (XXIV) in the presence of a base in the absence of a solvent or in an appropriate solvent (alone or as a mixture) by reference to S. Chiou et al., J.
Heterocyclic Chem., 26, 125 (1989).
The amount of the compound (XXIV) to be used in this reaction is 1 equivalent or more, preferably 1 to 3 equivalents, based on the compound (XXIII).

Examples of the base to be used include amines (e.g., pyridine, triethylamine, etc.). The amount of the base to be used is 1 equivalent or more, preferably 3 to 20 equivalents, based on the compound (XXIII).
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., THF, dioxane, etc.), mixed solvents thereof, etc.
The reaction temperature is 20C to 180C, preferably 50C to 140C. The reaction time varies with the kind of compound, and is 0.5 to 80 hours.
If necessary, the desired compound (Ib) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).
The compound (XXIII) used as the starting material in this reaction can be prepared, for example, according to Japanese Patent Application No. 5-56143, for example, by subjecting the corresponding ~-methoxyimino(substituted)-benzyl cyanide to hydrolysis with a base (e.g., sodium hydroxide, potassium hydroxide, etc.) to give a carboxylic acid, and then halogenating the carboxylic acid with a thionyl halide (e.g., thionyl chloride, etc.), phosphoryl halide (e.g., phosphoryl chloride, etc.), etc.

[Route 6]
(Scheme 17) R1 l R1 ~,(CH2)n ~,(CH2)n R4 ~N,~OR2 + NH2NH2 ~ R4~N~R2 CoOR7 XXIa CONHNH2 XXV XXVI

wherein R7 is alkyl (e.g., lower alkyl such as methyl, ethyl, propyl, etc.), and the other symbols are as defined above.
The compound of the formula (XXVI) can be prepared by reacting the compound (xxV) with a monohydrate of the compound (XXIa) or a salt thereof (e.g., hydrochloric acid salt, sulfuric acid salt) in an appropriate solvent (alone or as a mixture).
The amount of the compound (XXIa) to be used in this reaction is 1 equivalent or more, preferably 1 to 5 equivalents, based on the compound (XXV).
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), alcohols (e.g., methanol, ethanol, propanol, etc.), ethers (e.g., THF, dioxane, etc.), water, mixed solvents thereof, etc.

The reaction temperature is 0C to 160C, preferably 10C to 130C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
The compound (XXVI) thus obtained can be used in the next step as the reaction mixture or the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
The compound (xxV) used as the starting material in this reaction can be prepared, for example, according to JP-A 4-295454, for example, by subjecting the corresponding a-ketocarboxylic acid ester or a ketal at the a-position of the ester to oximation.
[Route 6 (continued)]
(Scheme 18) ~,(CH2)n ~,(CH2)n R4~NrR + R5C(oR7)3 ~ R ~N",R2 CONHNH2 ~ N
~arvl ~ N
R5 Ic wherein each symbol is as defined above.
The compound of the formula (Ic) of the present invention can be prepared by reacting the compound (XXVI) with the compound (XXVII) in the absence of a solvent or in an appropriate solvent (alone or as a mixture) by reference to C. Ainaworth, J. Am. Chem. Soc., 77, 1148 (1955).
The amount of the compound (XXVII) to be used in this reaction is 1 equivalent or more, preferably 1 to 20 equivalents, based on the compound (XXVI).
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., THF, dioxane, etc.), mixed solvents thereof, etc.
The reaction temperature is 20C to 200C, preferably 50C to 170C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
If necessary, the desired compound (Ic) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 7]
(Scheme 19) MRl Ml R1 (CH2)n (CH2)n R4 ~ ~oR2 + HONH2 R4 ~ N~OR2 xxvm ~, 25wherein each symbol is as defined above.

The compound of the formula (XXIX) can be prepared by reacting the compound (XXVIII) with hydroxylamine or a salt thereof (e.g., hydrochloric acid salt, sulfuric acid salt) in the presence or absence of a base in an appropriate solvent (alone or as a mixture).
The amount of the hydroxylamine or a salt thereof to be used in this reaction is 1 equivalent or more, preferably 1 to 3 equivalents, based on the compound (XXVIII).
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), amines (e.g., pyridine, triethylamine, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 2 equivalents.
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), alcohols (e.g., methanol, ethanol, propanol, etc.), water, mixed solvents thereof, etc.
The reaction temperature is 0C to 160C, preferably 20C to 110C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
The compound (XXIX) thus obtained can be used in the next step as the crude product, or after purifying it by -- `---a conventional method (e.g., chromatography, recrystallization, etc.).
The compound (XXVIII) used as the starting material in this reaction can be prepared, for example, according to Route 13, 14 or 15, or Japanese Patent Application No. 4-324120, for example, by introducing the cyano moiety to the corresponding (substituted)benzyl halide using an alkaline metal cyanide (e.g., sodium cyanide, etc.), and then subjecting the resulting compound to oximation.
[Route 7 (continued)]
(Scheme 20) (CH2)n R4 ~ + R5C(OR7)3(or (R5Co)2 X~X ~ X~

(CH2)n R4~ ~roR2 ~N

R5 ~

- ` -wherein each symbol is as defined above except that R5 of the compound (XXx) is other than hydrogen and preferably lower alkyl such as methyl, ethyl, propyl, etc.
The compound of the formula (Id) of the present 5 invention can be prepared by reacting the compound (XXIX) with the compound (XXVII) or (xxx) in the absence of a solvent or in an appropriate solvent (alone or as a mixture) by reference to U.S. Patent No. 3,910,942.
The amount of the compound (XXVII) or (XXX) to be used in this reaction is 1 equivalent or more, preferably 1 to 20 equivalents, based on the compound (XXIX).
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., THF, dioxane, etc.), mixed solvents thereof, etc.
The reaction temperature is 40C to 200C, preferably 60C to 180C. The reaction time varies with the kind of compound, and is 0.5 to 120 hours.
If necessary, the desired compound (Id) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).
The compounds of the formulas (Ie), (If) and (Ig) of the present invention can be prepared according to the following Route 8.

[Route 8]
(Scheme 21) l R1 l R1 R4~ Azide ~HN)rR2 CN H--N~ N

Ie wherein each symbol is as defined above.
The compound of the formula (Ie) of the present invention can be prepared by reacting the compound (XXVIII) with an azide compound in the presence of ammonium chloride in an appropriate solvent (alone or as a mixture) by reference to K. Kubo, J. Med. Chem., 36, 2182 (1993).
Examples of the azide compound to be used include alkaline metal azides (e.g., sodium azide, potassium azide, etc.), etc. The amount of the azide compound to be used is 1 equivalent or more, preferably 1 to 15 equivalents, based on the compound (XXVIII). The amount of the ammonium chloride to be used is 1 equivalent or more, preferably 1 to 15 equivalents, based on the compound (XXVIII).
Examples of the solvent to be used include N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic - ` -hydrocarbons (e.g., toluene, benzene, xylene, etc.), ethers (e.g., dioxane, etc.), mixed solvents thereof, etc.
The reaction temperature is 40C to 200C, preferably 60C to 180C. The reaction time varies with the kind of compound, and is 0.5 to 120 hours.
The desired compound (Ie) thus obtained can be used in the next step as the reaction mixture or the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 8 (continued)]
(Scheme 22) ~,(CH2)n R4 ~N +R7-Y Base -H--N, N--N

20" ~ (CH2)n " ~_(CH2)n R4~ oR2 R4 ~N,~R2 R7--N N N/~ N
N=N N--N~R7 Ig wherein each symbol is as defined above.

- ` -The compound of the formula (If) or (Ig) of the present invention can be prepared by reacting the compound (Ie) with the compound (XXXI) in the presence of a base in an appropriate solvent (alone or as a mixture).
The amount of the compound (XXXI) be used in this reaction is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound (Ie).
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 3 equivalents.
Examples of the solvent to be used include N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), water, mixed solvents thereof, etc.

The reaction temperature is -30C to 150C, preferably -10C to 100C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
If necessary, the desired compound (If) and (Ig) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).
The compounds of the formulas (Ih) and (Ii) of the present invention can be prepared according to the following Route 9.
[Route 9]
(Scheme 23) MR1 Ml R1 15R4~fH2)n MeOH, AcidR4{3~N)noR2 CN MeO NH
XXVIII XxXll wherein each symbol is as defined above.
The compound of the formula (XXXII) can be prepared by reacting the compound (XXVIII) with methanol in the presence of an acid by reference to, for example, JP-A 5-271223.

- ` -` 2186947 The amount of the methanol to be used in this reaction is 1 equivalent or more, preferably 1 to 1.2 equivalents, based on the compound tXXVIII).
Examples of the acid to be used include 5 hydrochloric acid, hydrobromic acid, etc. The amount of the acid to be used is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound (XXVIII).
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, ethyl ether, etc.), mixed solvents thereof, etc.
The reaction temperature is -30C to 150C, preferably 0C to 120C. The reaction time varies with the kind of compound, and is 0.5 to 120 hours.
The compound (XXXII) thus obtained can be used in the next step as the reaction mixture or the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 9 (continued)]
(Scheme 24) 21 8b947 Ml R1 ~_(CH2)n R4~N +(R 0)2CHCH2NH2 MeO/~NH
XXXll XXXlll Ml R1 ~,(CH2)n R4 ~N,~,OR2 (R70)2CHCH2N H/~NH
XXXl~l wherein each symbol is as defined above.
The compound of the formula (XXXIV) can be prepared by reacting the compound (XXXII) or a salt thereof (e.g., hydrochloric acid, hydrobromic acid, etc.) with the compound (XXXIII) by reference to, for example, JP-A 5-271223.
The amount of the compound (XXXIII) to be used in this reaction is 1 equivalent or more, preferably 1 to 1.2 equivalents, based on the compound (XXXII).

Examples of the solvent to be used include alcohols (e.g., methanol, ethanol, propanol, etc.), ethers (e.g., THF, dioxane, etc.), mixed solvents thereof, etc.
The reaction temperature is -30C to 150C, preferably 0C to 120C. The reaction time varies with the kind of compound, and is 0.5 to 120 hours.
The compound (XXXIV) thus obtained can be used in the next step as the reaction mixture or the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 9 (continued)]
(Scheme 25) (CH2)n ~_ (CH2)n 15R4 ~ ~oR2 AcidR4~N~oR2 (R70)2CHCH2NH NH H~ N
x~v n wherein each symbol is as defined above.
The compound of the formula (Ih) of the present invention can be prepared by subjecting the compound (XXXIV) or a salt thereof (e.g., hydrochloric acid, hydrobromic acid, etc.) to ring closure reaction in the presence of an acid in the absence of a solvent or in an appropriate solvent (alone or as a mixture) by reference to, for example, JP-A 5-271223.

Examples of the acid to be used include hydrochloric acids, hydrobromic acid, etc. The amount of the acid to be used is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound (XXXIV).
Examples of the solvent to be used include alcohols (e.g., methanol, ethanol, propanol, etc.), ethers (e.g., THF, dioxane, etc.), mixed solvents thereof, etc.
The reaction temperature is 10C to 150C, preferably 30C to 120C. The reaction time varies with the kind of compound, and is 0.5 to 120 hours.
If necessary, the desired compound (Ih) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 9 (continued)]
(Scheme 26) Rl l R1 ~ (CH2)n ~_(CH2)n R4_~N +R7--Y ase~t~N,~oR2 20H--N~ XXXI R7--N~ ~N

Ih Ii wherein each symbol is as defined above.
The compound of the formula (Ii) of the present invention can be prepared by reacting the compound (Ih) with the compound (XXXI) in the presence of a base in an appropriate solvent (alone or as a mixture).
The amount of the compound (XXXI) to be used in this reaction is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound (Ih).
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 2 equivalents.
Examples of the solvent to be used is N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), water, mixed solvents thereof, etc.
The reaction temperature is -30C to 150C, preferably -10C to 100C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.

If necessary, the desired compound (Ii) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).
The compound of the formula (Ij) of the present invention can be prepared according to the following Route 10 .
[Route 10]
(Scheme 27) l l ~_(CH2)n ~(CH2)n R4 ~N~+ H--WcH2cH2NH2 R ~N,~,OR2 CN N
xxvm ~ \

Ij wherein W is oxygen, sulfur or N-R5, and R5 and the other symbols are as defined above.
The compound of the formula (Ij) of the present invention can be prepared by reacting the compound (XXVIII) with the compound (XXXV) or a salt thereof (e.g., hydrochloric acid salt, hydrobromic acid salti etc.) in the presence or absence of a base in the presence or absence of a metal salt in the absence of a solvent or in an appropriate solvent (alone or as a mixture) by reference to Doris P.
Schumacher et al., J. Org. Chem., 55, 5291 (1990).

2 1 ~6q47 The amount of the compound (XXXV) to be used in this reaction is 1 equivalent or more, preferably 1 to 5 equivalents, based on the compound (XXVIII).
Examples of the base to be used include amines (e.g., triethylamine, etc.). The amount of the base to be used is 1 equivalent or more, preferably 1 to 6 equivalents, based on the compound (XXVIII).
Examples of the metal salt to be used include potassium carbonate, zinc acetate, etc. The amount of the metal salt to be used is 0.01 to 0.5 equivaient, preferably 0.02 to 0.2 equivalent, based on the compound (XXVIII).
Examples of the solvent to be used include N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ~thers (e.g., THE, dioxane, etc.), alcohols (e.g., butanol, 2-methoxyethanol, ethylene glycol, glycerol, etc.), mixed solvents thereof, etc.
The reaction temperature is 20C to 200C, preferably 50C to 160C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
If necessary, the desired compound (Ij) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).

21 P,6947 The compound of the formula (Ik) of the present invention can be prepared according to the following Route 11 .
[Route 11]
(Scheme 28) MRl / MR1 I H ) \ Reducing R4~ ~oR2 R4~oR2 g CN \ CoOR7 XXVIII \ XXV /

~_(CH2)n R4 ~N'`~O R2 CHO
X~VI

wherein each symbol is as defined above.
The compound of the formula (XXXVI) can be prepared by reacting the compound (XXVIII) or the compound (XXV) with a reducing agent in an appropriate solvent (alone or as a mixture) by reference to, for example, L.-F Tietze and Th. Eicher, "Reaktionen und Synthesen im organisch-chemischen Praktikum", pp. 84-97 (1981).

Examples of the reducing agent to be used include alkylaluminum hydrides (e.g., diisobutylaluminum hydride, etc.). The amount of the reducing agent to be used is 1 equivalent or more, preferably 1 to 2 equivalents.
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, ethyl ether, etc.), mixed solvents thereof, etc.
The reaction temperature is -100C to 80C, preferably -70C to 30C. The reaction time varies with the kind of compound, and is 0.5 to 120 hours.
The compound (XXXVI) thus obtained can be used in the next step as the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).

[Route 11 (continued)]
(Scheme 29) ~ ,(CH2)n ~=~ Base R4~ ,~oR2 + Me~SO2CH2N_C

CHO
X~ X~
l R1 1 0 ~(CH2)n R4~f"N"~OR2 ~`N1 Ik wherein each symbol is as defined above.
The compound of the formula (Ik) of the present invention can be prepared by reacting the compound (XXXVI) with the compound (xxxVII) in the presence of a base in an appropriate solvent (alone or as a mixture) according to, for example, JP-A 58-131984.
The amount of the compound (XXXVII) to be used in this reaction is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound (XXXVI).
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, - ` -etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 2 equivalents.
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), alcohols (e.g., methanol, ethanol, propanol, etc.), mixed solvents thereof, etc.
The reaction temperature is 30C to 150C, preferably 50C to 100C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
If necessary, the desired compound (Ik) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).
The compound of the formula (In) of the present invention can be prepared according to the following Route 12.
[Route 12]
(Scheme 30) -~13 R8 Lewis R4~N~oR2 acid ~N~OR2 R3 hydrogen R3 XXXVIII XXXlXa wherein R8 is hydrogen, alkyl (e.g., lower alkyl such as methyl, ethyl, propyl, etc.) or halogen (e.g., fluorine, chlorine, bromine, iodine), and the other symbols are as defined above.
The compound of the formula (XXXIXa) can be prepared by reacting the compound (XXXVIII) with a Lewis acid in an appropriate solvent (alone or a mixture).
The compound (XXXVIII) is synthesized by a modified method of Routes 1 to 11.
Examples of the Lewis acid to be used include aluminium chloride, aluminium bromide, boron trifluoride, boron trichloride, ferric chloride, etc.
The amount of the Lewis acid to be used is 1 equivalent or more, preferably 1 to 3 equivalents, based on the compound (XXXVIII).
Examples of the solvent to be used include anisole, nitromethane, nitroethane, mixed solvents thereof, etc.

The reaction temperature is -30C to 120C, preferably -10C to 80C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
Alternatively, the compound (XXXIXa) can be prepared by reacting the compound (XXXVIII) with hydrogen in the presence of a catalyst in an appropriate solvent (alone or as a mixture).
The amount of the hydrogen to be used is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound (XXXVIII).
Examples of the catalyst to be used include palladium-carbon, etc. The amount of the catalyst to be used is 0.01 equivalent or more, preferably 0.01 to 0.2 equivalent, based on the compound (XXXVIII).
Examples of the solvent to be used include ethyl acetate, alcohols (e.g., methanol, ethanol, propanol, etc.), water, mixed solvents thereof, etc.
The reaction temperature is -30C to 120C, preferably -10C to 80C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
The compound (XXXIXa) thus obtained can be used in the next step as the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystalli~ation, etc.).

21 ~6947 [Route 12 (continued)]
(Scheme 31) IH olR1 (CH2)n , (CH2)n R4 ~N~OR Base R4 ~N,~R2 XXXlX XL

wherein each symbol is as defined above.
The compound of the formula (In) of the present invention can be prepared by reacting the compound (XXXIX) with the compound (XL) in the presence of a base in an appropriate solvent (alone or as a mixture).
The amount of the compound (XL) to be used in this reaction is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound (XXXIX).
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 2 equivalents.
Examples of the solvent to be used is N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), water, mixed solvents thereof, etc.
The reaction temperature is 0C to 190C, preferably 10C to 160C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
If necessary, the desired compound (In) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).
The compound (XXVIII) which can be used as the starting material in the above Schemes 19, 21, 23, 27 and 28 can be prepared according to the following Route 13, 14 or 15.
[Route 13]
(Scheme 32) Alkaline metal R4--,~2) oR2 cyanide ~N)~,OR2 A CN
V XXVIII
wherein each symbol is as defined above.

21~6947 The compound of the formula (XXVIII) can be prepared by reacting the compound (V) with an alkaline metal cyanide (e.g., sodium cyanide, potassium cyanide, etc.) in an appropriate solvent (alone or as a mixture).
The amount of the alkaline metal cyanide to be used in this reaction is 1 equivalent or more, preferably 1 to 3 equivalents, based on the compound (V).
Examples of the solvent to be used is N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), water, mixed solvents thereof, etc.
The reaction temperature is 0C to 190C, preferably 20C to 160C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
The compound (XXVIII) thus obtained can be used in the next step as the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.
[Route 14]
(Scheme 33) R1 Acidl R1 ~,(CH2)n anhydride ~(CH2)n R4~"N~OR2 ~ R4 ~N~R2 xvm xxvm wherein each symbol is as defined above.
The compound of the formula (XXVIII) can be prepared by reacting the compound (XVIII) with an acid anhydride in the presence or absence of a base in the absence of a solvent or in an appropriate solvent (alone or as a mixture) by reference to, for example, J. Goto et al., J.
Antibiotics, 37, 557 (1984).
Examples of the acid anhydride to be used include acetic anhydride, trifluoroacetic anhydride, etc. The amount of the acid anhydride to be used is 1 equivalent or more, preferably 1 to 5 equivalents, based on the compound (XVIII).
Examples of the base to be used include amines (e.g., pyridine, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 30 equivalents, based on the compound (XVIII). Examples of the solvent to be used is aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), mixed solvents thereof, etc.
The reaction temperature is -30C to 160C, preferably -10C to 110C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
The compound (XXVIII) thus obtained can be used in the next step as the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 15]
(Scheme 34) R4--~ Base ~HN3~0 H
CN CN
XLI XLII

wherein Rg is as defined above.
The compound of the formula (XLII~ can be prepared by reacting the compound (XLI) with an alkyl nitrite in the presence of a base in an appropriate solvent (alone or as a mixture) in the presence or absence of a phase-transfer catalyst.
Examples of the alkyl nitrite to be used include methyl nitrite, ethyl nitrite, propyl nitrite, isopropyl nitrite, butyl nitrite, isoamyl nitrite, etc. The amount of the alkyl nitrite to be used is 1 equivalent or more, preferably 1 to 2 equivalents.
Examples of the phase-transfer catalyst to be used include tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium hydrogensulfate, tetramethylammonium bromide, benzyltriethylammonium chloride, tris(3,6-dioxaheptyl)amine, etc. The amount of the phase-transfer catalyst to be used is 0.005 to 0.5 equivalent, preferably 0.01 to 0.2 equivalent.
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 2 equivalents.
Examples of the solvent to be used is N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), alcohols (e.g., methanol, butanol, etc.), water, mixed solvents thereof, etc.

The reaction temperature is -10C to 120C, preferably 0C to 80C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
The compound (XLII) or a salt thereof (e.g., sodium salt, potassium salt, etc.) thus obtained can be used in the next step as the reaction mixture or the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
The compound (XLI) used as the starting material in this reaction is commercially available from Aldrich.
[Route 15 (continued)]
(Scheme 35) R4--~N~H + R2--Y ~ R4~HN~'R2 CN CN
~.. II XVII xLm wherein each symbol is as defined above.
The compound of the formula (XLIII) can be prepared by reacting the compound (XLII) or a salt thereof (e.g., sodium salt, potassium salt, etc.) with the compound (XVII) in the presence or absence of a base in the presence or absence of a phase-transfer catalyst in an appropriate solvent (alone or as a mixture).

The amount of the compound (XVII) to be used in this reaction is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound (XLII).
Examples of the phase-transfer catalyst to be used include tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium hydrogensulfate, tetramethylammonium bromide, benzyltriethylammonium chloride, tris(3,6-dioxaheptyl)amine, etc. The amount of the phase-transfer catalyst to be used is 0.005 to 0.5 equivalent, preferably 0 01 to 0.2 equivalent.
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 2 equivalents.
Examples of the solvent to be used is N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles -(e.g., acetonitrile, etc.), water, mixed solvents thereof, etc.
The reaction temperature is -20C to 140C, preferably 10C to 120C. The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
The compound (XLIII) thus obtained can be used in the next step as the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 15 (continued)]
(Scheme 36) Halogenating ~CH3 agent R4~N,~R2 R4~N~,R2 CN
xLm C N

wherein each symbol is as defined above.
The compound of the formula (XLIV) can be prepared by reacting the compound (XLIII) with a halogenating agent in the presence of a reaction initiator in an appropriate solvent (alone or as a mixture).
Examples of the halogenating agent to be used include halogenated succinimide (e.g., N-chlorosuccinimide, N-bromosuccinimide, etc.), chlorine, and bromine. The amount -of the halogenating agent to be used is 1 equivalent or more, preferably 1 to 1.5 equivalent.
Examples of the reaction initiator to be used include peroxides (e.g., benzoyl peroxide, etc.), azobisisobutyronitrile, etc.~ The amount of the reaction initiator to be used is 0.01 equivalent or more, preferably 0.03 to 0.3 equivalent.
Examples of the solvent to be used include aromatic hydrocarbons (e.g., benzene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., carbon tetrachloride, l,2-dichloroethane, etc.), mixed solvents thereof, etc.
The reaction temperature is 20C to 160C, preferably 50C to 120C. The reaction time varies with the kind of compound, and is 0.1 to 48 hours.
The compound (XLIV) thus obtained can be used in the next step as the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 15 (continued)]
(Scheme 37) R4 ~IJ ~oR2 Base ~ 2 ~N + R1--MH , R4~N~OR
C N C N
xxvm~

wherein each symbol is as defined above.
The compound of the formula (XXVIIIa) can be prepared by reacting the compound (XLIV) with the compound (IX) in the presence of a base in the presence or absence of a phase-transfer catalyst in the absence of a solvent or in an appropriate solvent (alone or as a mixture).
The amount of the compound (IX) to be used in this reaction is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound (XLIV).
Examples of the phase-transfer catalyst to be used include tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium hydrogensulfate, tetramethylammonium bromide, benzyltriethylammonium chloride, tris(3,6-dioxaheptyl)amine, etc. The amount of the phase-transfer catalyst to be used is 0.005 to 0.5 equivalent, preferably 0.01 to 0.2 equivalent.
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, potassium 21`86947 carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 2 equivalents.
Examples of the solvent to be used include N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), water, mixed solvents thereof, etc.
The reaction temperature is -30C to 150C, preferably -10C to 100C. The reaction time varies with the kind of compound, and is 0.5 to 80 hours.
The compound (XXVIIIa) thus obtained can be used in the next step as the reaction mixture or the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
The compound (XXXIX) which can be used as the starting material in Scheme 31 described above can also be prepared according to the following Route 16.
[Route 16]
(Scheme 38) ~ - `

" - 90 -fH I P
R4~CH2)n ~CH2)n XLV XLVI

wherein P is a protective group of a hydroxyl group, and the other symbols are as defined above.
The compound (XLVI) can be prepared by protecting the hydroxyl group of the commercially available compound (XLV) with an appropriate protective group.
The hydroxyl group can be protected with a group represented by P by a conventional method for protecting a hydroxyl group described in, for example, T. W. Green, ~Protective Groups in Organic Synthesis", p. 1-113, John Willy & Sons (1981); C. B. Reese, ~Protective Groups in Organic Chemistry", J. F. McOmie (ed.), p.95-143, Plenum Press (1973), etc.
For example, the compounds (XLVI) protected with tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, l-ethoxyethyl and l-methyl-l-methoxyethyl can be prepared by reacting the compound (XLV) with the corresponding olefins in the presence of an acid catalyst in an appropriate solvent or in the absence of a solvent.

- i The corresponding olefins are 3,4-dihydro-2H-pyran, 2,3-dihydro-4H-thiin, dihydrofuran, dihydrothiofuran, ethyl vinyl ether, and 2-methoxypropene, respectively, and they are commercially available or can be prepared by known methods.
The amount of the olefin to be used is 1 to 3 equivalents, preferably 1 to 2 equivalents, based on the compound (XLV).
Examples of the acid catalyst include hydrogen chloride, phosphorus oxychloride, p-toluenesulfonic acid, p-toluenesulfonic acid pyridine salt, montmorillonite, bistrimethyl sulfate, acetic acid, p-toluenesulfonic acid polyvinyl pyridinium, trifluoroacetic acid, boron trifluoride etherate (BF3-OEt2) and acidic ion-exchange resins, etc.

When a solvent is used, non-alcoholic solvents can be used. Examples of the solvent include hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane, etc.), esters (e.g., ethyl acetate, etc.), N,N-dimethylformamide, mixed solvents thereof, etc.
The reaction temperature is -30C to 100C, preferably 0C to 60C. The reaction time is normally 15 minutes to 24 hours.

` - -The compound (XLVI) protected with a silyl enol type protective group can be obtained by reacting the compound tXLV) with an appropriate silylating agent. In general, it can be obtained by reacting the compound (XLV) with chlorosilane in the presence of a base in an appropriate solvent.
Chlorosilane is commercially available or can be prepared by a known method.
The amount of the chlorosilane to be used is 1 to 5 equivalents, preferably 1 to 2 equivalents, based on the compound ( XLV).
Examples of the base to be used include organic bases (e.g., N,N-dimethylaniline, pyridine, triethylamine, imidazole, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal hydrides (e.g., sodium hydride, potassium hydride, etc.), metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 2 equivalents.
Examples of the solvent to be used include hydrocarbons (e.g., hexane, benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles te.g., acetonitrile, etc.), N,N-dimethylformamide, dimethyl sulfoxide, mixed solvents thereof, etc.
The reaction temperature is -20C to 100C, preferably 0C to 60C.
The reaction time-is 5 minutes to 30 hours, preferably 30 minutes to 15 hours.
The compound (XLVI) protected with methoxymethyl or triphenylmethyl and the compound (XLVI) protected with tetrahydrofuranyl or 1-ethoxyethyl described above can be obtained by reacting the compound (XLV) with the corresponding halide in the presence of a base.
The corresponding halides are halomethyl methyl ether, triphenylmethyl halide, 2-halotetrahydrofuran and 1-haloethyl ether, respectively, and they are commercially available or can be prepared by a known method.
Examples of the halide to be used include chlorides, and bromides.
The amount of the halide to be used, the kind of base and solvent, and the reaction conditions, etc., are similar to those in the above reaction of the compound (XLV) with chlorosilane.
Alternatively,the compound (XLVI) protected with methoxymethyl described above can also be obtained by reacting the compound (XLV) with dimethoxymethane in the presence of an appropriate catalyst (e.g., phosphorus pentaoxide, etc.).
The solvent to be used and the reaction conditions are similar to those in the reaction of the compound (XLV) with olefin.
The compound (XLVI) thus obtained can be used in the next step as the reaction mixture or the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 16 (continued)]
(Scheme 39) IP IP

R4~CH2)n P4~cH2)n XLVI XLV~
wherein each symbol is as defined above.
The compound (XLVII) can be prepared by reacting the compound (XLVI) with lithium or magnesium in an appropriate solvent.
The amount of the lithium or magnesium to be used is 1 to 4 equivalents, preferably 1 to 2 equivalents, based on the compound ( XLVI).
Examples of the solvent to be used include ethers such as dry THF, diethyl ether, dibutyl ether, etc. These solvents can be used alone or as mixtures with other solvents such as hydrocarbons (e.g., toluene, etc.), amines (e.g., triethylamine, etc.), etc.
The reaction temperature is room temperature to 150C, preferably 40C to 100C.
The reaction time is 10 minutes to 48 hours, preferably 30 minutes to 6 hours.
If necessary, as a reaction activating agent, a small amount of iodine, dibromoethane, ethyl bromide, etc., can be used. The amount thereof is 0.001 to 0.4 equivalent, preferably 0.005 to 0.2 equivalent.
The compound (XLVII) thus obtained can be used in the next step as the reaction mixture or the crude product.
[Route 16 (continued)]
(Scheme 40) f I P
R4~ + R3--COL (orR3 CN) . R4~Ho~n 2 0 XLVII XLVm wherein each symbol is as defined above.
The compound of the formula (XLVIII ) can be prepared by reacting the compound (XLVII ) with the compound (XII) or (XIII) in an appropriate solvent (alone or as a mixture).

The amount of the compound (XII) or (XIII) to be used in this reaction is 1 equivalent or more, preferably 1 to 3 equivalents, based on the compound (XLVII).
Examples of the solvent to be used is aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), ethers (e.g., THF, diethyl ether, dioxane, etc.), triethylamine, mixed solvents thereof, etc.
The reaction temperature is -100C to 100C, preferably -80C to 40C.
The reaction time varies with the kind of compound, and is 0.5 to 80 hours.
The compound (XLVIII) thus obtained can be used in the next step as the crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 16 (continued)]
(Scheme 41) QP OP
20R4 ~ + R~ONH2 R4 ~ ~oR2 R3 m R3 XLVIII XLIX

wherein each symbol is as defined above.

The compound (XLIX) can be prepared by reacting the compound (XLVIII ) with the compound (III) or a salt thereof in an appropriate solvent.
The amount of the compound (III) to be used is 1 to 4 equivalents, preferably 1 to 2.5 equivalents, based on the compound ( XLVI I I ) .
Examples of the salt of the compound (III) include mineral acid salts such as a hydrochloric acid salt, sulfuric acid salt, etc. When the salt is used, it is neutralized with a base for the reaction. Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), etc. The amount of the base to be used is 1 to 3 equivalents, preferably 1 to 2 equivalents, based on the compound (III).
Examples of the solvent to be used is hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., chloroform, 1,2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, dioxane, etc.), alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, etc.), water, mixed solvents thereof, etc.
The reaction temperature is 0C to 150C, preferably 20C to 100C.

-The reaction time is normally 15 minutes to 24 hours.
The compound (XLIX) thus obtained can be used in the next step as the reaction mixture or crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
[Route 16 (continued)]
(Scheme 42) f fH
R4~R3 ~OR2 R4~F3 ",OR2 XLIX XXXlX

wherein each symbol is as defined above.
The compound (XXXIX) can be obtained by deprotecting the protective group of the hydroxyl group of the compound (XLIX).
The hydroxyl group can be deprotected by a conventional method for deprotecting a protected hydroxyl group described in, e.g., T. W. Green, "Protective Groups in Organic Synthesis~, p. 1-113, John Willy & Sons (1981); C. B.
Reese, "Protective Groups in Organic Chemistry", J. F. McOmie (ed.), p.95-143, Plenum Press (1973).

For example, the deprotection can be carried out by treating the compound (XLIX~ with an acid when the protective group of the hydroxyl group is alkyl (e.g., t-butyl, etc.), alkenyl (e.g., allyl, etc.), aralkyl (e.g., triphenylmethyl, etc.), trialkylsilyl (e.g., t-butyldimethylsilyl, triisopropylsilyl, etc.j, alkyldiarylsilyl (e.g., t-butyldiphenylsilyl, etc.), triaralkylsilyl (e.g., tribenzylsilyl, etc.), alkoxyalkyl (e.g., methoxymethyl, l-ethoxyethyl, l-methyl-l-methoxyethyl, etc.), alkoxyalkoxyalkyl (e.g., methoxyethoxymethyl, etc.), alkylthioalkyl (e.g., methylthiomethyl, etc.), tetrahydropyranyl (e.g., tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, etc.), tetrahydrothiopyranyl (e.g., tetrahydrothiopyran-2-yl, etc.), tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl, etc.), tetrahydrothiofuranyl (e.g., tetrahydrothiofuran-2-yl, etc.), aralkyloxyalkyl (e.g., benzyloxymethyl, etc.), etc.
In general, the acid to be used includes, for example, inorganic acids such as hydrohalogenic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), hydrogen halides (e.g., hydrogen chloride, hydrogen bromide, hydrogen iodide, etc.), boric acid, phosphoric acid, sulfuric acid, etc., sulfonic acids te.g., aliphatic sulfonic acids such as trifluoromethanesulfonic acid, etc., and aromatic sulfonic acids such as toluenesulfonic acid, etc.), carboxylic acids (e.g., acetic acid, trifluoroacetic acid, etc.), silica gel, Lewis acids [e.g., aluminium halides (e.g., aluminium chloride, etc.), zinc chloride, titanium tetrachloride, etc.], etc. One or more suitable acids can be selected from these acids to use them in the reaction.
The amount of the acid to be used is a trace amount to 1 equivalent. Alternatively, a carboxylic acid can be used as a solvent.
Examples of the solvent to be used is hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, dioxane, etc.), alcohols (e.g., methanol, ethanol, etc.), nitriles (e.g., acetonitrile, etc.), water, mixed solvents thereof, etc.
The reaction temperature is -80C to 150C, preferably -10C to 80C.
The reaction time is 1 minute to 3 hours, preferably 5 minutes to 1 hour.
When the protective group is substituted silyl, for example, the deprotection can be carried out in basic conditions (e.g., sodium hydroxide / water-containing ethanol, etc.) or in the presence of fluoride ion (e.g., n-Bu~N+F-, C5H5N+HF-, etc.).
The compound (XXXIX) thus obtained can be used in the next step as the reaction mixture or crude product.

If necessary, the product can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.).
[Route 16 (continued)]
(Scheme 43) IP OIH
~(CH2)n (CH2)n R4~ + R20NH2 ' R4~oR2 R3 m R3 10XLVm XXXIX

wherein each symbol is as defined above.
The compound (XXXIX) can be prepared by reacting the compound (XLVIII) with the compound (III) or a salt thereof in the presence of a base in an appropriate solvent.
The amount of the compound (III) to be used is 1 to 4 equivalents, preferably 1 to 2.5 equivalents, based on the compound (XLVIII).
Examples of the salt of the compound (III) include mineral acid salts such as a hydrochloric acid salt, sulfuric acid salt, etc. When the salt is used, the salt is neutralized with a base for the reaction.
Examples of the base to be used include amines (pyridine, etc.), etc. The amount of the base to be used is 1 to 3 equivalents, preferably 1 to 2 equivalents, based on the salt of the compound (III).
Examples of the solvent to be used is hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., chloroform, 1,2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, dioxane, etc.), alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, etc.), water, mixed solvents thereof, etc.
The reaction temperature is 0C to 150C, preferably 20C to 200C.
The reaction time is normally 15 minutes to 24 hours.
The compound (XXXIX) thus obtained can be used in the next step as the reaction mixture or crude product, or after purifying it by a conventional method (e.g., column chromatography, recrystallization, etc.).
[Route 16 (continued)]
(Scheme 44) OP QP

R~H2)n + 'R~RCHN~nOH

XLVIII L

wherein each symbol is as defined above.
The compound (L) can be prepared by reacting the compound (XLVIII) with hydroxylamine or a salt thereof in an appropriate solvent.
The amount of the hydroxylamine to be used is 1 to 4 equivalents, preferably 1 to 2.5 equivalents, based on the compound (XLVIII).
Examples of the salt of hydroxylamine include mineral acid salts such as a hydrochloric acid salt, sulfuric acid salt, etc. When the salt is used, it is neutralized with a base for the reaction. Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), etc. The amount of the base to be used is 1 to 3 equivalents, preferably 1 to 2 equivalents, based on the salt of hydroxylamine.
Examples of the solvent to be used include hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., chloroform, 1,2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, dioxane, etc.), alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, etc.), water, mixed solvents thereof, etc.

2 1~ 86947 The reaction temperature ls 0C to 150C, preferably 20C to 100C.
The reaction time is normally 15 minutes to 24 hours.
The compound (L) thus obtained can be used in the next step as the reaction mixture or crude product, or after purifying it by a conventional method (e.g., column chromatography, recrystallization, etc.).
[Route 16 (continued)]
(Scheme 45) OP OP

R4~N~OH+ R2_y ~ R4~HN)~R2 L ~rv~ F3 XL~

wherein each symbol is as defined above.
The compound of the formula (XLIX) can be prepared by reacting the compound (L) with the compound (XVII) in the presence of a base in an appropriate solvent (alone or as a mixture). The amount of the compound (XVII) to be used in this reaction is 1 equivalent or more, preferably 1 to 2 equivalents, based on the compound (L).
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 2 equivalents.
Examples of the solvent to be used include N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), water, mixed solvents thereof, etc.
The reaction temperature is -30C to 150C, preferably -10C to 100C.
The reaction time varies with the kind of compound, and is 0.5 to 90 hours.
The compound (XLIX) thus obtained can be used in the next step as the reaction mixture or crude product, or after purifying it by a conventional method (e.g., chromatography, recrystallization, etc.).
The compound of the formula (Il) of the present invention can be prepared according to the following Route 17.

[Route 17]
(Scheme 46) MR1 . MR

R~"OR + H-WCH~CH2V-H ~ )"OR~

CHO W~V
X~VI Ll Il wherein V is oxygen, sulfur or N-R5, and Rs and the other symbols are as defined above.
The compound of the formula (Il) of the present invention can be prepared by reacting the compound (XXXVI) with the compound (LI) or a salt thereof (e.g., hydrochloric acid salt, hydrobromic acid salt, etc.) in the presence or absence of a base, or in the presence or absence of an acid, or in the presence or absence of a metal salt, in the absence of a solvent or in an appropriate solvent (alone or as a mixture) by reference to, e.g., T. W. Green, ~Protective Groups in Organic Synthesis", p. 109-151, John Willy & Sons (1981).
The amount of the compound (LI) to be used in this reaction is 1 equivalent or more, preferably 1 to 5 equivalents, based on the compound (XXXVI).
Examples of the base to be used include amines (e.g., triethylamine, etc.), etc. The amount of the base to be used is 1 equivalent or more, preferably 1 to 6 equivalents, based on the compound (XXXVI).
Examples of the acid to be used include inorganic acids (e.g., hydrochloric acid, sulfuric acid, etc.) and sulfonic acids (e.g., p-toluenesulfonic acid, etc.). The amount of the acid to be used is 0.01 to 0.5 equivalent, preferably 0.02 to 0.2 equivalent, based on the compound (XXXVI).
Examples of the metal salt to be used include potassium carbonate, zinc acetate, etc. The amount of the metal salt to be used is 0.01 to 0.5 equivalent, preferably 0.02 to 0.2 equivalent, based on the compound (XXXVI).
Examples of the solvent to be used include N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, etc.), alcohols ~e.g., butanol, 2-methoxyethanol, ethylene glycol, glycerol, etc.), mixed solvents thereof, etc.
The reaction temperature is 20C to 200C, preferably 50C to 160C.
The reaction time varies with the kind of compound, and is 0.5 to 90 hours.

If necessary, the desired compound (Il) thus obtained can be purified by a conventional method (e.g., chromatography, recrystallization, etc.).
The compound of the formula (Im) of the present invention can be prepared, for example, according to the following Route 18.
[Route 18]
(Scheme 47) ~ R ~ R4 ~ N~OR2 XXXL~b wherein each symbol is as defined above.
The compound of the formula (LII) can be prepared by reacting the compound (XXXT~h) with a halogenating agent in the absence of a solvent or in an appropriate solvent (alone or as a mixture).
Examples of the halogenating agent to be used include thionyl halides (e.g., thionyl chloride, thionyl bromide, etc.), phosphoryl halides (e.g., phosphoryl chloride, phosphoryl bromide, etc.), phosphorus halides (e.g., phosphorus pentachloride, phosphorus trichloride, phosphorus pentabromide, phosphorus tribromide, etc.), phosgene, oxalyl halides (e.g., oxalyl chloride, etc.), triphenylphosphine / carbon tetrachloride, triphenylphosphine / carbon tetrabromide, etc. The amount of the halogenating agent to be used is 1 equivalent or more.
Examples of the solvent to be used include aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), nitriles (e.g., acetonitrile, etc.), mixed solvents thereof, etc.
The reaction temperature is -30C to 150C, preferably -10C to 120C.
The reaction time varies with the kind of compound, and is 0.1 to 48 hours.
The compound (LII) thus obtained can be used in the next step as the crude product, or after purifying it by a conventional method (e.g., column chromatography, recrystallization, etc.).
[Route 18 (continued)]
(Scheme 48) R4 ~ N~,R2 Base R4 ~J N~,R2 ~~ + R1--MH , LlI ~ h wherein each symbol is as defined above.

The compound of the formula (Im) can be prepared by reacting the compound (LII) with the compound (IX) in the presence of a base in the absence of a solvent or in an appropriate solvent (alone or as a mixture).
The amount of the compound (IX) to be used in this reaction is 1 equivalent or more based on the compound (LII).
Examples of the base to be used include metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), etc. The amount of the base to be used is 1 equivalent or more.
Examples of the solvent to be used include N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., THF, dioxane, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), water, mixed solvents thereof, etc.
The reaction temperature is -30C to 150C, preferably -10C to 100C. The reaction time varies with the kind of compound, and is 0.5 to 120 hours.

If necessary, the desired compound (Im) thus obtained can be purified by a conventional method (e.g., column chromatography, recrystallization, etc.).
The compound of the formula (I) of the present invention is effective against a wide variety of phytopathogenic fungi on crop plants (e.g., rice, wheat, barley, rye, corn, common millet, millet, buckwheat, soybean, redbean, peanut, etc.), fruit trees (e.g., citrus fruits, grape, apple, pear, peach, etc.), vegetables (e.g., cucumber, eggplant, tomato, pumpkin, kidney bean, etc.), etc., or seeds thereof. It is also effective against phytopathogenic fungi in soil. The compound of the present invention shows potent fungicidal activity particularly against PYricularia orvzae, Rhizoctonia solani, Ervsiphe qraminis, Sphaerotheca fuliqinea, Ervsi~he cichoracearum, PhYto~hthora infestans, PseudoPeronos~ora cubensis, PeronosPora manshurica, Plasmo~ara viticola, sotrYtis cinerea of vegetables, grape, etc., PYthium a~hanidermatum, Sclerotinia sclerotiorum of buckwheat, soybean, colza, etc., Corticium rolfsii of soybean, redbean, potato, peanut, etc., PseudocercosPorella her~otrichoides, of cereals, etc. Therefore, the compound (I) of the present invention is useful as fungicides, particularly as agricultural fungicides.
Application of the compound (I) of the present invention may be made to plants by any conventional procedure such as atomizing, scattering or spreading of the active compound. Application may also be made through treatment of seeds of plants, soil where plants grow, soil for seeding, paddy field or water for perfusion with the active compound.
Application may be performed before or after the infection with phytopathogenic fungi on plants.
The compound can be used in a conventional formulation form suitable for agricultural fungicides such as solutions, wettable powders, emulsions, suspensions, concentrated liquid preparations, tablets, granules, aerosols, powders, pastes, dusts, etc.
Such formulation form can be prepared in a conventional manner by mixing at least one compound of the present invention with an appropriate solid or liquid carrier(s) and, if necessary, an appropriate adjuvant(s) (e.g., surfactants, spreaders, dispersants, stabilizers, etc.) for improving the dispersibility and other properties of the active ingredient.
Examples of the solid carriers or diluents include botanical materials (e.g., flour, tobacco stalk powder, soybean powder, walnut-shell powder, vegetable powder, saw dust, bran, bark powder, cellulose powder, vegetable extract residue, etc.), fibrous materials (e.g., paper, corrugated cardboard, old rags, etc.), artificial plastic powders, clays (e.g., kaolin, bentonite, fuller~s earth, etc.), talc, other inorganic materials (e.g., pyrophyllite, sericite, pumice, sulfur powder, active carbon, etc.), chemical fertilizers (e.g., ammonium sulfate, ammonium phosphate, ammonium nitrate, urea, ammonium chloride, etc.), etc.
Examples of the liquid carriers or diluents include water, alcohols (e.g., methanol, ethanol, etc.), ketones (e.g., acetone, ethyl methyl ketone, etc.), ethers (e.g., diethyl ether, dioxane, cellosolve, tetrahydrofuran, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, methylnaphthalene, etc.), aliphatic hydrocarbons (e.g., gasoline, kerosene, lamp oil, etc.), esters, nitriles, acid amides (e.g., dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons (e.g., dichloroethane, carbon tetrachloride, etc.), etc.
Examples of the surfactants include alkyl sulfates, alkyl sulfonates, alkylaryl sulfonates, polyethylene glycol ethers, polyhydric alcohol esters, etc.
Examples of the spreaders or dispersants include casein, gelatin, starch powder, carboxymethyl cellulose, gum arabic, alginic acid, lignin, bentonite, molasses, polyvinyl alcohol, pine oil, agar, etc.
Examples of the stabilizers include PAP (a mixture of isopropylphosphate), tricresyl phosphate (TCP), tolu oil, epoxidized oil, surfactants, fatty acids and their esters, etc.

The composition of the present invention may contain other fungicides, insecticides, herbicides or fertilizers in addition to the above ingredients.
In general, the above composition contains at least one compound of the formula (I) of the present invention in a concentration of 1 to 95% by weight, preferably 2.0 to 80% by weight. The composition can be used as such or in a diluted form. About 1.0 g to 5 kg/hectare, preferably about 10 g to 1000 g/hectare, of the compound of the present invention is used in a concentration of normally about 1 to 5,000 ppm, preferably about 10 to 1,000 ppm.

EXAMPLES
The following Examples and Test Examples further illustrate the present invention in detail, but are not to be construed to limit the scope thereof. The lH-NMR (CDCl3) data in Examples were determined at 270 MHz in CDC13 using tetramethylsilane as an internal standard and indicated in values (ppm). The coupling constants (J) are indicated in Hz. In the data, s is a singlet, d is a doublet, t is a triplet, q is a quartet, m is a multiplet, brs is a broad singlet.
Example 1 Synthesis of a-ethoxyimino-2-phenoxymethylbenzyl chloride Dichloroethane (50 ml), thionyl chloride (6.54 g, 0.055 mol) and dimethylformamide (0.25 ml) were added to 2-phenoxymethylbenzoic acid (11.41 g, 0.05 mol), and the mixture was stirred at 80C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (25 ml). The solution was added to a mixture of ethoxyamine hydrochloride (5.85 g, 0.06 mol), pyridine (9.89 g, 0.125 mol) and dry dichloromethane (50 ml) under ice-cooling over 20 minutes, and then the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (200 ml) was added, adjusted to pH < 2 with conc. hydrochloric acid, and extracted with dichloromethane.
The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
Acetonitrile (150 ml), triphenylphosphine (20.98 g, 0.08 mol) and carbon tetrachloride (24.61 g, 0.16 molj were added to the residue, and the mixture was stirred under reflux for 1.5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give a-ethoxyimino-2-phenoxymethylbenzyl chloride (13.51 g, 93.2%) as a colorless oil.

lH-NMR(CDC13) ~ppm: 3.14(3H,t,J=6.7), 4.27(2H,q,J=6.7), 5.28(2H,s), 6.93-7.70(9H,m).
Synthesis of l-(a-ethoxyimino-2-phenoxymeth benzyl)-lH-1,2,4-triazole Dimethylformamide (3 ml) and 60% sodium hydride (0.12 g, 3 mmol) were added to lH-1,2,4-triazole (0.20 g, 3 mmol), and the mixture was stirred at room temperature for 10 minutes. Then a-ethoxyimno-2-phenoxymethylbenzyl chloride (0.43 g, 1.5 mmol) was added, and the mixture was stirred at 120C for 5 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with brine (80 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give l-(a-ethoxyimino-2-phenoxymethylbenzyl)-lH-1,2,4-triazole (0.42 g, 86.9%) as colorless crystals. mp.
78.5-80.5C.
lH-NMR(CDC13) ~ppm: 1.35(3H,t,J=6.7), 4.30 (2H,q,J=6.7), 4.93(2H,s), 6.76-7.55(9H,m), 7.94(1H,s), 9.14(lH,s).
Example 2 Synthesis of 2-chloromethyl-a-methoxyiminobenzyl chloride 2-Chloromethylbenzoyl chloride (18.90 g, 0.1 mol) was dissolved in dichloromethane (50 ml). The solution was added to a mixture of methoxyamine hydrochloride (12.53 g, 0.15 mol), pyridine (19.78 g, 0.25 mol) and dry dichloromethane (150 ml) under ice-cooling over 1 hour, and then the resulting mixture was stirred at 0C for 2 hours.
After completion of the reaction, water (300 ml) was added, adjusted to pH < 2 with conc. hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 ml), and phosphorus pentachloride (20.82 g, 0.1 mol) was added under ice-cooling over 5 minutes. The mixture was stirred at 0C for 1 hour. After completion of the reaction, saturated aqueous sodium bicarbonate solution (400 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated under reduced - pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-chloromethyl-a-methoxyiminobenzyl chloride (18.15 g, 83.2%) as a colorless oil.

1H-NMR(CDC13) ~ppm: 4.12(3H,s), 4.83(2H,s), 7.40-7.62(4H,m).
Synthesis of 2-(3-chlorophenoxymethyl) -a-methoxyiminobenzyl chloride 3-Chlorophenol (3.09 g, 0.024 mol), dimethyl-formamide (20 ml) and potassium carbonate (4.15 g, 0.03 mol) were added to 2-chloromethyl-a-methoxyiminobenzyl chloride (4.36 g, 0.02 mol), and the mixture was stirred at room temperature for 4 days. After completion of the reaction, ether (250 ml) was added, and the mixture was washed with brine (200 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(3-chlorophenoxymethyl)-~-methoxyiminobenzyl chloride (5.66 g, 91.2%) as a colorless oil.
1H-NMR(CDCl3) ~ppm: 4.02(3H,s), 5.25(2H,s), 6.80-7.70(8H,m).
Synthesis of 1-[2-(3-chlorophenoxymethyl)-~-methoxy-iminobenzyl]imidazole Dimethylformamide (3 ml) and 60% sodium hydride (0.16 g, 3.9 mmol) were added to imidazole (0.27 g, 3.9 mmol), and the mixture was stirred at room temperature for 10 minutes. Then, 2-(3-chlorophenoxymethyl)-~-methoxyiminobenzyl chloride (0.40 g, 1.3 mmol) was added, and the mixture was stirred at 110C for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with brine (80 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 1-[2-(3-chlorophenoxymethyl)-a-methoxyiminobenzyl]imidazole (0.29 g, 65.3%) as colorless crystals. mp. 96.5-97.5C.
1H-NMR(CDCl3) ~ppm: 3.97(3H,s), 5.00(2H,s), 6.63-7.60(lOH,m), 7.98(lH,s).
According to the same manner as that of the synthesis of the intermediate in Example 1 or 2, various compounds of the formula (V) of the present invention, which are intermediates for production of the compound (I), were synthesized. The compounds thus obtained and their physical data are as follows. In the following tables, the physical data of the compounds obtained in Examples 1 and 2 are also listed.

Rl ~_(CH2)n ~N~O R

No R1 R2 n Physical data V-1 C6H5 Me 0 1 H-NMR(CDCI3) ~ ppm: 4.02(3H, s), 6.94-7.55(9H, m) V-2 C6H5 Me 1 1H-NMR(CDCI3) ~ppm :4.02(3H, s), 5.28(2H, s), 6.93-7.69(9H, m) V-3 C6H5 Et 1 1H-NMR(CDCI3) ~ppm :1.34(3H,t, J=6.7), 4.27(2H, q, J=6.7), 5.28(2H, s), 6.93-7.70(9H, m) 1 H-NMR(CDCI3) ~ ppm: 4.69-4.72(2H, m), 5.24-V-4 C6H5 Allyl 1 5.38(2H, m), 5.25(2H, s), 5.94-6.08(1 H, m), 6.93-7.71(9H, m) V-5 2-CI-C6H4 Me 1 1H-NMR(CDCI3) ~ppm: 4.07(3H, s), 5.37(2H, s), 6.88-7.79(8H, m) V-6 3-CI-C6H4 Me 1 1H-NMR(CDCI3) ~ppm: 4.02t3H, s), 5.25(2H, s), 6.80-7.70(8H, m) No R1 R2 n Physical data V-7 4-CI-C6H4 M 1 1 H-NMR(CDCI3) ~ ppm: 4.01 (3H, s), 5.24(2H, s), 6.85-7.70(8H, m) V-8 2-Me-C6H4 Me 1 H-NMR(CDC13) ~ppm: 2-30(3H, s),4.03(3H, s), 5.23(2H, s), 6.80-7.70(8H, m) V-g 4-Me-C6H4 Me 1 H-NMR(CDC13) ~ppm :2.28(3H, s), 4.03(3H, s), 5.25(2H, s), 6.84(2H, d, J=8.5), 7.08(2H, d, J=8.5) 1 H-NMR(CDCI3) ~ ppm: 1.24(3H, t, J=7.3), V-10 2-Et-C6H4 Me 1 2.73(2H, q, J=7.3), 4.05(3H, s), 5.29(2H, s), 6.81-7.70(8H, m) V-112,5-Me2- M 1 1 H-NMR(CDCI3) ~ ppm: 2.25(3H, s), 2.30(3H, s), C6H3 4.05(3H, s), 5.26(2H, s), 6.65-7.70(7H, m) V-122,6-Me2- M 1 1 H-NMR(CDCI3) ~ ppm: 2.28(6H, s), 4.02(3H, s), C6H3 5.02(2H, s), 6.93-7.62(6H, m), 7.90(1 H, d, J=7.9) V-13pyridjn-3 yl Me 1 mp 65-66oc Example 3 Synthesis of 2-(2,5-dimethylphenoxymethyl)phenyl 3-methylisoxazol-5-yl ketone THF (2 ml) and bromoethane (0.1 ml) were added to magnesium (0.49 g, 0.02 mol) in a stream of nitrogen, and the mixture was stirred at 50C for 10 minutes. Then, a mixture of 1-bromo-2-(2,5-dimethylphenoxymethyl)benzene (2.91 g, 0.01 mol) and THF (8 ml) was added at 50 to 60C over 30 minutes, and the mixture was stirred at 50 to 60C for 1 hour. After completion of the reaction, the reaction mixture was added to a mixture of 3-methylisoxazol-5-carbonyl chloride (1.45 g, 0.01 mol) and THF (15 ml) at -70 to -60C over 15 minutes, and then the mixture was stirred at -70 to -60C for 0.5 hours. After completion of the reaction, saturated aqueous ammonlum chloride solution (150 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl 3-methylisoxazol-5-yl ketone (0.56 g, 17.4%) as colorless crystals. mp. 106-108C.
1H-NMR(CDC13) ~ppm: 2.13(3H,s), 2.28(3H,s), 2.38(3H,s), 5.28(2H,s), 6.66(1H,s), 6.67(1H,d,J=6.7), 6.72(1H,s), 7.00(1H,d,J=7.9), 7.46-7.83(4H,m).

Synthesis of 2-t2,5-dimethylphenoxymethyl)phenyl 3-methylisoxazol-5-yl ketone O-methyloxime n-Propanol (2 ml) and methoxyamine hydrochloride (0.25 g, 3 mmol) were added to 2-(2,5-dimethylphenoxymethyl)-phenyl 3-methylisoxazol-5-yl ketone (0.33 g, 1 mmol), and the mixture was stirred under reflux for 15 hours. After completion of the reaction, water (200 ml) was added, the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (0.18 g, 51.4%, as colorless crystals) and isomer B (0.15 g, 42.8%, as colorless crystals) of 2-(2,5-dimethylphenoxymethyl)phenyl 3-methylisoxazol-5-yl ketone O-methyloxime. One of the isomers A and B is the E-isomer and the other is Z-isomer.
Isomer A: mp. 113-114C
1H-NMR(CDCl3) ~ppm: 2.11(3H,s), 2.25(3H,s), 2.33(3H,s), 4.12(3H,s), 4.98(2H,s), 6.51(lH,s), 6.64(1H,d,J=7.3), 6.91(1H,s), 6.97(1H,d,J=7.3), 7.38-7.62(4H,m).
Isomer B: mp. 107-108C
lH-NMR(CDC13) ~ppm: 2.13(3H,s), 2.24(3H,s), 2.26(3H,s), 4.04(3H,s), 4.93(2H,s), 5.99(lH,s), 6.53(lH,s), 6.65(1H,d,J=7.9), 6.99(1H,d,J=7.3), 7.21-7.52(3H,m), 7.68(1H,d,J=7.9).
Example 4 Synthesis of 2-(2,5-dimethylphenoxymethyl)phenyl isoxazol-3-yl ketone THF (2 ml) and bromoethane (0.1 ml) were added to magnesium (0.49 g, 0.02 mol) in a stream of nitrogen, and the mixture was stirred at 50C for 10 minutes. Then, a mixture of 1-bromo-2-(2,5-dimethylphenoxymethyl)benzene (2.91 g, 0.01 mol) and THF (8 ml) was added at 50 to 60C over 30 minutes, and the mixture was stirred at 50 to 60C for 1 hour. After completion of the reaction, the reaction mixture was added to a mixture of 3-cyanoisoxazole (1.45 g, 0.015 mol) and THF (15 ml) at 20C or lower over 15 minutes, and then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 2N sulfuric acid (200 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl isoxazol-3-yl ketone (0.20 g, 6.3%) as colorless crystals. mp. 90.5-92C.
1H-NMR(CDCl3) ~ppm: 2.16(3H,s), 2.29(3H,s), 5.32(2H,s), 6.66(1H,s), 6.67(1H,d,J=6.7), 6.86(1H,d,J=1.2), 7.00(lH,d,J=7.3), 7.47(lH,t,J=7.3), 7.60-8.03(3H,m), 8.50(1H,d,J=1.8).
Synthesis of 2-(2,5-dimethylphenoxymethyl)phenyl isoxazol-3-yl ketone O-methyloxime n-Propanol (2 ml) and methoxyamine hydrochloride (0.50 g, 6 mmol) were added to 2-(2,5-dimethylphenoxymethyl)-phenyl isoxazol-3-yl ketone (0.64 g, 2 mmol), and the mixture was stirred under reflux for 17 hours. After completion of the reaction, water (100 ml) was added, the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (benzene/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl isoxazol-3-yl ketone O-methyloxime (a mixture of isomers A/B) (0.55 g, 81.8%) as colorless crystals. mp. 104-108C
lH-NMR(CDCl3) ~ppm: 2.13(2.15)(3H,s), 2.23(2.25)(3H,s), 4.01(4.08)(3H,s), 4.95(5.01)(2H,s), 6.52-7.00(4H,m), 7.29-7.64(4H,m), 8.39(8.45)(lH,d,J=1.8).
Example 5 Synthesis of 2-(2,5-dimethylphenoxymethyl)phenyl l-methylpyrazol-5-yl ketone Dichloroethane (20 ml), thionyl chloride (1.31 g, 0.011 mol) and dimethylformamide (0.1 ml) were added to 2-(2,5-dimethylphenoxymethyl)benzoic acid (2.56 g, 0.01 mol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride. 1.6M n-butyllithium / n-hexane solution (6.25 ml, 0.01 mol) was added to a mixture of 1-methylpyrazole (0.99 g, 0.012 mol) and THF (10 ml) at -70 to -60C over 15 minutes, and then the mixture was stirred at -70C to room temperature for 1 hour. The reaction mixture was cooled to -70C, and a solution of the crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride in THF
(10 ml) was added, and the mixture was stirred at -70C for 1 hour. After completion of the reaction, lN hydrochloric acid (100 ml) was added, and the mixture was extracted with ether.
The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone (0.50 g, 15.6%) as colorless crystals.
mp. 88-89C
1H-NMR(CDC13) ~ppm: 2.04(3H,s), 2.28(3H,s), 4.22(3H,s), 5.23(2H,s), 6.50(1H,d,J=2.4), 6.65(1H,s), 6.66(lH,d,J=6.7), 6.97(lH,d,J=7.3), 7.38-7.76(4H,m).
Synthesis of 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone O-ethyloxime n-Propanol (2 ml) and ethoxyamine hydrochloride (0.18 g, 1.8 mmol) were added to 2-(2,5-dimethylphenoxy-methyl)phenyl 1-methylpyrazol-5-yl ketone (0.20 g, 0.6 mmol), and the mixture was stirred under reflux for 3 days. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (0.11 g, 50.4%, as colorless crystals) and isomer B (0.10 g, 45.9%, as colorless crystals) of 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone O-ethyloxime.
Isomer A: mp. 74-76C
1H-NMR(CDC13) ~ppm: 1.30(3H,t,J=7.3), 2.13(3H,s), 2.23(3H,s), 4.13(3H,s), 4.24(2H,q,J=7.3), 4.95(2H,s), 5.92(1H,d,J=2.4), 6.51(1H,s), 6.64(1H,d,J=7.9), 6.99(lH,d,J=7.3), 7.17-7.64(5H,m).
Isomer B: mp. 84-86C
1H-NMR(CDC13) ~ppm: 1.33(3H,t,J=6.7), 2.23(3H,s), 2.29(3H,s), 3.68(3H,s), 4.29(2H,q,J=6.7), 5.14(2H,s), 6.30(1H,d,J=1.8), 6.58(1H,s), 6.68(1H,d,J=7.3), 7.03(1H,d,J=7.3), 7.16-7.47(3H,m), 7.52(1H,d,J=1.8), 7.73(lH,d,J=7.9).

According to the same manner as that of the syntheses of the intermediates in Examples 3 to 5, various compounds of the formula (XIV) of the present invention, which are intermediates for production of the compound (I), were synthesized. The compounds thus obtained and their physical data are as follows. In the following tables, the physical data of the compounds obtained in Examples 3 to 5 are also listed.

olR1 ~(CH2)n ~0 No R1 R3 n Physical data 1-Me-i", '---l 1 H-NMR(CDCI3) ~ ppm: 3.94(3H, s), XIV-1 C6H5 2-yl 6.92-7.30(7H, m), 7.43(1H, td, J=8.6, 1.8), 7.64(1H, dd, J=7.9, 1.8) 1 H-NMR(CDCI3) ~ ppm: 2.07(3H, s), 1-Me-il" '---' 2.26(3H, s), 4.01(3H, s), 5.23(2H, s), XIV-22,5-Me2-C6H3 2-yl 1 6.00(1H, s), 6.64(1H, d, J=7.3), 6.97(1 H, d, J=7.3), 7.05(1 H, s), 7.19(1H, s), 7.40-7.83(4H, m) 1 H-NMR(CDCI3) ~ ppm: 5.34(2H, s), - 6.85-7.28(6H, m), 7.46(1 H, t, J=7.3), XIV-3 C6H5 Isoxazol-3-yl 1 7.61(1H. td, J=7.9, 1.2), 7.74(1H, d, J=7.9), 7.99(1 H, dd, J=7.3, 1.2), 8.50(1 H, dd, J=1.2) 1 H-NMR(CDCI3) ~ ppm: 2.21 (3H, s), XIV-4 2-Me-C6H4 Isoxazol-3-yl 1 s.34(2H, s), 6.80-7.14(5H. m), 7.44-8.02(4H, m), 8.49(1H, d, J=1.2) XIV-52,5-Me2-C6H3 Isoxazol-3-yl 1 mp 90 5-92C
5-Me-isoxazol- 1 H-NMR(CDCI3) ~ ppm: 2.49(3H, s), XIV-6 C6H5 3-yl 1 5.34(2H, s), 6.46(1H, d, J=1.2), 6.88-7.99(9H, m) No R1 R3 n Physical data 1 H-NMR(CDCI3) ~ ppm: 2.1 7(3H, s), XIV-72,5-Me2-C6H3 5-Me- 1 2-28(3H, s), 2.49(3H, s), 5.32(2H, s), isoxazol-3-yl 6.46(1 H, s), 6.66-7.02(3H, m), 7.42-8.00(4H, m) 1 H-NMR(CDC13) ~ ppm: 2.18(3H, s), XIV-82~Me~C6H4isoxazol 5-yl 1 2.38(3H, s), 5.30(2H, s), 6.71(1 H, s), 6.81-7.80(8H, m) XIV-92'5~Me2~C6H3isoxazol 5 yl 1 mp 106-108C
1 H-NMR(CDCI3) ~ ppm: 2.17(3H, s), XIV-102,5-Me2-C6H32-lsoxazolin- 1 2.31(3H, s), 3.20(2H, t, J=11.0), 3-yl 4.42(2H, t, J=11.0), 5.20(2H, s), 6.68-7.84(7H, m) 5,5-Me2-2- 1 H-NMR(CDC13) ~ ppm: 1 .35(6H, s), XIV-112~5-Me2-C6H3isoxazolin-3- 1 2.16(3H, s), 2.30(3H, s), 2.96(2H, s), yl 5.22(2H, s), 6.67-7.80(7H, m) XIV-122,5-Me2-C6H3 a 1e5 1 1 mp 88-89C
1H-NMR(CDCI3) ~ppm:2.10(3H,s), XIV-132,5-Me2-C6H3 2-Furyl 1 2-26(3H, s), 5.25(2H, s), 6.55-6.67(3H, m), 6.97(1H, d, J=7.3), 7.06(1H, d, J=3.7), 7.39-7.80(5H, m) 1 H-NMR(CDCI3) ~ ppm: 2.11 (3H, s), XIV-142,5-Me2-C6H3Thiazol-2-yl 1 2.27(3H, s), 5.30(2H, s), 6.64(1H, s), 6.65(1 H, d, J=2.5), 6.98(1 H, d, J=7.9), 7.45-8.10(6H, m) 3-Me- 1 H-NMR(CDCI3) ~ ppm: 2.07(3H, s), XIV-152~5-Me2-c6H3isothiazol-5- 1 2.27(3H, s), 2.53(3H, s), 5-25(2H~ s)~
yl 6.60-7.82(8H, m) XIV-16 4-CI-2-Me-C6H3 j 5 Mel 3 1 1 mp 103-104C

No R1 R3 n Physical data 1 H-NMR(CDCI3) ~ ppm: 2.30(3H, s), 5.32(2H, s), 6.66-6.77(3H, m), XIV-173-Me-C6H4Isoxazol-3-yl 1 6.87(1H, s), 7.12(1H, t, J=7.3), 7.46-7.76(3H, m), 8.00(1 H, d, J=7.9), 8.50(1H, s) 1 H-NMR(CDCI3) ~ ppm: 2.26(3H, s), 5.30(2H, s), 6.77(2H, d, J=8.6), XIV-184-Me-C6H4Isoxazol-3-yl 1 6.86(1H, d, J=1.8), 7.04(2H, d, J=8.6), 7.45-7.98(4H, m), 8.50(1H, d, J=1 .8) XIV-192-CI-C6H4Isoxazol-3-yl 1 mp 92.0-93.0C

XIV-208-CI-C6H4Isoxazol-3-yl 1 mp 75.0-76.0C
1 H-NMR(CDCI3) ~ ppm: 5.32(2H, s), XIV-214-CI-C6H4Isoxazol-3-yl 1 6-80-6-83(2H, m), 6.86(1H, d, J=1.8), 7.19-7.22(2H, m), 7.45-8.02(4H, m), 8.52(1H, d, J=1.2) 1 H-NMR(CDCI3) ~ ppm: 5.38(2H, s), XIV-223-CF3-C6H4Isoxazol-3-yl 1 6.87(1H, d, J=1.8), 7.04-7.75(7H, m), 8.04(1H, d, J=7.9), 8.52(1H, d, J=1 .8) XIV23C6H3 Isoxazol-3-yl 1 mp 107.0-108.0C

XIV-242-Me-C6H4 s-Me- 1 mp 77.5-78.5C
1 H-NMR(CDCI3) ~ ppm: 2.30(3H, s), XIV-253-Me-C6H4 5-Me- 1 2.49(3H, s), 5.32(2H, s), 6.47(1H, d, isoxazol-3-yl J=1.2), 6.67-6.85(3H, m), 7.12(1H, t, J=7.3), 7.41-7.98(4H, m) 1 H-NMR(CDCI3) ~ ppm: 2.26(3H, s), XIV-264-Me-C6H4 s-Me- 1 2-49(3H, s), 5.30(2H, s), 6.46(1 H, s), isoxazol-3-yl 6.77-6.80(2H, m), 7.05(2H, d, J=7.9), 7.40-7.97(4H, m) No R1 R3 n Physical data XIV-27 2-CI-C6H4 isoxazol 3-yl 1 mp 93.5-94.5C

XIV-28 3-CI-C6H4 isoxazol 3-yl 1 mp 72.0-73.0C

XIV-29 4-CI-C6H4 isoxazol 3-yl 1 mp 95.0-96.0C
XIV-303-CF3{~6H4 isoxazol 3-yl 1 mp 58.5-59.5C
XIV-31 4-Ph-C6H4 isoxazol 3-yl 1 mp 116.5-117.5C

XIV-32 2-Me-C6H4 Isoxazol-5-yl 1 mp 67.5-68.5C
2,5-Me2-XIV-33 Isoxazol-5-yl 1 mp 103.5-105.0C

4-Ct-2-lVte- Isoxazol-5-yl 1 mp 109.5-111.0C

3-Me- 1 H-NMR(Ct~CI3) ~ ppm: 2.30(3H, s), XIV-35 C6H5 isoxazol-5-yl 6.76(1 H, s), 6.91(1 H, d, J=7.3), 6.99-7.51(7H, m), 7.63(1H, dd, J=7.3, 1.8) XIV-363-Me-C6H4 3-Me 1 mp 68.0-69.0C

-No R1 R3 n Physical data XIV-37 2-CI-C6H4 3-Me- 1 mp 104.0-105.0C
XIV-38 3-CI-C6H4 3-Me- 1 mp 92.5-93.5C
XIV-39 3-CF3-C6H4 3-Me- 1 mp 80.5-81.5C
4-CI-2-Me- 3-Me-XIV-40 C6H3 isoxazol-5-yl 1 mp 125.5-126.5C

XIV-41 4-Ph-C6H4 3-Me- 1 mp 127.0-128.0C

1 H-NMR(CDC13) ~ ppm: 4.01 (3H, s), XIV-42 C6H5 1-Me- 1 5-24(2H, s), 6.80-6.83(2H, m), imidazol-2-yl 6.91(1H, t, J=7.3), 7.04(1H, s), 7.18-7.81(7H, m) 1 H-NMR(CDCI3) ~ ppm: 2.13(3H, s), XIV-43 2-Me-C6H4 1-Me- 1 4.01 (3H, s), 5.25(2H, s), 6.78-6.85(2H, imidazol-2-yl m), 7.05(1H, s), 7.10(1H, d, J=7.3), 7.18(1H, s), 7.39-7.83(4H, m) 1 H-NMR(CDCI3) ~ ppm: 2.28(3H, s), XIV-44 3-Me-C6H4 1-Me- 1 4.01(3H, s), 5.21(2H, s), 6.59-6.74(3H, imidazol-2-yl m), 7.04(1 H, s), 7.09(1 H, t, J=7.9), 7.18(1H, s), 7.39-7.80(4H, m) 1 H-NMR(CDCI3) ~ ppm: 2.25(3H, s), XlV-4s 4-Me-C6H4 1-Me- 1 4.02(3H, s), 5.20(2H, s), 6.69-6.72(2H, imldazol-2-yl m), 6.99-7.02(2H, m), 7.05(1 H, s), 7.18(1H, s), 7.38-7.79(4H, m) XIV-46 2-cl-c6H4 1-Me- 1 mp 87.0-88.0C

No R1 R3 n Physical data 1 H-NMR(CDCI3) ~ ppm: 4.03(3H, s), 1-Me- 5.23(2H, s), 6.70(1H, dd, J=8.6, 1.8), XIV-473-CI-C6H4 imidazol-2-yl 1 6.82(1 H, t, J=1.8), 6.90(1 H, dd, J=7.3,1.2), 7.06(1 H, s), 7.13(1 H, t, J=7.9), 7.19(1H, d, J=1.2), 7.40-7.81(3H, m) 1 H-NMR(CDCI3) ~ ppm: 4.03(3H, s), XIV-484-CI-C6H4 1-Me- 1 5-22(2H, s), 6.73-6.78(2H, m), midazol-2-yl 7.06(1H, s), 7.13-7.59(6H, m), 7.80(1H, dd, J=7.3, 1.2) XIV-492~4-CI2-C6H3imidazol-2-yl 1 mp 141.0-142.0C
XIV-503~4-CI2-C6H3imidazol-2-yl 1 mp 78.0-79.0C

XIV-51C6H3 1-Me- 1 mp 101.0-102.0C
1 H-NMR(CDCI3) ~ ppm: 4.01 (3H, s), XIV-523-CF3-C6H4 1-Me- 1 5.28(2H, s), 6,97-7.61(9H, m), 7.80(1H, dd, J=7.9, 1.8) XIV-532-MeO-C6H4 1-Me- 1 mp 88.0-89.0C
1 H-NMR(CDCI3) ~ ppm: 3.74(3H, s), XIV-543-MeO-C6H4 1-Me- 1 4.02(3H, s), 5.21(2H, s), 6.38-6.50(3H, imidazol-2-yl m), 7.05(1H, s), 7.11(1H, t, J=7.9), 7.18(1H, s), 7.42-7.79(4H, m) 1 H-NMR(CDCI3) ~ ppm: 4.03(3H, s), XIV 554-F-C H 1 -Me- 1 5.21 (2H, s), 6.72-6.95(4H, m), - 6 4 imidazol-2-yl 7.06(1H, s), 7.18(1H, d, J=1.2), 7.42-7.80(4H, m) 1 H-NMR(CDCI3) ~ ppm: 1 .20(6H, d, XIV-563-i-Pr-C6H4 1-Me- 1 J=7.3), 2.83(1H, sept, J=7.3), 4.00(3H, imidazol-2-yl s), 5.21(2H, s), 6.60-6.80(3H, m), 7.03(1H, s), 7.11-7.79(6H, m) No R1 R3 n Physicai data 1 H-NMR(CDCI3) ~ ppm: 4.03(3H, s), XIV-574-Ph-C6H4 1-Me- 1 5.28(2H, s), 6.87-6.90(2H, m), imidazol-2-yl 7.06(1H, s), 7.19(1H, s), 7.28-7.84(11H, m) 1 H-NMR(CDCI3) ~ ppm: 2.1 7(3H, s), XIV-58C6H5 3,5-Me2- 1 2.25(3H, s), 5.1 9(2H, s), 6.78-6.82(2H, isoxazol4-yl m), 6.93(1H, t, J=7.3), 7.21-7.67(6H, m) 2,5-Me2- 3,5-Me2-XIV-59 H 1 mp 109.0-110.5C
C6 3 Isoxazol4-yl 1 H-NMR(CDCI3) ~ ppm: 2.02(3H, s), 2.32(3H, s), 3.08(1H, m), 3.53-XIV-602-Me-C6H43-Me-2-isox~7c '~ 1 3.62(1H, m), 5.33-5-46(2H, m), 5-yl 5.69(1H, dd, J=11.6, 6.7), 6.88(1H, s), 6.91(1H, s), 7.15(1H, t, J=8.5), 7.43-8.01 (4H, m) XIV-61 , 23-Me-2-isoxazolin- 1 mp 88 o-90.0C

1 H-NMR(CDCI3) ~ ppm: 2.77(3H, s), XIV-62C6H5 4-Me-1,2,3- 1 5-26(2H, s), 6.76(1H, s), 6.79(1H, d, thiadiazol-5-yl J=1.2), 6.94(1 H, t, J=7.3), 7.21-7.74(6H, m) XIV-632,5-Me2- 4-Me-1,2,3- 1 mp 98.5-99.5C
C6H3 thiadiazol-5-yl XIV-64 2-Me-c6H4 5-Me-2-isoxazoljn- 1 XIV-65C6H5 3-yl No R1 R3 n Physical data 5-Me-2-isoxazolin-XIV-66 4-CI-C6H4 3-yl 5-Me-2-isoxazolin-XIV-673-CF3-C6H4 3-yl XIV-68 C 2HMe 5-Me-2-isoxazolin- 1 XIV-694-Cl-c6H42-lsoxazolin-3-yl XIV-703-CF3-c6H42-lsoxazolin-3-yl 4-CI-2-Me-XIV-71C6H3 2-lsoxazolin-3-yl XIV-722-Me-C6H42-lsoxazolin-3-yl XIV-73C6H5 2-lsoxazolin-3-yl 0 XIV-74C6H5 Isoxazol-3-yl 0 Example 6 Synthesis of 2-(4-chlorophenoxymethyl)phenyl 1-methyl-lH-1,2,4-triazol-5-yl ketone O-methyloxime Dimethylformamide dimethylacetal (0.53 g, 4.5 mmol) was added to 2-(4-chlorophenoxymethylj-a-methoxyiminophenylacetamide (0.48 g, 1.5 mmol), and the mixture was stirred under reduced pressure (ca. 40 mmHg) at 60C for 0.5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and a mixture of methylhydrazine (0.08 g, 1.8 mmol) and acetic acid (3 ml) was added to the residue. The mixture was stirred at 90C for 1 hour. After completion of the reaction, ether (150 ml) was added, and the mixture was washed with saturated aqueous sodium bicarbonate solution (100 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(4-chlorophenoxymethyl)phenyl 1-methyl-lH-1,2,4-triazol-5-yl ketone O-methyloxime (0.31 g, 57.9%) as colorless crystals.
mp. 113-114C
1H-NMR(CDCl3) ~ppm: 4.01(3H,s), 4.08(3H,s), 4.91(2H,s), 6.67-6.70(2H,m), 7.15-7.18(2H,m), 7.26-7.54(4H,m), 7.83(1H,s).

Example 7 Synthesis of 2-(4-chlorophenoxymethyl)-N-hydroxyaminomethylene-a-methoxyiminophenylacetamide Dimethylformamide dimethylacetal (0.53 g, 4.5 mmol) was added to 2-(4-chlorophenoxymethyl)-a-methoxyiminophenylacetamide (0.48 g, 1.5 mmol), and the mixture was stirred under reduced pressure (ca. 40 mmHg) at 60C for 0.5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and a mixture of aqueous 50% hydroxylamine solution (0.20 g, 2 mmol) and acetic acid (3 ml) was added to the residue under ice-cooling. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate (150 ml) was added, and the mixture was washed with saturated aqueous sodium bicarbonate solution (100 ml) twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give 2-(4-chlorophenoxymethyl)-N-hydroxyaminomethylene-a-methoxyiminophenylacetamide (0.41 g, 75.6%) as colorless crystals.
mp. 185-186C (decomposition) 1H-NMR(CDCl3) ~ppm: 4.00(3H,s), 4.93(2H,s), 6.76-6.80(2H,m), 6.86(1H,d,J=8.5), 7.18-7.22(2H,m), 7.37-7.52(3H,m), 7.70(1H,d,J=10.4), 9.50(1H,d,J=9.8).
Synthesis of 2-(4-chlorophenoxymethyl)phenyl 1,2,4-oxadiazol-5-yl ketone O-methyloxime Dioxane (2 ml) and acetic acid (1.5 ml) were added to 2-(4-chlorophenoxymethyl)-N-hydroxyaminomethylene-~-methoxyiminophenylacetamide tO.36 g, 1 mmol), and the mixture was stirred at 120C for 4 hours. After completion of the reaction, ether (150 ml) was added, and the mixture was washed with saturated aqueous sodium bicarbonate solution (100 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(4-chlorophenoxymethyl)phenyl 1,2,4-oxadiazol-5-yl ketone O-methyloxime (0.14 g, 40.8%) as colorless crystals.
mp. 96-97.5C
lH-NMR(CDC13) ~ppm: 4.09(3H,s), 4.94(2H,s), 6.66-6.70(2H,m), 7.14-7.17(2H,m), 7.28-7.60(4H,m), 8.44(1H,s).
Example 8 Synthesis of 2-(2,5-dimethylphenoxymethyl)phenyl 3-ethyl-1,2,4-oxadiazol-5-yl ketone O-methyloxime Dichloroethane (5 ml), thionyl chloride (0.65 g, 5.5 mmol) and dimethylformamide (0.05 ml) were added to 2-(2,5-dimethylphenoxymethyl)-a-methoxyiminophenylacetic acid (1.57 g, 5 mmol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, pyridine (3 ml) and 1-hydroxyimino-1-propylamine (0.88 g, 10 mmol) were added to the residue, and the mixture was stirred under reflux for 0.5 hours. After completion of the reaction, ether (150 ml) was added, and the mixture was washed with lN hydrochloric acid (150 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl 3-ethyl-1,2,4-oxadiazol-5-yl ketone O-methyloxime (0.63 g, 34.5%) as colorless crystals.
mp. 111.5-112.5C
1H-NMR(CDCl3) ~ppm: 1.30(3H,t,J=7.3), 2.09(3H,s), 2.25(3H,s), 2.77(2H,q,J=7.3), 4.11(3H,s), 4.95(2H,s), 6.54(1H,s), 6.65(1H,d,J=7.9), 6.98(1H,d,J=7.3), 7.27-7.66(4H,m).
Example 9 2 1 8b947 Synthesis of 2-(2,5-dimethylphenoxymethyl)-a-methoxyiminophenylacetohydrazide Methanol (10 ml), THF (10 ml) and hydrazine monohydrate (1.68 g, 0.03 mol) were added to methyl 2-(2,5-dimethylphenoxymethyl)-a-methoxyiminophenylacetate (3.27 g, 0.01 mol), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water (200 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)-a-methoxyiminophenylacetohydrazide (2.93 g, 89.6%) as colorless crystals.
mp. 124.5-126C
1H-NMR(CDCl3) ~ppm: 2.18(3H,s), 2.29(3H,s), 3.88 (2H,d,J=4.3), 3.96(3H,s), 4.92(2H,s), 6.61(1H,s), 6.67 (lH,d,J=7.3), 7.01(1H,d,J=7.3), 7.21-7.59(4H,m), 7.76(lH,brs).
Synthesis of 2-(2,5-dimethylphenoxymethyl)phenyl 1,3,4-oxadiazol-2-yl ketone O-methyloxime Ethyl orthoformate (2 ml) was added to 2-(2,5-dimethylphenoxymethyl)-a-methoxyiminophenylacetohydrazide (0.49 g, 1.5 mmol), and the mixture was stirred under reflux for 4 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl 1,3,4-oxadiazol-2-yl ketone O-methyloxime (0.10 g, 19.8%) as colorless crystals.
mp. 134-135C

1H-NMR(CDCl3) ~ppm: 2.08(3H,s), 2.25(3H,s), 4.08(3H,s), 4.96(2H,s), 6.54(1H,s), 6.65(1H,d,J=7.3), 6.97(1H,d,J=7.9), 7.32-7.64(4H,m), 8.93(1H,s).
Example 10 Synthesis of a-amino-2-(4-chlorophenoxymethyl)-a-hydroxyiminoacetophenone O-methyloxime 28~ sodium methoxide/methanol solution (1.31 g, 6.8 mmol) was added to a mixture of hydroxylamine hydrochloride (0.47 g, 6.8 mmol) and methanol (10 ml) under ice-cooling over 5 minutes. Then, 2-(4-chlorophenoxymethyl)-a-methoxyiminophenylacetonitrile (1.02 g, 3.4 mmol) was added, and the mixture was stirred under reflux for 1.5 hours. After completion of the reaction, water (200 ml) was added, and the mixture was extracted with dichloromethane.

The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give a-amino-2-(4-chlorophenoxymethyl)-a-hydroxyiminoacetophenone O-methyloxime (0.87 g, 76.7%) as colorless crystals.
mp. 200C (decomposition) lH-NMR(CDCl3) ~ppm: 3.92(3H,s), 4.93(2H,s), 5.04(2H,brs), 6.79-6.87(2H,m), 7.15-7.21(3H,m), 7.33-7.52(3H,m).
Synthesis of 2-(4-chlorophenoxymethyl)phenyl 1,2,4-oxadiazol-3-yl ketone O-methyloxime Ethyl orthoformate (2 ml) was added to a-amino-2-(4-chlorophenoxymethyl)-a-hydroxyiminoacetophenone O-methyloxime (0.40 g, 1.2 mmol), and the mixture was stirred under reflux for 4 hours. After completion of the reaction, toluene (10 ml) was added, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(4-chlorophenoxymethyl)phenyl 1,2,4-oxadiazol-3-yl ketone O-methyloxime (0.36 g, 87.3%) as colorless crystals.
mp. 107-108C

1H-NMR(CDCl3) ~ppm: 4.08(3H,s), 4.96(2H,s), 6.72-6.75(2H,m), 7.14-7.18(2H,m),- 7.28-7.60(4H,m), 8.76(1H,s).
Example 11 Synthesis of 2-(4-chlorophenoxymethyl)phenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime Acetic anhydride (2 ml) was added a-amino-2-(4-chlorophenoxymethyl)-a-hydroxyiminoacetophenone O-methyloxime (0.40 g, 1.2 mmol), and the mixture was stirred under reflux for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, ether (100 ml) was added, and the mixture was washed with saturated aqueous sodium bicarbonate solution (50 ml) twice.
The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(4-chlorophenoxymethyl)phenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime (0.35 g, 81.5%) as colorless crystals.
mp. 125-126C
lH-NMR(CDC13) ~ppm: 2.65(3H,s), 4.07(3H,s), 4.96(2H,s), 6.74-6.77(2H,m), 7.15-7.1&(2H,m), 7.26-7.59(4H,m).
Example 12 Synthesis of 2-(2,5-dimethylphenoxymethyl)phenyl lH-tetrazol-5-yl ketone O-methyloxime Sodium azide (1.30 g, 20 mmol), ammonium chloride (1.07 g, 20 mmol) and dimethylformamide (10 ml) were added to 2-(2,5-dimethylphenoxymethyl) -a-methoxyiminophenylacetonitrile (0.59 g, 2 mmol), and the mixture was stirred at 115C for 9 hours. After completion of the reaction, ethyl acetate (150 ml) was added, and the mixture was washed with saturated brine (100 ml) twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl lH-tetrazol-5-yl ketone O-methyloxime (0.59 g, 87.4%) as colorless crystals.
mp. 168-170C
lH-NMR(CDC13) ~ppm: 2.00(3H,s), 2.25(3H,s), 4.05(3H,s), 4.95(2H,s), 6.52(lH,s), 6.65(lH,d,J=7.3), 6.96(1H,d,J=7.3), 7.32-7.63(4H,m).
Example 13 Synthesis of 2-(2,5-dimethylphenoxymethyl)phenyl 1-methyl-lH-tetrazol-5-yl ketone O-methyloxime and 2-(2,5-dimethylphenoxymethyl)phenyl 2-methyl-2H-tetrazol-5-yl ketone O-methyloxime Dimethylformamide (3 ml) and potassium carbonate (0.33 g, 2.4 mmol) were added to 2-(2,5-dimethylphenoxy-methyl)phenyl lH-tetrazol-5-yl ketone O-methyloxime (0.40 g, 1.2 mmol), and the mixture was stirred at room temperature for 5 minutes. Then, dimethyl sulfate (0.23 g, 1.8 mmol) was added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, ether (150 ml) was added, and the mixture was washed with brine (50 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl l-methyl-lH-tetrazol-5-yl ketone O-methyloxime as colorless crystals (0.16 g, 37.9%) [mp.
115.5-116.5C; lH-NMR(CDCl3) ~ppm: 1.97(3H,s), 2.26(3H,s), 4.06(3H,s), 4.13(3H,s), 4.89(2H,s), 6.50(lH,s), 6.65(1H,d,J=7.9), 6.97(1H,d,J=7.9), 7.34-7.58(4H,m)] and 2-(2,5-dimethylphenoxymethyl)phenyl 2-methyl-2H-tetrazol-5-yl ketone O-methyloxime as colorless crystals (0.08 g, 19.0%) [mp. 131-132C; lH-NMR(CDC13) ~ppm: 2.12(3H,s), 2.24(3H,s), 4.09(3H,s), 4.34(3H,s), 4.96(2H,s), 6.54(lH,s), 6.64(1H,d,J=7.9), 6.98(1H,d,J=7.3), 7.29-7.53(3H,m), 7.69(lH,d,J=7.3)].
Example 14 Synthesis of 2-(3-chlorophenoxymethyl)phenyl 1-methyl-2-imidazolin-2-yl ketone O-methyloxime Xylene (5 ml) and benzene (5 ml) were added to 2-(3-chlorophenoxymethyl)-~-methoxyiminophenylacetonitrile (1.0 g, 3.3 mmol), N-methylethylenediamine (740 mg, 10 mmol) and zinc acetate dihydrate (100 mg, 0.46 mmol), and the mixture was subjected to azeotropic dehydration and stirred at 140C for 18 hours. After allowing the mixture to stand for cooling, ethyl acetate was added to the reaction mixture.
The mixture was washed successively with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on activated alumina containing water (5%) (ethyl acetate/n-hexane) and column chromatography on silica gel (ethyl acetate/n-hexane) to give isomer A (720 mg, 60%, as an oil) and isomer B (220 mg, 19%, as an oil) of 2-(3-chlorophenoxymethyl)phenyl 1-methyl-2-imidazolin-2-yl ketone O-methyloxime.
Isomer A: 1H-NMR(CDC 13) ~ppm: 2.75(3H,s), 3.41(2H,t,J=9.8), 3.92(2H,t,J=9.8), 3.97(3H,s), 5.35(2H,s), 6.84(1H,ddd,J=8.0,2.4,0.9), 6.93(lH,ddd,J=8.0,1.8,0.9), 6.99(1H,dd,J=2.4,1.8), 7.19(1H,t,J=8.0), 7.32-7.44(2H,m), 7.51(1H,dd,J=7.3,1.4), 7.64(1H,d,J=7.0).
Isomer B: 1H-NMR(CDCl3) ~ppm: 3.03(3H,s), 3.38(2H,t,J=9.9), 3.77(2H,t,J=9.9), 3.97(3H,s), 4.99(2H,s), 6.83(1H,dd,J=8.5,2.5), 6.91(1H,d,J=7.8), 6.94(1H,brs), 7.16(lH,dd,J=8.3,7.8), 7.23(lH,d,J=7.6), 7.34-7.39(2H,m), 7.49(1H,d,J=6.4).
Example 15 Synthesis of 2-(3-methylphenoxymethyl)phenyl 2-oxazolin-2-yl ketone O-methyloxime Ethylene glycol (2 ml) and benzene (10 ml) were added to 2-(3-methylphenoxymethyl)-~-methoxyiminophenyl-acetonitrile (1.0 g, 3.6 mmol), 2-aminoethanol (400 mg, 6.6 mmol) and zinc acetate dihydrate (100 mg, 0.46 mmol), and the mixture was subjected to azeotropic dehydration and stirred at 100C for 20 hours. After allowing the mixture to stand for cooling, ethyl acetate was added to the reaction mixture.
The mixture was washed successively with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-(3-methylphenoxymethyl)phenyl 2-oxazolin-2-yl ketone O-methyloxime (280 mg,24%) as an oil.
lH-NMR(CDC13) ~ppm: 2.31(3H,s), 4.00(2H,t,J=9.8), 4.03(3H,s), 4.32(2H,t,J=9.8), 5.21(2H,s), 6.72-6.78(3H,m), 7.14(1H,t,J=7.6), 7.31-7.48(3H,m), 7.62(1H,d,J=7.6).
Example 16 Synthesis of 2-(2,5-dimethylphenoxymethyl)phenyl 2-thiazolin-2-yl ketone O-methyloxime 2-Aminoethanethiol hydrochloride (2.80 g, 24.6 mmol), zinc acetate dihydrate (600 mg, 2.7 mmol), toluene (12 ml) and triethylamine (3.12 g, 30.8 mmol) were added to 2-(2,5-dimethylphenoxymethyl)-a-methoxyiminophenylacetonitrile (6.00 g, 20.4 mmol), and the mixture was stirred under reflux for 14 hours. After completion of the~reaction, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 2-thiazolin-2-yl ketone O-methyloxime (5.71 g, 79.0%) as crystals.
mp. 79-82C
1H-NMR(CDCl3) ~ppm: 2.24(2.23)(3H,s), 2.29(2.28) (3H,s), 3.21(3.27)(2H,t,J=8.6), 4.07(4.02)(3H,s), 4.24(3.36) (2H,t,J=8.6), 5.11(4.93)(2H,s), 6.56-7.63(7H,m).
Example 17 Synthesis of 2-(2,5-dimethylphenoxymethyl)-a-methoxyiminophenylacetaldehyde lM diisobutylaluminum hydride/toluene solution (5.5 ml, 5.5 mmol) was added dropwise to a mixture of methyl 2-(2,5-dimethylphenoxymethyl)-a-methoxyiminophenylacetate (1.64 g, 5 mmol) and dichloromethane (15 ml) at -70C over 0.5 hours, and then the mixture was stirred at -70C to room temperature for 3 hours. Methanol (3 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitated insoluble materials were removed, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to 2-(2,5-dimethylphenoxymethyl)-~-methoxyiminophenylacetaldehyde (0.54 g, 36.3%) as a colorless oil.
1H-NMR(CDC13) ~ppm: 2.16(3H,s), 2.28(3H,s), 4.11(3H,s), 4.86(2H,s), 6.55(1H,s), 6.67(1H,d,J=7.3), 6.99-7.58(5H,m), 9.69(lH,s).
Synthesis of 2-(2,5-dimethylphenoxymethyl)phenyl oxazol-5-yl ketone O-methyloxime p-Toluenesulfonylmethylisocyanide (0.23 g, 1.2 mmol), potassium carbonate (0.18 g, 1.3 mmol) and methanol (2 ml) were added to 2-(2,5-dimethylphenoxymethyl)-~-methoxy-iminophenylacetaldehyde (0.30 g, 1 mmol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with brine (80 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxy-methyl)phenyl oxazol-5-yl ketone O-methyloxime (0.15 g, 44.6%) as colorless crystals.
mp. 90-91C
lH-NMR(CDC13) ~ppm: 2.12(3H,s), 2.24(3H,s), 4.01(3H,s), 4.96(2H,s), 6.54(1H,S), 6.65(1H,d,J=7.3), 6.88(1H,s), 6.98(1H,d,J=7.3), 7.24-7.69(4H,m), 7.94(1H,s).
Example 18 Synthesis of 2-(4-chlorobenzyloxy)phenyl 2-oxazolin-2-yl ketone o-methyloxime zinc acetate dihydrate (400 mg, 1.8 mmol), ethanolamine (975 mg, 15.9 mmol) and xylene (8 ml) were added to 2-(4-chlorobenzyloxy)-a-methoxyiminophenylacetonitrile (4.00 g, 13.3 mmol), and the mixture was stirred under reflux for 63 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was drled over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (1.31 g, 28.6~, as crystals) and isomer B (0.45 g, 9.8%, as crystals) of 2-(4-chlorobenzyloxy)phenyl 2-oxazolin-2-yl ketone O-methyloxime.
Isomer A: mp. 97-100C

lH-NMR(CDCl3) ~ppm: 3.73(2H,t,J=7.9), 3.96 (2H,t,J=7.9), 4.07(3H,s), 5.00(2H,s), 6.92-7.65(8H,m).
Isomer B: mp. 109-112C
lH-NMR(CDC13) ~ppm: 3.92(2H,t,J=9.8), 4. 02 (3H,s), 4.39(2H,t,J=9.8), 5.07(2H,s)-, 6.94-7.46(8H,m).
Synthesis of 2-hydroxyphenyl 2-oxazolin-2-yl ketone O-methyloxime Anisole (152 ml) and aluminium chloride (16.3 g, 122 mmol) were added to 2-(4-chlorobenzyloxy)phenyl 2-oxazolin-2-yl ketone O-methyloxime (19.08 g, 55.3 mmol), and the mixture was stirred under ice-cooling for 1. 5 hours.
After completion of the reaction, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-hydroxyphenyl 2-oxazolin-2-yl ketone O-methyloxime (6.82 g, 56%) as an oil.
lH-NMR(CDCl3) ~ppm: 4. 07(3H,s), 4. 15(2H, t, J=9.5), 4. 50(2H,t,J=9.5), 6.85-7.35(5H,m).
Synthesis of 2-(5-trifluoromethyl 2-pyridyloxy)-phenyl 2-oxazolin-2-yl ketone O-methyloxime DMF (2.2 ml), potassium carbonate (210 mg, 1.5 mmol) and 2-chloro-5-trifluoromethylpyridine (220 mg, 1.2 mmol) were added to 2-hydroxyphenyl 2-oxazolin-2-yl ketone O-methyloxime (220 mg, 1.0 mmol), and the mixture was stirred at 100C for 2.5 hours. After completion of the reaction, lN
NaOH (100 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(5-trifluoromethyl-2-pyridyloxy)phenyl 2-oxazolin-2-yl ketone O-methyloxime (190 mg, 52.1%) as an oil.
1H-NMR(CDC13) ~ppm: 3.78(2H,t,J=9.8), 3.98(3H,s), 4.16(2H,t,J=9.8), 6.94-7.87(6H,m), 8.43(1H,brs).
Isomer A: mp. 97-100C
lH-NMR(CDCl 3) ~ppm: 3.73(2H,t,J=7.9), 3.96 (2H,t,J=7.9), 4.07(3H,s), 5.00(2H,s), 6.92-7.65(8H,m).
Isomer B: mp. 109-112C
1H-NMR(CDCl3) ~ppm: 3.92(2H,t,J=9.8), 4.02(3H,s), 4.39(2H,t,J=9.8), 5.07(2H,s), 6.94-7.46(8H,m).
Synthesis of 2-hydroxyphenyl 2-oxazolin-2-yl ketone O-methyloxime Anisole (152 ml) and aluminium chloride (16.3 g, 122 mmol) were added to 2-(4-chlorobenzyloxy)phenyl 2-oxazolin-2-yl ketone O-methyloxime (19.08 g, 55.3 mmol), and the mixture was stirred under ice-cooling for 1.5 hours.
After completion of the reaction, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-hydroxyphenyl 2-oxazolin-2-yl ketone O-methyloxime (6.82 g, 56.0%) as an oil.
lH-NMR(CDCl3) ~ppm: 4.07(3H,s), 4.15(2H,t,J=9.5), 4.50(2H,t,J=9.5), 6.85-7.35(5H,m).
Synthesis of 2-(5-trifluoromethyl-2-pyridyloxy)-phenyl 2-oxazolin-2-yl ketone O-methyloxime DMF (2.2 ml), potassium carbonate (210 mg, 1.5 mmol) and 2-chloro-5-trifluoromethylpyridine (220 mg, 1.2 mmol) were added to 2-hydroxyphenyl 2-oxazolin-2-yl ketone O-methyloxime (220 mg, 1.0 mmol), and the mixture was stirred at 100C for 2.5 hours. After completion of the reaction, lN
NaOH (100 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(5-trifluoromethyl-2-pyridyloxy)phenyl 2-oxazolin-2-yl ketone O-methyloxime (190 mg, 52.1%) as an oil.
lH-NMR(CDCl3) ~ppm: 3.78(2H,t,J=9.8), 3.98(3H,s), 4.16(2H,t,J=9.8), 6.94-7.87(6H,m), 8.43(lH,brs).
Example 19 Synthesis of 5-chloro-2-(4-chlorobenzyloxy)-a-methoxyiminophenylacetonitrile Dimethyl sulfoxide (3 ml) and 95% sodium cyanide (0.31 g, 6 mmol) were added to 5-chloro-2-(4-chlorobenzyloxy)-~-methoxyiminobenzyl chloride (1.03 g, 3 mmol), and the mixture was stirred at 100C for 4 hours.
After completion of the reaction, ethyl acetate (150 ml) was added, and the mixture was washed with saturated brine (100 ml) twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 5-chloro-2-(4-chlorobenzyloxy)-~-methoxyiminophenylacetonitrile (0.92 g, 91.5%) as crystals.
1H-NMR(CDCl3) ~ppm: 4.20(3H,s), 5.15(2H,s), 6.90-7.41(6H,m), 7.52(1H,d,J=2.4).
Synthesis of 5-chloro-2-(4-chlorobenzyloxy)phenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime 28% sodium methoxide/methanol solution (1.04 g, 5.4 mmol) was added to a mixture of hydroxylamine hydrochloride (0.38 g, 5.4 mmol) and methanol (6 ml) under ice-cooling over 5 minutes. Then, 5-chloro-2-(4-chlorobenzyloxy)-~-methoxyiminophenylacetonitrile (0.91 g, 2.7 mmol) was added, and the mixture was stirred under reflux for 1.5 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a-amino-5-chloro-2-(4-chlorobenzyloxy)-o~-hydroxyiminoacetophenone O-methyloxime as a crude product.
Acetic anhydride (2 ml) was added to the crude product, and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, ethyl acetate (100 ml) was added, and the mixture was washed with saturated aqueous sodium bicarbonate solution (80 ml) twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 5-chloro-2-(4-chlorobenzyloxy)phenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime (0.35 g, 33.0%) as colorless crystals.
mp. 127-128.5C

1H-NMR(CDC13) ~ppm: 2.38(3H,s), 4.12(3H,s), 4.85(2H,s), 6.84-7.61(7H,m).
Synthesis of 5-chloro-2-hydroxyphenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime Aluminium chloride (0.27 g, 2 mmol) was added to a mixture of 5-chloro-2-(4-chlorobenzyloxy)phenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime (0.39 g, 1 mmol) and anisole (3 ml) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, aqueous sodium bicarbonate solution (100 ml) was added, and the mixture was extracted with ethyl acetate.
The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 5-chloro-2-hydroxyphenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime (0.22 g, 82.2%) as colorless crystals. A part of the crystals was recrystallized from ether/n-hexane to give crystals (mp. 92-93.5C).
lH-NMR(CDC13) ~ppm: 2.75(3H,s), 4.06(3H,s), 6.82-7.27(3H,m), 10.22(1H,s).
Synthesis of 5-chloro-2-(5-trifluoromethyl-2-pyridyloxy)phenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime Dimethylformamide (1 ml), potassium carbonate (0.10 g, 0.74 mmol) and 5-trifluoromethyl-2-chloropyridine (0.10 g, 0.56 mmol) were added to 5-chloro-2-hydroxyphenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime (0.10 g, 0.37 mmol), and the mixture was stirred at 110C for 2 hours.

After completion of the reaction, ether (100 ml) was added, and the mixture was washed with saturated brine (80 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 5-chloro-2-(5-trifluoromethyl-2-pyridyloxy)phenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime (0.14 g, 91.7%) as a colorless oil.
lH-MMR(CDCl3) ~ppm: 2.46(3H,s), 4.03(3H,s), 6.77(1H,d,J=9.2), 7.16(1H,d,J=9.2), 7.44-7.86(3H,m), 8.36(lH,d,J=1.8).
Example 20 Synthesis of 2-(2,5-dimethylphenoxymethyl)-a-methoxyiminophenylacetonitrile Dimethyl sulfoxide (2 ml) and 95% sodium cyanide (0.21 g, 0.004 mol) were added to 2-(2,5-dimethylphenoxy-methyl)-a-methoxyiminobenzyl chloride (0.60 g, 0.002 mol), and the mixture was stirred at 110C for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with water twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)-a-methoxyiminophenylacetonitrile (0.45 g, 76.4%) as colorless crystals.
lH-NMR(CDCl3) ~ppm: 2.24(s,3H), 2.30(s,3H), 4.13(s,3H), 5.26(s,2H), 6.62-7.76(m,7H).
Example 21 Synthesis 2-(4-chlorophenoxymethyl)-a-methoxyiminophenylacetonitrile Trifluoroacetic anhydride (3.15 g, 15 mmol) was added to a mixture of 2-(4-chlorophenoxymethyl)-a-methoxy-iminophenylacetamide (1.19 g, 6 mmol) and pyridine (12 ml) under ice-cooling over 20 minutes, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, ether (150 ml) was added, and the mixture was washed with lN hydrochloric acid (150 ml), water (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(4-chlorophenoxymethyl) -a-methoxyiminophenylacetonitrile (1.57 g, 87.0%) as colorless crystals.
mp. 69-71C

lH-NMR(CDC13) ~ppm: 4.02(3H,s), 4.99(2H,s), 6.86-6.89(2H,m), 7.23-7.26(2H,m), 7.36-7.56(4H,m).
Example 22 Synthesis of a-methoxyimino-2-methylphenyl-acetonitrile 85% potassium hydroxide (4.0 g, 61 mmol) and 2-methylphenylacetonitrile (6.6 g, 50 mmol) were added to toluene (33 ml), and the mixture was ice-cooled. Methanol (6.6 ml) was added dropwise, and then butyl nitrite (7.0 ml, 60 mmol) was added dropwise while maintaining the temperature of the mixture at 25 to 35C. The resulting mixture was stirred under ice-cooling for 3 hours. After allowing the mixture to stand at room temperature overnight, water was added to the reaction mixture, and the resulting potassium salt of ~-hydroxyimino-2-methylphenylacetonitrile was extracted. Water was added to the extract to a volume of 100 ml. Toluene (50 ml) and tetrabutylammonium bromide (800 mg, 2.5 mmol) were added, and dimethyl sulfate (5.7 ml, 60 mmol) was added under ice-cooling in 4 divided portions. The mixture was stirred at room temperature for additional 30 minutes, and then the organic layer was separated, washed successively with aqueous lN sodium hydroxide solution and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give two geometrical isomers A (6.0 g, 69%, as an oil) and B (1.2 g, 14%, as an oil) of a-methoxyimino-2-methylphenylacetonitrile.
Isomer A: 1H-NMR(CDCl3) ~ppm: 2.51(3H,s), 4.20 (3H,s), 7.25-7.36(3H,m), 7.54(1H,d,J=7.9).
Isomer B: 1H-NMR(CDCl3) ~ppm: 2.31(3H,s), 4.06 (3H,s), 7.25-7.39(4H,m).
Synthesis of 2-bromomethyl-a-methoxyiminophenyl-acetonitrile Benzene (80 ml) was added to a-methoxyimino-2-methylphenylacetonitrile (isomer A)(4.0 g, 23 mmol) and N-bromosuccinimide (4.9 g, 28 mmol), and the mixture was heated under reflux for 1 hour in the presence of azobisiso-butyronitrile (190 mg, 1.2 mmol) as a radical initiator.
After allowing the mixture to stand for cooling, n-hexane (100 ml) was added, and the mixture was allowed to stand overnight, and the resulting insoluble materials were filtered off. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-bromomethyl-a-methoxyiminophenyl-acetonitrile (4.4 g, 76%) as an oil.

lH-NMR(CDC13) ~ppm: 4.30(3H,s), 4.79(2H,s), 7.42-7.50(3H,m), 7.66-7.69(lH,m).
Synthesis of 2-(3-chlorophenoxymethyl)-a-methoxy-iminophenylacetonitrile 2-Bromomethyl-~-methoxyiminophenylacetonitrile (5.0 g, 20 mmol) and 3-chlorophenol (3.0 g, 23 mmol) were dissolved in dimethylformamide (25 ml), and the mixture was stirred at room temperature for 2 hours in the presence of potassium carbonate (3.3 g, 24 mmol). After completion of the reaction, diethyl ether (ca. 100 ml) was added to the reaction mixture, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) and crystallized from diethyl ether/n-hexane to give 2-(3-chlorophenoxymethyl)-~-methoxyiminophenylacetonitrile (3.7 g, 62%) as colorless crystals.
mp. 62-63C
lH-NMR(CDCl3) ~ppm: 4.11(3H,s), 5.25(2H,s), 6.82(1H,d,J=8.3), 6.95-6.97(2H,m), 7.21(1H,t,J=8.3), 7.45-7.53(2H,m), 7.67(1H,d,J=7.3), 7.75(1H,dd,J=7.3,1.5).
Example 23 Synthesis of 1-bromo-2-(2-tetrahydropyranyloxy-methyl)benzene Pyridinium p-toluenesulfonate (0.30 g, 0.0012 mol) was added to a solution of 2-bromobenzylalcohol (25 g, 0.134 mol) in dichloromethane (100 ml), and thé mixture was stirred at room temperature. 3,4-Dihydro-2H-pyran (16.86 g, 0.20 mol) was added thereto. The mixture was stirred at room temperature for 2 hours. Then, saturated aqueous sodium bicarbonate solution (200 ml) was added, and the mixture was extracted with dichloromethane (200 ml). After drying over anhydrous magnesium sulfate, the solvent was evaporated to give the desired 1-bromo-2-(2-tetrahydropyranyloxymethyl)-benzene (36.00 g, yield: 99.3%) as an oil.
lH-NMR(CDC13) ~ppm: 1.45-1.80(6H,m), 3.45-3.55(1H,m), 3.80-3.90(1H,m), 4.52(1H,d,J=15.0), 4.80(1H,m), 4.90(1H,d,J=15.0), 7.16(1H,t,J=7.3), 7.31(1H,t,J=7.3), 7.51(1H,d,J=7.3), 7.54(1H,d,J-7.3).
Example 24 Synthesis of 2-(2-tetrahydropyranyloxymethyl)phenyl 3-methylisoxazol-5-yl ketone Magnesium (0.73 g, 0.03 mol) and bromoethane (0.2 ml) were added to a mixture of 1-bromo-2-(2-tetrahydro-pyranyloxymethyl)benzene (5.42 g, 0.02 mol) and THF (50 ml) under an atmosphere of nitrogen gas, and the resulting mixture was stirred at 50 to 60C for 1 hour to prepare Grignard reagent. The Grignard reagent was added dropwise to a mixture of N-methoxy-3, N-dimethyl-5-isoxazolcarboxamide (3.40 g, 0.02 mol) and THF (40 ml). The mixture was stirred at -60C to room temperature for 1 hour, water (200 ml) was added, and the mixture was extracted with ether (200 ml).
The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purifi-ed by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2-tetrahydropyranyloxymethyl)phenyl 3-methylisoxazol-5-yl ketone (4.09 g, yield: 67.9%) as a colorless oil.
1H-NMR(CDCl3) ~ppm: 1.41-1.74(6H,m), 2.39(3H,s), 3.45-3.51(1H,m), 3.75-3.83(1H,m), 4.59-4.60(1H,m), 4.71(lH,d,J=12.8), 4.94(lH,d,J=12.8), 6.69(lH,s), 7.38-7.63(4H,m).
Example 25 Synthesis of 2-hydroxymethylphenyl 3-methylisoxazol-5-yl ketone O-methyloxime Methanol (25 ml), methoxyamine hydrochloride (2.17 g, 0.026 mol) and pyridine (2.1 ml, 0.026 mol) were added to 2-(2-tetrahydropyranyloxymethyl)phenyl 3-methylisoxazol-5-yl ketone (4.09 g, 0.013 mol), and the mixture was stirred under reflux for 3 hours. After completion of the reaction, half-saturated brine (200 ml) was added, and the mixture was extracted with dichloromethane (100 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A
(0.63 g, yield: 19.7%, as a colorless oil) and isomer B (1.62 g, yield: 50.7%, as a colorless oil) of 2-hydroxymethylphenyl 3-methylisoxazol-5-yl ketone O-methyloxime.
Isomer A: lH-NMR(CDC13) ~ppm: 2.39(3H,s), 2.74(1H,t,J=6.7), 4.17(3H,s), 4.54(2H,d,J=6.7), 7.02(1H,s), 7.33-7.55(4H,m).
Isomer B: lH-NMR(CDC13) ~ppm: 1.89(1H,t,J=6.1), 2.28(3H,s), 4.03(3H,s), 4.52(2H,d,J=6.1), 6.05(1H,S), 7.17-7.62(4H,m).
Example 26 Synthesis of 2-(3-chloro-5-trifluoromethyl-2-pyridyloxymethyl)phenyl 3-methylisoxazol-5-yl ketone O-methyloxime THF (7.5 ml), 2,3-dichloro-5-trifluoromethylpyridine (0.81 g, 3.75 mmol) and 60% sodium hydride (0.12 g, 3.0 mmol) were added to 2-`
hydroxymethylphenyl 3-methylisoxazol-5-yl ketone O-methyloxime (0.62 g, 2.5 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ether (150 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A
(0.29 g, yield: 27.2%) and isomer B (0.76 g, yield: 71.4%) of 2-(3-chloro-5-trifluoromethyl-2-pyridyloxymethyl)phenyl 3-methylisoxazol-5-yl ketone o-methyloxime.
Isomer A: mp. 77-79C, lH-NMR(CDC13) ~ppm:

2.37(3H,s), 4.14(3H,s), 5.45(2H,s), 6.97(lH,s), 7.36-7.63(4H,m), 7.79(1H,d,J=2.4), 8.09(1H,d,J=2;4).
Isomer B: 1H-NMR(CDCl3) ~ppm: 2.28(3H,s), 4.04(3H,s), 5.33(2H,s), 6.01(1H,s), 7.20-7.65(4H,m), 7.80(1H,d,J=2.2), 8.08(1H,d,J=2.2).
Example 27 Synthesis of 2-(2,5-dimethylphenoxymethyl)phenyl thiazolidin-2-yl ketone O-methyloxime Toluene (3 ml), butanol (3 ml), cysteamine hydrochloride (0.34 g, 3.0 mmol) and triethylamine (0.42 ml, 3 mmol) were added to 2-(2,5-dimethylphenoxymethyl)-~-methoxyiminophenylacetoaldehyde (0.45 g, 1.5 mmol), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, half-saturated brine (100 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl thiazolidin-2-yl ketone O-methyloxime (0.49 g, yield 91.6%) as a colorless oil.
1H-NMR(CDC13) ~ppm: 2.28(6H,s), 2.40(1H,brs), 2.81-3.06(3H,m), 3.38-3.55(lH,m), 3.87(3H,s), 4.85-5.50(3H,m), 6.67-7.64(7H,m).
Example 28 Synthesls of 2-(2,5-dimethylphenoxymethyl)phenyl 1,3-dioxolan-2-yl ketone O-methyloxime Benzene (4 ml), ethylene glycol (0.12 g, 2.0 mmol) and p-toluenesulfonic acid monohydrate (0.01 g, 0.05 mmol) were added to 2-(2,5-dimethylphenoxymethyl)-~-methoxyiminophenylacetaldehyde (0.3 g, 1.0 mmol), and the mixture was subjected to azeotropic dehydration for 2 hours.
After completion of the reaction, half-saturated brine (100 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 1,3-dioxolan-2-yl ketone O-- methyloxime (0.30 g, yield 87.9%) as colorless crystals. mp 136-137C.

lH-NMR(CDC13) ~ppm: 2.28(3H,m), 2.29(3H,s), 3.59-3.85(4H,m), 3.92(3H,s), 5.04(lH,s), 5.09(lH,s), 5.63(lH,s), 6.66-7.62(7H,m).
Example 29 Synthesis of 1-bromo-2-(1-ethoxyethyl)oxymethyl-benzene Pyridinium p-toluenesulfonate (0.50 g, 0.002 mol) was added to a mixture of 2-bromobenzylalcohol (18.70 g, 0.1 mol), dichloromethane (150 ml) and ethyl vinyl ether (14.42 g, 0.2 mol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, half-saturated aqueous sodium bicarbonate solution (300 ml) was added, and the mixture was extracted with dichloromethane (100 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1-bromo-2-(1-ethoxyethyl)oxymethylbenzene (25.44 g, yield: 98.2%) as a colorless oil.
1H-NMR(CDCl3) ~ppm: 1.22(3H,t,J=7.3), 1.41 (3H,t,J=5.5), 3.49-3.77(2H,m), 4.59(1H,d,J=12.8), 4.70 (lH,d,J=12.8), 4.87(1H,q,J=5.5), 7.11-7.55(4H,m).
Example 30 Synthesis of 2-(1-ethoxyethyl)oxymethylphenyl 5-methylisoxazol-3-yl ketone A mixture of 1-bromo-2-(1-ethoxyethyl)oxymethyl-benzene (12.96 g, 0.05 mol) and THF (45 ml) was added to a mixture of magnesium (1.82 g, 0.075 mol) and bromoethane (0.2 ml) and THF (5 ml) at 45 to 55C under an atmosphere of nitrogen gas, and the resulting mixture was stirred at 50 to 55C for 1 hour to prepare a Grignard reagent. The Grignard reagent was added dropwise to a mixture of N-methoxy-5, N-dimethyl-3-isoxazolcarboxamide (5.62 g, 0.033 mol) and THF
(40 ml) cooled to -50C. The mixture was stirred at -60C to room temperature for 1 hour, water (200 ml) was added, and the mixture was extracted with ether (200 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(1-ethoxyethyl)oxymethylphenyl 5-methylisoxazol-3-yl ketone (8.61 g, yield: 90.2%) as a colorless oil.
lH-NMR(CDC13) ~ppm: 1.16(3H,t,J=6.7), 1.27 (3H,d,J=5.5), 2.52(3H,s), 3.43-3.65(2H,m), 4.68-4.92(3H,m), 6.50l1H,s), 7.36-7.84(4H,m).
Example 31 - Synthesis of 2-(1-ethoxyethyl)oxymethylphenyl 5-methylisoxazol-3-yl ketone O-methyloxime 2-(1-Ethoxyethyl)oxymethylphenyl 5-methylisoxazol-3-yl ketone (4.34 g, 0.015 mol) was added to a mixture of methanol (30 ml), methoxyamine hydrochloride (2.51 g, 0.03 mol) and 28% sodium methylate / methanol solution (7.23 g, 0.0375 mol), and the mixture was stirred under reflux for 3 hours. After completion of the reaction, half-saturated brine (200 ml) was added, and the mixture was extracted with dichloromethane (100 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(1-ethoxyethyl)oxymethylphenyl 5-methylisoxazol-3-yl ketone O-methyloxime (4.32 g, yield: 90.5%) as a colorless oil.
lH-NMR(CDCl3) ~ppm: 1.11-1.26(6H,m), 2.47(2.43) (3H,s), 3.39-3.60(2H,m), 4.08(3.97)(3H,s), 4.11-4.70(3H,m), 6.61(6.37)(lH,s), 7.19-7.56(4H,m).
Example 32 Synthesis of 2-hydroxymethylphenyl 5-methylisoxazol-3-yl ketone O-methyloxime Methanol (26 ml) and pyridinium p-toluene-sulfonate (0.33 g, 0.0013 mol) were added to 2-(1-ethoxyethyl)oxymethylphenyl 5-methylisoxazol-3-yl ketone O-methyloxime (4.14 g, 0.013 mol), and the mixture was stirred under reflux for 0.5 hour. After completion of the reaction, half-saturated brine (300 ml) was added, and the mixture was extracted with dichloromethane (100 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-hydroxymethylphenyl 5-methylisoxazol-3-yl ketone O-methyloxime (2.95 g, yield: 92.1%) as a colorless oil.
lH-NMR(CDC13) ~ppm: 2.43(3.18)(lH,t,J=6.7), 2.44(2.50)(3H,s), 3.99(4.11)(3H,s), 4.47(4.57)(2H,d,J=6.7), 6.44(6.62)(lH,s), 7.19-7.60(4H,m).
Example 33 Synthesis of 2-(5-chloro-3-trifluoromethyl-2-pyridyloxymethyl)phenyl 5-methylisoxazol-3-yl ketone O-methyloxime THF (3 ml), 2,5-dichloro-3-trifluoromethylpyridine (0.32 g, 1.5 mmol) and 60% sodium hydride (0.05 g, 1.2 mmol) were added to 2-hydroxymethylphenyl 5-methylisoxazol-3-yl ketone O-methyloxime (0.25 g, 1.0 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight.
Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ether (150 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(5-chloro-3-trifluoromethyl-2-pyridyloxymethyl)phenyl 5-methylisoxazol-3-yl ketone O-methyloxime (0.41 g, yield: 96.3%) as colorless crystals.
mp. 120-121C (ether/n-hexane) lH-NMR(CDC13) ~ppm: 2.45(3H,s), 3.99(3H,s), 5.34 (2H,s), 6.39(1H,s), 7.23-7.64(2H,m), 7.79(1H,d,J=2.5), 8.06(lH,d,J=2.5).
Example 34 Synthesis of 2-chloromethylphenyl 3-methylisoxazol-5-yl ketone O-methyloxime Benzene (5 ml) and thionyl chloride (0.36 g, 3.0 mmol) were added to 2-hydroxymethylphenyl 3-methylisoxazol-5-yl ketone O-methyloxime (0.62 g, 2.5 mmol), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-chloro-methylphenyl 3-methylisoxazol-5-yl ketone O-methyloxime (0.26 g, yield: 39.3%) as a colorless oil.
lH-NMR(CDCl3) ~ppm: 2.29(3H,s), 4.04(3H,s), 4.47 (2H,s), 6.05(1H,s), 7.18-7.60(4H,m).
Example 35 Synthesis of 2-(3,4-dichloro-~-methylbenzylidene-aminooxymethyl)phenyl 3-methylisoxazol-5-yl ketone O-methyloxime DMF (3 ml), 3,4-dichloroacetophenone oxime (0.31 g, 1.5 mmol) and potassium carbonate (0.28 g, 2.0 mmol) were added to 2-chloromethylphenyl 3-methylisoxazol-5-yl ketone O-methyloxime (0.26 g, 1.0 mmol), and the mixture was stirred at 60C for 2 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ether (150 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(3,4-dichloro-a-methylbenzylideneaminooxymethyl)phenyl 3-methylisoxazol-5-yl ketone O-methyloxime (0.37 g, yield: 85.6%) as colorless crystals.
lH-NMR(CDCl3) ~ppm: 2.01(3H,s), 2.21(3H,s), 4.04 (3H,s), 5.13(2H,s), 5.96(1H,s), 7.20-7.64(7H,m). mp. 84-85C.
Example 36 Synthesis of 2-[(a-methyl-3-trifluoromethyl-benzylidene)aminooxy]-a-methoxyiminophenylacetaldehyde lM diisobutylaluminum hydride / toluene solution (11 ml, 16.5 mmol) was added dropwise to a mixture of methyl 2-[(a-methyl-3-trifluoromethylbenzylidene)aminooxy]-a-methoxyiminophenylacetate (4.83 g, 11.8 mmol) and dichloromethane (47 ml) at -65C or lower over 4 minutes, and the mixture was stirred at -78C to room temperature for 3 hours. Methanol (7 ml ) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour.

The precipitated insoluble materials were removed, and the remaining mixture was concentrated under reduced pressure.
The residue was purified by silica gel chromatography ~ethyl acetate/n-hexane) to give 2-[(a-methyl-3-trifluoromethylbenzylidene)aminooxy]-a-methoxyiminophenylacetaldehyde (2.11 g, 47.3%) as a colorless oil.
lH-NMR(CDC13) ~ppm: 2.19(3H,s), 4.11(3H,s), 5.09 (2H,s), 7.09-7.12(1H,m), 7.36-7.52(4H,m), 7.59(1H,d,J=7.9), 7.77(lH,d,J=7.9), 7.85(lH,s), 9.70(1H,s).
Example 37 Synthesis of 2-[(a-methyl-3-trifluoromethyl-benzylidene)aminooxy]phenyl thiazolidin-2-yl ketone O-methyloxime Toluene (2.5 ml), butanol (2.5 ml), cysteamine hydrochloride (0.29 g, 2.54 mmol) and triethylamine (0.26 g, 2.54 mmol) were added to 2-[(a-methyl-3-trifluoromethyl-benzylidene)aminooxy]-a-methoxyiminophenylacetaldehyde (0.48 g, 1.27 mmol), and the mixture was stirred at room -20 temperature for 1 hour. After completion of the reaction, half-saturated brine (100 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[(a-methyl-3-trifluoromethylbenzylidene)aminooxy]phenyl thiazolidin-2-yl ketone O-methyloxime (0.52 g, yield 93.6%) as a colorless oil.
lH-NMR(CDC13) ~ppm: 2.39(3H,s), 2.75-3.10(3H,m), 3.50(2H,m), 3.86(3H,s), 5.20-5.30(2H,m), 5.45(lH,m), 7.37-7.61(6H,m), 7.82(1H,d,J=7.9), 7.91(1H,s).
According to the same manner as that in Examples 24 and 30, various compounds of the formula (XLVIII), which are intermediates for production of the compound (I), were synthesized. The compounds thus obtained and their physical data are as follows. In the following tables, the physical data of the compounds (XLVIII-7) and (XLVIII-4) obtained in Examples 24 and 30, respectively, are also listed.

No R3 R4 P Physical data XLVI11-1 Isoxazol-3-yl H Tetrahydropyranyl 1 H-NMR(CDCI3) ~ ppm :1 .1 6(3H, t, J=7.3), 1.26(3H, d, J=5.5), 3.40-XLVI11-2 Isoxazol-3-yl H1-C2H5OC2H4 3.6s(2H, m), 4.70-4.93(3H, m), 6.89(1H, d, J=1.8), 7.37-7.87(4H, m), 8.53(1H, J=1.8) XLV111-3 isoxazol 3 yl H Tetrahydropyranyl 1 H-NMR(CDCI3) ~ ppm :1 .16(3H, t, XLVI11-4 . H1-C2H5OC2H4 J=6-7), 1.27(3H, d, J=5.5), 2.52(3H, soxazol-3-yl s), 3.43-3.65(2H, m), 4.68-4.92(3H, m), 6.50(1H, s), 7.36-7.84(4H, m).
XLVI11-5 Isoxazol-5-yl H Tetrahydropyranyl XLV111-6 Isoxazol-5-yl H1-C2H5OC2H4 1 H-NMR(CDCI3) ~ ppm :1.41-1.74 (6H, m), 2.39(3H, s), 3.45-3.51 (1 H, XLV111-7 j 3MIe-5 I HTetrahydropyranyl m), 375-383 (1H, m), 459-4.60 (1H, d, J=12.8), 6.69(1H, s), 7.38-7.63(4H, m).
1H-NMR(CDC13) ~ppm :1.16(3H, t, XLV111-8 . H1-C2H5OC2H4 J=7 3), 1.25(3H, d, J=5.5), 2.40(3H, soxazol-5-yl s), 3.42-3.61 (2H, m), 4.68-4.88(3H, m), 6.70(1 H, s), 7.37-7.66(4H, m) 9 Oxadiazo;2-yl H Tetrahydropyranyl XLVI11-10 Oxadiazol 2 yl H 1-c2H5oc2H4 No R3 R4 P Physical data XLVIll 11 1-Me-irnidazol- H Tetrahydropyranyl XLVIll 121-Me-irnidazol- H1-C2HsOc2H4 XLVIII 13 2-lS9Y~ -~ ,-3-Tetrahydropyranyl XLVlll-142-l5Xazolin-3- H1-C2HsOc2H4 XLV111-15 isoY~ -~ 3 yl H Tetrahydropyranyl XLVIII 165-Me-2- H1-C2H5OC2H4 Isoxazolin-3-yl XLV111-172-Furyl HTetrahydropyranyl XLV111-182-Furyl H1-C2H5OC2H4 XLV111-19oY~ 7l 3 yl HTetrahydropyranyl XLVIII 205-Me-1,2,4- H1-C2HsOc2H4 According to the same manner as that in Examples described above, various compounds of the formula (I) were synthesized. The compounds thus obtained and their physical data are as follows. In the following tables, the physical data of the compounds obtained in the above Examples are also listed. ~'No." represents a compound number. When the product is obtained as a mixture of isomers A/B, the ~ values of either isomer are indicated in the parentheses.
The basic structures of the compound (I) in the tables are as follows:

I Rl I R1 ~2)n R4~OHN)~OMe Comp. No. 1~2100 Comp. No. 2101~2320 R1Q~R9 Il 2 0 O~
~XN~OMe Comp. No. 2321~3140 No R1 R2 R3 n Physical data C6H5 MeImidazol-1-yl 1 mp 66-67.5C

2 2-F-C6H4 MeIllld- :11-yl 3 3-F-C6H4 MeImidazol-1-yl 4 4-F-C6H4 Me Imidazol-1-yl 5 2-CI-C6H4 Mellll:'- -'1-yl 1 mp 79.5-80.5C

6 8-CI-C6H4 MeImidazol-1-yl 1 mp 96.5-97.5C

7 4-CI-C6H4 MeImidazol-1-yl 1 mp 88-88.5 C

8 2-Br-c6H4 Me Imidazol-1-yl 9 3-Br-C6H4 Me llll:'---' 1-yl 10 4-Br-C6H4 Me Imidazol-1-yl No R1 R2 R3 n Physical data 113-l-C6H4 Me Imidazol-1-yl 124-l-C6H4 Me l~ -'1-yl 'H-NMR(CDCI3)~ ppm:
132-Me-C6H4 Me 4 98(2H s) 6.68-7.66(10H, m), 7.96(1H,s) 14 3-Me-C6H4 Me Imidazol-1-yl 154-Me-C6H4 Me Imidazol-1-yl 1 mp 58-65C
'H-NMR(CDCI3)~ ppm:
1.16(3H,t,J=7.3),2.60(2H,q, 162-Et-C6H4 Me llll:' -11-yl 1 J=7.3),3.99(3H,s),4.98(2H, s),6.69-7.67(10H, m), 7.96(1H,s) 173-Et-C6H4 Me Imidazol-1-yl 18 4-Et-C6H4 Me Imidazol-1-yl 19 2-MeO-C6H4 Me Imidazol-1-yl 20 3-MeO-C6H4 Me Imidazol-1-yl No R1 R2 R3 n Physical data 214-MeO-C6H4 MeImidazol-1-yl 222-CF3-C6H4 MeIr" 1~ ~' 1-yl 233-CF3-C6H4 MeImidazol-1-yl 244-CF3-C6H4 MeImidazol-1-yl 252~3-F2-C6H3 MeImidazol-1-yl 262~4-F2-C6H3 MeImidazol-1-yl 272,5-F2~6H3 MeImidazol-1-yl 282~6-F2-C6H3 MeImidazol-1-yl 293~4-F2-C6H3 MeImidazol-1-yl 303,5-F2~6H3 MeImidazol-1-yl No R1 R2 R3 nPhysical data 312,3-CI2-C6H3 Melll,. ~c,11-yl 322,4-CI2-C6H3 MeImidazol-1-yl 332,5-CI2-C6H3 MeIm~ -'1-yl 342~6-CI2-C6H3 MeIlll'-zc'1-yl 353,4-CI2-C6H3 MeImidazol-1-yl 363,5-CI2-C6H3 MeIll,'-~c,11 yl 372,3-Me2-C6H3 MeImidazol-1-yl 382,4-Me2-C6H3 MeImidazol-1-yl 1H-NMR(CDCI3) ~ ppm:
2.11(3H,s),2.26(3H,s), 392,5-Me2-C6H3 MeImidazol 1 yl 13 99(3H s) 4 96(2H,s)~
J=7.3),6.98-7.66(7H, m), 7.96(1H,s) 1H-NMR(CDCI3) ~ ppm:
402,6-Me2-C6H3 MeImidazol-1 -yl 12 17(6H s) 4 01(3H,s)~
8.04(1H,s) No R1 R2 R3 n Physical data 413,4-Me2-C6H3 MeImidazol-1-yl 423,5-Me2-C6H3 MeIllm'--~l 1-yl 432-CI- 4-Me-C6H3 MeImidazol-1-yl 442-CI-5-Me-C6H3 Mellll '---11-yl 454-Cl-2-Me-c6H3 MeImidazol-1-yl 464-CI- 3-Me-C6H3 MeImidazol-1-yl 472.3.5-Me3-C6H2 Mellll~ 11-yl 48 3-Ph-C6H4 Me Imidazol-1-yl 49 4-Ph-C6H4 Me Imidazol-1-yl 502-i-Pr-C6H4 Me lll '- ~11-yl No R1 R2 R3 n Physical data 513-i-Pr-C6H4 Me llll. '--c11-yl 524-i-Pr-C6H4 Me Illl;d -11-yl 533-t-Bu-C6H4 Me Imidazol-1-yl 544-t-Bu-C6H4 Me Illld--~11-yl 55 3-i-PrO-C6H4 Me Imidazol-1-yl 564-i-PrO-C6H4 Me Inl.~ 11-yl 572 Cl Me Illm'~ ~11-yl 1 mp 107.5-108.5C
pyndln-3-yl 584-MeS-C6H4 Me llll. ' -11-yl 59Pyridin-3-yl Me 11" ~'~7cl 1-yl 602,4.5-CI3-C6H2 Me Imidazol-1-yl -No R1 R2 R3 n Physical data 'H-NMR(CDCI3) ~ ppm:
61C6H5 Et l~ yl 1 1 30(3H, t, J=6 7), 4 21(2H, q, 7.64(11H, m), 8.04(1H, s) 622-F-C6H4 Et Imidazol-1-yl 638-F-C6H4 Et l~ 11-yl 644-F-C6H4 Et ll"~c'-~cl 1-yl 652-CI-C6H4 Et llll '- :11-yl 663-CI-C6H4 Et llll-'- '11 yl 674-CI-C6H4 Et Illl '--cl 1-yl 68 2-Br-C6H4 Et Imidazol-1-yl 693-Br-C6H4 Et Illm'- -11-yl 70 4-Br-C6H4 Et Imidazol-1-yl No R1 R2 R3 n Physical data 71~I-C6H4 EtImidazol-1-yl 72 2-Me-C6H4 Et llll '-~cl 1-yl 73 3-Me-C6H4 Et Imidazol-1-yl 74 4-Me-C6H4 Et Imidazol-1-yl 752-Et-C6H4 Et ll I 1 ' -; 11 -yl 763-Et-C6H4 Et ll I 1 ' -,11 -yl 774-Et-C6H4 Et llll.'- -11-yl 782-MeO-C6H4 Et ll I I d-~ 11 -yl 793-MeO-C6H4 Et Illl;d- ~11-yl 804-MeO-C6H4 Et llll '- 11-yl 2 1 86q47 No R1 R2 R3 nPhysical data ' H-NMR(CDCI3) ~ ppm: 4.63-81 C6H5 5 33(2H m) 5 86-6 01(1 H, m), 6.77-7.64(11H, m), 8.03(1H, s) 82 2-F-C6H4 Allyl Imidazol-1-yl 83 8-F-C6H4 Allyl Imidazol-1-yl 84 4-F-C6H4 Allyl Imidazol-1-yl 85 2-CI-C6H4 Allyl Imidazol-1-yl 868-CI-C6H4 Allyl~ ''t'- 311-yl 87 4-CI-C6H4 Allyl Imidazol-1-yl 88 2-Br-C6H4 Allyl Imidazol-1-yl 893-Br-C6H4 AllylIllm'- -11 yl go 4-Br-C6H4 Allyl Imidazol-1-yl No R1 R2 R3 n Physical data 91 3-l-C6H4 Allyl Imidazol-1-yl 92 2-Me-C6H4 Allyl Illm' ~11-yl 93 3-Me-C6H4 Allyl Imidazol-1-yl 94 4-Me-C6H4 Allyl Imidazol-1-yl 95 2-Et-c6H4 Allyl Imidazol-1-yl 96 3-Et-C6H4 Allyl Imidazol-1-yl 97 4-Et-C6H4 Allyl IIHc'---l 1-yl 982-MeO-C6H4 Allyl II~I;c'- :11-yl 993-MeO-C6H4 Allyl Imidazol-1-yl 1004-MeO-C6H4 Allyl IIII('-'GI 1-yl No R1 R2 R3 n Physical data Isomer A: ' H-NMR(CDCI3) ~
ppm: 3.85(3H, s), 3.95(3H, s), 1 -Me- 1 4.93(2H, s), 6.80-7.57(1 1 H, m) 101C6H5 Meimidazol-2-yl IsomerB: 1H-NMR(CDCI3)~
ppm: 3.51 (3H, s), 3.99(3H, s), 4.91(2H, s), 6.83-7.57(11H, m) 1022-F-C6H4 Me i~ cl 2-yl 1033-F-C6H4 Me 1-Me-1-Me- 1 IsomerA: mp99.5-100.5C
1044-F-C6H4 Meimidazol-2-yl IsomerB: mp114.5-115.5C
Isomer A: 1H-NMR(CDCI3) ~
1-Me- 1 ppm: 3.91(3H, s), 3.96(3H, s), 1052-CI-C6H4 Meimidazol-2-yl 5.04(2H, s), 6.81-7.65(10H, m) IsomerB: mp146.5-147.5C
Isomer A: ' H-NMR(CDCI3) ~
ppm: 3.88(3H, s), 3.96(3H, s), 1-Me- 1 4.94(2H, s), 6.69-7.54(10H, m) 1063-CI-C6H4 Meimidazol-2-yl IsomerB: 'H-NMR(CDCI3)~
ppm: 3.53(3H, s), 4.00(3H, s), 4.94(2H, s), 6.74-7.55(10H, m) 1-Me- 1 IsomerA: mp122.0-123.0C
1074-CI-C6H4 Meimidazol-2-yl IsomerB: mp144.5-145.5C

1082-Br-C6H4 Me 1-Me-1093-Br-C6H4 Me 1-Me- 1 1104-Br-C6H4 Me 1-Me-No R1 R2 R3 n Physical data 111 3-l-C6H4 Me 1-Me-lsomer A: 1 H-NMR(CDCI3) ~
1-Me ppm: 2.18(3H, s), 3.85(3H, s), 1122-Me-C6H4 Meimidazol-2-yl 1 3.96(3H, s), 4.93(2H, s), 6.73-7.60(10H, m) Isomer B: mp1 26.0-1 27.0C
IsomerA: mp88.0-91.0C
Isomer B: 1H-NMR(CDCI3) ~
1133-Me-C6H4 Meimidazol-2- 1 1 ppm: 2.31(3H, s), 3.51(3H, s), Y 4.01(3H, s), 4.89(2H, s), 6.63-7.65(10H, m) 1 -Me- 1 Isomer A: mp105.5-1 06.5C
1144-Me-C6H4 Meimidazol-2-yl IsomerB: mp118.5-119.5C

1152-Et-C6H4 Me i ~ 1 2 yl 11 63-Et-C6H4 Me 1-Me-1174-Et-C6H4 Me 1-Me-lsomer A: 1 H-NMR(CDCI3) ~
ppm: 3.85(3H, s), 3.91 (3H, s), 11 82-Meo-c6H4 Meimidazol-2-yl 1 5 04((2H sj 6 74-7.65(1 OH, m) IsomerB: mp108.5-109.5C
Isomer A: 1H-NMR(CDCI3) ~
ppm: 3.74(3H, s), 3.85(3H, s), 3.95(3H, s), 4.91 (2H, s), 1-Me- 1 6.38-7.56(1OH, m) 1193-MeO-C6H4 Meimidazol-2-yl IsomerB: 1H-NMR(CDCI3)~
ppm: 3.52(3H, s), 3.77(3H, s), 4.00(3H,s), 4.89(2H, s), 6.44-7.56(10H, m) 1204-MeO-C6H4 Meimidazol 2-yl No R1 R2 R3 n Physical data 1212-CF3-C6H4 Me 1-Me-lsomer A: 1H-NMR(CDCI3) ~
1 -Me- 1 ppm: 3.86(3H, s), 3.95(3H, s), 1223-CF3-C6H4 Meil" ' -I 2-yl 4.99(2H, s), 6.92-7.54(10H, m) Isomer B: mp1 06.0-1 07.0C
1234-CF3-C6H4 Me1 Me-1242,4-F2-C6H3 Me 1-Me-1252,5-F2-C6H3 Me 1-Me-1262,6-F2-C6H3 Meilll -'---l 2 yl 12734-F2-C6H3 Me1 Me-1283,5-F2-C6H3 Me 1-Me-1292,3-CI2-C6H3 Meilll -'---l 2 yl 1 -Me- Isomer A: mp115.0-116.0 C
1302,4-CI2-C6H3 Meilll '---l ? yl 1 IsomerB: mp157.5-158.5C
Isomer A: ' H-NMR(CDCI3) ~
1 -Me- 1 ppm: 3.94(3H, s), 3.98(3H, s), 1312 5-CI2-C6H3 Meil,~: ' -I 2-yl 5.04(2H, s), 6.82-7.65(9H, m) Isomer B: mp1 28.5-1 30.0 C

No Rl R2 R3 n Physical data Isomer A: ' H-NMR(CDCI3) ~
1 -Me- ppm: 3.91 (3H, s), 3.96(3H, s), 13234-CI2-C6H3 Me i~ l 2-yl 1 4.94(2H, s), 6.67-7.65(9H, m) Isomer B: mp124.5-125.5 C
1 333,5-CI2-C6H3 Me 1 -Me-1 342,3-Me2-C6H3 Me 1 -Me-1 352,4-Me2-C6H3 Me 1-Me-Isomer A1 H-NMR(CDCI3) ~
ppm: 2.13(3H, s), 2.24(3H, s), 3.86(3H, s), 3.97(3H, s), 4.92(2H, s), 6.55(1H, s), 6.63(1H, d, J=7.9), 6.91(1H, s), 6.98(1H, d, J=7.9), 1-M 7.26(1H, s), 7.29-7.60(4H, m) 1 362~5-Me2-c6H3 Me imidazol-2-yl 1 Isomer B'H-NMR(CDCI3) 3 ppm: 2.21 (3H, s), 2.29(3H, s), 3.49(3H, s), 4.03(3H, s), 4.92(2H, s), 6.53(1 H, s), 6.67(1H, d, J=7.3), 6.95(1H, d, J=1.2), 7.01(1H, d, 7.3), 7.17(1H, d, J=1.2), 7.30-7.65(4H, m) 1 373,4-Me2-C6H3 Me illli('-~cl 2-yl 1 383,5-Me2-C6H3 Me ill -'- I 2 yl 1 392-CI-4-Me-C6H3 Me 1 -Me-1402-CI-5-Me-C6H3 Me illl ~ l 2 yl No R1 R2 R3 n Physical data 1-Me- 1 IsomerA: mp87.0-88.0C
1414-Cl-2-Me-c6H3 Meimidazol-2-yl IsomerB: mp134.0-135.0C

1424-Cl-3-Me-c6H3 Me 1-Me-1433-Ph-C6H4 Me 1-Me-IsomerA: 'H-NMR(CDCI3)~
ppm: 3.87(3H, s), 3.97(3H, 1444-Ph-C6H4 Me 1-Me- 1 s)j 4.98(2H, s), 6.88-7.64(15H, IsomerB: mp141.5-142.5C
1453-i-PrO-C6H4 Meimidazol-2-yl Isomer A: 'H-NMR(CDCI3) ppm: 1.20(6H, d, J=7.3), 2.83(1H, sept, J=7.3), 3.82(3H, s), 3.96(3H, s), 1-Me- 1 4.91(2H, s), 6.61-7.57(10H, m) 1463-l-Pr-C6H4 Meil"M-~cl 2-yl IsomerB: 'H-NMR(CDCI3)~
ppm: 1.23(6H, d, J=7.3), 2.86(1H, sept, J=7.3), 3.50(3H, s), 4.00(3H, s), 4.88(2H, s), 6.64-7.58(10H, m) 1 -Me-1474-l-Pr-C6H4 Mei",id---l 2-yl 1483-t-Bu-C6H4 Me 1-Me-1492-MeS-C6H4 Meimidazol-2-yl 1504-MeS-C6H4 Me 1-Me-No R1 R2 R3 n Physical data 1512,3,6-F3~6H2 Me 1-Me-1522,4.5-CI3-C6H2 Me 1-Me-1533-PhO-C6H4 Meill~`d. :1 2-yl 3,4,5-(MeO)3- 1-Me-154 C6H2 Meimidazol-2-yl 1552,3,5-Me3-C6H2 Me 1-Me-1563,4,5-Me3-C6H2 Me 1-Me-157 C6F5 Me 1-Me-1584-Cl~3-Et-c6H3 Me 1-Me-1593-EtO-C6H4 Me i" ~. ~cl 2-yl 1604-EtO-C6H4 Me 1-Me-No R1 R2 R3 n Physical data ~ H-NMR(CDCI3) ~ ppm:
1-Me- 0 3.48(3H, s), 4.02(3H, s), 6.67-161C6H5 Meil" -'- l 2-yl 7.36(10H, m), 7.75(1H, dd, J=7.3, 1 8) 1624-F-C6H4 Me 1-Me- 0 1633-CI-C6H4 Me il~ 7cl 2-yl 1644-CI-C6H4 Me 1-Me- 0 1653-Me-C6H4 Me j" ~ 1 2 yl 1664-Me-C6H4 Me 1-Me- 0 1674-Et-C6H4 Me 1-Me- 0 1684-NO2-C6H4 Me 1-Me- 0 1693,4-CI2~6H3 Me 1-Me- 0 1703,5-CI2~6H3 Me 1-Me- 0 No R1 R2 R3 n Physical data 17 13,4-Me2-C6H3 Me 1 -Me- 0 1723,5-Me2~C6H3 Me 1-Me- 0 1733-PhO-C6H4 Me 1-Me- 0 1744-Cl-3-Et-c6H3 Me 1-Me- 0 1753-EtO-C6H4 Me 1-Me- 0 1763-CF3-C6H4 Me 1-Me- 0 1774-CF3 C6H4 Me 1-Me- 0 1783-i-PrO-C6H4 Me 1-Me- 0 1793-i-Pr-C6H4 Me 1-Me- 0 1804-Cl-3-Me-c6H3 Me 1-Me- 0 No R1 R2 R3 n Physical data 18 1 Pyridin-2-yl Me 1-Me-182 Pyridin-3-yl Me illm' --I 2 yl 183 pyridin-2-yl Me i~ cl 2-yl 3-CI- 1-Me-184 pyridin-2-yl Meimidazol-2-yl 185 pyridin 2 yl Me 1-Me-186 pyridin-3-yl Me 1-Me-187 pyridin-2-yl Me il,.' 7cl 2-yl 188 pyridin-2-yl Me 1-Me-6-CF3-3-CI- 1-Me-1 89 pyridin-2-yl Me ill.'-~cl 2-yl 190 5-CF3-3-CI- Me 1-Me-No R1 R2 R3 n Physical data 191 Benzothiazol Me 1-Me- 1 -2-yl imidazol-2-yl Benzoxazol 1-Me-192 -2-yl Me imidazol-2-yl 193 Quinolin-2-yl Me 1-Me-imldazol-2-yl 5-CF3-1,3,4- Me 1-Me-thiadiazol-2-yl i", -'- 7cl 2 yl 195 Pyrimidin-2-yl Me 1-Me-I 2-yl 196 5-CI-6-Me- Me 1-Me-pyrimidin-4-yl imidazol-2-yl 5-Et-6-Me- Me 1-Me-pyrimidin-4-yl imidazol-2-yl 198 pyrazin 2-yl Me imidazol-2-yl 199 3,6-Me2- Me 1-Me-pyrazin-2-yl imidazol-2-yl 200 5-Me- Me 1-Me-isoxazol-3-yl i" ,.~ - 7C I 2-yl No R1 R2 R3 n Physical data 1H-NMR(CDCI3) ~ ppm:
201C6H5 Me 5-Me- 1 1.95(3H,s),3.92(3H,s), ~midazol-1-yl 5.18(2H,s),6.86-7.71(11H,m) 2022-F-C6H4 Me5-Me;

2033-F-C6H4 Me 5-Me-2044-F-C6H4 Me 5-Me-imidazol-1 -yl 'H-NMR(CDCI3)~ppm:
5-Me- 1 1.94(3H, d, J=1.2),3.96(3H, 2052-CI-C6H4 Meimidazol-1-yl s), 5.24(2H,s),6.86-7.82(10H, m) 1H-NMR(CDCI3)~ppm:
2063-CI-C6H4 Meimidazol-;-yl 1 1.96(3H,s),3.93(3H,s), 5.18(2H,s),6.79-7.67(10H, m) 1H-NMR(CDCI3)~ ppm:
2074-CI-C6H4 Me5-Me; 1 1.94(3H,s),3.92(3H,s), Y 5.13(2H,s),6.82-7.66(10H, m) 208 2-Me-C6H4 Me imidazol-;-yl 209 3-Me-C6H4 Me imidazol;-yl 210 4-Me-C6H4 Me imidazol-; -yl No R1 R2 R3 n Physical data 2112-MeO-C6H4 Me s-Me-2123-MeO-C6H4 Me 5-Me-2134-MeO-C6H4 Me 5-Me;

2142.5-Me2-C6H3 Me 5-Me-'H-NMR(CDCI3) ~ ppm:
5-Me- 1 1.28(3H, t, J=7.3), 1.96(3H, s), 215C6H5 Etimidazol-1-yl 4.19(2H, q, J=7.3), 5.20(2H, s), 6.86-7.72(11H, m) 2164-CI-C6H4 Et 5-Me-217 4-Me-C6H4 Et imidazol;-yl 218C6H5 Allyl 5-Me-219 4-CI-C6H4 Allyl imidazol-;-yl 2204-Me-C6H4 Allyl 5-Me-No R1 R2 R3 n Physical data 1H-NMR(CDCI3) ~ ppm:
4-Me- 1 2-19(3H, s), 3.95(3H, s), 221C6H5 Mei", ~'~ ~' 1-yl 5.00(2H, s), 6.79-7.63(10H, m),7.90(1 H ,s) 2222-F-C6H4 Meimidazol;-yl 2233-F-C6H4 Me4-Me;

2244-F-C6H4 Me4-Me;
'H-NMR(CDCI3) ~ ppm:
4-Me- 1 2-18(3H, d, J=1.2), 3.99(3H, 2252-CI-C6H4 Meimidazol-1-yl s), 5.05(2H, s), 6.77-7.72(9H, m), 7.90(1 H, d, J=1.2) 1H-NMR(CDCI3) ~ ppm:
4-Me- 1 2.19(3H, s), 3.96(3H, s), 2263-CI-C6H4 Meil":d-7c,11-yl 4.99(2H, s), 6.95-7.59(9H, m), 7.88(1H, d, J=1.2) 1H-NMR(CDCI3) ~ ppm:
4-Me- 1 2.18(3H, s), 3.95(3H, s), 2274-CI-C6H4 Meill,!d---' 1-yl 4.97(2H, s), 6.70-7.59(9H, m), 7.88(1H, d, J=1.2) 2282-Me-C6H4 Me4-Me;

2293-Me-C6H4 Me4-Me;

2304-Me-C6H4 Me4-Me;

- ` -No R1 R2 R3 n Physical data 2312-MeO-C6H4 Me 4-Me;

2323-MeO-C6H4 Me 4-Me;

2334-MeO-C6H4 Me 4-Me;

2342.5-Me2-C6H3 Meimidazol-;-yl 'H-NMR(CDCI3) ~ ppm:
1.30(3H, t, J=7.3),2.19(3H, s), 235C6H5 Et y si, 6 78-7.63(10H, mj, 7.96(1H, s) 236 4-CI-C6H4 Et imidazol-;-yl 2374-Me-C6H4 Et 4-Me;

238C6H5 Allyljl~ 7C~;-2394-CI-C6H4 4-Me;

2404-Me-C6H4 Allyl4-Me;

No R1 R2 R3 n Physical data 'H-NMR(CDCI3)~ ppm:
241C6H5 Meimidazol-;-yl 1 221(3H,s) 3.93(3H,s) 2422-F-C6H4 Me2-Me;

2433-F-C6H4 Me2-Me;

244 4-F-C6H4 Me imidazol-;-yl 2452-CI-C6H4 Me2-Me;

2463-CI-C6H4 Me2-Me;

2474-CI-C6H4 Me2-Me;

2482-Me-C6H4 Me2-Me;

2493-Me-C6H4 Me2-Me;

250 4-Me-C6H4 Me imidazol-;-yl No R1 R2 R3 n Physical data 2512-MeO-C6H4 Me 2-Me;

2523-MeO-C6H4 Me 2-Me;

2534-MeO-C6H4 Me 2-Me;

2542,5-Me2-C6H3 Me imidazol-;-yl 255 C6H5 Et imidazol-;-yl 256 4-CI-C6H4 Et il"~'~~c,l;-yl 257 4-Me-C6H4 Et il,.i~; :I;-yl 258C6H5 Allylimidazol-;-yl 2594-CI-C6H4 Allyl 2-Me;

2604-Me-C6H4 Allyl 2-Me;

No R1 R2 R3 n Physical data 261C6H5 Me 1 H-1,2;4- 1 mp 86-87C

2622-F-C6H4 Me 1 H-1,2;4-263 3-F-C6H4 Me Tnazol-;-yl 2644-F-C6H4 Me 1 H-1,2,4-2652-CI-C6H4 Me Triazol-;-yl 1 mp 101.5-102.5C
1H-NMR(CDCI3) ~ ppm:
C H 1H-1,2,4- 1 4.06(3H, s),4.94(2H, s),6.63-2663-CI- 6 4 Me Triazol-1-yl 7.65(8H, m),7.96(1H, s), 9.12(1H, s) 2674-CI-C6H4 Me Triazol-1-yl 1 mp 101-102C

268 2-Me-C6H4 Me Triazol-;-yl 269 3-Me-C6H4 Me Triazol-;-yl 2704-Me-C6H4 Me 1H-1,2,4- 1 mp 98.5-99.5C

No R1 R2 R3 n Physical data 271 2-MeO-C6H4 Me Triazol-i-yl 272 3-MeO-C6H4 Me Triazol-i-yl 2734-MeO-C6H4 Me 1 H-1,2,4-2742,5-Me2-C6H3 Me 1 H-1 ,2j4- 1 mp 96-98C

275C6H5 Et 1 H-1,2;4- 1 mp 78.5-80.5C

2764-CI-C6H4 Et 1 H-1 ,2i4-2774-Me-C6H4 Et 1 H-1,2;4-' H-NMR(CDC13) ~ ppm: 4.71-4.74(2H, m), 4.94(2H, s), 5.25-278C6H5 AllylTriazol-i -yl 1 5 37(2H, m), 5 91-6 06(1 H m), 9.13(1H, s) 279 4-CI-C6H4 Allyl Triazol-i-yl 2804-Me-C6H4 Allyl1 H-1 ,2j4-- ` --No R1 R2 R3 n Physical data 1H-NMR(CDCI3) ~ ppm:
4.02(3H, s)~ 4 7s(2H~ s), 281 C6H5 Me Pyrazol-1-yl 1 6.40(1H, dd, J=3.1,1~s)~ 6.7s-7.62(10H, m), s~42(1H~ d, J=2.4) 282 2-F-C6H4 Me Pyrazol-1-yl 283 8-F-C6H4 Me Pyrazol-1-yl 284 4-F-C6H4 Me Pyrazol-1-yl 285 2-CI-C6H4 Me Pyrazol-1-yl 1 mp so-s1oc lH-NMR(CDCI3) ~ ppm:
286 8-CI-C6H4 Me Pyrazol-1-yl 1 4 26(3H, s)~ 4.78(2H, s)~ 6.42-J=2.4) 287 4-CI-C6H4 MePyrazol-1-yl 1 mp 94-95 C

288 2-Me-C6H4 MePyrazol-1-yl 289 3-Me-C6H4 MePyrazol-1-yl 290 4-Me-C6H4 MePyrazol-1-yl 1 mp s2-s3Oc No R1 R2 R3 n Physical data 291pyndin-3-yl MePyrazol-1-yl 1 mp 87.5-88.5C

2923-MeO-C6H4 MePyrazol-1-yl 2934-MeO-C6H4 MePyrazol-1-yl 2942,5-Me2-C6H3 MePyrazol-1-yl 1 mp 78-80C
H-NMR(CDCI3) ~ ppm:
1.36(3H, t, J=6.7), 4.27(2H, q, 295C6H5 EtPyrazol-1-yl 1 J=6.7), 4.79(2H, s), 6.40-7.61(11H, m), 8.48(1H, d, J=3.1) 2964-CI-C6H4 EtPyrazol-1-yl 2974-Me-C6H4 EtPyrazol-1-yl ' H-NMR(CDC13) ~ ppm: 4.69-4.73(2H, m), 4.80(2H, s), 5.23-298C6H5 AllylPyrazol-1-yl 1 5.38(2H, m), 5.96-6.10(1H, m), 6.40-7.62(11H, m),8.48(1H, d, J=2.4) 2994-CI-C6H4 AllylPyrazol-1-yl 1H-NMR(CDCI3) ~ ppm:
4 03(3H, s), 6.34(1 H, t, J=2.9) 300C6H5 MePyrazol-1-yl 6 82-7.63(10H, m), 8.37(1H, d, J=2-9) -No R1 R2 R3 n Physical data 1H-NMR(CDC13) ~ ppm:
4.06(3.99)(3H, s), 301 C6H5 MeIsoxazol-3-yl 1 5.05(4.96)(2H, s), 6.73-7.61(10H, m), 8.46(8.39)(1H, d, J=1.8) 3022-F-C6H4 MeIsoxazol-3-yl 3033-F-C6H4 MeIsoxazol-3-yl 3044-F-C6H4 MeIsoxazol-3-yl 1H-NMR(CDCI3) ~ ppm:
4.08(4.01)(3H, s), 3052-cl-c6H4 MeIsoxazol-3-yl 1 5.14(5.12)(2H, s), 6.76-7.68(9H, m), 8.46(8.40)(1H, d, J=1.8) 'H-NMR(CDCI3) ~ ppm:
4.07(4.01)(3H, s), 3063-CI-C6H4 MeIsoxazol-3-yl 1 5.04(4.95)(2H, s), 6.70-7.56(9H, m), 8.48(8.40)(1 H, d, J=1.8) 4.06(3.99)(3H, s), 3074-CI-C6H4 MeIsoxazol-3-yl 6 72-7 56(9H, m) 8.47(8.39)(1H, d, J=1.8) 3082-Br-C6H4 MeIsoxazol-3-yl 3093-Br-C6H4 MeIsoxazol-3-yl 3104-Br-C6H4 MeIsoxazol-3-yl No R1 R2 R3 n Physical data 3113-l-C6H4 MeIsoxazol-3-yl 1H-NMR(CDCI3) ~ ppm:
2.20(2.17)(3H, s), 3122-Me-C6H4 Me Y 5 03(4 97)(2H s) 6.68-7.64(9H, m), 8.44(8.39)(1H, d, J= 1.8) 1 H-NMR(CDCI3) ~ ppm:
2.29(2.27)(3H, s), 3133-Me-C6H4 Me Y 5 03(4 95)(2H s) 6.62-7.61(9H, m), 8.47(8.39)(1H, d, J=1.8) ~ H-NMR(CDCI3) ~ ppm:
2.25(3H, s), 4.06(3.99)(3H, s), 3144-Me-C6H4 MeIsoxazol-3-yl 1 5.01(4.93)(2H, s), 6.70-7.60(9H, m), 8.46(8.39)(1 H, d, J= 1.8) 3152-Et-C6H4 MeIsoxazol-3-yl 3163-Et-C6H4 MeIsoxazol-3-yl 3174-Et-C6H4 MeIsoxazol-3-yl 3182-MeO-C6H4 MeIsoxazol-3-yl 3193-MeO-C6H4 MeIsoxazol-3-yl 3204-MeO-C6H4 MeIsoxazol-3-yl ~ 2 1 86q47 ~, r ~

No R1 R2 R3 n Physical data 3212-CF3-C6H4 MeIsoxazol-3-yl 1H-NMR(CDCI3) ~ ppm:
4.05(3.98)(3H, s), 3223-CF3-C6H4 MeIsoxazol-3-yl 1 5.10(5.01)(2H, s), 6.74(1H, d, J=1.8), 6.94-7.57(8H, m), 8.47(8.40)(1H, d, J=1.8) 3234-CF3-C6H4 MeIsoxazol-3-yl 3242,4-F2-C6H3 MeIsoxazol-3-yl 3252,5-F2-C6H3 MeIsoxazol-3-yl 3262,6-F2-C6H3 MeIsoxazol-3-yl 3273,4-F2-C6H3 MeIsoxazol-3-yl 3283,5-F2-C6H3 MeIsoxazol-3-yl 3292,3-CI2-C6H3 MeIsoxazol-3-yl 3302,4-CI2-C6H3 MeIsoxazol-3-yl No R1 R2 R3 n Physical data 8312,6-CI2~6H3 MeIsoxazol-3-yl 3323,4-CI2-C6H3 MeIsoxazol-3-yl 8333,5-CI2-C6H3 MeIsoxazol-3-yl 3342,3-Me2-C6H3 MeIsoxazol-3-yl 3352,4-Me2-C6H3 MeIsoxazol-3-yl 3362,5-Me2~6H3 MeIsoxazol-3-yl 1 mp 104-108C

3373,4-Me2-C6H3 MeIsoxazol-3-yl 3383,5-Me2-C6H3 MeIsoxazol-3-yl 8392-CI-4-Me-C6H3 MeIsoxazol-3-yl 3402~CI-5~Me-C6H3 MeIsoxazol-3-yl 21 ~6947 No R1 R2 R3 nPhysical data 1H-NMR(CDCI3) ~ ppm:
2.16(2.13)(3H, s), 3414-Cl-2-Me-c6H3 MeIsoxazol-3-yl 145 01 (4 95)(2H s) 6 59-7.58(8H, m), 8.45(8.40)(1H, d, J=1.8) 3424-Cl-3-Me-c6H3 MeIsoxazol-3-yl 3433-Ph-C6H4 MeIsoxazol-3-yl 3444-Ph-C6H4 MeIsoxazol-3-yl 3453-i-PrO-C6H4 MeIsoxazol-3-yl 3463-i-Pr-C6H4 MeIsoxazol-3-yl 3474-i-Pr-C6H4 MeIsoxazol-3-yl 3483-t-Bu-C6H4 MeIsoxazol-3-yl 3492-MeS-C6H4 MeIsoxazol-3-yl 3504-MeS-C6H4 MeIsoxazol-3-yl No R1 R2 R3 n Physical data 3512,3,6-F3-C6H2 MeIsoxazol-3-yl 3522,4,5-CI3-C6H2 MeIsoxazol-3-yl 3533-PhO-C6H4 MeIsoxazol-3-yl 3,4,5-(MeO)3-354 MeIsoxazol-3-yl 1 . .

3552,3,5-Me3-C6H2 MeIsoxazol-3-yl 3563,4,5-Me3-C6H2 MeIsoxazol-3-yl 357 C6F5 MeIsoxazol-3-yl 3584-Cl-3-Et-c6H3 MeIsoxazol-3-yl 3593-EtO-C6H4 MeIsoxazol-3-yl 3604-EtO-C6H4 MeIsoxazol-3-yl ` - -No R1 R2 R3 n Physical data 361C6H5 MeIsoxazol-3-yl 0 3624-F-C6H4 MeIsoxazol-3-yl 0 3633-CI-C6H4 MeIsoxazol-3-yl 0 3644-CI-C6H4 MeIsoxazol-3-yl 0 3653-Me-C6H4 MeIsoxazol-3-yl 0 3664-Me-C6H4 MeIsoxazol-3-yl 0 3674-Et-C6H4 MeIsoxazol-3-yl 0 3684-N02-C6H4 MeIsoxazol-3-yl 0 3693,4-CI2-C6H3 MeIsoxazol-3-yl 0 3703 5-CI2-C6H3 MeIsoxazol-3-yl 0 2186q47 No R1 R2 R3 n Physical data 3713,4-Me2-C6H3 MeIsoxazol-3-yl 0 3723,5-Me2-C6H3 MeIsoxazol-3-yl 0 3733-PhO-C6H4 MeIsoxazol-3-yl 0 3744-Cl-3-Et-c6H3 MeIsoxazol-3-yl 0 3753-EtO-C6H4 MeIsoxazol-3-yl 0 3763-CF3-C6H4 MeIsoxazol-3-yl 0 3774-CF3-C6H4 MeIsoxazol-3-yl 0 3783-i-PrO-C6H4 MeIsoxazol-3-yl 0 3793-i-Pr-C6H4 MeIsoxazol-3-yl 0 3804-Cl-3-Me-c6H3 MeIsoxazol-3-yl 0 2 1 86q47 No R1 R2 R3 n Physical data 381pyridin-2-yl MeIsoxazol-3-yl 382pyridin-3-yl MeIsoxazol-3-yl 383pyr din-2-yl MeIsoxazol-3-yl 384pyridin-2-yl MeIsoxazol-3-yl 385pyridin-2-yl MeIsoxazol-3-yl 386pyridin-3-yl MeIsoxazol-3-yl ' H-NMR(CDCI3) ~ ppm:
5-CF3- 3.98(3H, s), 5.32(2H, s), 387 MeIsoxazol-3-yl 1 6.63(1H, d, J=8.5), 6.73(1H, d, pyridin-2-yl J=1.8), 7.27-7.71 (5H, m), 8.30(1H, s), 8.39(1 H, d, J=1.8) 388pyridin-2-yl MeIsoxazol-3-yl 1 mp 125-126.5C

389 . . MeIsoxazol-3-yl pyndln-2-yl ' H-NMR(CDCI3) ~
5-CF -3-CI- ppm:4.00(3H, s), 5.41(2H, s), 390 3 MeIsoxazol-3-yl 1 6.76(1H, d, J=1.8), 7.27-pyridin-2-yl 7.78(5H, m), 8.15(1H, s), 8.46(1H, d, J=1.8) No R1 R2 R3 n Physical data 391 Benzothiazol MeIsoxazol-3-yl 392 Benzoxazol MeIsoxazol-3-yl 393 Quinolin-2-yl MeIsoxazol-3-yl 5-CF -1 ,3,4-394 3 MeIsoxazol-3-yl thiadiazol-2-yl 395 pyrimidin-2-yl MeIsoxazol-3-yl 396 5-CI-6-Me- MeIsoxazol-3-yl pyrimidin-4-yl 397 5-Et-6-Me- MeIsoxazol-3-yl pyrimidin-4-yl 398 pyrazin 2 yl MeIsoxazol-3-yl 3,6-Me2- MeIsoxazol-3-yl pyrazin-2-yl 0 5-Me- MeIsoxazol-3-yl isoxazol-3-yl No R1 R2 R3 n Physical data 2.43(3H, s), 3.97(4.04)(3H, s), 5-Me- 1 4.96(5.06)(2H, s), 401C6H5 Meisoxazol-3-yl 6.35(6.55)(1H, s), 6.83-7.60(9H, m) 4022-F-C6H4 Me 5-Me-4033-F-C6H4 Me 5-Me-4044-F-C6H4 Me 5-Me-1H-NMR(CDCI3) ~ ppm:
5-Me- 1 2.44(3H, s), 4.07(3.98)(3H, s), 4052-CI-C6H4 Meisoxazol-3-yl 5.15(5.06)(2H, s), 6.38( 6.57)(1 H, s), 6.78-7.66(8H, m) 406~CI-C6H4 Me 5-Me- 1 mp111.0-123.0C

4074-CI-C6H4 Me 5-Me- 1 mp74.0-85.0C

4082-Br-C6H4 Me 5-Me-4093-Br-C6H4 Me 5-Me-4104-Br-C6H4 Me 5-Me-No R1 R2 R3 n Physical data 4113-l-C6H4 Me 5-Me-'H-NMR(CDCI3) ~ ppm:
2.20(2.22)(3H, s), 4122-Me-C6H4 Me 5-Me- 4.97(504}(2H, s}, 6.35(6.53)(1H, s), 6.69-7.63(8H, m) 4133-Me-C6H4 Meisoxazol-3-yl 1 mp92.0-93.0C

4144-Me-C6H4 Meisoxazol-3-yl 1 mp104.0-105.5 C

4152-Et-C6H4 Me 5-Me-4163-Et-C6H4 Meisoxazol-3-yl 4174-Et-C6H4 Me 5-Me-4182-Meo-c6H4 Meisoxazol-3-yl 4193-MeO-C6H4 Meisoxazol-3-yl 4204-MeO-C6H4 Me 5-Me-isoxazol-3-yl No R1 R2 R3 n Physical data 4212-CF3-C6H4 Me 5-Me-' H-NMR(CDCI3) ~ ppm:
2.43(2.44)(3H, s), 5-Me- 1 4.03(3.97)(3H, s), 4223-CF3-C6H4 Meisoxazol-3-yl 5.00(5.09)(2H, s),6.35(1H, s), 6,56(6.57)(1H, s), 7.00-7.64(7H, m) 4234-CF3-C6H4 Me 5-Me-4242,4-F2-C6H3 Me 5-Me-4252,5-F2-C6H3 Me 5-Me-4262,6-F2-C6H3 Me 5-Me-4273,4-F2-C6H3 Me 5-Me-4283,5-F2-C6H3 Me 5-Me-4292,3-CI2-C6H3 Me 5-Me-4302,4-CI2-C6H3 Me 5-Me-No R1 R2 R3 n Physical data 4312,5-CI2-C6H3 Me 5-Me-4323,4-CI2-C6H3 Me 5-Me-4333,5-CI2-C6H3 Me 5-Me-4342.3-Me2-C6H3 Me 5-Me-4352,4-Me2-C6H3 Me 5-Me-1H-NMR(CDCI3)~ppm:
2.15(2.16)(3H,s), 4362,5-Me2-C6H3 Meisoxazol3yl 1 2.42I2.43)(3H,S), 4.95(5.01)(2H,s),6.36-7.64(8H,m) 4373,4-Me2-C6H3 Me 5-Me-4383,5-Me2-C6H3 Me 5-Me-439 2-CI-4-Me-C6H3 Me 5-Me-440 2-CI-5-Me-C6H3 Me 5-Me-21 ~6947 No R1 R2 R3 n Physical data 441 4-Cl-2-Me-c6H3 Me 5-Me- 1 mp79-83C

442 4-Cl-3-Me-c6H3 Me 5-Me-4433-Ph-C6H4 Me 5-Me-4444-Ph-C6H4 Me 5-Me- 1 mp105.0-115.0C

4453-i-PrO-C6H4 Me 5-Me-4463-i-Pr-C6H4 Me 5-Me-4474-i-Pr-C6H4 Me 5-Me-4483-t-Bu-C6H4 Me 5-Me-4492-MeS-C6H4 Me 5-Me-4504-MeS-C6H4 Me 5-Me-No R1 R2 R3 n Physical data 4512,3.6-F3-C6H2 Meisoxazol-3-yl 4522,4,5-CI3-C6H2 Me 5-Me-4533-PhO-C6H4 Me 5-Me-3,4,5-(MeO)3- 5-Me-C6H2 Meisoxazol-3-yl 2,3,5-Me3- 5-Me-C6H2 Meisoxazol-3-yl 3,4,5-Me3- 5-Me-456C6H2 Meisoxazol-3-yl 5-Me-457C6F5 Meisoxazol-3-yl 4584-Cl-3-Et-c6H3 Me 5-Me-4593-EtO-C6H4 Me 5-Me-4604-EtO-C6H4 Me 5-Me-- 225 - .

No R1 R2 R3 n Physical data 461C6H5 Me 5-Me- O

4624-F-C6H4 Me 5-Me- O

4638-CI-C6H4 Me 5-Me- O

4644-CI-C6H4 Me 5-Me- O

4653-Me-C6H4 Me 5-Me- O

4664-Me-C6H4 Me 5-Me- O

4674-Et-C6H4 Me 5-Me- O

4684-N02-C6H4 Me 5-Me- O

4693,4-CI2-C6H3 Me 5-Me- O

4703,5-CI2-C6H3 Me 5-Me- O

21 ~6947 No R1 R2 R3 n Physical data 4713,4-Me2-C6H3 Me 5-Me- 0 4723,5-Me2-C6H3 Me 5-Me- 0 4733-PhO-C6H4 Me 5-Me- 0 474 4-Cl-3-Et-c6H3 Me 5-Me- 0 4753-EtO-C6H4 Me 5-Me- 0 4763-CF3-C6H4 Me 5-Me- 0 4774-CF3-C6H4 Me 5-Me- 0 5-Me-4783-i-PrO-C6H4 Meisoxazol-3-yl 0 5-Me-4793-i-Pr-C6H4 Meisoxazol-3-yl 5-Me-480 4-Cl-3-Me-c6H3 Meisoxazol-3-yl No R1 R2 R3 n Physical data 481Pyridin-2-yl Me 5-Me-482Pyridin-3-yl Me 5-Me-483 pyridin-2-yl Me isoxazol-3-yl ' H-NMR(CDCI3) ~
3-CI- 5-Me- 1 ppm:2.42(3H, s), 3.97(3H, s), 484pyridin-2-yl Meisoxazol-3-yl 5.35(2H, s), 6.35(1 H, s), 6.76-6.81(1H, m), 7.24-7.93(6H, m).
485pyridin-2-yl Me 5-Me-2-CI- 5-Me-486pyridin-3-yl Meisoxazol-3-yl ' H-NMR(CDCI3) ~
5-CF - 5-Me- ppm:2.43(3H, s), 3.96(3H, s), 487 3 Me . 1 5.32(2H, s), 6.34(1H, d, pyridin-2-yl Isoxazol-3-yl J=1.2), 6.67(1H, d, J=8.5), 7.24-7.72(5H, m), 8.31(1 H, s) 3-CF3- 5-Me-488pyridin-2-yl Meisoxazol-3-yl 6-CF3-3-CI- 5-Me-489pyridin-2-yl Meisoxazol-3-yl ' H-NMR(CDCI3) ~
5-CF3-3-CI- Me 5-Me- 1 ppm:2.43(3H, s), 3.97(3H, s), pyridin-2-yl isoxazol-3-yl 5.40(2H, s), 6.37(1 H, s), 7.25-8.17(6H, m).

No R1 R2 R3 n Physical data 491Benzothiazol Me 5-Me- 1 -2-yl isoxazol-3-yl 492Benzoxazol Me 5-Me--2-yl isoxazol-3-yl 493Quinolin-2-yl Me 5-Me-isoxazol-3-yl thiadiazol-2-yl Me 5-Me-495Pyrimidin-2-yl Me 5-Me-isoxazol-3-yl 4965-CI-6-Me- Me 5-Me-pyrimidin-4-yl isoxazol-3-yl 497py;imidin 4 yl Me 5-Me-498pyrazin-2-yl Me 5-Me-py;azin-2-yl Me 5-Me-500isoxazol-3-yl Me 5-Me--No R1 R2 R3 n Physical data 501C6H5 MeIsoxazol-5-yl 5022-F-C6H4 MeIsoxazol-5-yl 5033-F-C6H4 MeIsoxazol-5-yl 5044-F-C6H4 MeIsoxazol-5-yl 5052-CI-C6H4 MeIsoxazol-5-yl 5063-CI-C6H4 MeIsoxazol-5-yl Isomer A: 1H-NMR(CDCI3) ~
ppm: 4.11(3H, s), 4.99(2H, s), 6.68-6.73(2H, m), 7.11(1H, d, J=1.8), 7.14-7.18(2H, m), 7.40-7.57(4H, m), 8.34(1H, d, 5074-CI-C6H4 MeIsoxazol-5-yl IsomerB: 1H-NMR(CDCI3)~
ppm: 4.03(3H, s), 4.92(2H, s), 6.21(1H, d, J=1.8), 6.68-6.74(2H, m), 7.13-7.23(3H, m), 7.41-7.61(3H, m), 8.24(1H, d, J=1 .8) 5082-Br-C6H4 MeIsoxazol-5-yl 509 ~Br-C6H4 Me Isoxazol-5-yl 5104-Br-C6H4 MeIsoxazol-5-yl No R1 R2 R3 n Physical data 5113-l-C6H4 MeIsoxazol-5-yl IsomerA: mp71.5-72.5C
5122-Me-C6H4 MeIsoxazol-5-yl 1 IsomerB: mp68.0-69.0C

5133-Me-C6H4 MeIsoxazol-5-yl 5144-Me-C6H4 MeIsoxazol-5-yl 5152-Et-C6H4 MeIsoxazol-5-yl 5163-Et-C6H4 MeIsoxazol-5-yl 5174-Et-C6H4 MeIsoxazol-5-yl 5182-Meo-c6H4 MeIsoxazol-5-yl 5193-MeO-C6H4 MeIsoxazol-5-yl 5204-MeO-C6H4 MeIsoxazol-5-yl No R1 R2 R3 n Physical data 5212-CF3-C6H4 Me Isoxazol-5-yl Isomer A: ' H-NMR(CDCI3) ~
ppm: 4.10(3H, s),5.07(2H, s), 6.91-7.02(2H, m), 7.11(1H, d, J=1.8), 7.15-7.59(6H, m), 5223-CF3-C6H4 Me Isoxazol-5-yl 1 Isom(er B ~H-NMR(CDCI3) ~
ppm: 4.03(3H~ s),4.99(2H, s), 6.22(1H, d, J=1.8), 6.92-7.62(8H, m),8.24(1 H, d, J=1.8) 5234-CF3-C6H4 Me Isoxazol-5-yl 5242,4-F2-C6H3 Me Isoxazol-5-yl 5252,5-F2-C6H3 Me Isoxazol-5-yl 5262,6-F2-C6H3 Me Isoxazol-5-yl 5273,4-F2-C6H3 Me Isoxazol-5-yl 5283,5-F2-C6H3 Me Isoxazol-5-yl 5292,3-CI2-C6H3 Me lsoxazol-5 5302,4-C12-C6H3 Me Isoxazol-5-yl No R1 R2 R3 n Physical data 5312,5-CI2-C6H3 MeIsoxazol-5-yl 5323,4-CI2~6H3 MeIsoxazol-5-yl 5333,5-CI2-C6H3 MeIsoxazol-5-yl 5342.3-Me2-C6H3 MeIsoxazol-5-yl 5352,4~Me2-C6H3 MeIsoxazol-5-yl Isomer A mp137.5-138.5 C
5362.5-Me2-C6H3 MeIsoxazol-5-yl IsomerB mp93.0-94.5C

5373.4~Me2~C6H3 MeIsoxazol-5-yl 5383,5-Me2-C6H3 MeIsoxazol-5-yl 5392-CI-4-Me-C6H3 MeIsoxazol-5-yl 5402-CI-5-Me-C6H3 MeIsoxazol-5-yl No R1 R2 R3 n Physical data IsomerA: mp84.0-85.0C
Isomer B: 1H-NMR(CDCI3) ~
ppm: 2.16(3H, s),4.04(3H, s), 5414-Cl-2-Me-c6H3 MeIsoxazol-5-yl 1 4.93(2H, s),6.20(1H, d, J=1.8),6.62(1H, d, J=8.5), 6.99-7.63(6H, m), 8.22(1H, d, J=1.8) 5424-Cl-3-Me-c6H3 MeIsoxazol-5-yl 5433-Ph-C6H4 MeIsoxazol-5-yl 5444-Ph-C6H4 MeIsoxazol-5-yl 5453-i-PrO-C6H4 MeIsoxazol-5-yl 5463-i-Pr-C6H4 MeIsoxazol-5-yl 5474-i-Pr-C6H4 MeIsoxazol-5-yl 5483-t-Bu-C6H4 MeIsoxazol-5-yl 5492-MeS-C6H4 MeIsoxazol-5-yl 5504-MeS-C6H4 MeIsoxazol-5-yl No R1 R2 R3 n Physical data 5512.3,6-F3-C6H2 MeIsoxazol-5-yl 5522.4.5-CI3-C6H2 MeIsoxazol-5-yl 5533-PhO-C6H4 MeIsoxazol-5-yl 3,4,5-(MeO)3-554 MeIsoxazol-5-yl 5552.3.5-Me3-C6H2 MeIsoxazol-5-yl 5563.4.5-Me3-C6H2 MeIsoxazol-5-yl 557 C6F5 MeIsoxazol-5-yl 5584-Cl-3-Et-c6H3 MeIsoxazol-5-yl 5593-EtO-C6H4 MeIsoxæol-5-yl 5604-EtO-C6H4 MeIsoxazol-5-yl No R1 R2 R3 n Physical data 561 C6H5 MeIsoxazol-5-yl 0 5624-F-C6H4 MeIsoxazol-5-yl 0 5633-CI-C6H4 MeIsoxazol-5-yl 0 5644-CI-C6H4 MeIsoxazol-5-yl 0 5653-Me-C6H4 MeIsoxazol-5-yl 0 5664-Me-C6H4 MeIsoxazol-5-yl 0 5674-Et-C6H4 MeIsoxazol-5-yl 0 5684-N02-C6H4 MeIsoxazol-5-yl 0 5693,4-CI2-C6H3 MeIsoxazol-5-yl 0 5703,5-CI2-C6H3 MeIsoxazol-5-yl 0 - ` -No R1 R2 R3 n Physical data 5713,4-Me2-C6H3 MeIsoxazol-5-yl 0 5723.5-Me2-C6H3 MeIsoxazol-5-yl 0 5733-PhO-C6H4 MeIsoxazol-5-yl 0 5744-Cl-3-Et-c6H3 MeIsoxazol-5-yl 0 5753-EtO-C6H4 MeIsoxazol-5-yl 0 5763-CF3-C6H4 MeIsoxazol-5-yl 0 5774-CF3-C6H4 MeIsoxazol-5-yl 0 5783-i-Pro-c6H4 MeIsoxazol-5-yl 0 5793-i-Pr-C6H4 MeIsoxazol-5-yl 0 5804~Cl-3-Me-c6H3 MeIsoxazol-5-yl 0 No R1 R2 R3 n Physical data 581Pyridin-2-yl MeIsoxazol-5-yl 582Fyridin-3-yl MeIsoxazol-5-yl 583 5-CI- MeIsoxazol-5-yl pyridin-2-yl 584pyridin-2-yl MeIsoxazol-5-yl 585pyridin-2-yl MeIsoxazol-5-yl 586pyridin-3-yl MeIsoxazol-5-yl 587 5-CF3- MeIsoxazol-5-yl pyridin-2-yl 588 3-CF3- MeIsoxazol-5-yl pyridin-2-yl 5896-CF3-3-CI- MeIsoxazol-5-yl pyridin-2-yl 5905-CF3-3-CI- MeIsoxazol-5-yl pyridin-2-yl No R1 R2 R3 n Physical data 591 -2-yl MeIsoxazol-5-yl 592 Benzoxazol Me Isoxazol-5-yl 593 Quinolin-2-yl Me Isoxazol-5-yl 594 5-CF3-1~3~4- Me Isoxazol-5-yl thiadiazol-2-yl 595 Pyrimidin-2-yl MeIsoxazol-5-yl 596 py;imidin-4-YI MeIsoxazol-5-yl 597 5-Et-6-Me- MeIsoxazol-5-yl pyrimidin-4-yl 598 Pyrazin 2-yl MeIsoxazol-5-y 3,6-Me2-599 MeIsoxazol-5-yl Pyrazin-2-yl 600 5-Me- MeIsoxazol-5-yl 21 86~47 No R1 R2 R3 n Physical data Isomer A: mp99.0-1 00.0C
IsomerB: 'H-NMR(CDCI3)~
601 C6H5 Me .ol 5 1 1 ppm: 2.27(3H, s), 4.02(3H, s), soxaz - -y 4.95(2H, s), 5.99(1H, s), 6.80-7.65(9H, m) 602 2-F-C6H4 Me 3-Me-603 8-F-C6H4 Me 3-Me-604 4-F-C6H4 Me 3-Me-lsomerA: mp87.0-88.0C
Isomer B: 'H-NMR(CDCI3) ~
605 2-CI-C6H4 Me 3-Me- 1 ppm:2.27(3H, s), 4.04(3H, s), soxazol-5-yl 5.01(2H, s), 6.02(1H, s), 6.81-7.74(8H, m) Isomer A: 1H-NMR(CDCI3) ~
ppm: 2.35(3H, s), 4.10(3H, s), 5.00(2H, s), 6.66-6.91(3H, m), H 3-Me- 6.94(1 H, s),7.1 0-7.57(5H, m).
606 3-CI-C6 4 Meisoxazol-5-yl 1 IsomerB: 'H-NMR(CDCI3)~
ppm: 2.28(3H, s), 4.03(3H, s), 4.94(2H, s), 6.01(1 H, s), 6.68-7.65(8H, m) IsomerA: mp110.0-111.0C
Isomer B: 'H-NMR(CDCI3) ~
6074-CI-C6H4 Me 3-Me- 1 ppm: 2.27(3H, s), 4.01 (3H, s), isoxazol-5-yl 4.92(2H, s), 5.99(1 H, s), 6.71-7.60(8H, m) 6082-Br-C6H4 Me 3-Me-6093-Br-C6H4 Me 3-Me-6104-Br-C6H4 Me 3-Me-No R1 R2 R3 n Physical data 6113-l-C6H4 Me 3-Me-lsomerA: mp80.0-81.0C
Isomer B: 1 H-NMR(CDCI3) 6122-Me-C6H4 Me 3-Me- 4.03(3H, s),4.93(2H, s), 5.98(1 H, s), 6.71 -7.68(8H, m) 3-Me- 1 IsomerA: mp109.0-110.0C
6133-Me-C6H4 Meisoxazol-5-yl IsomerB: mp94.5-95.5C
IsomerA: mp126.0-127.0C
Isomer B: 1H-NMR(CDCI3) 6144-Me-C6H4 Me 3-Me- 4.02(3H, s),4.92(2H, s), 5.99(1H, s), 6.70-7.64(8H, m) 6152-Et-C6H4 Me 3-Me-6163-Et-C6H4 Me 3-Me-6174-Et-C6H4 Me 3-Me-6182-MeO-C6H4 Me 3-Me-6193-MeO-C6H4 Me 3-Me-6204-MeO-C6H4 Me 3-Me-No R1 R2 R3 n Physical data 6212-CF3-C6H4 Me 3-Me-IsomerA: lH-NMR(CDCI3)~
ppm: 2.34(3H, s), 4.08(3H, s), 5.05(2H, s), 6.92(1H, s), 6.94-6223-CF3~6H4 Me 3-Me- 1 Isomer B ?H-NMR(CDCI3) ~
ppm: 2.27(3H, s), 4.02(3H, s), 4.99(2H, s), 6.01(1H, s), 6.96-7.61(8H, m) 6234-CF3-C6H4 Me 3-Me-6242,4-F2-C6H3 Me 3-Me-6252,5-F2{~6H3 Me 3-Me-6262,6-F2-C6H3 Me 3-Me-6273,4-F2-C6H3 Me 3-Me-6283,5-F2-C6H3 Me 3-Me-6292,3-CI2-C6H3 Me 3-Me-6302,4-C12{:6H3 Me 3-Me-No R1 R2 R3 n Physical data 6312,5-C12-C6H3 Me 3-Me-6323,4-C12-C6H3 Me 3-Me-6833,5-CI2~6H3 Me 3-Me-6342,3-Me2-C6H3 Me 3-Me-6352.4-Me2-C6H3 Me 3-Me-3-Me- 1 Isomer Amp 113-11 4C
6362,5~Me2-C6H3 Meisoxazol-5-yl Isomer Bmp 107-108C

6373,4~Me2-C6H3 Me 3-Me-6383,5-Me2-C6H3 Me 3-Me-6392-CI-4-Me-C6H3 Meisoxazol-5-yl 6402-CI-5-Me-C6H3 Me 3-Me--No R1 R2 R3 n Physical data IsomerA: mp76.5-77.5C
Isomer B: 'H-NMR(CDCI3) ~
C 3-Me- 1 ppm: 2.12(3H, s), 2.26(3H, s), 6414-CI-2-Me- 6H3 Meisoxazol-5-yl 4.03(3H, s), 4.93(2H, s), 5.97(1 H, s), 6.62(1H, d, J=8.5), 6.99-7.62(6H, m) 6424-Cl-3-Me-c6H3 Me 3-Me-6433-Ph-C6H4 Me 3-Me-3-Me- 1 IsomerA : mp130.5-131.5C
6444-Ph-C6H4 Meisoxazol-5-yl Isomer B: mp102.5-103.5 C

6453-i-PrO-C6H4 Me 3-Me-6463-i-Pr-C6H4 Me 3-Me-6474-i-Pr-C6H4 Me 3-Me-6483-t-Bu-C6H4 Me 3-Me-6492-MeS-C6H4 Me 3-Me-6504-MeS-C6H4 Me 3-Me-No R1 R2 R3 n Physical data 6512,3,6-F3-C6H2 Meisoxazol-5-yl 6522,4,5-C13-C6H2 Me 3-Me-6533-PhO-C6H4 Me 3-Me-3,4,5-(MeO)3- 3-Me-654 C6H2 Meisoxazol-5-yl 6552,3,5-Me3-C6H2 Me 3-Me-6563,4,5-Me3-C6H2 Me 3-Me-657 C6F5 Me 3-Me-6584-Cl-3-Et-c6H3 Me 3-Me-6593-EtO-C6H4 Me 3-Me-6604-EtO-C6H4 Me 3-Me-No R1 R2 R3 n Physical data IsomerA: mp100.0-105.5C
Isomer B: 'H-NMR(CDCI3) ~
661 C6H5 Me 3-Me- 0 ppm 2 28(3H, s),3.94(3H, s), 6.92-7.41(9H, m) 6624-F-C6H4 Meisoxazol-5-yl 6633-CI-C6H4 Me 3-Me- 0 6644-CI-C6H4 Me 3-Me- 0 6653-Me-C6H4 Me 3-Me- 0 6664-Me-C6H4 Me 3-Me- 0 6674-Et-C6H4 Me 3-Me- 0 6684-NO2-C6H4 Me 3-Me- 0 6693,4-CI2-C6H3 Me 3-Me- 0 6703,5-CI2-C6H3 Me 3-Me- 0 No R1 R2 R3 n Physical data 6713.4-Me2-C6H3 Me 3-Me- 0 6723,5-Me2-C6H3 Me 3-Me- 0 6733-PhO-C6H4 Me 3-Me- 0 674 4-Cl-3-Et-c6H3 Me 3-Me- 0 6753-EtO-C6H4 Me 3-Me- 0 6763-CF3-C6H4 Me 3-Me- 0 6774-CF3-C6H4 Me 3-Me- 0 6783-i-PrO-C6H4 Me 3-Me- 0 6793-i-Pr-C6H4 Me 3-Me- 0 680 4-Cl-3-Me-c6H3 Me 3-Me- 0 No R1 R2 R3 n Physical data 681Pyridin-2-yl Me 3-Me-isoxazol-5-yl 682Pyridin-3-yl Me 3-Me-683pyridin-2-yl Me 3-Me-684pyridin-2-yl Me 3-Me-685pyridin-2-yl Me 3-Me-686pyridin-3-yl Me 3-Me-lsomerA: mp88.0-90.0C
Isomer B: 'H-NMR(CDCI3) ~
5-CF - 3-Me- ppm: 2.28(3H, s), 4.01 (3H, s), 687 3 Me . 1 5.32(2H, s), 6.00(1H, s), pyridin-2-yl Isoxazol-5-yl 6.64(1H, d, J=9.2),7.22-7.73(5H, m), 8.30(1H, d, J=1.2) 6883-CF3- Me 3-Me-pyridin-2-yl Isoxazol-5-yl 6896-CF3-3-CI- Me 3-Me-pyridin-2-yl Isoxazol-5-yl IsomerA: mp77.0-79.0~C
Isomer B: 1H-NMR(CDCI3) ~
6905-CF3-3-CI- Me 3-Me- 1 ppm: 2 27(3H, s), 4.03(3H, s), pyridin-2-yl isoxazol-5-yl 5.39(2H, s), 6.02(1 H, s), 7.22-7.67(4H, m), 7.79(1H, d, J=1.8), 8.17(1H, d, J=1.8) No R1 R2 R3 n Physical data 691Benzothiazol Me 3-Me--2-yl isoxazol-5-yl Benzoxazol 3-Me-692 -2-yl Meisoxazol-5-yl 3-Me-693 Quinolin-2-yl Me isoxazol-5-yl 5-CF3-1,3,4- 3-Me-thiadiazol-2-yl Meisoxazol-5-yl 695Pyrimidin-2-yl Me 3-Me-isoxazol-5-yl 6965-CI-6-Me- Me 3-Me-pyrimidin-4-yl isoxazol-5-yl 6975-Et-6-Me- Me 3-Me-pyrimidin-4-yl Isoxazol-5-yl 698pyrazin 2-yl Me 3-Me-3,6-Me2- 3-Me-699pyrazin-2-yl Meisoxazol-5-yl 5-Me- 3-Me-isoxazol-3-yl Meisoxazol-5-yl No R1 R2 R3 n Physical data 701 C6H5 M1l3l4-oxadiazol-2- 1 mp88.0-89.0 C

702 2-F-C6H4 yl 703 3-F-C6H4 yl 704 4-F-C6H4 yl 705 2-cl-c6H4 1,3,4-Oxadiazol-2- 1 mp120 0-121.0 C

706 3-CI-C6H4 Me1~3l4-oxadiazol-2- 1 mpg7.o-98-o C

707 4-CI-C6H4 M1,3,4-Oxadiazol-2- 1 mp 120-122C

708 2-Br-C6H4 M1,3,4-Oxadiazol-2-709 3-Br-C6H4 yl 710 4-Br-C6H4 yl No R1 R2 R3 n Physical data 7113-l-C6H4 Me1,3,4-Oxadiazol-2- 1 7122-Me-C6H4 M1,3,4-Oxadiazol-2- 1 mp 95-96.5C

7133-Me-C6H4 M1,3,4-0xadiazol-2- 1 mp78.s-7s.5 C
1,3,4-Oxadiazol-2-7144-Me-C6H4 Me yl 7152-Et-C6H4 yl 1H-NMR(CDCI3) ~ ppm:
7163-Et-C6H4 Meyl 1 J-7 3), i.o8(3H, s), 4.99(2H, s), 6.73-7.65(8H, m), 8.43(1 H, s) 7174-Et-C6H4 yl 7182-Meo-c6H4 M1,3,4-OxadiaZI-2- 1 mpg5.0-86.5 C

7193-MeO-C6H4 yl 7204-MeO-C6H4 Me1,3,4 Oxaldiazol2 NoR1 R2 R3 n Physical data 7212-CF3-C6H4 Me1~3l4-oxadiazol-2-'H-NMR(CDCI3) ~ ppm:
7223-CF3-C6H4 M1~3l4-oxadiazol-2- 1 406(3H s) 5.03(2H, s)- 6-92-7.59(8H, m), 8.44(1 H, s) 7234-CF3-C6H4 yl 7242,4-F2-C6H3 yl 7252,5-F2-C6H3 yl 7262,6-F2-C6H3 Me1,3,4-Oxadiazol-2- 1 7273,4-F2-C6H3 Me1,3,4-Oxadiazol-2- 1 H 1,3.4-Oxadiazol-2-7283,5-F2-C6 3 Me yl H 1,3,4-Oxadiazol-2-7292,3-CI2-C6 3 Me yl 7302,4-CI2-C6H3 Me1~3,4-Oxadiazol-2- 1 - 2s2 -No R1 R2 R3 n Physical data 7312~5^cl2-c6H3 Me1~3~4-oxadiazol-2- 1 mp152.0-153 0 ~

1H-NMRtCDCI3) ~ ppm:
7323,4-CI2-C6H3 Meyl 1 6 63(1 H, dd, J=2 4,8.5) 6.89(1H, d, J=3.1),7.24-7.57(5H, m),8.46(1 H, s) 7333,5-C12-C6H3 Me1~3~4-oxadiazol-2 7342,3-Me2-C6H3 yl 7352,4-Me2-C6H3 yl 7362~5-Me2-c6H3 Me1,3,4-Oxadiazol-2 7373~4-Me2-C6H3 Me1,3,4-Oxadiazol-2-7383,5-Me2-C6H3 yl 7392-cl-4-Me-c6H3 Me1,3,4-Oxadiazol-2-7402-cl-5-Me-c6H3 Me1,3,4-Oxadiazol-2-No R1 R2 R3 n Physical data 7414-cl-2-Me-c6H3 Me1,3,4-Oxadiazol-2 1 85 5 C

7424~Cl-3-Me-c6H3 Me1,3,4-Oxadiazol-Z-7433-Ph-C6H4 Me1,3,4-Oxadiazol-2- 1 7444-Ph-C6H4 y 745 3-i-PrO-C6H4 yl 746 3-i-Pr-C6H4 Me1~3~4-oxadiazol-2- 1 747 4-i-Pr-C6H4 y 748 3-t-Bu-C6H4 yl 749 2-MeS-C6H4 y 750 4-MeS-C6H4 y No R1 R2 R3 n Physical data 7512,3,6-F3-C6H2 Me1~3~4-Oxadiazol-2 7522.4.5-CI3-C6H2 Me1,3,4-Oxadiazol-2 7533-PhO-C6H4 Me1,3,4 0xadiazol-2-754 C H Me' ' yl 755 2,3,5-Me 3-C6H2 Me 1,3,4-Oxadiazol-2-756 3,4,5-Me 3-C6H2 Me 1.3,4-Oxadiazol-2-757C6F5 Me1~3~4-oxadiazol-2 1 3,4-Oxadiazol-2-7584-Cl-3-Et-c6H3 Me' yl 7593-EtO-C6H4 Me1 ~3~4-Oxadiazol 2 7604-EtO-C6H4 Me1,3,4-Oxadiazol-2 No R1 R2 R3 n Physical data 1,3,4-Oxadiazol-2- 0 761 C6H5 Me yl 1,3,4-Oxadiazol-2- 0 7624-F-C6H4 Me yl 1,3,4-Oxadiazol-2- 0 7633-CI-C6H4 Me yl 1,3,4-Oxadiazol-2- 0 7644-CI-C6H4 Me yl 1,3,4-Oxadiazol-2- 0 7653-Me-C6H4 Me yl 1 3,4-Oxadiazol-2- 0 7664-Me-C6H4 Me ' yl 1,3,4-Oxadiazol-2- 0 7674-Et-C6H4 Me yl 1 3 4-Oxadiazol-2-7684-NO2-C6H4 Me ~ ~ yl 0 1 3 4-Oxadiazol-2-7693,4-CI2-C6H3 Me ~ ~ yl 0 1 3 4-Oxadiazol-2-7703,5-CI2-C6H3 Me ~ ~ yl 0 No R1 R2 R3 n Physical data 7713,4-Me2-C6H3 yl 1,3,4-Oxadiazol-2-7723,5-Me2-C6H3 Me yl 773 3-PhO-C6H4 yl 774 4-C1-3-Et-C6H3 yl 775 3-EtO-C6H4 Me1~3~4-oxadiazol-2- 0 776 3-CF3-C6H4 Me1~3~4-oxadiazol-2- 0 777 4-CF3-C6H4 Me1~3~4-oxadiazol-2- 0 778 3-i-pro-c6H4 yl 779 3-i-Pr-C6H4 yl 7804-cl-3-Me-c6H3 Me1,3,4-Oxadiazol-2-No R1 R2 R3 n Physical data 781Pyridin-2-yl Me1,3,4-Oxadiazol-2- 1 1,3,4-Oxadiazol-2-782Pyridin-3-yl Me yl 5-CI- 1,3,4-Oxadiazol-2-783pyridin-2-yl Me yl 784 3-CI- M1,3,4-Oxadiazol-2- 1 pyndin-2-yl yl 785 6-CI- Me1,3,4-Oxadiazol-2- 1 pyridin-2-yl yl 786 2-CI- Me1,3,4-Oxadiazol-2- 1 pyridin-3-yl yl 7875-CF3- Me1,3,4-Oxadiazol-2- 1 pyridin-2-yl yl 7883-CF3- M1,3,4-Oxadiazol-2- 1 pyridln-2-yl yl 7896-CF3-3-CI- M1,3,4-Oxadiazol-2- 1 pyridin-2-yl yl 5-CF3-3-CI- M1,3,4-Oxadiazol-2- 1 pyridin-2-yl yl No R1 R2 R3 n Physical data 791Benzothiazol Me1,3,4-Oxadiazol-2 792Benzoxazol yl 1 3 4-Oxadiazol-2-793 Quinolin-2-yl Me ' ' yl 5-CF3-1,3,4- Me1,3,4-Oxadiazol-2-thiadiazol-2-yl yl 795Pyrimidin-2-yl Me1~3~4-oxadiazol-2- 1 7965-CI-6-Me- Me1~3~4-oxadiazol-2- 1 - pyrimidin4-yl yl 7975-Et-6-Me- Me1~3~4-oxadiazol-2- 1 pyrimidin-4-yl yl 6-CI- 1 3,4-Oxadiazol-2-798pyrazin-2-yl Me' yl 3,6-Me2- M1,3,4-Oxadiazol-2- 1 pyrazin-2-yl yl 5-Me- 1 3 4-Oxadiazol-2-80ûisoxazol-3-yl Me ' ' yl No R1 R2 R3 n Physical data 801 C6H5 M1l2~4-oxadiazol-3- 1 mp70.s-71-5 C
1,2,4-Oxadiazol-3-8022-F-C6H4 Me yl 8033-F-C6H4 yl 1 2,4-Oxadiazol-3-804 4-F-C6H4 Me ' yl 8052-CI-C6H4 Me1~2~4-oxadiazol-3- 1 mp139.0-140.0 C

8063-CI-C6H4 yl 8074-CI-C6H4 M1~2~4-oxadiazol~- 1 mp 107-108 C

8082-Br-C6H4 yl 8093-Br-C6H4 yl 1 2 4-Oxadiazol-3-810 4-Br-C6H4 Me ' ' yl No R1 R2R3 n Physical data 8113-l-C6H4 Me1,2,4-Oxadiazol~ 1 8122-Me-C6H4 M1 ,2,4-oxadiazol-3- 1 mp 79-80C
1 ,2,4-Oxadiazol-3-8133-Me-C6H4 Meyl 8144-Me-C6H4 M1 ,2,4-oxadiazol-3- 1 mpg2 5-93.5 C

8152-Et-C6H4 Me1,2,4-Oxadiazol-3- 1 1,2,4-Oxadiazol-3-8163-Et-C6H4 Meyl 8174-Et-C6H4 yl 8182-MeO-C6H4 yl 8193-Meo-c6H4 Me1,2,4 Oxaldiazol3 1 2 4-Oxadiazol~-820 4-MeO-C6H4 Me ' ' yl No R1 R2 R3 n Physical data H 1 2,4-Oxadiazol 3 821 2-CF3-C6 4 Me' yl 822 3-CF3-C6H4 yl 1,2,4-Oxadiazol~-823 4-CF3-C6H4 Me yl 824 2,4-F2-C6H3 yl 1,2,4-Oxadiazol~-825 2,5-F2-C6H3 Me yl 826 2,6-F2-C6H3 yl 827 3 4-F2-C6H3 yl 1,2 4-Oxadiazol-3-828 3,5-F2-C6H3 Me 1,2 4-Oxadiazol-3-829 2,3-CI2-C6H3 Me 830 2,4-CI2-c6H3 yl No R1 R2R3 n Physical data 1 2,4-Oxadiazol-3- 1 8312,5-CI2-C6H3 Me' yl 8323,4-CI2-C6H3 yl 8333,5-CI2-C6H3 yl 1 2 4-Oxadiazol~-8342,3-Me2-C6H3 Me'' yl 8352,4-Me2-C6H3 Me1,2,4-Oxadiazol3 1,2 4-Oxadiazol-3- 1 IsomerA:mp116.5-117.5 C
8362,5-Me2-C6H3 Me' IsomerB:mp 69-71 C
1,2,4-Oxadiazol-3- 1 8373,4-Me2-C6H3 Meyl 1,2,4-Oxadiazol-3-8383,5-Me2-C6H3 Meyl 1 2 4-Oxadiazol~-8392-CI-4-Me-C6H3 Me'' yl 1,2 4-Oxadiazol-3-8402-CI-5-Me-C6H3 Me No R1 R2 R3 n Physical data 8414-cl-2-Me-c6H3 Me1,2,4-Oxadiazol-3 1,2,4-Oxadiazol-3-8424-Cl-3-Me-c6H3 Me yl 8433-Ph-C6H4 yl 8444-Ph-C6H4 M1,2,4-Oxadiazol-3- 1 mp147.5-148.5 C

8453-i-PrO-C6H4 yl 8463-i-Pr-C6H4 yl 8474-i-Pr-C6H4 Me1,2,4-Oxadiazol-3- 1 8483-t-Bu-C6H4 yl 1,2,4-Oxadiazol-3- 1 8492-MeS-C6H4 Meyl 8504-MeS-C6H4 yl No R1 R2 R3 n Physical data 1,2 4-Oxadiazol-3-8512,3,6-F3-C6H2 Me 1,2,4-Oxadiazol~-8522,4,5-CI3-C6H2 Me yl 1,2 4-Oxadiazol-3-853 3-PhO-C6H4 Me 3,4,5-(MeO) 3- 1,2,4-Oxadiazol-3-854C6H2 Meyl 1,2 4-Oxadiazol~-8552,3,5-Me 3-C6H2 Me 8563,4,5-Me 3-C6H2 Me1,2,4-Oxadiazol~ 1 1 2 4-Oxadiazol-3-857C6F5 Me' ' I

8584-C1-3-Et-C6H3 yl 1,2,4-Oxadiazol-3- 1 8593-EtO-C6H4 Meyl 1,2,4-Oxadiazol-3- 1 8604-EtO-C6H4 Meyl -No R1 R2 R3 n Physical data 861C6H5 Me1,2,4-Oxadiazol~ 0 1,2 4-Oxadiazol-3-8624-F-C6H4 Me ' 0 1 2 4-Oxadiazol~-8633-CI-C6H4 Me' ' yl 0 8644-CI-C6H4 yl 8653-Me-C6H4 Me1~2~4-0Xadiazol~ 0 8664-Me-C6H4 Me1,2,4-Oxadiazol-3 0 8674-Et-C6H4 Me1~2~4-Oxadiazol-3 0 8684-NO2-C6H4 M1,2,4-Oxadiazol~- 0 8693,4-CI2-C6H3 yl 8703,5-CI2-C6H3 yl No R1 R2 R3 n Physical data 1,2,4-Oxadiazol-3- 0 8713.4-Me2-C6H3 Me yl 1,2,4-Oxadiazol-3- 0 8723,5-Me2-C6H3 Me yl 1,2,4-Oxadiazol-3- 0 8733-PhO-C6H4 Me yl 1 2 4-Oxadiazol-3-8744-CI-3-Et-C6H3 Me ' ' yl 1,2 4-Oxadiazol-3- 0 8753-EtO-C6H4 Me 1,2,4-Oxadiazol-3- 0 8763-CF3-C6H4 Me yl 1,2,4-Oxadiazol-3- 0 8774-CF3-C6H4 Me yl 1,2,4-Oxadiazol-3- 0 8783-i-PrO-C6H4 Me yl 1,2,4-Oxadiazol-3- 0 8793-i-Pr-C6H4 Me yl 1,2,4-Oxadiazol-3- 0 8804-Cl-3-Me-c6H3 Me yl No R1 R2R3 n Physical data 1 2 4-Oxadiazol-3-881 Pyridin-2-yl Me '' I

1 2 4-Oxadiazol-3- -882 Pyridin-3-yl Me '' yl 5-CI- 1,2,4-Oxadiazol-3-883pyridin-2-yl Me yl 3-CI- 1,2,4-Oxadiazol-3-884pyridin-2-yl Me yl 885pyridln 2 yl Me1,2,4-Oxadiazol-3 886 2-CI- Me1~2~4-oxadiazol-3- 1 mp 177-1785 C
pyridin-3-yl yl 8875-CF3- Me1,2,4-Oxadiazol-3- 1 pyridin-2-yl yl 3-CF3- 1 2 4-Oxadiazol-3-888pyridin-2-yl Me'' I
6-CF3-3-CI- 1 2 4-Oxadiazol-3-889pyridin-2-yl Me'' yl 5-CF3-3-CI- 1 2,4-Oxadiazol-3-890pyridin-2-yl Me ' yl No R1 R2 R3 n Physical data 891 Benzot~iazol yl 892 Benzoxazol Me1,2,4-Oxadiazol-3- 1 1,2,4-Oxadiazol-3-893 Quinolin-2-yl Me yl 894 5-CF3-1,3,4- Me1,2,4-Oxadiazol-3- 1 thiadiazol-2-yl yl 895 Pyrimidin-2-yl Me1,2,4-Oxadiazol 3 896 5-CI-6-Me- Me1~2,4-Oxadiazol-3- 1 pyrimidin-4-yl yl 897 5-Et-6-Me- Me1,2,4-Oxadiazol-3- 1 pyrimidin-4-yl yl 898 6-CI- Me1,2,4-Oxadiazol-3- 1 pyrazin-2-yl yl 899 3,6-Me2- yl pyrazln-2-yl 900 isoxazol-3-yl yl No R1 R2 R3 n Physical data 1H-NMR(CDCI3) ~ ppm: -H 5-Me-1,2,4- 1 2.64(3H, s), 4.07(3H, s), 901C6 5 Meoxadiazol-3-yl 4.98(2H, s), 6.82-6.94(2H, m), 7.18-7.63(7H, m) 9022-F-C6H4 Meoxadiazol-3-yl 9033-F-C6H4 Meoxadiazol-3-yl 9044-F-C6H4 Me5-Me-1,2,4-9052-CI-C6H4 Meoxa~;~,OI3 yl 1 mp88-5 89.5 C

9063-CI-C6H4 Meoxadiazol-3-yl 9074-CI-C6H4 Me5-Me-1,2,4- 1 mp 125-126C

9082-Br-C6H4 Me5-Me-1,2,4-9093-Br-C6H4 Meoxadiazol-3-yl 9104-Br-C6H4 Me5-Me;1,2,4-No R1 R2 R3 n Physical data 9113-l-C6H4 Meoxadiazol-3-yl 9122-Me-C6H4 Me5-Me-1,2,4- 1 mp 86 87 5C
5-Me-1 ,2 ,4-9133-Me-C6H4 Meoxadiazol-3-yl 9144-Me-C6H4 Me5-Me-1,2,4- 1 mp92 5 93 5 C

9152-Et-C6H4 Meoxadiazol-3-yl 9163-Et-C6H4 Me5-Me-1,2,4-9174-Et-C6H4 Meoxadiazol-3-yl 9182-MeO-C6H4 Meoxadiazol-3-yl 5-Me-1 ,2,4-9193-Meo-c6H4 Meoxadiazol-3-yl 9204-MeO-C6H4 Me oY~ 7ol 3 yl No R1 R2 R3 n Physical data 9212-CF3-C6H4 Meoxadiazol-3-yl 9223-CF3-C6H4 Meoxadiazol-3-yl 9234-CF3-C6H4 Meoxadiazol-3-yl 9242,4-F2-C6H3 Me5-Me-1,2,4-9252,5-F2-C6H3 Me5-Me-1,2,4-9262,6-F2-C6H3 Me5-Me-1,2,4-9273,4-F2-C6H3 Meoxadiazol-3-yl 9283,5-F2-C6H3 Meoxadiazol-3-yl 9292,3-CI2-C6H3 Meoxadiazol-3-yl 9302,4-C12-C6H3 Me5-Me-1,2 4-No R1 R2 R3 n Physical data 9312,5-CI2-C6H3 Meoxadiazol-3-yl 9323,4-CI2-C6H3 Meoxadiazol-3-yl 9333,5-CI2-C6H3 Me5-Me-1,2,4-9342,3-Me2-C6H3 Meoxadiazol-3-yl 9352,4-Me2-C6H3 Meoxadiazol-3-yl - 5-Me-1,2,4- 1 Isomer Amp 98-100C
9362,5-Me2-C6H3 Meoxadiazol-3-yl Isomer Bmp 130-131.5 C

9373,4-Me2-C6H3 Meoxadiazol-3-yl 9383,5-Me2-C6H3 Meoxadiazol-3-yl 9392-CI-4-Me-C6H3 Meoxadiazol-3-yl 9402-CI-5-Me-C6H3 Meoxadiazol-3-yl No R1 R2 R3 n Physical data 9414-Cl-2-Me-c6H3 Meoxadiazol-3-yl 1 mp 115-116C

9424-Cl-3~Me-c6H3 Meoxadiazol-3-yl 5-Me-1,2,4-9433-Ph-C6H4 Meoxadiazol-3-yl 9444-Ph-C6H4 MeS-Me-1,2,4- 1 124 5 125 5 C

9453-i-PrO-C6H4 Meoxadiazol-3-yl 9463-i-Pr-C6H4 Meo)xa~i~70l 3 y 9474-i-Pr-C6H4 Me5-Me-1,2,4-9483-t-Bu-C6H4 Meoxa~i~7ol 3 yl 9492-MeS-C6H4 Meoxadiazol-3-yl 9504-MeS-C6H4 Meoxadiazol-3-yl No R1 R2 R3 n Physical data 9512.3,6-F3-C6H2 Meoxadiazol-3-yl 9522.4,5-CI3-C6H2 Me5-Me-1,2,4-9533-PhO-C6H4 Meoxadiazol-3-yl 3,4,5-(MeO) 3- 5-Me-1,2,4-C6H2 Meoxadiazol-3-yl 9552,3,5-Me 3-C6H2 Me5-Me-1,2,4-9563,4,5-Me 3-C6H2 Me5-Me-1,2,4-5-Me-1,2,4-957 C6F5 Meoxadiazol-3-yl 9584-Cl-3-Et-c6H3 Meoxadiazol-3-yl 9593-EtO-C6H4 Meoxadiazol-3-yl 9604-EtO-C6H4 Meoxadiazol-3-yl No R1 R2 R3 n Physical data 961C6H5 Meoxadiazol-3-yl 9624-F-C6H4 Meoxadiazol-3-yl 9633-CI-C6H4 Mes-Me-1~2~4- 0 9644-CI-C6H4 Meoxadiazol-3-yl 9653-Me-C6H4 Meoxadlazol-3-yl 9664-Me-C6H4 Me5-Me-1,2,4- 0 9674-Et-C6H4 Meoxadiazol-3-yl 9684-N02-C6H4 Meoxadiazol-3-yl 9693,4-CI2-C6H3 Meoxadiazol-3-yl 9703,5-CI2-C6H3 Meoxadiazol-3-yl -No R1 R2 R3 n Physical data 9713,4-Me2-C6H3 Me5-Me-1,2,4- 0 9723,5-Me2-C6H3 Me~XA~; 7~13 yl 9733-Pho-c6H4 Meoxadiazol-3-yl 9744-CI-3-Et-C6H3 Meoxadlazol-3-yl 9753-EtO-C6H4 Meoxadiazol-3-yl 9763-CF3-C6H4 Meoxadiazol-3-yl 9774-CF3-C6H4 Me5-Me-1,2,4- 0 5-Me-1,2,4-9783-i-PrO-C6H4 Meoxadiazol-3-yl 9793-i-Pr-C6H4 Meoxadiazol-3-yl 9804-Cl-3-Me-c6H3 Meoxadiazol-3-yl 21 8694~

No R1 R2 R3 n Physical data 981Pyridin-2-yl Meo~ ol 3 yl 982Pyridin-3-yl Meo.y~ 70l 3 y 983pyridin-2-yl Me5-Me-1,2,4-984 pyridin-2-yl Me oxadiazol-3-yl 985 6-CI- Me5-Me-1,2,4- 1 pyridin-2-yl oxadiazol-3-yl 986 2-CI- Me5-Me-1,2,4- 1 mp 82.5-84.5 C
pyridin-3-yl oxadiazol-3-yl 9875-CF3- Me5-Me-1,2,4-pyridin-2-yl oxadiazol-3-yl 988 pyridin-2-yl Me oxadiazol-3-yl 6-CF3-3-CI- 5-Me-1,2,4-989pyridin-2-yl Meoxadiazol 3-yl 5-CF3-3-CI- 5-Me-1,2,4-pyridin-2-yl Meoxadiazol-3-yl -No R1 R2 R3 n Physical data 991Benzothiazol Me5-Me-1,2,4- 1 -2-yl oxadiazol-3-yl 992Benzoxazol Me5-Me-1,2,4--2-yl oxadiazol-3-yl 993 Quinolin-2-yl Me oxadiazol-3-yl 994 thi di3 12 I Me 5-Me-1,2,4-995Pyrimidin-2-yl Me5-Me-1,2,4-oxadiazol-3-yl 9965-CI~-Me- Me5-Me-1,2,4-pyrimidin-4-yl oxadiazol-3-yl 5-Et~-Me- M5-Me-1,2,4-pyrimidin4-yl oxadiazol-3-yl 998pyrazin-2-yl MeoY~ 70l-3-y 3,6-Me2- 5-Me-1,2,4-pyrazin-2-yl Meoxadiazol-3-yl 5-Me- 5-Me-1,2,4-isoxazol-3-yl Meoxadiazol-3-yl -No R1 R2 R3 n Physical data 1001C6H5 Metet;azol-5-yl 1 mp 83.0-84.5C

10022-F-C6H4 Metet;azol-5-yl 10033-F-C6H4 Metet;azol-5-yl 10044-F-C6H4 Me1 ;Me-1 H-10052-CI-C6H4 Metet;azol-5-yl 1 mp 118-119C

10063-CI-C6H4 Me1 -Me-1 H-10074-CI-C6H4 Me1 -Me-1 H- 1 mp 95-96 C

10082-Br-C6H4 Metet;azol-5-yl 10093-Br-C6H4 Metet;azol-5-yl 10104-Br-C6H4 Metet;azol-5-yl 2t 86947 No R1 R2 R3 n Physical data 10113-l-C6H4 Metet;azol-5-yl 10122-Me-C6H4 Metet;azol-5-yl 1 mp 111-112C

10133-Me-C6H4 Me1 ;Me-1 H-10144-Me-C6H4 Metet;azol-5-yl 1 mp 138.5-139.5C

10152-Et-C6H4 Me1 ;Me-1 H-10163-Et-C6H4 Metet;azol-5-yl 10174-Et-C6H4 Metet;azol-5-yl 10182-MeO-C6H4 Metet;azol-5-yl 10193-MeO-C6H4 Metet;azol-5-yl 10204-MeO-C6H4 Metet;azol-5-yl No R1 R2 R3 n Physical data 10212-CF3-C6H4 Metet;azol-5-yl 'H-NMR(CDCI3) ~ ppm:
10223-CF3-C6H4 Metet;azol-5-yl 1 4.03(3H, s),4.21 (3H, s), 4.99(2H, s),6.82-7.53(8H, m) 10234-CF3-C6H4 Metet;azol-5-yl 10242,4-F2-C6H3 Metet;azol-5-yl 10252,5-F2-C6H3 Me1 ;Me-1 H-10262,6-F2-C6H3 Metet;azol-5-yl 10273,4-F2-C6H3 Metet;azol-5-yl 10283,5-F2-C6H3 Metet;azol-5-yl 10292,3-CI2-C6H3 Metet;azol-5-yl 10302,4~CI2-C6H3 Metet;azol-5-yl No R1 R2 R3 n Physical data 10312,5-CI2-C6H3 Me1 ;Me-1 H-10823,4-CI2~6H3 Metet;azol-5-yl 1 mp 127-127.5C

10333,5-Cl2-c6H3 Metet;azol-5-yl 10342,3-Me2-C6H3 Metet;azol-5-yl 10352.4-Me2-C6H3 Metet;azol-5-yl 10362,5~Me2-C6H3 Metet;azol-5-yl 1 mp 115.5-116.5C

10373,4-Me2-C6H3 Metet;azol-5-yl 10383.5-Me2-C6H3 Metet;azol-5-yl 10392-CI-4-Me-C6H3 Metet;azol-5-yl 10402-CI-5-Me-C6H3 Metet;azol-5-yl No R1 R2 R3 n Physical data 10414-Cl-2-Me-c6H3 Metet;azol-5-yl 1 mp126.5-127.5C

10424-Cl-3-Me-c6H3 Me1 ;Me-1 H-1-Me-1 H-10433-Ph-C6H4 Metetrazol-5-yl 10444-Ph-C6H4 Me1;Me-1H- 1 mp130.5-131.5C

10453-i-PrO-C6H4 Me1 -Me-1 H-10463-i-Pr-C6H4 Me1-Me-1 H-10474-i-Pr-C6H4 Me1 -Me-1 H-10483-t-Bu-C6H4 Me1 ;Me-1 H-10492-MeS-C6H4 Me1 ;Me-1 H-10504-MeS-C6H4 Me1 ;Me-1 H-No R1 R2 R3 n Physical data 10512,3,6-F3~6H2 Me 1 -Me-1 H-10522,4,5-CI3-C6H2 Me1 ;Me-1 H-10533-PhO-C6H4 Metet;azol-5-yl 3,4,5-(MeO)3- 1-Me-1 H-1054 C6H2 Metetrazol-5-yl 10552.3,5-Me3-C6H2 Me 1 -Me-1 H-10563,4,5~Me3-C6H2 Me1 ;Me-1 H-1057 C6F5 Metet;azol-5-yl 10584~Cl~3~Et-c6H3 Me1 ;Me-1 H-10593-EtO-C6H4 Me 1 -Me-1 H-10604-EtO-C6H4 Me 1 -Me-1 H-No R1 R2 R3 n Physical data 1061 C6H5 Metet;azol-5-yl 10624-F-C6H4 Metet;azol-5-yl 10638-CI-C6H4 Metet;azol-5-yl 10644-CI-C6H4 Metet;azol-5-yl 10653-Me-C6H4 Me1 -Me-1 H- 0 10664-Me-C6H4 Metet;azol-5-yl 10674-Et-C6H4 Metet;azol-5-yl 10684-NO2-C6H4 Me1 ;Me-1 H-10693.4-Cl2-c6H3 Metet;azol-5-yl 10703.5-Cl2-c6H3 Metet;azol-5-yl No R1 R2 R3 n Physical data 10713,4-Me2-C6H3 Metet;azol-5-yl 10723,5-Me2-C6H3 Metet;azol-5-yl 10733-PhO-C6H4 Me1 -Me-1 H-10744-Cl-3-Et-c6H3 Metetrazol-5-yl 10753-EtO-C6H4 Metetrazol-5-yl 10763-CF3-C6H4 Metet;azol-5-yl 10774-CF3-C6H4 Me1 -Me-1 H- 0 10783-i-PrO-C6H4 Me1 -Me-1 H- 0 10793-i-Pr-C6H4 Me1 -Me-1 H- 0 10804-Cl-3-Me-c6H3 Metet;azol-5-yl No R1 R2 R3 n Physical data 1081 Pyridin-2-yl Me tet;azol-5-yl 1082 Pyridin-3-yl Me tet;azol-5-yl 1083 pyridin-2-yl Me tet;azol-5-yl 1084 pyridin-2-yl Me tet;azol-5-yl 1085pyridin-2-yl Me 1 -Me-1 H-1086pyridin-3-yl Me 1 -Me-1 H-10875-CF3- Me 1 -Me-1 H-pyridin-2-yl tetrazol-5-yl 1088pyridin-2-yl Me 1 -Me-1 H
6-CF3-3-CI- 1-Me-1 H-1089pyridin-2-yl Metetrazol-5-yl 1090pyridin-2-yl Me 1-Me-1 H-No R1 R2 R3 n Physical data 1091 Benzothiazol Me 1-Me-1 H--2-yl tetrazol-5-yl 1092 Benzoxazol Me 1-Me-1 H- 1 1093 Quinolin-2-yl Me 1 -Me-1 H-1094 thi di3 12 I Metet;azol-5-yl 1095 Pyrimidin-2-yl Me 1 -Me-1 H-1096 5-CI-6-Me- Me 1 -Me-1 H-pyrimidin4-yl tetrazol-5-yl 1097 5-Et-6-Me- Me 1 -Me-1 H-pyrimidin4-yl tetrazol-5-yl 1098 pyrazin 2-yl Me tet;azol-5-yl 3,6-Me2- 1-Me-1 H-1099 pyrazin-2-yl Me tetrazol-5-yl 1100 s-Me- Me 1 ;Me-1 H-No R1 R2 R3 n Physical data 1H-NMR(CDCI3) ~ ppm: 2.75(3H, s), 1-Me-2- 3.40(2H, t, J=9.8), 3.92(2H, t, J=9.8), 1101 C6H5 Me imidazolin-2- 1 3.97(3H, s), 5.37(2H, s), 6.93-6.98(3H, yl m), 7.25-7.35(3H, m), 7.40(1H, t, J=7.5), 7.52(1 H, d, J=7.5), 7.68(1 H, d, J=7.5) 1 -Me-2-11022-F-C6H4 Me imidazolin-2- 1 yl 1 -Me-2-11033-F-C6H4 Me i",~ -2-yl 1 -Me-2-11044-F-C6H4 Me i"~'d 7rl ~-2-yl 1 -Me-2-11052-CF3-C6H4 Me imidazolin-2- 1 yl 1 -Me-2-11063-CF3-c6H4 Me imidazolin-2- 1 yl 1 -Me-2-11074-CF3~c6H4 Me imidazolin-2- 1 yl 1 -Me-2-11082-Br-C6H4 Me i", ~ -'i ,-2-yl 1 -Me-2-11093-Br-C6H4 Me i", ' -a' ~-2- 1 yl 1 -Me-2-11104-Br-C6H4 Me illl~d-~ -2-yl No R1 R2 R3 n Physical data 1 -Me-2-11113-l-C6H4 Meimidazolin-2-yl 1H-NMR(CDCI3) ~ ppm: 2.33(3H, s), 1-Me-2- 2.74(3H, s), 3.40(2H, t, J=9.8), 3.93(2H, 111 22-Me-C6H4 Meimidazolin-2- 1 t, J=9.8), 4 02(3H, s), 5.38(2H, s), 6.82-yl 6.88(2H, m), 7.31-7.35(2H, m), 7.33(1H, t, J=7.7), 7.41(1H, t, J=7.7), 7.51(1H, d, J=7.7), 7.76(1 H, d, J=7.7) 1H-NMR(CDCI3)~ppm: 2.32(3H, s), 1-Me-2- 2.75(3H, s), 3.40(2H, t, J=9.8), 3.92(2H, 111 33-Me-C6H4 Meimidazolin-2- 1 t, J=9-8), 3.90(3H, s), 5.35(2H, s), 6.75-yl 6.80(3H, m), 7.16(1H, t, J=7.6), 7.30-7.43(2H, m), 7.51(1H, dd, J=7.6, 1.5), 7.68(1H, d, J=7.6) 'H-NMR(CDCI3) ~ ppm: 2.28(3H, s), 1-Me-2- 2.75(3H, s), 3.40(2H, t, J=9.8), 3.92(2H, 111 44-Me-C6H4 Meimidazolin-2- 1 t~ J=9.8)~ 3 98(3H~ s)~ 5-34(2H~ s)~
yl 6.85(2H, d, J=8.5), 7.07(2H, d, J=8.5), 7.29-7.42(2H, m), 7.51(1H, dd, J=7.6, 1.5), 7.67(1 H, d, J=7.6) 1 -Me-2-111 52-Et-C6H4 Meimidazolin-2-yl 1 -Me-2-111 63-Et-C6H4 Meimidazolin-2-yl 1 -Me-2-11174-Et-C6H4 Me i".. '-7c' ~-2-yl 1 -Me-2-111 82-Me-C6H4 Me imidazolin-2-yl 1 -Me-2-111 93-Me-C6H4 Me imidazolin-2-yl 1 -Me-2-11204-Me-C6H4 Me imidazolin-2-yl No R1 R2R3 n Physical data ~ H-NMR(CDCI3) ~ ppm: 2.75(3H, s), 1 -Me-2- 3.41 (2H, t, J=9.8), 3.93(2H, t, J=9.8), 6 4 1 7 18(1 H ddd, J=8.5 7 6, 1.5;, 7.31-Y 7.45(3H, m), 7.49(1 H, dd, J=7.6, 1.5), 7.81(1H, d, J=7.6) Isomer A1H-NMR(CDCI3) ~ ppm: 2.75(3H, s), 3.41 (2H, t, J=9.8), 3.92(2H, t, J=9.8), 3.97(3H, s), 5.35(2H, s), 6.84- 6.99(3H, m), 7.19(1H, t, J=8.0), 7.32-7.44(2H, m), 1 -Me-2- 7.51(1 H, dd, J=7.3, 1.4), 7.64(1 H, d, 1122 3-Cl-c6H4 Me i", 'o~ -2- 1 J=7.0) yl Isomer B 1H-NMR(CDCI3) ~ ppm: 3.03(3H, s), 3.38(2H, t, J=9.9), 3.77(2H, t, J=9.9), 3.97(3H, s), 4.99(2H, s), 6.83- 7.16(4H, m), 7.23(1H, d, J=7.6), 7.34-7.39(2H, m), 7.49(1H, d, J=6.4) 1 -Me-2-1123 4-Cl-c6H4 Me i",~ l ,-2- 1 mp53-56C
yl 1 -Me-2-1124 2,4-F2-C6H3 Me imidazolin-2- 1 yl 1 -Me-2-1125 2,5-F2-C6H3 Me imidazolin-2- 1 yl 1 -Me-2-1126 2,6-F2-C6H3 Me imidazolin-2- 1 yl 1 -Me-2-1127 3,4-F2-C6H3 Me i",-'---l ,-2- 1 yl 1 -Me-2-1128 3,5-F2-C6H3 Me imidazolin-2- 1 yl 1 -Me-2-1129 2,3-CI2-C6H3 Me imidazolin-2- 1 yl 1 -Me-2-1130 2,4-c12-c6H3 Me imidazolin-2- 1 yl No R1 R2 R3 n Physical data 1 -Me-2-1131 2,5-CI2-C6H3Me imidazolin-2- 1 yl 1 -Me-2-1132 3,4-Cl2-c6H3Me imidazolin-2- 1 yl 1 -Me-2-1133 3.5-Cl2-c6H3Me imidazolin-2- 1 yl 2,3-Me2- 1-Me-2-1~34 C Me i~ -2- 1 6H3 yl 2,4-Me2- 1-Me-2-1135 C H Me i",~ cl ~-2- 1 6 3 yl 2,5-Me2- 1-Me-2-1136 C H Me imidazolin-2- 1 mp 88-90C
6 3 yl 3,4-Me2- 1-Me-2-1~37 C Me imidazolin-2- 1 6H3 yl 3,5-Me2- 1-Me-2-1138 Me imidazolin-2- 1 C6H3 yl 2-CI-4-Me- 1-Me-2-1139 C HMe imidazolin-2- 1 6 3 yl 2-CI-5-Me- 1-Me-2-1140 Me imidazolin-2- 1 C6H3 yl No R1 R2 R3 n Physical data 11414-cl-2-Me-c6H3 Me1-Me-2-imidazolin- 1 1 -Me-2-imidazolin-11424-Cl-3-Me-c6H3 Me 2-yl 1 -Me-2 -imidazolin-11433-Ph-C6H4 Me 2-yl 11444-Ph-C6H4 Me1-Me-2-imidazolin-11453-i-PrO-C6H4 Me1-Me-2-imidazolin- 1 11463-i-Pr-C6H4 Me1-Me-2-imidazolin- 1 11474-i-Pr-C6H4 Me1-Me-2-i",. ~
1 -Me-2-imidazolin-11483-t-Bu-C6H4 Me 2-yl 1 -Me-2-imidazolin-11492-MeS-C6H4 Me 2-yl 11504-MeS-C6H4 Me 2-yl No R1 R2 R3 n Physical data 1 -Me-2-imidazolin-1151 2.3,6-F3-C6H2 Me 2-yl 1 -Me-2-imidazolin-1152 2,4,5-CI3-C6H2 Me 2-yl 1 -Me-2-imidazolin-1153 3-PhO-C6H4 Me 2-yl 3,4,5-(MeO)3- 1-Me-2-i", '~
1154 C6H2 Me 2-yl 1 -Me-2-imidazolin-1155 2,3,5-Me3-C6H2 Me 2-yl 1156 3 4 5-Me3-C6H2 Me 1-Me-2-imidazolin-1157 C6F5 Me1-Me-2-imidazolin- 1 13 E C H 1-Me-2-imidazolin-1158 4-C-- t- 6 3 Me2-yl 1159 3-EtO-C6H4 Me1-Me-2-imidazolin- 1 E O 1-Me-2-imidazolin-1160 4- t-C6H4 Me 2-yl -No R1 R2 R3 n Physical data ' H-NMR(CDCI3) ~ ppm:
2.80(2.91)(3H, s), 1161 C H M 1-Me-2-imidazolin- 0 3.03(3.14)(2H, s), 6 5 2-yl 3.53(3.61)(2H, t, J=9.8), 4.05(3.95)(3H, s), 6.96-7.72(9H, m) 11624-F-C6H4 Me 1-Me-2-imidazolin- 0 11633-CI-C6H4 Me 1-Me-2-i", ~ - 0 1 -Me-2-imidazolin-11644-CI-C6H4 Me 2-yl 11653-Me-C6H4 1-Me-2-i"ld~-~' )-11664-Me-C6H4 2-yl 11674-Et-C6H4 Me 1-Me-2-imidazolin- 0 11684-NO2-C6H4 Me 1~Me-2-imidazoljn 0 11693 4-CI2-C6H3 2-yl 11703 5-CI2-C6H3 2-yi No R1 R2 R3 n Physical data 1 -Me-2-imidazolin-11713.4-Me2-C6H3 Me 2-yl 1 -Me-2-imidazolin-11723.5-Me2-C6H3 Me 2-yl 11733-PhO-C6H4 M1-Me-2-i"l~d~ - 0 1 -Me-2-imidazolin-11744-Cl-3-Et-c6H3 Me 2-yl 11753-EtO-C6H4 2-yl 1 -Me-2-imidazolin-11763-CF3-C6H4 Me 2-yl 1 -Me-2-imidazolin-11774-CF3-C6H4 Me 2-yl 11783-i-PrO-C6H4 Me1-Me-2-imidazolin- 0 11793-i-Pr-C6H4 1 Me 2 i '~

1180 4-CI-3-Me-C6H3 Me 1-Me-2-imidazolin- 0 No R1 R2 R3 n Physical data 1 -Me-2-imidazolin-1181Pyridin-2-yl Me 2-yl 1182Pyridin-3-yl 2-yl 5-CI- 1-Me-2-imidazolin-1183pyridin-2-yl Me 2-yl 3-CI- 1-Me-2-imidazolin-1184pyridin-2-yl Me 2-yl 1185pyridin-2-yl Me 2-yl 2-CI- 1-Me-2-imidazolin-1186pyridin-3-yl Me 2-yl 1187 5-CF3- Me1-Me-2-imidazolin-pyridin-2-yl 2-yl 3-CF3- 1-Me-2-i",idA,o~
1188pyridin-2-yl Me 2-yl 6-CF3-3-CI- 1-Me-2-imidazolin-1189pyridin-2-yl Me 2-yl 5-CF3-3-CI- 1-Me-2-imidazolin-pyridin-2-yl Me 2-yl No R1 R2 R3 n Physical data 1191 Benzothiazol Me1-Me-2-imidazolin- 1 1192 Benzoxazol Me1 Me-2-imidazolin-1 -Me-2-imidazolin-1193 Quinolin-2-yl Me 2-yl 5-CF3-1,3,4- M1-Me-2-i~
thiadiazol-2-yl 2-yl . . . 1-Me-2-imidazolin-1195 Pynmldln-2-yl Me 2-yl 1196 5-CI-6-Me- Me1-Me-2-imidazolin-pyrimidin4-yl 2-yl 1197 5-Et-6-Me- Me1-Me-2-imidazolin-pyrimidin4-yl 2-yl 6-CI- 1-Me-2-imidazolin-1198 pyrazin-2-yl Me 2-yl 3,6-Me2- 1-Me-2-ill,.'- ~' I-pyrazin-2-yl Me 2-yl 5-Me- 1-Me-2-imidazolin-isoxazol-3-yl Me 2-yl No R1 R2 R3 n Physical data 1201 C6H5 Me2-lsoxazolin-3-yl 12022-F-C6H4 Me2-lsoxazolin-3-yl 12033-F-C6H4 Me2-lsox~o' 1-3-yi 12044-F-C6H4 Me2-lsoxazolin~-yl 12052-CI-C6H4 Me2-lsoxazolin-3-yl 12063-CI-C6H4 Me2-isoxazolin-3-yl 12074-CI-C6H4 Me2-lsoxazolin-3-yl .

1208 2 gr c6H4 Me 2-lsoxazolin-3-yl 1209 3-Br-C6H4 Me 2-lsoxazolin-3-yl 1210 4-Br-C6H4 Me 2-lsoxazolin-3-yl -No R1 R2 R3 n Physical data 12113-l-C6H4 Me2-lsoxazolin-3-yl 12122-Me-C6H4 Me2-lsoxazolin-3-yl 12133-Me-C6H4 Me2-lsoxazolin-3-yl 12144-Me-C6H4 Me2-lsoxazolin-3-yl 12152-Et-C6H4 Me2-lsoxazolin-3-yl 12163-Et-C6H4 Me2-lsoxazolin-3-yl 12174-Et-C6H4 Me2-lsoxazolin-3-yl 12182-MeO-C6H4 Me2-lsoxazolin~-yl 12193-MeO-C6H4 Me2-lsoxazolin-3-yl 12204-MeO-C6H4 Me2-lsoxazolin-3-yl .
DEMANDES OU BR~Vt ~ ~ VO~UMINEUX

LA P~TE PARl IE- DE CEl~ DEMANDE OU C~ BREVET
COMPREIYD PLUS D'UN TOM~
.
CECl EST 1~ TOME / DE 2 NO~E: ,P~u~ les tomes additicnels, veuiilez con~acser le Bureau canadien des bfevets ~2 ~ 8 ~ q '~

JUMBO APPLICA~IONSIPATENTS

~HIS SE~CTION OF THE APPLICATION/PATENT CONTAINS MORE
THAN ONE VOLUME

THlS IS V~UME ~/` OF 2 NOTE: F~r additi~nal v~umes please c~3ntact ~he Canadian Patent ~ffic~

Claims (30)

1. A compound of the formula (I):

wherein R1 is optionally substituted aryl, an optionally substituted heterocyclic group, mono or disubstituted methyleneamino, optionally substituted (substituted imino)methyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, substituted carbonyl or substituted sulfonyl; R is alkyl, alkenyl, alkynyl or cycloalkyl; R3 is an optionally substituted heterocyclic group; R4 is hydrogen, alkyl, alkoxy, halogen, nitro, cyano or halogenated alkyl; M is an oxygen atom, S(O)i (in which i is 0, 1 or 2), NR16 (in which R16 is hydrogen, alkyl or acyl) or a single bond; n is 0 or 1, provided that, when R3 is imidazol-1-yl or 1H-1,2,4-triazol-1-yl, n is 1; and - indicates an E- or Z-isomer or a mixture thereof; or a salt thereof.

2. A compound according to claim 1, wherein the optionally substituted heterocyclic group represented by is pyridyl, pyrimidinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyridazinyl, pyrrolyl, pyrazolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, quinolyl, indolyl, benzisothiazolyl, benzisoxazolyl or pyrazinyl, each of which is unsubstituted or substituted, or a salt thereof.

3. A compound according to claim 1, wherein R1 is phenyl or a heterocyclic group, each of which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, lower alkyl, halogenated lower alkyl, lower alkoxy, lower alkylthio, phenyl, phenoxy and nitro, or a salt thereof.

4. A compound according to claim 1, wherein R1 is phenyl; phenyl substituted with halogen and/or lower alkyl;
or pyridyl substituted with halogen and/or halogenated lower alkyl; or a salt thereof.

5. A compound according to claim 1, wherein R1 is phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 2, 5-dimethylphenyl, 2, 6-dimethylphenyl, 4-chloro-2-methyl-phenyl, 2-chloropyridin-3-yl, 3,5-dichloropyridin-2-yl, 5-trifluoromethylpyridin-2-yl, 5-trifluoromethyl-3-chloro-pyridin-2-yl or 3-trifluoromethyl-5-chloropyridin-2-yl, or a salt thereof.

6. A compound according to claim 1, wherein R1 is a group of the formula (a):

(a) wherein R9 and R10 are the same or different and are hydrogen, optionally substituted alkyl, acyl, alkylthio, alkylsulfinyl alkylsulfonyl, optionally substituted amino, cycloalkyl, optionally substituted aryl or an optionally substituted heterocyclic group, or R9 and R10 are linked together to form a monocyclic or polycyclic ring which may contain a heteroatom, or a salt thereof.

7. A compound according to claim l, wherein R9 and R10 are the same or different and are hydrogen, alkyl, haloalkyl, alkoxyalkyl, alkylcarbonyl, optionally substituted phenyl, optionally substituted naphthyl or an optionally substituted heterocyclic group, or R9 and R10 are linked together to form a cyclopentane or cyclohexane ring which may form a condensed ring with another ring, or a salt thereof.

8. A compound according to claim 1, wherein R9 is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, optionally substituted alkyl, optionally substituted hydroxyl, alkylthio, optionally substituted amino, nitro, phenyl and cyano, or a salt thereof.

9. A compound according to claim 1, wherein R9 is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of chlorine, methyl, trifluoromethyl and methoxy, or a salt thereof.

10. A compound according to claim 1, wherein R9 is morpholino, pyridyl, pyridazinyl, pyrazolyl, pyrimidinyl, furyl, thienyl, oxazolyl, isoxazolyl, benzothiazolyl, quinolyl, quinazolinyl or pyrazinyl, each of which is unsubstituted or substituted, or a salt thereof.

11. A compound according to claim 1, wherein R10 is hydrogen or alkyl, or a salt thereof.

12. A compound according to claim 1, wherein R10 is hydrogen, methyl or ethyl, or a salt thereof.

13. A compound according to claim 1, wherein R2 is alkyl or alkenyl, or a salt thereof.

14. A compound according to claim 1, wherein R2 is methyl, ethyl or allyl, or a salt thereof.

15. A compound aording to claim 1, wherein R3 is isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, furyl, thienyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiazolinyl, isoxazolinyl, imidazolinyl, oxazolinyl or thiazolidinyl, each of which is unsubstituted or substituted, or a salt thereof.

16. A compound according to claim 1, wherein R3 is imidazolyl; imidazolyl substituted with lower alkyl;
imidazolinyl; triazolyl; imidazolinyl substituted with lower alkyl; isoxazolyl; isoxazolyl substituted with lower alkyl;
oxadiazolyl; oxadiazolyl substituted with lower alkyl;
isoxazolinyl; isoxazolinyl substituted with lower alkyl;
oxazolinyl; pyrazolyl; pyrazolyl substituted with lower alkyl; thiazolinyl; furyl; tetrazolyl substituted with lower alkyl; oxazolyl; isothiazolyl substituted with lower alkyl;
thiazolidinyl; or thiazolidinyl substituted with lower alkyl or a salt thereof.

17. A compound according to claim 1, wherein R3 is imidazol-1-yl, imidazol-2-yl, 1-methylimidazol-2-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methyl-imidazol-1-yl, 2-imidazolin-2-yl, 1H-1,2,4-triazol-1-yl, 1-methyl-2-imidazolin-2-yl, isoxazol-3-yl, 3-methylisoxazol-5-yl, 5-methylisoxazol-3-yl, 5-methyl-1, 2, 4-oxadiazol-3 -yl, 3-ethyl-1,2,4-oxadiazol-5-yl, 2-isoxazolin-3-yl, 2-oxazolin-2-yl, 3-methyl-2-isoxazolin-5-yl, pyrazol-l-yl, 1-methylpyrazol-5-yl, 2-thiazolin-2-yl, 2-furyl, 3-methylisothiazol-5-yl, 1, 2, 4-oxadiazol-3-yl, 1, 2, 4-oxadiazol-5-yl, 1, 3, 4-oxadiazol-2-yl, 5-methyl-1, 3, 4-oxadiazol-2-yl, 2-methyltetrazol-5-yl, oxazol-5-yl, isoxazol-5-yl, thiazolidin-2-yl or 3-methylthiazolidin-2-yl, or a salt thereof.

18. A compound according to claim 1, wherein R4 is hydrogen, or a salt thereof.

19. A compound according to claim 1, wherein M is an oxygen atom, or a salt thereof.

20. A compound according to claim 19, wherein R1 is phenyl, R2 is methyl, R3 is imidazol-1-yl, R4 is hydrogen, and n is 1 (Compound No. 1);
R1 is 4-chlorophenyl, R2 is methyl, R3 is imidazol-1-yl, R4 is hydrogen, and n is 1 (Compound No. 7);
R1 is 2-methylphenyl, R2 is methyl, R3 is imidazol-1-yl, R4 is hydrogen, and n is 1 (Compound No. 13);
R1 is 4-methylphenyl, R2 is methyl, R3 is imidazol-1-yl, R4 is hydrogen, and n is 1 (Compound No. 15);
R1 is 2-ethylphenyl, R2 is methyl, R3 is imidazol-1-yl, R4 is hydrogen, and n is 1 (Compound No. 16);
R1 is 2,5-dimethylphenyl, R2 is methyl, R3 is imidazol-1-yl, R4 is hydrogen, and n is 1 (Compound No. 39);
R1 is phenyl, R2 is ethyl, R3 is imidazol-1-yl, R4 is hydrogen, and n is 1 (Compound No. 61);
R1 is phenyl, R2 is allyl, R3 is imidazol-1-yl, R4 is hydrogen, and n is 1 (Compound No. 81);

R1 is 2, 5-dimethylphenyl, R2 is methyl, R3 is 1-methylimidazol-2-yl, R4 is hydrogen, and n is 1 (Compound No.
136);
R1 is 4-chloro-2-methylphenyl, R2 is methyl, R3 is 1-methylimidazol-2-yl, R4 is hydrogen, and n is 1 (Compound No.
141);
R1 is 2,5-dimethylphenyl, R2 is methyl, R3 is isoxazol-3-yl, R4 is hydrogen, and n is 1 (Compound No. 336);
R1 is 5-trifluoromethylpyridin-2-yl, R2 is methyl, R3 is isoxazol-3-yl, R4 is hydroyen, and n is 1 (Compound No. 387);
R1 is 5-trifluoromethyl-3-chloropyridin-2-yl, R2 is methyl, R3 is isoxazol-3-yl, R4 is hydrogen, and n is 1 (Compound No. 390);
R1 is 2,5-dimethylphenyl, R2 is methyl, R3 is 5-methylisoxazol-3-yl, R4 is hydrogen, and n is 1 (Compound No.
436);
R1 is 2, 5-dimethylphenyl, R2 is methyl, R3 is 3-methylisoxazol-5-yl, R4 is hydrogen, and n is 1 (Compound No.
636);
R1 is 5-trifluoromethyl-3-chloropyridin-2-yl, R2 is methyl, R3 is 3-methylisoxazol-5-yl, R4 is hydrogen, and n is 1 (Compound No. 690);
R1 is 2-methylphenyl, R2 is methyl, R3 is 1, 3, 4-oxadiazol-2-yl, R4 is hydrogen, and n is 1 (Compound No.
712);

R1 is 2, 5-dimethylphenyl, R2 is methyl, R3 is 1, 3, 4-oxadiazol-2-yl, R4 is hydrogen, and n is 1 (Compound No.
736);
R1 is 4-chloro-2-methylphenyl, R2 is methyl, R3 is l, 3, 4-oxadiazol-2-yl, R4 is hydrogen, and n is 1 (Compound No.
741);
R1 is 4-chlorophenyl, R2 is methyl, R3 is 1, 2, 4-oxadiazol-3-yl, R4 is hydrogen, and n is 1 (Compound No.
807);
R1 is 2-methylphenyl, R2 is methyl, R3 is 1, 2, 4-oxadiazol-3-yl, R4 is hydrogen, and n is 1 (Compound No.
812);
R1 is 2, 5-dimethylphenyl, R2 is methyl, R3 is 1, 2, 4-oxadiazol-3-yl, R4 is hydrogen, and n is 1 (Compound No.
836);
R1 is 2-methylphenyl, R2 is methyl, R3 is 5-methyl-1,2,4-oxadiazol-3-yl, R4 is hydrogen, and n is 1 (Compound No.
912);
R1 is 2,5-dimethylphenyl, R2 is methyl, R3 is 5-methyl-1, 2, 4-oxadiazol-3-yl, R4 is hydrogen, and n is 1 (Compound No. 936);
R1 is 2, 5-dimethylphenyl, R2 is methyl, R3 is 1-methyl-2-imidazolin-2-yl, R4 is hydrogen, and n is 1 (Compound No.
1136);

R1 is 4-chlorophenyl, R2 is methyl, R3 is 1,2,4-oxadiazol-5-yl, R4 is hydrogen, and n is 1 (Compound No.
1584);
R1 is 2, 5-dimethylphenyl, R2 is methyl, R3 is 2-methyl-2H-tetrazol-5-yl, R4 is hydrogen, and n is 1 (Compound No.
2036);
R1 is 3, 5-dichloropyridin-2-yl, R2 is methyl, R3 is isoxazol-3-yl, R4 is hydrogen, and n is 1 (Compound No.
2276);
R1 is 5-chloro-3-trifluoromethylpyridin-2-yl, R2 is methyl, R3 is isoxazol-3-yl, R4 is hydrogen, and n is 1 (Compound No. 2306);
R1 is a group represented by the formula (a), R9 is 4-chlorophenyl, R10 is methyl, R2 is methyl, R3 is isoxazol-3-yl, R4 is hydrogen, and n is 1 (Compound No. 2387);
R1 is a group of by the formula (a), R9 is 3-trifluoromethylphenyl, R10 is rnethyl, R2 is methyl, R3 is isoxazol-3-yl, R4 is hydrogen, and n is 1 (Compound No.
2399);
R1 is a group of the formula (a), R9 is 3,4-dichlorophenyl, R10 is methyl, R2 is methyl, R3 is isoxazol-3-yl, R4 is hydrogen, and n is 1 (Compound No. 2408);
R1 is a group represented by the formula (a), R9 is 4-chlorophenyl, R10 is methyl, R2 is methyl, R3 is 3-methylisoxazol-5-yl, R4 is hydrogen, and n is 1 (Compound No.
2507);
R1 is a group of the formula (a), R9 is 3-trifluoromethylphenyl, R10 is methyl, R2 is methyl, R3 is thiazolidin-2-yl, R4 is hydrogen, and n is 1 (Compound No.
2799); or R1 is a group of the formula (a), R9 is 3-trifluoromethylphenyl, R10 is methyl, R2 is methyl, R3 is 3-methylthiazolidin-2-yl, R4 is hydrogen, and n is 1 (Compound No. 2839).

21. A fungicidal composition comprising a compound according to any one of claims 1 to 20 or a salt thereof as an active ingredient.

22. A process for producing a compound of the formula (I):

I

wherein each symbol is as defined in claim 1, which comprises reacting the compound of the formula (V):

V

wherein A is halogen and the other symbols are as defined in claim 1, with a compound of the formula (X):
R3-H (X) wherein R3 is an optionally substituted heterocyclic group.

23. A process according to claim 22, wherein R3 is pyrrolyl, imidazolyl, pyrazolyl or triazolyl, each of which is unsubstituted or substituted.

24. A compound of the formula (V):

V

wherein A is halogen and the other symbols are as defined in claim 1, or a salt thereof.

25. A compound according to claim 24, wherein M
is an oxygen atom, or a salt thereof.

26. A compound of the formula (XIV):

XIV
wherein each symbol is as defined in claim 1, provided that, when M is an oxygen atom and R3 is isoxazol-4-yl, n is 1, or a salt thereof.

27. A compound according to claim 26, wherein M
is an oxygen atom, or a salt thereof.

28. A compound of the formula (XLVIII):

XLVIII

wherein P is a protective group of a hydroxyl group, and the other symbols are as defined in claim 1, or a salt thereof.

29. A method for controlling or preventing phytopathogenic fungi which comprises applying as an active ingredient a compound according to claim 1 to a locus where phytopathogenic fungi propagate or will propagate.

30. Use of a compound according to claim 1 in the manufacture of a fungicidal composition.