US20090069333A1

US20090069333A1 - Fungicides

Info

Publication number: US20090069333A1
Application number: US12/187,072
Authority: US
Inventors: Patrick Jelf Crowley; Markus Dobler; Urs Mueller; John Williams
Original assignee: Syngenta Crop Protection LLC
Current assignee: Syngenta Crop Protection LLC
Priority date: 2002-12-23
Filing date: 2008-08-06
Publication date: 2009-03-12
Also published as: EP1575948B1; CN1732168A; IL169186A0; MXPA05006648A; RU2005123331A; CA2509451C; JP4847017B2; CA2509451A1; BR0317678A; GT200300298A; DK1575948T3; KR20050095830A; EP1575948A1; GB0230020D0; TWI326683B; JP2006516129A; ZA200504296B; RU2352570C2; DE60311876D1; WO2004056825A1

Abstract

This invention relates to novel derivatives of pyridopyrazines and pyridopyridazines, to processes for preparing them, to intermediate chemicals used in their manufacture, to compositions containing them and to methods of using them to combat fungi, especially fungal infections of plants. The fungicidal compounds have the general formula (1) wherein R, R¹, R², W, X Y and Z are defined in the specification

Description

This application is a division of application Ser. No. 10/540,035 filed Jun. 22, 2006, still pending, which is the National Stage of International Application No. PCT/GB2003/005250, filed Dec. 3, 2003, which claims the benefit of Great Britain Application No. 0230020.0, filed Dec. 23, 2002, all of which are incorporated herein by reference.
This invention relates to novel derivatives of pyridopyrazines and pyridopyridazines, to processes for preparing them, to certain intermediate chemicals used in their manufacture, to compositions containing them and to methods of using them to combat fungi, especially fungal infections of plants.
Derivatives of the nitrogen-containing 5,6 ring system s-1,2,4-triazolo[1,5-a]pyrimidine are known from the patent literature as being useful for controlling phytopathogenic fungi. Examples of recent patent publications include EP-A-1249452, WO 02/051845, WO 02/083676, WO 02/083677, WO 02/088125, WO 02/088126, WO 02/088127. Condensed nitrogen heterocycles used as antimycotics are known from U.S. Pat. No. 5,821,244. Derivatives of pyridopyrazines are known in the chemical literature, for example from J. Med. Chem. (1968), 11(6), 1216-18, J. Med. Chem. (1970), 13(5), 853-7 and U.S. Pat. No. 3,984,412, but not for agrochemical purposes.
The present invention is concerned with the provision of novel pyridopyrazines and pyridopyridazines for combating phytopathogenic diseases on plants and harvested food crops.
Thus, according to the present invention, there is provided a compound of the general formula (1):
wherein
W and X, W and Z, X and Y or Y and Z are N and the other two are CR⁸;
R⁸is H, halo, C_1-4alkyl, C_1-4alkoxy or halo(C_1-4)alkyl;
R is halo;
R¹is halo, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_3-8cycloalkyl, C_3-8cycloalkyl(C_1-6)alkyl, C_1-8alkoxy, C_1-8alkylthio, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, aryl(C_1-4)alkyl, aryl(C_1-4)alkoxy, heteroaryl(C_1-4)alkyl, heteroaryl(C_1-4)alkoxy, aryl(C_1-4)alkylthio, heteroaryl(C_1-4)alkylthio, morpholino, piperidino or pyrrolidino;

R²is NR³R⁴;

R³and R⁴are independently H, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, aryl, aryl(C_1-8)alkyl, C_3-8cycloalkyl, C_3-8cycloalkyl(C_1-6)alkyl, heteroaryl, heteroaryl(C_1-8)alkyl, NR⁵R⁶, provided that not both R³and R⁴are H or NR⁵R⁶, or
R³and R⁴together form a C_3-7alkylene or C_3-7alkenylene chain optionally substituted with one or more C_1-4alkyl or C_1-4alkoxy groups, or,
together with the nitrogen atom to which they are attached, R³and R⁴form a morpholine, thiomorpholine, thiomorpholine S-oxide or thiomorpholine S-dioxide ring or a piperazine or piperazine N—(C_1-4)alkyl (especially N-methyl) ring; and
R⁵and R⁶are independently H, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, aryl, aryl(C_1-8)alkyl, C_3-8cycloalkyl, C_3-8cycloalkyl(C_1-6)alkyl, heteroaryl or heteroaryl(C_1-8)alkyl;
any of the foregoing alkyl, alkenyl, alkynyl or cycloalkyl groups or moieties (other than for R⁸) being optionally substituted with halogen, cyano, C_1-6alkoxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6haloalkoxy, C_1-6alkylthio, tri(C_1-4)alkylsilyl, C_1-6alkylamino or C_1-6dialkylamino,
any of the foregoing morpholine, thiomorpholine, piperidine, piperazine and pyrrolidine rings being optionally substituted with C_1-4alkyl (especially methyl), and
any of the foregoing aryl or heteroaryl groups or moieties being optionally substituted with one or more substituents selected from halo, hydroxy, mercapto, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_2-6alkenyloxy, C_2-6alkynyloxy, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, C_1-6alkylthio, halo(C_1-6)alkylthio, hydroxy(C_1-6)alkyl, C_1-4alkoxy(C_1-6)alkyl, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl, phenoxy, benzyloxy, benzoyloxy, cyano, isocyano, thiocyanato, isothiocyanato, nitro, —NR′″R″″, —NHCOR′″, —NHCONR′″R″″, —CONR′″R″″, —SO₂R′″, —OSO₂R′″, —COR′″, —CR′″═NR″″ or —N═CR′″R″″, in which R′″ and R″″ are independently hydrogen, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy, halo(C_1-4)alkoxy, C_1-4alkylthio, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl, phenyl or benzyl, the phenyl and benzyl groups being optionally substituted with halogen, C_1-4alkyl or C_1-4alkoxy.
The invention includes a compound of the general formula (1) as defined immediately above except that: C_1-8alkoxy and C_1-8alkylthio are excluded as values of R and R²; C₇alkylene and C_3-7alkenylene are excluded as chains formed by R³and R⁴; the C_3-6chain that R³and R⁴may form may only be optionally substituted with one or more methyl groups; thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide and piperazine are excluded as rings that R³and R⁴may form; tri(C_1-4)alkylsilyl is excluded as a substituent of any alkyl, alkenyl, alkynyl or cycloalkyl group or moiety and any morpholine, piperidine or pyrrolidine ring is unsubstituted.
The compounds of the invention may contain one or more asymmetric carbon atoms and may exist as enantiomers (or as pairs of diastereoisomers) or as mixtures of such. They may also exist as diastereoisomers by virtue of restricted rotation about a bond. However, mixtures of enantiomers or diastereoisomers may be separated into individual isomers or isomer pairs, and this invention embraces such isomers and mixtures thereof in all proportions. It is to be expected that for any given compound, one isomer may be more fungicidally active than another.
Except where otherwise stated, alkyl groups and alkyl moieties of alkoxy, alkylthio, etc., contain from 1 to 8, suitably from 1 to 6 and typically from 1 to 4, carbon atoms in the form of straight or branched chains. Examples are methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, n-pentyl and n-hexyl. Cycloalkyl groups contain from 3 to 8, typically from 3 to 6, carbon atoms and include bicycloalkyl groups such as the bicyclo[2.2.1]heptyl group. Haloalkyl groups or moieties are typically trichloromethyl or trifluoromethyl or contain a trichloromethyl or trifluoromethyl terminal group.
Except where otherwise stated, alkenyl and alkynyl moieties also contain from 2 to 8, suitably from 2 to 6 and typically from 2 to 4, carbon atoms in the form of straight or branched chains. Examples are allyl, 2-methylallyl and propargyl. Optional substituents include halo, typically fluoro. An example of halo-substituted alkenyl is 3,4,4-trifluoro-n-butenyl.
Halo includes fluoro, chloro, bromo and iodo. Most commonly it is fluoro, chloro or bromo and usually fluoro or chloro.
Aryl is usually phenyl but also includes naphthyl, anthryl and phenanthryl.
Heteroaryl is typically a 5- or 6-membered aromatic ring containing one or more O, N or S heteroatoms, which may be fused to one or more other aromatic or heteroaromatic rings, such as a benzene ring. Examples are thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl, isothiazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, benzofuryl, benzothienyl, dibenzofuryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indolyl, quinolinyl and quinoxalinyl groups and, where appropriate, N-oxides thereof.
The 6,6-ring systems embraced by the general formula (1) are pyrido[2,3-c]pyridazines (where W and X are both CR⁸and Y and Z are both N), pyrido[2,3-d]pyridazines (where W and Z are both CR⁸and X and Y are both N), pyrido[3,2-c]pyridazines (where Y and Z are both CR⁸and W and X are both N) and pyrido[2,3-b]pyrazine (where X and Y are both CR⁸and W and Z are both N). Of particular interest are pyrido[2,3-b]pyrazines.
R⁸, which may be the same or different for the two CR⁸values of W, X, Y and Z, is H, halo (for example bromo), C_1-4alkyl (for example methyl), C_1-4alkoxy (for example methoxy) or halo(C_1-4)alkyl (for example trifluoromethyl). Usually R⁸will be H.
R is halo, especially chloro or fluoro, and R²is NR³R⁴. In the case of pyrido[2,3-b]pyrazine ring systems, the more active compounds are those where R²is NR³R⁴. R³is typically C_1-8alkyl (for example ethyl, n-propyl, n-butyl, sec-butyl (the S- or R-isomer or the racemate) and tert-butyl), halo(C_1-8)alkyl (for example 2, 2,2-trifluoroethyl, 2,2,2-trifluoro-1-methylethyl (the S- or R-isomer or the racemate), 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl), hydroxy(C_1-8)alkyl (for example hydroxyethyl), C_1-4alkoxy(C_1-8)alkyl (for example methoxymethyl and methoxy-iso-butyl), C_1-4alkoxyhalo(C_1-8)alkyl (for example 2-methoxy-2-trifluoromethylethyl), tri(C_1-4)alkylsilyl(C_1-6)alkyl (for example trimethylsilylmethyl), C_1-4alkylcarbonyl(C_1-8)alkyl (for example 1-acetylethyl and 1-tert-butylcarbonylethyl), C_1-4alkylcarbonylhalo(C_1-8)alkyl (for example 1-acetyl-2,2,2-trifluoroethyl), phenyl(_1-4)alkyl (for example benzyl), C_2-8alkenyl (for example allyl and methylallyl), halo(C_2-8)alkenyl (for example 3-methyl-4,4-difluorobut-3-enyl), C_2-8alkynyl (for example propargyl), C_3-8cycloalkyl (for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl) optionally substituted with chloro, fluoro or methyl, C_3-8cycloalkyl(C_1-4)alkyl (for example cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl), phenylamino, piperidino or morpholino, the phenyl ring of phenylalkyl or phenylamino being optionally substituted with one, two or three substituents selected from halo (typically fluoro, chloro or bromo), C_1-4alkyl (typically methyl), halo(C_1-4)alkyl (typically trifluoromethyl), C_1-4alkoxy (typically methoxy) and halo(C_1-4)alkoxy (typically trifluoromethoxy). R⁴is typically H, C_1-4alkyl (for example ethyl and n-propyl), halo(C_1-4)alkyl (for example 2,2,2-trifluoroethyl) or amino. Alternatively R³and R⁴together form a C_4-6alkylene chain optionally substituted with methyl, for example 3-methylpentylene, or, together with the nitrogen atom to which they are attached, R³and R⁴form a morpholine, thiomorpholine, thiomorpholine S-oxide or thiomorpholine S-dioxide ring or a piperazine or piperazine N—(C_1-4)alkyl (especially N-methyl) ring, in which the morpholine or piperazine rings are optionally substituted with methyl.
Typically R¹is phenyl optionally substituted with from one to five halogen atoms, particularly fluorine and chlorine atoms and especially fluorine atoms or with from one to three substituents selected from halo (for example fluoro and chloro), C_1-4alkyl (for example methyl), halo(C_1-4)alkyl (for example trifluoromethyl), C_1-4alkoxy (for example methoxy) or halo(C_1-4)alkoxy (for example trifluoromethoxy). Examples are 2,6-difluorophenyl, 2-fluoro-6-chlorophenyl, 2,5,6-trifluorophenyl, 2,4,6-trifluorophenyl, 2,6-difluoro-4-methoxyphenyl, pentafluorophenyl, 2-fluorophenyl, 2,3,5,6-tetrafluorophenyl, 2-chloro-4,6-difluorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, 2,3,6-tri-chlorophenyl, pentachlorophenyl, 2-fluoro-4,6-dichlorophenyl, 4-fluoro-2,6-dichlorophenyl, 2-bromophenyl, 2-fluoro-6-bromophenyl, 2-bromo-4,6-difluorophenyl, 2-fluoro-6-methylphenyl, 2-chloro-6-methylphenyl, 2-methoxyphenyl, 2,6-dimethoxyphenyl, 2-fluoro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-fluoro-6-trifluoromethylphenyl, 2,6-di-(trifluoromethyl)phenyl, 2-chloro-6-trifluoromethylphenyl, 2,4-difluoro-6-trifluoromethylphenyl, 2,4-difluoro-6-methoxyphenyl and 2,4-difluoro-6-methylphenyl.
Also of particular interest are compounds where R¹is pyridyl optionally substituted with from one to four halogen atoms or with from one to three substituents selected from halo (for example fluoro and chloro), C_1-4alkyl (for example methyl), halo(C_1-4)alkyl (for example trifluoromethyl), C_1-4alkoxy (for example methoxy) or halo(C_1-4)alkoxy (for example trifluoromethoxy). Examples are 2,4-difluoropyrid-3-yl, 3,5-difluoropyrid-4-yl, tetrafluoropyrid-4-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-3-yl, 3-fluoropyrid-4-yl, 2-fluoropyrid-3-yl, 2,4,6-trifluoropyrid-3-yl, 3,5-difluoropyrid-2-yl, 2,6-difluoropyrid-3-yl, 2,4-difluoro-6-methoxypyrid-3-yl, 2-fluoro-4-chloropyrid-3-yl, 3-fluoro-5-chloropyrid-4-yl, 2-chloro-4-fluoropyrid-3-yl, 2,4-dichloropyrid-3-yl, 3-chloropyrid-2-yl 1,4-chloropyrid-3-yl, 3-chloropyrid-4-yl, 2-chloropyrid-3-yl, 3-trifluoromethylpyrid-2-yl, 4-trifluoromethylpyrid-3-yl, 3,5-dichloropyrid-2-yl, 4,6-dichloropyrid-3-yl, 3-trifluoromethylpyrid-4-yl, 2-trifluoromethylpyrid-3-yl, 2-fluoro-4-trifluoromethylpyrid-3-yl, 3-fluoro-5-trifluoromethylpyrid-4-yl, 4-fluoro-2-trifluoromethylpyrid-3-yl, 2,6-dichloropyrid-3-yl, 3,5-dichloropyrid-4-yl, 3-chloro-6-trifluoromethylpyrid-2-yl, 3-fluoro-6-trifluoromethylpyrid-2-yl, pyrid-2-yl, pyrid-3-yl and pyrid-4-yl.
Also of particular interest are compounds where R¹is 2- or 3-thienyl optionally substituted with from one to three halogen atoms or with from one to three substituents selected from halo (for example fluoro and chloro), C_1-4alkyl (for example methyl), halo-(C_1-4)alkyl (for example trifluoromethyl), C_1-4alkoxy (for example methoxy) or halo(C_1-4)alkoxy (for example trifluoromethoxy). Examples are 3-fluorothien-2-yl, 3-chlorothien-2-yl, 2,4-difluorothien-3-yl, 2,4-dichlorothien-3-yl and 2,4,5-trichlorothien-3-yl.
Examples of other values of R¹of especial interest are unsubstituted piperidino and morpholino, 2-methylpiperidino, 2,6-dimethylpiperidino and 2,6-dimethylmorpholino.
In one aspect the invention provides a compound of the general formula (1) wherein W and X, W and Z, X and Y or Y and Z are N and the other two are CR⁸;
R⁸is H, halo, C_1-4alkyl, C_1-4alkoxy or halo(C_1-4)alkyl;
R is halo;
R¹is halo, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_3-8cycloalkyl, C_3-8cycloalkyl(C_1-6)alkyl, C_1-8alkoxy, C_1-8alkylthio, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, aryl(C_1-4)alkyl, aryl(C_1-4)alkoxy, heteroaryl(C_1-4)alkyl, heteroaryl(C_1-4)alkoxy, aryl(C_1-4)alkylthio, heteroaryl(C_1-4)alkylthio, morpholino, piperidino or pyrrolidino;

R²is NR³R⁴;

R³and R⁴are independently H, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, aryl, aryl(C_1-8)alkyl, C_3-8cycloalkyl, C_3-8cycloalkyl(C_1-6)alkyl, heteroaryl, heteroaryl(C_1-8)alkyl, NR⁵R⁶, provided that not both R³and R⁴are H or NR⁵R⁶, or
R³and R⁴together form a C_3-7alkylene or C_3-7alkenylene chain optionally substituted with one or more C_1-4alkyl or C_1-4alkoxy groups, or,
together with the nitrogen atom to which they are attached, R³and R⁴form a morpholine, thiomorpholine, thiomorpholine S-oxide or thiomorpholine S-dioxide ring or a piperazine or piperazine N—(C_1-4)alkyl (especially N-methyl) ring; and
R⁵and R⁶are independently H, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, aryl, aryl(C_1-8)alkyl, C_3-8cycloalkyl, C_3-8cycloalkyl(C_1-6)alkyl, heteroaryl or heteroaryl(C_1-8)alkyl;
any of the foregoing alkyl, alkenyl, alkynyl or cycloalkyl groups or moieties (other than for R⁸) being optionally substituted with halogen, cyano, C_1-6alkoxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6haloalkoxy, C_1-6alkylthio, tri(C_1-4)alkylsilyl, C_1-6alkylamino or C_1-6dialkylamino,
any of the foregoing morpholine, thiomorpholine, piperidine, piperazine and pyrrolidine rings being optionally substituted with C_1-4alkyl (especially methyl), and any of the foregoing aryl, heteroaryl, aryloxy or heteroaryl groups being optionally substituted with one or more substituents selected from halo, hydroxy, mercapto, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_2-6alkenyloxy, C_2-6alkynyloxy, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, C_1-6alkylthio, halo(C_1-6)alkylthio, hydroxy(C_1-6)alkyl, C_1-4alkoxy(C_1-6)alkyl, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl, phenoxy, benzyloxy, benzoyloxy, cyano, isocyano, thiocyanato, isothiocyanato, nitro, —NR′″R″″, —NHCOR′″, —NHCONR′″R″″, —CONR′″R″″, —SO₂R′″, —OSO₂R′″, —COR′″, —CR′″═NR″″ or —N═CR′″R″″, in which R′″ and R″″ are independently hydrogen, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy, halo-(C_1-4)alkoxy, C_1-4alkylthio, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl, phenyl or benzyl, the phenyl and benzyl groups being optionally substituted with halogen, C_1-4alkyl or C_1-4alkoxy.
Of particular interest are compounds where W and Z are both N and X and Y are both CH.
The invention includes a compound of the general formula (1) as defined immediately above except that: C₇alkylene and C_3-7alkenylene are excluded as chains formed by R³and R⁴; the C_3-6chain that R³and R⁴may form may only be optionally substituted with one or more methyl groups; thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide and piperazine are excluded as rings that R³and R⁴may form; tri(C_1-4)alkylsilyl is excluded as a substituent of any alkyl, alkenyl, alkynyl or cycloalkyl group or moiety, and any morpholine, piperidine or pyrrolidine ring is unsubstituted.
In another aspect the invention provides a compound of the general formula (1) wherein
W and X, W and Z, X and Y or Y and Z are N and the other two are CR⁸;
R³is H, halo, C_1-4alkyl, C_1-4alkoxy or halo(C_1-4)alkyl;
R is halo;
R¹is halo, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_3-8cycloalkyl, C_3-8cycloalkyl(C_1-6)alkyl, C_1-8alkoxy, C_1-8alkylthio, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, aryl(C_1-4)alkyl, aryl(C_1-4)alkoxy, heteroaryl(C_1-4)alkyl, heteroaryl(C_1-4)alkoxy, aryl(C_1-4)alkylthio, heteroaryl(C_1-4)alkylthio, morpholino, piperidino or pyrrolidino;

R²is NR³R⁴;

R³is C_1-4alkyl, halo(C_1-4)alkyl, C_2-4alkenyl, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl or phenylamino in which the phenyl ring is optionally substituted with one, two or three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy and halo(C_1-4)alkoxy; and
R⁴is H, C_1-4alkyl or amino, or
R³and R⁴together form a C_4-6alkylene chain optionally substituted with C_1-4alkyl or
C_1-4alkoxy, or,
together with the nitrogen atom to which they are attached, R³and R⁴form a morpholine, thiomorpholine, thiomorpholine S-oxide or thiomorpholine S-dioxide ring or a piperazine or piperazine N—(C_1-4)alkyl (especially N-methyl) ring;
any of the foregoing alkyl, alkenyl, alkynyl or cycloalkyl groups or moieties (other than for R⁸) being optionally substituted with halogen, cyano, C_1-6alkoxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6haloalkoxy, C_1-6alkylthio, tri(C_1-4)alkylsilyl, C_1-6alkylamino or C_1-6dialkylamino,
any of the foregoing morpholine, thiomorpholine, piperidine, piperazine and pyrrolidine rings being optionally substituted with C_1-4alkyl (especially methyl), and
any of the foregoing aryl or heteroaryl groups or moieties being optionally substituted with one or more substituents selected from halo, hydroxy, mercapto, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_2-6alkenyloxy, C_2-6alkynyloxy, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, C_1-6alkylthio, halo(C_1-6)alkylthio, hydroxy(C_1-6)alkyl, C_1-4alkoxy(C_1-6)alkyl, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl, phenoxy, benzyloxy, benzoyloxy, cyano, isocyano, thiocyanato, isothiocyanato, nitro, —NR′″R″″, —NHCOR′″, —NHCONR′″R″″, —CONR′″R″″, —SO₂R′″, —OSO₂R′″, —COR′″, —CR′″═NR″″ or —N═CR′″R″″, in which R′″ and R″″ are independently hydrogen, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy, halo(C_1-4)alkoxy, C_1-4alkylthio, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl, phenyl or benzyl, the phenyl and benzyl groups being optionally substituted with halogen, C_1-4alkyl or C_1-4alkoxy.
Of particular interest are compounds where W and Z are both N and X and Y are both CH.
The invention includes a compound of the general formula (1) as defined immediately above except that: the C_4-6chain that R³and R⁴may form may only be optionally substituted with methyl; thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide and piperazine are excluded as rings that R³and R⁴may form; tri(C_1-4)alkylsilyl is excluded as a substituent of any alkyl, alkenyl, alkynyl or cycloalkyl group or moiety, and any morpholine, piperidine or pyrrolidine ring is unsubstituted.
In yet another aspect the invention provides a compound of the general formula (1) wherein
W and X, W and Z, X and Y or Y and Z are N and the other two are CR³;
R³is H, halo, C_1-4alkyl, C_1-4alkoxy or halo(C_1-4)alkyl;
R is halo;
R¹is optionally substituted phenyl;

R²is NR³R⁴;

R³and R⁴are independently H, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, aryl, aryl(C_1-8)alkyl, C_3-8cycloalkyl, C_3-8cycloalkyl(C_1-6)alkyl, heteroaryl, heteroaryl(C_1-8)alkyl, NR⁵R⁶, provided that not both R³and R⁴are H or NR⁵R⁶, or
R³and K⁴together form a C_3-7alkylene or C_3-7alkenylene chain optionally substituted with one or more C_1-4alkyl or C_1-4alkoxy groups, or,
together with the nitrogen atom to which they are attached, R³and R⁴form a morpholine, thiomorpholine, thiomorpholine S-oxide or thiomorpholine S-dioxide ring or a piperazine or piperazine N—(C_1-4)alkyl (especially N-methyl) ring; and
R⁵and R⁶are independently H, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, aryl, aryl(C_1-8)alkyl, C_3-8cycloalkyl, C_3-8cycloalkyl(C_1-6)alkyl, heteroaryl or heteroaryl(C_1-8)alkyl;
any of the foregoing alkyl, alkenyl, alkynyl or cycloalkyl groups or moieties (other than for R⁸) being optionally substituted with halogen, cyano, C_1-6alkoxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6haloalkoxy, C_1-6alkylthio, tri(C_1-4)alkylsilyl, C_1-6alkylamino or C_1-6dialkylamino,
any of the foregoing morpholine, thiomorpholine, piperidine, piperazine and pyrrolidine rings being optionally substituted with C_1-4alkyl (especially methyl), and
any of the foregoing aryl or heteroaryl groups or moieties, including the phenyl group of R¹, being optionally substituted with one or more substituents selected from halo, hydroxy, mercapto, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_2-6alkenyloxy, C_2-6alkynyloxy, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, C_1-6alkylthio, halo(C_1-6)alkylthio, hydroxy(C_1-6)alkyl, C_1-4alkoxy(C_1-6)alkyl, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl, phenoxy, benzyloxy, benzoyloxy, cyano, isocyano, thiocyanato, isothiocyanato, nitro, —NR′″R″″, —NHCOR′″, —NHCONR′″R″″, —CONR′″R″″, —SO₂R′″, —OS₂R′″, —COR′″, —CR′″═NR″″ or —N═CR′″R″″, in which R′″ and R″″ are independently hydrogen, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy, halo(C_1-4)alkoxy, C_1-4alkylthio, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl, phenyl or benzyl, the phenyl and benzyl groups being optionally substituted with halogen, C_1-4alkyl or C_1-4alkoxy. Of particular interest are compounds where W and Z are both N and X and Y are both CH.
The invention includes a compound of the general formula (1) as defined immediately above except that: C_1-8alkoxy and C_1-8alkylthio are excluded as values of R and R²; C₇alkylene and C_3-7alkenylene are excluded as chains formed by R³and R⁴; the C_3-6chain that R³and R⁴may form may only be optionally substituted with one or more methyl groups; thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide and piperazine are excluded as rings that R³and R⁴may form; tri(C_1-4)alkylsilyl is excluded as a substituent of any alkyl, alkenyl, alkynyl or cycloalkyl group or moiety, and the morpholine ring that R³and R⁴may form is unsubstituted.
In still yet another aspect the invention provides a compound of the general formula (1) wherein W and X, W and Z, X and Y or Y and Z are N and the other two are CR⁸;
R⁸is H, halo(e.g. fluoro, chloro or bromo), C_1-4alkyl (e.g. methyl), C_1-4alkoxy (e.g. methoxy) or halo(C_1-4)alkyl (e.g. trifluoromethyl);
R is halo (e.g. fluoro, chloro or bromo);
R¹is phenyl optionally substituted with from one to five halogen atoms or with from one to three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy or halo(C_1-4) alkoxy, pyridyl optionally substituted with from one to four halogen atoms or with from one to three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy or halo(C_1-4)alkoxy, 2- or 3-thienyl optionally substituted with from one to three halogen atoms or with from one to three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy or halo(C_1-4)alkoxy, or piperidino or morpholino both optionally substituted with one or two methyl groups;

R is NR³R⁴;

R³is C_1-8alkyl, halo(C_1-8)alkyl, hydroxy(C_1-8)alkyl, C_1-4alkoxy(C_1-8)alkyl, C_1-4alkoxyhalo-(C_1-8)alkyl, tri(C_1-4)alkylsilyl(C_1-6)alkyl, C_1-4alkylcarbonyl(C_1-8)alkyl, C_1-4alkylcarbonylhalo(C_1-8)alkyl, phenyl(1-4)alkyl, C_2-8alkenyl, halo(C_2-8)alkenyl, C_2-8alkynyl, C_3-8cycloalkyl optionally substituted with chloro, fluoro or methyl, C_3-8cycloalkyl(C_1-4)alkyl, phenylamino, piperidino or morpholino, the phenyl ring of phenylalkyl or phenylamino being optionally substituted with one, two or three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy and halo(C_1-4)alkoxy; and
R⁴is H, C_1-4alkyl, halo(C_1-4)alkyl or amino, or
R³and R⁴together form a C_3-7alkylene or C_3-7alkenylene chain optionally substituted with methyl, or,
together with the nitrogen atom to which they are attached, R³and R⁴form a morpholine, thiomorpholine, thiomorpholine S-oxide or thiomorpholine S-dioxide ring or a piperazine or piperazine N—(C_1-4)alkyl (especially N-methyl) ring, in which the morpholine or piperazine rings are optionally substituted with methyl.
Of particular interest are compounds where W and Z are both N and X and Y are both CH.
In still yet another aspect the invention provides a compound of the general formula (1) wherein
W and X, W and Z, X and Y or Y and Z are N and the other two are CR⁸;
R⁸is H, halo, C_1-4alkyl, C_1-4alkoxy or halo(C_1-4)alkyl;
R is halo;
R¹is phenyl optionally substituted with from one to five halogen atoms or with from one to three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy or halo(C_1-4) alkoxy;

R²is NR³R⁴;

R³is C_1-4alkyl, halo(C_1-4)alkyl, C_2-4alkenyl, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl or phenylamino in which the phenyl ring is optionally substituted with one, two or three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy and halo(C_1-4)alkoxy; and
R⁴is H, C_1-4alkyl or amino, or R³and R⁴together form a C_4-6alkylene chain optionally substituted with methyl, or, together with the nitrogen atom to which they are attached, R³and R⁴form a morpholine ring.
Of particular interest are compounds where W and Z are both N and X and Y are both CH.
Compounds that form part of the invention are illustrated in Tables 1 to 127 below. Characterising data are given later in the Examples and in Table 133.
In Table 1 the compounds have the general formula (1A), where W and Z are N, X and Y are CH, R is Cl, R¹is 2,4,6-trifluorophenyl and R³and R⁴are as shown in the table.

TABLE 1

Cmpd
No	R³	R⁴

1	C₂H₅	H
2	n-C₃H₇	H
3	i-C₃H₇	H
4	n-C₄H₉	H
5	t-C₄H₉	H
6	CH₂═CHCH₂	H
7	CH₂═C(CH₃)CH₂	H
8	CF₃CH₂	H
9	CF₃CH₂CH₂	H
10	CF₃CH₂CH₂CH₂	H
11	CF₃(CH₃)CH	H
12	(S)-CF₃(CH₃)CH	H
13	(R)-CF₃(CH₃)CH	H
14	cyclo-C₃H₅	H
15	cyclo-C₄H₇	H
16	cyclo-C₅H₉	H
17	cyclo-C₆H₁₁	H
18	cyclo-C₃H₅CH₂	H
19	cyclo-C₄H₇CH₂	H

20	—(CH₂)₂O(CH₂)₂—

21

cyclo-C₆H₁₁CH₂

H

22	—(CH₂)₂CH(CH₃)(CH₂)₂—

23	CH₃CH₂(CH₃)CH	H
24	(S)-CH₃CH₂(CH₃)CH	H
25	(R)-CH₃CH₂(CH₃)CH	H
26	C₂H₅	C₂H₅
27	n-C₃H₇	n-C₃H₇
28	CH₂═C(CH₃)CH₂	C₂H₅
29	CF₃CH₂	C₂H₅
30	C₂H₅	NH₂
31	n-C₃H₇	NH₂
32	i-C₃H₇	NH₂
33	n-C₄H₉	NH₂
34	CH₂═CHCH₂	NH₂
35	CH₂═C(CH₃)CH₂	NH₂
36	CF₂═CFCH₂CH₂	NH₂
37	CF₃CH₂	NH₂
38	CF₃CH₂CH₂	NH₂
39	CF₃CH₂CH₂CH₂	NH₂
40	4-t-C₄H₉-C₆H₄NH	H
41	4-F—C₆H₄NH	H
42	C₆H₅NH	H
43	4-CH₃—C₆H₄NH	H
44	4-Br—C₆H₄NH	H
45	2-F—C₆H₄NH	H
46	3,4-Cl₂—C₆H₃NH	H
47	3-CF₃—C₆H₄NH	H
48	3,5-Cl₂—C₆H₃NH	H
49	4-CF₃O—C₆H₅NH	H
50	2-CF₃—C₆H₄NH	H
51	4-CF₃—C₆H₄NH	H
52	2-Br—C₆H₄NH	H
53	2-Cl—C₆H₄NH	H
54	2-CH₃-4-Cl—C₆H₃NH	H
55	2-CH₃-5-F—C₆H₃NH	H
56	3-Cl—C₆H₄NH	H
57	CH₃	H
58	(CH₃)₂CHCH₂	H
59	(CH₃)₃CCH₂	H
60	(CH₃)₃C(CH₃)CH	H
61	CH₃CH₂(CH₃)₂C	H
62	CH₃CH₂(CF₃)CH	H
63	(S)-CH₃CH₂(CF₃)CH	H
64	(R)-CH₃CH₂(CF₃)CH	H
65	CH₃CH₂(CH₃CH₂)CH	H
66	(CH₃)₂CH(CH₃CH₂)CH	H
67	(CH₃)₂CH(CH₃)CH	H
68	(CH₃)₂CH(CF₃)CH	H
69	(S)-(CH₃)₂CH(CF₃)CH	H
70	(R)-(CH₃)₂CH(CF₃)CH	H
71	HC═C(CH₃)CH₂	H
72	CH₂═CH(CH₃CH₂)CH	H
73	CH₃CH₂CH₂(CH₃)CH	H
74	CH₃CH₂CH₂(CF₃)CH	H
75	(S)-CH₃CH₂CH₂(CF₃)CH	H
76	(R)-CH₃CH₂CH₂(CF₃)CH	H
77	CH₃CH₂CH₂(CH₃)₂C	H
78	CH₃CH₂(CH₃)CHCH₂	H
79	(CH₃)₂CHCH₂CH₂	H
80	(CH₃)₃CCH₂CH₂	H
81	CH₃CH₂(CH₃)CH(CH₃)—CH	H
82	CH₃CH₂(CH₃)CH(CF₃)—CH	H
83	(S)-CH₃CH₂(CH₃)CH—(CF₃)CH	H
84	(R)-CH₃CH₂(CH₃)CH—(CF₃)CH	H
85	CH₃(CH₃)CHCH₂(CH₃)—CH	H
86	CH₃(CH₃)CHCH₂(CF₃)—CH	H
87	(S)-CH₃(CH₃)CHCH₂—(CF₃)CH	H
88	(R)-CH₃(CH₃)CHCH₂—(CF₃)CH	H
89	(CH₃)₂CH(CH₃)CH—(CH₃)CH₂	H
90	(CH₃)₃CCH₂(CH₃)CH	H
91	E-CH₃CH═CH(CH₃)CH	H
92	E-CH₃CH═CH(CH₃CH₂)—CH	H
93	CH₃CH₂CH₂(CH₃CH₂)—CH	H
94	CH₃CH₂(CH₃CH₂)—CHCH₂	H
95	CF₂═CFCH₂CH₂	H
96	CF₃CH₂(CH₃)CHCH₂	H
97	CF₃CF₂CH₂CH₂	H
98	CF₃CF₂CF₂CH₂	H
99	CF₂═C(CH₃)CH₂CH₂	H
100	CH₃CH₂CH₂CH₂CH₂	H
101	CH₃CH₂CH₂CH₂—(CH₃)CH	H
102	CH₃CH₂CH₂(CH₃)—CHCH₂	H
103	CH₃CH₂(CH₃)CHCH_2-CH₂	H
104	CH₃CH₂CH₂(CH₃)CH—(CH₃)CH	H
105	CH₃CH₂(CH₃)CHCH_2-(CH₃)CH	H
106	HOCH₂CH₂	H
107	CH₃OCH₂CH₂	H
108	CH₃OCH₂(CH₃)CH	H
109	CH₃OCH₂(CF₃)CH	H
110	CH₃OCH₂(CH₃)₂C	H
111	CH₃O(CH₃)CHCH₂	H
112	CH₃O(CH₃)CH(CH₃)CH	H
113	HC≡CCH₂	H
114	CH₃C≡CCH₂	H
115	HC≡CCH₂CH₂	H
116	HOCH₂CH₂CH₂	H
117	CH₃OCH₂CH₂CH₂	H
118	(CH₃)₃SiCH₂	H
119	C₆H₅CH₂	H
120	C₆H₅(CH₃)CH	H
121	4-F—C₆H₄CH₂	H
122	4-Cl—C₆H₄CH₂	H
123	4-F—C₆H₅(CH₃)CH	H
124	4-Cl—C₆H₅(CH₃)CH	H
125	C₆H₅CH₂CH₂	H
126	4-F—C₆H₅CH₂CH₂	H
127	1-piperidino	H
128	1-pyrrolidino	H
129	cyclo-C₅H₉CH₂	H
130	Bicyclo[2.2.1]hept-2-yl	H
131	1-CH₃-cyclopropyl	H
132	cis-2-CH₃-cyclopropyl	H
133	trans-2-CH₃-cyclopropyl	H
134	2,2-(CH₃)₂-cyclopropyl	H
135	1-CH₃-cyclobutyl	H
136	cis-2-CH₃-cyclobutyl	H
137	trans-2-CH₃-cyclobutyl	H
138	cis-3-CH₃-cyclobutyl	H
139	trans-3-CH₃-cyclobutyl	H
140	2,2-(CH₃)₂-cyclobutyl	H
141	3,3-(CH₃)₂-cyclobutyl	H
142	1-CH₃-cyclopentyl	H
143	cis-2-CH₃-cyclopentyl	H
144	trans-2-CH₃-cyclopentyl	H
145	cis-3-CH₃-cyclopentyl	H
146	trans-3-CH₃-cyclopentyl	H
147	2,2-(CH₃)₂-cyclopentyl	H
148	3,3-(CH₃)₂-cyclopentyl	H
149	1-CH₃-cyclohexyl	H
150	cis-2-CH₃-cyclohexyl	H
151	trans-2-CH₃-cyclohexyl	H
152	cis-3-CH₃-cyclohexyl	H
153	trans-3-CH₃-cyclohexyl	H
154	2,2-(CH₃)₂-cyclohexyl	H
155	3,3-(CH₃)₂-cyclohexyl	H
156	cis-4-CH₃-cyclohexyl	H
157	trans-4-CH₃-cyclohexyl	H
158	4,4-(CH₃)₂-cyclohexyl	H
159	4-(CH₃)₃C-cyclohexyl	H

160	—(CH₂)₃—
161	—(CH₂)₄—
162	—(CH₂)₅—
163	—(CH₂)₆—
164	—(CH₂)₂(CH₃)₂C(CH₂)₂—
165	—(CH₃)CH(CH₂)₂—
166	—(CH₃)CH(CH₂)₃—
167	—(CH₃)CH(CH₂)₄—
168	—(CH₃)CH(CH₂)₅—
169	—CH₂CH═CH(CH₂)₂—
170	—(CH₂)₂NH(CH₂)₂—
171	—(CH₂)₂NCH₃(CH₂)₂—
172	—(CH₂)₂S(CH₂)₂—
173	—(CH₂)₂SO(CH₂)₂—
174	—(CH₂)₂SO₂(CH₂)₂—
175	—CH₂(CH₃)CHO(CH₃)CHCH₂—

176	C₂H₅	CH₃
177	n-C₃H₇	CH₃
178	i-C₃H₇	CH₃
179	n-C₄H₉	CH₃
180	t-C₄H₉	CH₃
181	CH₂═CHCH₂	CH₃
182	CH₂═C(CH₃)CH₂	CH₃
183	CF₃CH₂	CH₃
184	CF₃CH₂CH₂	CH₃
185	CF₃CH₂CH₂CH₂	CH₃
186	CF₃(CH₃)CH	CH₃
187	(S)-CF₃(CH₃)CH	CH₃
188	(R)-CF₃(CH₃)CH	CH₃
189	cyclo-C₃H₅	CH₃
190	cyclo-C₄H₇	CH₃
191	cyclo-C₅H₉	CH₃
192	cyclo-C₆H₁₁	CH₃
193	cyclo-C₃H₅CH₂	CH₃
194	cyclo-C₄H₇CH₂	CH₃
195	cyclo-C₆H₁₁CH₂	CH₃
196	CH₃CH₂(CH₃)CH	CH₃
197	(S)-CH₃CH₂(CH₃)CH	CH₃
198	(R)-CH₃CH₂(CH₃)CH	CH₃
199	cyclo-C₇H₁₃	CH₃
200	CH₂═C(CH₃)CH₂	CH₃
201	CF₃CH₂	CH₃
202	4-t-C₄H₉—C₆H₄NH	CH₃
203	4-F-C₆H₄NH	CH₃
204	C₆H₅NH	CH₃
205	4-CH₃—C₆H₄NH	CH₃
206	4-Br—C₆H₄NH	CH₃
207	2-F-C₆H₄NH	CH₃
208	3,4-Cl₂—C₆H₃NH	CH₃
209	3-CF₃—C₆H₄NH	CH₃
210	3,5-Cl₂—C₆H₃NH	CH₃
211	4-CF₃O—C₆H₅NH	CH₃
212	2-CF₃—C₆H₄NH	CH₃
213	4-CF₃—C₆H₄NH	CH₃
214	2-Br—C₆H₄NH	CH₃
215	2-Cl—C₆H₄NH	CH₃
216	2-CH₃-4-Cl—C₆H₃NH	CH₃
217	2-CH₃-5-F—C₆H₃NH	CH₃
218	3-Cl—C₆H₄NH	CH₃
219	CH₃	CH₃
220	(CH₃)₂CHCH₂	CH₃
221	(CH₃)₃CCH₂	CH₃
222	(CH₃)₃C(CH₃)CH	CH₃
223	CH₃CH₂(CH₃)₂C	CH₃
224	CH₃CH₂(CF₃)CH	CH₃
225	(S)-CH₃CH₂(CF₃)CH	CH₃
226	(R)-CH₃CH₂(CF₃)CH	CH₃
227	CH₃CH₂(CH₃CH₂)CH	CH₃
228	(CH₃)₂CH(CH₃CH₂)CH	CH₃
229	(CH₃)₂CH(CH₃)CH	CH₃
230	(CH₃)₂CH(CF₃)CH	CH₃
231	(S)-(CH₃)₂CH(CF₃)CH	CH₃
232	(R)-(CH₃)₂CH(CF₃)CH	CH₃
233	HC═C(CH₃)CH₂	CH₃
234	CH₂═CH(CH₃CH₂)CH	CH₃
235	CH₃CH₂CH₂(CH₃)CH	CH₃
236	CH₃CH₂CH₂(CF₃)CH	CH₃
237	(S)-CH₃CH₂CH₂(CF₃)CH	CH₃
238	(R)-CH₃CH₂CH₂(CF₃)CH	CH₃
239	CH₃CH₂CH₂(CF₃)₂C	CH₃
240	CH₃CH₂(CH₃)CHCH₂	CH₃
241	(CH₃)₂CHCH₂CH₂	CH₃
242	(CH₃)₃CCH₂CH₂	CH₃
243	CH₃CH₂(CH₃)CH(CH₃)—CH	CH₃
244	CH₃CH₂(CH₃)CH(CF₃)—CH	CH₃
245	(S)-CH₃CH₂(CH₃)CH—(CF₃)CH	CH₃
246	(R)-CH₃CH₂(CH₃)CH—(CF₃)CH	CH₃
247	CH₃(CH₃)CHCH₂—(CH₃)CH	CH₃
248	CH₃(CH₃)CHCH₂—(CF₃)CH	CH₃
249	(S)-CH₃(CH₃)CHCH₂—(CF₃)CH	CH₃
250	(R)-CH₃(CH₃)HCH₂—(CF₃)CH	CH₃
251	(CH₃)₂CH(CH₃)CH(CH₃)—CH₂	CH₃
252	(CH₃)₃CCH₂(CH₃)CH	CH₃
253	E-CH₃CH═CH(CH₃)CH	CH₃
254	E-CH₃CH═CH(CH₃CH₂)—CH	CH₃
255	CH₃CH₂CH₂(CH₃CH₂)—CH	CH₃
256	CH₃CH₂(CH₃CH₂)—CHCH₂	CH₃
257	CF₂═CFCH₂CH₂	CH₃
258	CF₃CH₂(CH₃)CHCH₂	CH₃
259	CF₃CF₂CH₂CH₂	CH₃
260	CF₃CF₂CF₂CH₂	CH₃
261	CF₂═C(CH₃)CH₂CH₂	CH₃
262	CH₃CH₂CH₂CH₂CH₂	CH₃
263	CH₃CH₂CH₂CH₂(CH₃)—CH	CH₃
264	CH₃CH₂CH₂(CH₃)—CHCH₂	CH₃
265	CH₃CH₂(CH₃)CHCH₂—CH₂	CH₃
266	CH₃CH₂CH₂(CH₃)CH—(CH₃)CH	CH₃
267	CH₃CH₂(CH₃)CHCH₂—(CH₃)CH	CH₃
268	HOCH₂CH₂	CH₃
269	CH₃OCH₂CH₂	CH₃
270	CH₃OCH₂(CH₃)CH	CH₃
271	CH₃OCH₂(CF₃)CH	CH₃
272	CH₃OCH₂(CH₃)₂C	CH₃
273	CH₃O(CH₃)CHCH₂	CH₃
274	CH₃O(CH₃)CH(CH₃)CH	CH₃
275	HC≡CCH₂	CH₃
276	CH₃C≡CCH₂	CH₃
277	HC≡CCH₂CH₂	CH₃
278	HOCH₂CH₂CH₂	CH₃
279	CH₃OCH₂CH₂CH₂	CH₃
280	(CH₃)₃SiCH₂	CH₃
281	C₆H₅CH₂	CH₃
282	C₆H₅(CH₃)CH	CH₃
283	4-F—C₆H₄CH₂	H
284	4-Cl—C₆H₄CH₂	CH₃
285	4-F—C₆H₅(CH₃)CH	CH₃
286	4-Cl—C₆H₅(CH₃)CH	CH₃
287	C₆H₅CH₂CH₂	CH₃
288	4-F—C₆H₅CH₂CH₂	CH₃
289	1-piperidino	CH₃
290	1-pyrrolidino	CH₃
291	cyclo-C₅H₉CH₂	CH₃
292	bicyclo[2.2.1]hept-2-yl	CH₃
293	1-CH₃-cyclopropyl	CH₃
294	cis-2-CH₃-cyclopropyl	CH₃
295	trans-2-CH₃-cyclopropyl	CH₃
296	2,2-(CH₃)₂-cyclopropyl	CH₃
297	1-CH₃-cyclobutyl	CH₃
298	cis-2-CH₃-cyclobutyl	CH₃
299	trans-2-CH₃-cyclobutyl	CH₃
300	cis-3-CH₃-cyclobutyl	CH₃
301	trans-3-CH₃-cyclobutyl	CH₃
302	2,2-(CH₃)₂-cyclobutyl	CH₃
303	3,3-(CH₃)₂-cyclobutyl	CH₃
304	1-CH₃-cyclopentyl	CH₃
305	cis-2-CH₃-cyclopentyl	CH₃
306	trans-2-CH₃-cyclopentyl	CH₃
307	cis-3-CH₃-cyclopentyl	CH₃
308	trans-3-CH₃-cyclopentyl	CH₃
309	2,2-(CH₃)₂-cyclopentyl	CH₃
310	3,3-(CH₃)₂-cyclopentyl	CH₃
311	1-CH₃-cyclohexyl	CH₃
312	cis-2-CH₃-cyclohexyl	CH₃
313	trans-2-CH₃-cyclohexyl	CH₃
314	cis-3-CH₃-cyclohexyl	CH₃
315	trans-3-CH₃-cyclohexyl	CH₃
316	2,2-(CH₃)₂-cyclohexyl	CH₃
317	3,3-(CH₃)₂-cyclohexyl	CH₃
318	cis-4-CH₃-cyclohexyl	CH₃
319	trans-4-CH₃-cyclohexyl	CH₃
320	4,4-(CH₃)₂-cyclohexyl	CH₃
321	4-(CH₃)₃C-cyclohexyl	CH₃
322	n-C₃H₇	C₂H₅
323	i-C₃H₇	C₂H₅
324	n-C₄H₉	C₂H₅
325	t-C₄H₉	C₂H₅
326	CH₂═CHCH₂	C₂H₅
327	CF₃CH₂CH₂	C₂H₅
328	CF₃CH₂CH₂CH₂	C₂H₅
329	CF₃(CH₃)CH	C₂H₅
330	(S)-CF₃(CH₃)CH	C₂H₅
331	(R)-CF₃(CH₃)CH	C₂H₅
332	cyclo-C₃H₅	C₂H₅
333	cyclo-C₄H₇	C₂H₅
334	cyclo-C₅H₉	C₂H₅
335	cyclo-C₆H₁₁	C₂H₅
336	cyclo-C₃H₅CH₂	C₂H₅
337	cyclo-C₄H₇CH₂	C₂H₅
338	cyclo-C₆H₁₁CH₂	C₂H₅
339	CH₃CH₂(CH₃)CH	C₂H₅
340	(S)-CH₃CH₂(CH₃)CH	C₂H₅
341	(R)-CH₃CH₂(CH₃)CH	C₂H₅
342	cyclo-C₇H₁₃	C₂H₅
343	4-t-C₄H₉—C₆H₄NH	C₂H₅
344	4-F—C₆H₄NH	C₂H₅
345	C₆H₅NH	C₂H₅
346	4-CH₃—C₆H₄NH	C₂H₅
347	4-Br—C₆H₄NH	C₂H₅
348	2-F—C₆H₄NH	C₂H₅
349	3,4-Cl₂—C₆H₃NH	C₂H₅
350	3-CF₃—C₆H₄NH	C₂H₅
351	3,5-Cl₂—C₆H₃NH	C₂H₅
352	4-CF₃O—C₆H₅NH	C₂H₅
353	2-CF₃—C₆H₄NH	C₂H₅
354	4-CF₃—C₆H₄NH	C₂H₅
355	2-Br—C₆H₄NH	C₂H₅
356	2-Cl—C₆H₄NH	C₂H₅
357	2-CH₃-4-Cl—C₆H₃NH	C₂H₅
358	2-CH₃-5-F—C₆H₃NH	C₂H₅
359	3-Cl—C₆H₄NH	C₂H₅
360	(CH₃)₂CHCH₂	C₂H₅
361	(CH₃)₃CCH₂	C₂H₅
362	(CH₃)₃C(CH₃)CH	C₂H₅
363	CH₃CH₂(CH₃)₂C	C₂H₅
364	CH₃CH₂(CF₃)CH	C₂H₅
365	(S)-CH₃CH₂(CF₃)CH	C₂H₅
366	(R)-CH₃CH₂(CF₃)CH	C₂H₅
367	CH₃CH₂(CH₃CH₂)CH	C₂H₅
368	(CH₃)₂CH(CH₃CH₂)CH	C₂H₅
369	(CH₃)₂CH(CH₃)CH	C₂H₅
370	(CH₃)₂CH(CF₃)CH	C₂H₅
371	(S)-(CH₃)₂CH(CF₃)CH	C₂H₅
372	(R)-(CH₃)₂CH(CF₃)CH	C₂H₅
373	HC═C(CH₃)CH₂	C₂H₅
374	CH₂═CH(CH₃CH₂)CH	C₂H₅
375	CH₃CH₂CH₂(CH₃)CH	C₂H₅
376	CH₃CH₂CH₂(CF₃)CH	C₂H₅
377	(S)-CH₃CH₂CH₂(CF₃)CH	C₂H₅
378	(R)-CH₃CH₂CH₂(CF₃)CH	C₂H₅
379	CH₃CH₂CH₂(CH₃)₂C	C₂H₅
380	CH₃CH₂(CH₃)CHCH₂	C₂H₅
381	(CH₃)₂CHCH₂CH₂	C₂H₅
382	(CH₃)₃CCH₂CH₂	C₂H₅
383	CH₃CH₂(CH₃)CH(CH₃)—CH	C₂H₅
384	CH₃CH₂(CH₃)CH(CF₃)—CH	C₂H₅
385	(S)-CH₃CH₂(CH₃)CH—(CF₃)CH	C₂H₅
386	(R)-CH₃CH₂(CH₃)CH—(CF₃)CH	C₂H₅
387	CH₃(CH₃)CHCH₂(CH₃)—CH	C₂H₅
388	CH₃(CH₃)CHCH₂(CF₃)—CH	C₂H₅
389	(S)-CH₃(CH₃)CHCH_2-(CF₃)CH	C₂H₅
390	(R)-CH₃(CH₃)CHCH_2-(CF₃)CH	C₂H₅
391	(CH₃)₂CH(CH₃)CH—(CH₃)CH₂	C₂H₅
392	(CH₃)₃CCH₂(CH₃)CH	C₂H₅
393	E-CH₃CH═CH(CH₃)CH	C₂H₅
394	E-C H₃CH═CH—(CH₃CH₂)CH	C₂H₅
395	CH₃CH₂CH₂(CH₃CH₂)—CH	C₂H₅
396	CH₃CH₂(CH₃CH₂)CH—CH₂	C₂H₅
397	CF₂═CFCH₂CH₂	C₂H₅
398	CF₃CH₂(CH₃)CHCH₂	C₂H₅
399	CF₃CF₂CH₂CH₂	C₂H₅
400	CF₃CF₂CF₂CH₂	C₂H₅
401	CF₂═C(CH₃)CH₂CH₂	C₂H₅
402	CH₃CH₂CH₂CH₂CH₂	C₂H₅
403	CH₃CH₂CH₂CH₂(CH₃)—CH	C₂H₅
404	CH₃CH₂CH₂(CH₃)CH—CH₂	C₂H₅
405	CH₃CH₂(CH₃)CHCH₂—CH₂	C₂H₅
406	CH₃CH₂CH₂(CH₃)CH—(CH₃)CH	C₂H₅
407	CH₃CH₂(CH₃)CHCH₂—(CH₃)CH	C₂H₅
408	HOCH₂CH₂	C₂H₅
409	CH₃OCH₂CH₂	C₂H₅
410	CH₃OCH₂(CH₃)CH	C₂H₅
411	CH₃OCH₂(CF₃)CH	C₂H₅
412	CH₃OCH₂(CH₃)₂C	C₂H₅
413	CH₃O(CH₃)CHCH₂	C₂H₅
414	CH₃O(CH₃)CH(CH₃)CH	C₂H₅
415	HC≡CCH₂	C₂H₅
416	CH₃C≡CCH₂	C₂H₅
417	HC≡CCH₂CH₂	C₂H₅
418	HOCH₂CH₂CH₂	C₂H₅
419	CH₃OCH₂CH₂CH₂	C₂H₅
420	(CH₃)₃SiCH₂	C₂H₅
421	C₆H₅CH₂	C₂H₅
422	C₆H₅(CH₃)CH	C₂H₅
423	4-F—C₆H₄CH₂	C₂H₅
424	4-Cl—C₆H₄CH₂	C₂H₅
425	4-F—C₆H₅(CH₃)CH	C₂H₅
426	4-Cl—C₆H₅(CH₃)CH	C₂H₅
427	C₆H₅CH₂CH₂	C₂H₅
428	4-F—C₆H₅CH₂CH₂	C₂H₅
429	1-piperidino	C₂H₅
430	1-pyrrolidino	C₂H₅
431	cyclo-C₅H₉CH₂	C₂H₅
432	Bicyclo[2.2.1]hept-2-yl	C₂H₅
433	1-CH₃-cyclopropyl	C₂H₅
434	cis-2-CH₃-cyclopropyl	C₂H₅
435	trans-2-CH₃-cyclopropyl	C₂H₅
436	2,2-(CH₃)₂-cyclopropyl	C₂H₅
437	1-CH₃-cyclobutyl	C₂H₅
438	cis-2-CH₃-cyclobutyl	C₂H₅
439	trans-2-CH₃-cyclobutyl	C₂H₅
440	cis-3-CH₃-cyclobutyl	C₂H₅
441	trans-3-CH₃-cyclobutyl	C₂H₅
442	2,2-(CH₃)₂-cyclobutyl	C₂H₅
443	3,3-(CH₃)₂-cyclobutyl	C₂H₅
444	1-CH₃-cyclopentyl	C₂H₅
445	cis-2-CH₃-cyclopentyl	C₂H₅
446	trans-2-CH₃-cyclopentyl	C₂H₅
447	cis-3-CH₃-cyclopentyl	C₂H₅
448	trans-3-CH₃-cyclopentyl	C₂H₅
449	2,2-(CH₃)₂-cyclopentyl	C₂H₅
450	3,3-(CH₃)₂-cyclopentyl	C₂H₅
451	1-CH₃-cyclohexyl	C₂H₅
452	cis-2-CH₃-cyclohexyl	C₂H₅
453	trans-2-CH₃-cyclohexyl	C₂H₅
454	cis-3-CH₃-cyclohexyl	C₂H₅
355	trans-3-CH₃-cyclohexyl	C₂H₅
456	2,2-(CH₃)₂-cyclohexyl	C₂H₅
457	3,3-(CH₃)₂-cyclohexyl	C₂H₅
458	cis-4-CH₃-cyclohexyl	C₂H₅
459	trans-4-CH₃-cyclohexyl	C₂H₅
460	4,4-(CH₃)₂-cyclohexyl	C₂H₅
461	4-(CH₃)₃C-cyclohexyl	C₂H₅
462	n-C₃H₇	CF₃CH₂
463	i-C₃H₇	CF₃CH₂
464	n-C₄H₉	CF₃CH₂
465	t-C₄H₉	CF₃CH₂
466	CH₂═CHCH₂	CF₃CH₂
467	CH₂═C(CH₃)CH₂	CF₃CH₂
468	CF₃CH₂	CF₃CH₂
469	CF₃CH₂CH₂	CF₃CH₂
470	CF₃CH₂CH₂CH₂	CF₃CH₂
471	CF₃(CH₃)CH	CF₃CH₂
472	(S)-CF₃(CH₃)CH	CF₃CH₂
473	(R)-CF₃(CH₃)CH	CF₃CH₂
474	cyclo-C₃H₅	CF₃CH₂
475	cyclo-C₄H₇	CF₃CH₂
476	cyclo-C₅H₉	CF₃CH₂
477	cyclo-C₆H₁₁	CF₃CH₂
478	cyclo-C₃H₅CH₂	CF₃CH₂
479	cyclo-C₄H₇CH₂	CF₃CH₂
480	cyclo-C₆H₁₁CH₂	CF₃CH₂
481	CH₃CH₂(CH₃)CH	CF₃CH₂
482	(S)-CH₃CH₂(CH₃)CH	CF₃CH₂
483	(R)-CH₃CH₂(CH₃)CH	CF₃CH₂
484	cyclo-C₇H₁₃	CF₃CH₂
485	CH₂═C(CH₃)CH₂	CF₃CH₂
486	CF₃CH₂	CF₃CH₂
487	4-t-C₄H₉—C₆H₄NH	CF₃CH₂
488	4-F—C₆H₄NH	CF₃CH₂
489	C₆H₅NH	CF₃CH₂
490	4-CH₃—C₆H₄NH	CF₃CH₂
491	4-Br—C₆H₄NH	CF₃CH₂
492	2-F—C₆H₄NH	CF₃CH₂
493	3,4-Cl₂—C₆H₃NH	CF₃CH₂
494	3-CF₃—C₆H₄NH	CF₃CH₂
495	3,5-Cl₂—C₆H₃NH	CF₃CH₂
496	4-CF₃O—C₆H₅NH	CF₃CH₂
497	2-CF₃—C₆H₄NH	CF₃CH₂
498	4-CF₃—C₆H₄NH	CF₃CH₂
499	2-Br—C₆H₄NH	CF₃CH₂
500	2-Cl—C₆H₄NH	CF₃CH₂
501	2-CH₃-4-Cl—C₆H₃NH	CF₃CH₂
502	2-CH₃-5-F—C₆H₃NH	CF₃CH₂
503	3-Cl—C₆H₄NH	CF₃CH₂
504	(CH₃)₂CHCH₂	CF₃CH₂
505	(CH₃)₃CCH₂	CF₃CH₂
506	(CH₃)₃C(CH₃)CH	CF₃CH₂
507	CH₃CH₂(CH₃)₂C	CF₃CH₂
508	CH₃CH₂(CF₃)CH	CF₃CH₂
509	(S)-CH₃CH₂(CF₃)CH	CF₃CH₂
510	(R)-CH₃CH₂(CF₃)CH	CF₃CH₂
511	CH₃CH₂(CH₃CH₂)CH	CF₃CH₂
512	(CH₃)₂CH(CH₃CH₂)CH	CF₃CH₂
513	(CH₃)₂CH(CH₃)CH	CF₃CH₂
514	(CH₃)₂CH(CF₃)CH	CF₃CH₂
515	(S)-(CH₃)₂CH(CF₃)CH	CF₃CH₂
516	(R)-(CH₃)₂CH(CF₃)CH	CF₃CH₂
517	HC═C(CH₃)CH₂	CF₃CH₂
518	CH₂═CH(CH₃CH₂)CH	CF₃CH₂
520	CH₃CH₂CH₂(CH₃)CH	CF₃CH₂
521	CH₃CH₂CH₂(CF₃)CH	CF₃CH₂
522	(S)-CH₃CH₂CH₂(CF₃)CH	CF₃CH₂
523	(R)-CH₃CH₂CH₂(CF₃)CH	CF₃CH₂
524	CH₃CH₂CH₂(CH₃)₂C	CF₃CH₂
525	CH₃CH₂(CH₃)CHCH₂	CF₃CH₂
526	(CH₃)₂CHCH₂CH₂	CF₃CH₂
527	(CH₃)₃CCH₂CH₂	CF₃CH₂
528	CH₃CH₂(CH₃)CH(CH₃)—CH	CF₃CH₂
529	CH₃CH₂(CH₃)CH(CF₃)—CH	CF₃CH₂
530	(S)-CH₃CH₂(CH₃)CH—(CF₃)CH	CF₃CH₂
531	(R)-CH₃CH₂(CH₃)CH—(CF₃)CH	CF₃CH₂
532	CH₃(CH₃)CHCH₂(CH₃)—CH	CF₃CH₂
533	CH₃(CH₃)CHCH₂(CF₃)—CH	CF₃CH₂
534	(S)-CH₃(CH₃)CHCH₂(CF₃)CH	CF₃CH₂
535	(R)-CH₃(CH₃)CHCH₂—(CF₃)CH	CF₃CH₂
536	(CH₃)₂CH(CH₃)CH—(CH₃)CH₂	CF₃CH₂
537	(CH₃)₃CCH₂(CH₃)CH	CF₃CH₂
538	E-CH₃CH═CH(CH₃)CH	CF₃CH₂
539	E-CH₃CH═CH(CH₃CH₂)—CH	CF₃CH₂
540	CH₃CH₂CH₂(CH₃CH₂)—CH	CF₃CH₂
541	CH₃CH₂(CH₃CH₂)CH—CH₂	CF₃CH₂
542	CF₂═CFCH₂CH₂	CF₃CH₂
543	CF₃CH₂(CH₃)CHCH₂	CF₃CH₂
544	CF₃CF₂CH₂CH₂	CF₃CH₂
545	CF₃CF₂CF₂CH₂	CF₃CH₂
546	CF₂═C(CH₃)CH₂CH₂	CF₃CH₂
547	CH₃CH₂CH₂CH₂CH₂	CF₃CH₂
548	CH₃CH₂CH₂CH₂(CH₃)—CH	CF₃CH₂
549	CH₃CH₂CH₂(CH₃)CH—CH₂	CF₃CH₂
550	CH₃CH₂(CH₃)CHCH₂—CH₂	CF₃CH₂
551	CH₃CH₂CH₂(CH₃)CH—(CH₃)CH	CF₃CH₂
552	CH₃CH₂(CH₃)CHCH₂—(CH₃)CH	CF₃CH₂
553	HOCH₂CH₂	CF₃CH₂
554	CH₃OCH₂CH₂	CF₃CH₂
555	CH₃OCH₂(CH₃)CH	CF₃CH₂
556	CH₃OCH₂(CF₃)CH	CF₃CH₂
557	CH₃OCH₂(CH₃)₂C	CF₃CH₂
558	CH₃O(CH₃)CHCH₂	CF₃CH₂
559	CH₃O(CH₃)CH(CH₃)CH	CF₃CH₂
560	HC≡CCH₂	CF₃CH₂
561	CH₃C≡CCH₂	CF₃CH₂
562	HC≡CCH₂CH₂	CF₃CH₂
563	HOCH₂CH₂CH₂	CF₃CH₂
564	CH₃OCH₂CH₂CH₂	CF₃CH₂
565	(CH₃)₃SiCH₂	CF₃CH₂
566	C₆H₅CH₂	CF₃CH₂
567	C₆H₅(CH₃)CH	CF₃CH₂
568	4-F—C₆H₄CH₂	CF₃CH₂
569	4-Cl—C₆H₄CH₂	CF₃CH₂
570	4-F—C₆H₅(CH₃)CH	CF₃CH₂
571	4-Cl—C₆H₅(CH₃)CH	CF₃CH₂
572	C₆H₅CH₂CH₂	CF₃CH₂
573	4-F—C₆H₅CH₂CH₂	CF₃CH₂
574	1-piperidino	CF₃CH₂
575	1-pyrrolidino	CF₃CH₂
576	cyclo-C₅H₉CH₂	CF₃CH₂
577	bicyclo[2.2.1]hept-2-yl	CF₃CH₂
578	1-CH₃-cyclopropyl	CF₃CH₂
579	cis-2-CH₃-cyclopropyl	CF₃CH₂
580	trans-2-CH₃-cyclopropyl	CF₃CH₂
581	2,2-(CH₃)₂-cyclopropyl	CF₃CH₂
582	1-CH₃-cyclobutyl	CF₃CH₂
583	cis-2-CH₃-cyclobutyl	CF₃CH₂
584	trans-2-CH₃-cyclobutyl	CF₃CH₂
585	cis-3-CH₃-cyclobutyl	CF₃CH₂
586	trans-3-CH₃-cyclobutyl	CF₃CH₂
587	2,2-(CH₃)₂-cyclobutyl	CF₃CH₂
588	3,3-(CH₃)₂-cyclobutyl	CF₃CH₂
589	1-CH₃-cyclopentyl	CF₃CH₂
590	cis-2-CH₃-cyclopentyl	CF₃CH₂
591	trans-2-CH₃-cyclopentyl	CF₃CH₂
592	cis-3-CH₃-cyclopentyl	CF₃CH₂
593	trans-3-CH₃-cyclopentyl	CF₃CH₂
594	2,2-(CH₃)₂-cyclopentyl	CF₃CH₂
595	3,3-(CH₃)₂-cyclopentyl	CF₃CH₂
596	1-CH₃-cyclohexyl	CF₃CH₂
597	cis-2-CH₃-cyclohexyl	CF₃CH₂
598	trans-2-CH₃-cyclohexyl	CF₃CH₂
599	cis-3-CH₃-cyclohexyl	CF₃CH₂
600	trans-3-CH₃-cyclohexyl	CF₃CH₂
601	2,2-(CH₃)₂-cyclohexyl	CF₃CH₂
602	3,3-(CH₃)₂-cyclohexyl	CF₃CH₂
603	cis-4-CH₃-cyclohexyl	CF₃CH₂
604	trans-4-CH₃-cyclohexyl	CF₃CH₂
605	4,4-(CH₃)₂-cyclohexyl	CF₃CH₂
606	4-(CH₃)₃C-cyclohexyl	CF₃CH₂
607	cis-1-CH₃-2-fluoro-cyclopropyl	H
608	trans-1-CH₃-2-fluoro-cyclopropyl	H
609	1-CH₃-2,2-difluoro-cyclopropyl	H
610	cis-1-CH₃-2-chloro-2-fluorocyclopropyl	H
611	trans-1-CH₃-2-chloro-2-fluorocyclopropyl	H
612	CH₃CO(CH₃)CH	H
613	CH₃CH₂CO(CH₃)CH	H
614	(CH₃)₂CHCO(CH₃)CH	H
615	(CH₃)₃CCO(CH₃)CH	H
616	CH₃CH₂CH₂CO(CH₃)CH	H
617	CH₃CO(CF₃)CH	H
618	CH₃CH₂CO(CF₃)CH	H
619	CH₃CO(CH₃)₂C	H
620	CH₃CH₂CO(CH₃)₂C	H
621	cis-1-CH₃-2-fluoro-cyclopropyl	CH₃
622	trans-1-CH₃-2-fluoro-cyclopropyl	CH₃
623	1-CH₃-2,2-difluoro-cyclopropyl	CH₃
624	cis-1-CH₃-2-chloro-2-fluorocyclopropyl	CH₃
625	trans-1-CH₃-2-chloro-2-fluorocyclopropyl	CH₃
626	CH₃CO(CH₃)CH	CH₃
627	CH₃CH₂CO(CH₃)CH	CH₃
628	(CH₃)₂CHCO(CH₃)CH	CH₃
629	(CH₃)₃CCO(CH₃)CH	CH₃
630	CH₃CH₂CH₂CO(CH₃)CH	CH₃
631	CH₃CO(CF₃)CH	CH₃
632	CH₃CH₂CO(CF₃)CH	CH₃
633	CH₃CO(CH₃)₂C	CH₃
634	CH₃CH₂CO(CH₃)₂C	CH₃
635	cis-1-CH₃-2-fluoro-cyclopropyl	C₂H₅
636	trans-1-CH₃-2-fluoro-cyclopropyl	C₂H₅
637	1-CH₃-2,2-difluoro-cyclopropyl	C₂H₅
638	cis-1-CH₃-2-chloro-2-fluorocyclopropyl	C₂H₅
639	trans-1-CH₃-2-chloro-2-fluorocyclopropyl	C₂H₅
640	CH₃CO(CH₃)CH	C₂H₅
641	CH₃CH₂CO(CH₃)CH	C₂H₅
642	(CH₃)₂CHCO(CH₃)CH	C₂H₅
643	(CH₃)₃CCO(CH₃)CH	C₂H₅
644	CH₃CH₂CH₂CO(CH₃)CH	C₂H₅
645	CH₃CO(CF₃)CH	C₂H₅
646	CH₃CH₂CO(CF₃)CH	C₂H₅
647	CH₃CO(CH₃)₂C	C₂H₅
648	CH₃CH₂CO(CH₃)₂C	C₂H₅
649	cis-1-CH₃-2-fluoro-cyclopropyl	CF₃CH₂
650	trans-1-CH₃-2-fluoro-cyclopropyl	CF₃CH₂
651	1-CH₃-2,2-difluoro-cyclopropyl	CF₃CH₂
652	cis-1-CH₃-2-chloro-2-fluorocyclopropyl	CF₃CH₂
653	trans-1-CH₃-2-chloro-2-fluorocyclopropyl	CF₃CH₂
654	CH₃CO(CH₃)CH	CF₃CH₂
655	CH₃CH₂CO(CH₃)CH	CF₃CH₂
656	(CH₃)₂CHCO(CH₃)CH	CF₃CH₂
657	(CH₃)₃CCO(CH₃)CH	CF₃CH₂
658	CH₃CH₂CH₂CO(CH₃)CH	CF₃CH₂
659	CH₃CO(CF₃)CH	CF₃CH₂
660	CH₃CH₂CO(CF₃)CH	CF₃CH₂
661	CH₃CO(CH₃)₂C	CF₃CH₂
662	CH₃CH₂CO(CH₃)₂C	CF₃CH₂

Table 2

Table 2 consists of 662 compounds of the general formula (1A), where W and Z are N, X and Y are CH, R is Cl, R¹is 2,5,6-trifluorophenyl, and the values of R³and R⁴are as listed in Table 1. Thus, compound 1 of Table 2 is the same as compound 1 of Table 1 except that in compound 1 of Table 2, R¹is 2,5,6-trifluorophenyl. Similarly, compounds 2 to 662 of Table 2 are the same as compounds 2 to 662 of Table 1 except that in the compounds of Table 2, R¹is 2,5,6-trifluorophenyl.

Table 3

Table 3 consists of 662 compounds of the general formula (1A), where W and Z are N, X and Y are CH, R is Cl, R¹is 2,3,4,5,6-pentafluorophenyl, and the values of R³and R⁴are as listed in Table 1. Thus, compound 1 of Table 3 is the same as compound 1 of Table 1 except that in compound 1 of Table 3, R¹is 2,3,4,5,6-pentafluorophenyl. Similarly, compounds 2 to 662 of Table 3 are the same as compounds 2 to 662 of Table 1 except that in the compounds of Table 3, R¹is 2,3,4,5,6-pentafluorophenyl.

Table 4

Table 4 consists of 662 compounds of the general formula (1A), where W and Z are N, X and Y are CH, R is Cl, R¹is 2,6-difluoro-4-methoxyphenyl, and the values of R³and R⁴are as listed in Table 1. Thus, compound 1 of Table 4 is the same as compound 1 of Table 1 except that in compound 1 of Table 4, R¹is 2,6-difluoro-4-methoxyphenyl. Similarly, compounds 2 to 662 of Table 4 are the same as compounds 2 to 662 of Table 1 except that in the compounds of Table 4, R¹is 2,6-difluoro-4-methoxyphenyl.

Table 5

Table 5 consists of 662 compounds of the general formula (1A), where W and Z are N, X and Y are CH, R is Cl, R¹is 2-fluoro-6-chlorophenyl, and the values of R³and R⁴are as listed in Table 1. Thus, compound 1 of Table 5 is the same as compound 1 of Table 1 except that in compound 1 of Table 5, R¹is 2-fluoro-6-chlorophenyl. Similarly, compounds 2 to 662 of Table 5 are the same as compounds 2 to 662 of Table 1 except that in the compounds of Table 5, R¹is 2-fluoro-6-chlorophenyl.

Table 11

Table 11 consists of 662 compounds of the general formula (1A), where W and X are N and Y and Z are CH, R is Cl, R¹is 2,4,6-trifluorophenyl, and the values of R³and K⁴are as listed in Table 1. Thus, compound 1 of Table 11 is the same as compound 1 of Table 1 except that in compound 1 of Table 11, the compound has the general formula (1A) where W and X are N and Y and Z are CH. Similarly, compounds 2 to 662 of Table 11 are the same as compounds 2 to 662 of Table 1 except that in the compounds of Table 11, the compounds have the general formula (1A) where W and X are N and Y and Z are CH.

Table 12

Table 12 consists of 662 compounds of the general formula (1A), where W and X are N and Y and Z are CH, R is Cl, R¹is 2,5,6-trifluorophenyl, and the values of R³and K⁴are as listed in Table 1. Thus, compound 1 of Table 12 is the same as compound 1 of Table 2 except that in compound 1 of Table 12, the compound has the general formula (1A) where W and X are N and Y and Z are CH. Similarly, compounds 2 to 662 of Table 12 are the same as compounds 2 to 662 of Table 2 except that in the compounds of Table 12, the compounds have the general formula (1A) where W and X are N and Y and Z are CH.

Table 13

Table 13 consists of 662 compounds of the general formula (1A), where W and X are N and Y and Z are CH, R is Cl, R¹is 2,3,4,5,6-pentafluorophenyl, and the values of R³and R⁴are as listed in Table 1. Thus, compound 1 of Table 13 is the same as compound 1 of Table 3 except that in compound 1 of Table 13, the compound has the general formula (1A) where W and X are N and Y and Z are CH. Similarly, compounds 2 to 662 of Table 13 are the same as compounds 2 to 662 of Table 3 except that in the compounds of Table 13, the compounds have the general formula (1A) where W and X are N and Y and Z are CH.

Table 14

Table 14 consists of 662 compounds of the general formula (1A), where W and X are N and Y and Z are CH, R is Cl, R¹is 2,6-difluoro-4-methoxyphenyl, and the values of R³and R⁴are as listed in Table 1. Thus, compound 1 of Table 14 is the same as compound 1 of Table 4 except that in compound 1 of Table 14, the compound has the general formula (1A) where W and X are N and Y and Z are CH. Similarly, compounds 2 to 662 of Table 14 are the same as compounds 2 to 662 of Table 4 except that in the compounds of Table 14, the compounds have the general formula (1A) where W and X are N and Y and Z are CH.

Table 15

Table 15 consists of 662 compounds of the general formula (1A), where W and X are N and Y and Z are CH, R is Cl, R¹is 2-fluoro-6-chlorophenyl, and the values of R³and R⁴are as listed in Table 1. Thus, compound 1 of Table 15 is the same as compound 1 of Table 5 except that in compound 1 of Table 15, the compound has the general formula (1A) where W and X are N and Y and Z are CH. Similarly, compounds 2 to 662 of Table 15 are the same as compounds 2 to 662 of Table 5 except that in the compounds of Table 15, the compounds have the general formula (1A) where W and X are N and Y and Z are CH.

Table 21

Table 21 consists of 662 compounds of the general formula (1A), where W and Z are CH and X and Y are N, R is Cl, R¹is 2,4,6-trifluorophenyl, and the values of R³and K⁴are as listed in Table 1. Thus, compound 1 of Table 21 is the same as compound 1 of Table 1 except that in compound 1 of Table 21, the compound has the general formula (1A) where W and Z are CH and X and Y are N. Similarly, compounds 2 to 662 of Table 21 are the same as compounds 2 to 662 of Table 1 except that in the compounds of Table 21, the compounds have the general formula (1A) where W and Z are CH and X and Y are N.

Table 22

Table 22 consists of 662 compounds of the general formula (1A), where W and Z are CH and X and Y are N, R is Cl, R¹is 2,5,6-trifluorophenyl, and the values of R³and K⁴are as listed in Table 1. Thus, compound 1 of Table 22 is the same as compound 1 of Table 2 except that in compound 1 of Table 22, the compound has the general formula (1A) where W and Z are CH and X and Y are N. Similarly, compounds 2 to 662 of Table 22 are the same as compounds 2 to 662 of Table 2 except that in the compounds of Table 22, the compounds have the general formula (1A) where W and Z are CH and X and Y are N.

Table 23

Table 23 consists of 662 compounds of the general formula (1A), where W and Z are CH and X and Y are N, R is Cl, R¹is 2,3,4,5,6-pentafluorophenyl, and the values of R³and R⁴are as listed in Table 1. Thus, compound 1 of Table 23 is the same as compound 1 of Table 3 except that in compound 1 of Table 23, the compound has the general formula (1A) where W and Z are CH and X and Y are N. Similarly, compounds 2 to 662 of Table 23 are the same as compounds 2 to 662 of Table 3 except that in the compounds of Table 23, the compounds have the general formula (1A) where W and Z are CH and X and Y are N.

Table 24

Table 24 consists of 662 compounds of the general formula (1A), where W and Z are CH and X and Y are N, R is Cl, R¹is 2,6-difluoro-4-methoxyphenyl, and the values of R³and R⁴are as listed in Table 1. Thus, compound 1 of Table 24 is the same as compound 1 of Table 4 except that in compound 1 of Table 24, the compound has the general formula (1A) where W and Z are CH and X and Y are N. Similarly, compounds 2 to 662 of Table 24 are the same as compounds 2 to 662 of Table 4 except that in the compounds of Table 24, the compounds have the general formula (1A) where W and Z are CH and X and Y are N.

Table 25

Table 25 consists of 662 compounds of the general formula (1A), where W and Z are CH and X and Y are N, R is Cl, R¹is 2-fluoro-6-chlorophenyl, and the values of R³and K⁴are as listed in Table 1. Thus, compound 1 of Table 25 is the same as compound 1 of Table 5 except that in compound 1 of Table 25, the compound has the general formula (1A) where W and Z are CH and X and Y are N. Similarly, compounds 2 to 662 of Table 25 are the same as compounds 2 to 662 of Table 5 except that in the compounds of Table 25, the compounds have the general formula (1A) where W and Z are CH and X and Y are N.

Table 26

Table 26 consists of 662 compounds of the general formula (1A), where W and X are CH and Y and Z are N, R is Cl, R¹is 2,4,6-trifluorophenyl, and the values of R³and K⁴are as listed in Table 1. Thus, compound 1 of Table 26 is the same as compound 1 of Table 1 except that in compound 1 of Table 26, the compound has the general formula (1A) where W and X are CH and Y and Z are N. Similarly, compounds 2 to 662 of Table 26 are the same as compounds 2 to 662 of Table 1 except that in the compounds of Table 26, the compounds have the general formula (1A) where W and X are CH and Y and Z are N.

Table 27

Table 27 consists of 662 compounds of the general formula (1A), where W and X are CH and Y and Z are N, R is Cl, R¹is 2,5,6-trifluorophenyl, and the values of R³and K⁴are as listed in Table 1. Thus, compound 1 of Table 27 is the same as compound 1 of Table 2 except that in compound 1 of Table 27, the compound has the general formula (1A) where W and X are CH and Y and Z are N. Similarly, compounds 2 to 662 of Table 27 are the same as compounds 2 to 662 of Table 2 except that in the compounds of Table 27, the compounds have the general formula (1A) where W and X are CH and Y and Z are N.

Table 28

Table 28 consists of 662 compounds of the general formula (1A), where W and X are CH and Y and Z are N, R is Cl, R¹is 2,3,4,5,6-pentafluorophenyl, and the values of R³and R⁴are as listed in Table 1. Thus, compound 1 of Table 28 is the same as compound 1 of Table 3 except that in compound 1 of Table 28, the compound has the general formula (1A) where W and X are CH and Y and Z are N. Similarly, compounds 2 to 662 of Table 28 are the same as compounds 2 to 662 of Table 3 except that in the compounds of Table 28, the compounds have the general formula (1A) where W and X are CH and Y and Z are N.

Table 29

Table 29 consists of 662 compounds of the general formula (1A), where W and X are CH and Y and Z are N, R is Cl, R¹is 2,6-difluoro-4-methoxyphenyl, and the values of R³and R⁴are as listed in Table 1. Thus, compound 1 of Table 29 is the same as compound 1 of Table 4 except that in compound 1 of Table 29, the compound has the general formula (1A) where W and X are CH and Y and Z are N. Similarly, compounds 2 to 662 of Table 29 are the same as compounds 2 to 662 of Table 4 except that in the compounds of Table 29, the compounds have the general formula (1A) where W and X are CH and Y and Z are N.

Table 30

Table 30 consists of 662 compounds of the general formula (1A), where W and X are CH and Y and Z are N, R is Cl, R¹is 2-fluoro-6-chlorophenyl, and the values of R³and K⁴are as listed in Table 1. Thus, compound 1 of Table 30 is the same as compound 1 of Table 5 except that in compound 1 of Table 30, the compound has the general formula (1A) where W and X are CH and Y and Z are N. Similarly, compounds 2 to 662 of Table 30 are the same as compounds 2 to 662 of Table 5 except that in the compounds of Table 30, the compounds have the general formula (1A) where W and X are CH and Y and Z are N.

Table 31

Table 31 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 31 R¹is 2,6-difluorophenyl instead of 2-fluoro-6-chlorophenyl.

Table 32

Table 32 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 32 R¹is 2-fluorophenyl instead of 2-fluoro-6-chlorophenyl.

Table 33

Table 33 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 33 R¹is 2,3,5,6-tetrafluorophenyl instead of 2-fluoro-6-chlorophenyl.

Table 34

Table 34 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 34 R¹is 2-chloro-4,6-difluorophenyl instead of 2-fluoro-6-chlorophenyl.

Table 35

Table 35 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 35 R¹is 2-chlorophenyl instead of 2-fluoro-6-chlorophenyl.

Table 36

Table 36 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 36 R¹is 2,6-dichlorophenyl instead of 2-fluoro-6-chlorophenyl.

Table 37

Table 37 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 37 R¹is 2,4-dichlorophenyl instead of 2-fluoro-6-chlorophenyl.

Table 38

Table 38 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 38 R¹is 2,4,6-trichlorophenyl instead of 2-fluoro-6-chlorophenyl.

Table 39

Table 39 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 39 R¹is 2,3,6-trichlorophenyl instead of 2-fluoro-6-chlorophenyl.

Table 40

Table 40 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 40 R¹is pentachlorophenyl instead of 2-fluoro-6-chlorophenyl.

Table 41

Table 41 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 41 R¹is 2-fluoro-4,6-dichlorophenyl instead of 2-fluoro-6-chlorophenyl.

Table 42

Table 42 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 42 R¹is 4-fluoro-2,6-dichlorophenyl instead of 2-fluoro-6-chlorophenyl.

Table 43

Table 43 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 43 R¹is 2-bromophenyl instead of 2-fluoro-6-chlorophenyl.

Table 44

Table 44 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 44 R¹is 2-fluoro-6-bromophenyl instead of 2-fluoro-6-chlorophenyl.

Table 45

Table 45 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 45 R¹is 2-bromo-4,6-difluorophenyl instead of 2-fluoro-6-chlorophenyl.

Table 46

Table 46 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 46 R¹is 2-fluoro-6-methylphenyl instead of 2-fluoro-6-chlorophenyl.

Table 47

Table 47 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 47 R¹is 2-chloro-6-methylphenyl instead of 2-fluoro-6-chlorophenyl.

Table 48

Table 48 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 48 R¹is 2-methoxyphenyl instead of 2-fluoro-6-chlorophenyl.

Table 49

Table 49 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 49 R¹is 2,6-dimethoxyphenyl instead of 2-fluoro-6-chlorophenyl.

Table 50

Table 50 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 50 R¹is 2-fluoro-6-methoxyphenyl instead of 2-fluoro-6-chlorophenyl.

Table 51

Table 51 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 51 R¹is 2-trifluoromethylphenyl instead of 2-fluoro-6-chlorophenyl.

Table 52

Table 52 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 52 R¹is 2-fluoro-6-trifluoromethylphenyl instead of 2-fluoro-6-chlorophenyl.

Table 53

Table 53 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 53 R¹is 2,6-di-(trifluoromethyl)phenyl instead of 2-fluoro-6-chlorophenyl.

Table 54

Table 54 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 54 R¹is 2-chloro-6-trifluoromethylphenyl instead of 2-fluoro-6-chlorophenyl.

Table 55

Table 55 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 55 R¹is 2,4-difluoro-6-trifluoromethylphenyl instead of 2-fluoro-6-chlorophenyl.

Table 56

Table 56 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 56 R¹is 2,4-difluoro-6-methoxyphenyl instead of 2-fluoro-6-chlorophenyl.

Table 57

Table 57 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 57 R¹is 2,4-difluoro-6-methylphenyl instead of 2-fluoro-6-chlorophenyl.

Table 58

Table 58 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 58 R¹is 2,4-difluoropyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 59

Table 59 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 59 R¹is 3,5-difluoropyrid-4-yl instead of 2-fluoro-6-chlorophenyl.

Table 60

Table 60 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 60 R¹is tetrafluoropyrid-4-yl instead of 2-fluoro-6-chlorophenyl.

Table 61

Table 61 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 61 R¹is 3-fluoropyrid-2-yl instead of 2-fluoro-6-chlorophenyl.

Table 62

Table 62 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 62 R¹is 4-fluoropyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 63

Table 63 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 63 R¹is 3-fluoropyrid-4-yl instead of 2-fluoro-6-chlorophenyl.

Table 64

Table 64 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 64 R¹is 2-fluoropyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 65

Table 65 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 65 R¹is 2,4,6-trifluoropyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 66

Table 66 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 66 R¹is 3,5-difluoropyrid-2-yl instead of 2-fluoro-6-chlorophenyl.

Table 67

Table 67 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 67 R¹is 2,6-difluoropyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 68

Table 68 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 68 R¹is 2,4-difluoro-6-methoxypyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 69

Table 69 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 69 R¹is 2-fluoro-4-chloropyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 70

Table 70 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 70 R¹is 3-fluoro-5-chloropyrid-4-yl instead of 2-fluoro-6-chlorophenyl.

Table 71

Table 71 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 71 R¹is 2-chloro-4-fluoropyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 72

Table 72 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 72 R¹is 2,4-dichloropyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 73

Table 73 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 73 R¹is 3-chloropyrid-2-yl instead of 2-fluoro-6-chlorophenyl.

Table 74

Table 74 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 74 R¹is 4-chloropyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 75

Table 75 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 75 R¹is 3-chloropyrid-4-yl instead of 2-fluoro-6-chlorophenyl.

Table 76

Table 76 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 76 R¹is 2-chloropyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 77

Table 77 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 77 R¹is 3-trifluoromethylpyrid-2-yl instead of 2-fluoro-6-chlorophenyl.

Table 78

Table 78 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 78 R¹is 4-trifluoromethylpyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 79

Table 79 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 79 R¹is 3,5-dichloropyrid-2-yl instead of 2-fluoro-6-chlorophenyl.

Table 80

Table 80 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 80 R¹is 4,6-dichloropyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 81

Table 81 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 81 R¹is 3-trifluoromethylpyrid-4-yl instead of 2-fluoro-6-chlorophenyl.

Table 82

Table 82 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 82 R¹is 2-trifluoromethylpyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 83

Table 83 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 83 R¹is 2-fluoro-4-trifluoromethylpyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 84

Table 84 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 84 R¹is 3-fluoro-5-trifluoromethylpyrid-4-yl instead of 2-fluoro-6-chlorophenyl.

Table 85

Table 85 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 85 R¹is 4-fluoro-2-trifluoromethylpyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 86

Table 86 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 86 R¹is 2,6-dichloropyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 87

Table 87 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 87 R¹is 3,5-dichloropyrid-4-yl instead of 2-fluoro-6-chlorophenyl.

Table 88

Table 88 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 88 R¹is 3-chloro-6-trifluoromethylpyrid-2-yl instead of 2-fluoro-6-chlorophenyl.

Table 89

Table 89 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 89 R¹is 3-fluoro-6-trifluoromethylpyrid-2-yl instead of 2-fluoro-6-chlorophenyl.

Table 90

Table 90 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 90 R¹is pyrid-2-yl instead of 2-fluoro-6-chlorophenyl.

Table 91

Table 91 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 91 R¹is pyrid-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 92

Table 92 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 92 R¹is pyrid-4-yl instead of 2-fluoro-6-chlorophenyl.

Table 93

Table 93 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 93 R¹is 3-fluorothien-2-yl instead of 2-fluoro-6-chlorophenyl.

Table 94

Table 94 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 94 R¹is 3-chlorothien-2-yl instead of 2-fluoro-6-chlorophenyl.

Table 95

Table 95 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 95 R¹is 2,4-difluorothien-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 96

Table 96 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 96 R¹is 2,4-dichlorothien-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 97

Table 97 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table R¹is 2,4,5-trichlorothien-3-yl instead of 2-fluoro-6-chlorophenyl.

Table 98

Table 98 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 98 R¹is piperidino instead of 2-fluoro-6-chlorophenyl.

Table 99

Table 99 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 99 R¹is 2-methylpiperidino instead of 2-fluoro-6-chlorophenyl.

Table 100

Table 100 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 100 R¹is 2,6-dimethylpiperidino instead of 2-fluoro-6-chlorophenyl.

Table 101

Table 101 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 101 R¹is morpholino instead of 2-fluoro-6-chlorophenyl.

Table 102

Table 102 consists of 2648 compounds. Compounds 1 to 662 are exactly the same as compounds 1 to 662 of Table 5 respectively, compounds 1325 to 1986 are exactly the same as compounds 1 to 662 of Table 15 respectively, compounds 2649 to 3310 are exactly the same as compounds 1 to 662 of Table 25 respectively, and compounds 3311 to 3972 are exactly the same as compounds 1 to 662 of Table 30 respectively, except that in all of the compounds of Table 102 R¹is 2,6-dimethylmorpholino instead of 2-fluoro-6-chlorophenyl.

Table 103

Table 103 consists of 201, 248 compounds. Each of these compounds is exactly the same as the corresponding compound in Tables 1 to 102 (thus, for example, compound 1 of Table 103 is the same as compound 1 of Table 1, compound 663 of Table 103 is the same as compound 1 of Table 2, compound 19,861 of Table 103 is the same as compound 1 of Table 31, compound 305,844 of Table 103 is the same as compound 3,972 of Table 102) except that in all of the compounds of Table 103 R is F instead of Cl.

Table 104

Table 104 consists of 201,248 compounds. Each of these compounds is exactly the same as the corresponding compound in Tables 1 to 102 (thus, for example, compound 1 of Table 104 is the same as compound 1 of Table 1, compound 663 of Table 104 is the same as compound 1 of Table 2, compound 19,861 of Table 104 is the same as compound 1 of Table 31, compound 305,844 of Table 104 is the same as compound 3,972 of Table 102) except that in all of the compounds of Table 104 R is Br instead of Cl.

Table 109

Table 109 consists of 3310 compounds. Each of these compounds is exactly the same as the corresponding compound in Tables 1 to 5 (thus, for example, compound 1 of Table 109 is the same as compound 1 of Table 1, compound 663 of Table 109 is the same as compound 1 of Table 2, etc.) except that in all of the compounds of Table 109 X is CF instead of CH.

Table 110

Table 110 consists of 3310c compounds. Each of these compounds is exactly the same as the corresponding compound in Tables 1 to 5 (thus, for example, compound 1 of Table 110 is the same as compound 1 of Table 1, compound 663 of Table 110 is the same as compound 1 of Table 2, etc.) except that in all of the compounds of Table 110 X is CCl instead of CH.

Table 111

Table 111 consists of 3310 compounds. Each of these compounds is exactly the same as the corresponding compound in Tables 1 to 5 (thus, for example, compound 1 of Table 111 is the same as compound 1 of Table 1, compound 663 of Table 111 is the same as compound 1 of Table 2, etc.) except that in all of the compounds of Table 111 X is CBr instead of CH.

Table 112

Table 112 consists of 3310 compounds. Each of these compounds is exactly the same as the corresponding compound in Tables 1 to 5 (thus, for example, compound 1 of Table 112 is the same as compound 1 of Table 1, compound 663 of Table 112 is the same as compound 1 of Table 2, etc.) except that in all of the compounds of Table 112 X is CCH₃instead of CH.

Table 113

Table 113 consists of 3310 compounds. Each of these compounds is exactly the same as the corresponding compound in Tables 1 to 5 (thus, for example, compound 1 of Table 113 is the same as compound 1 of Table 1, compound 663 of Table 113 is the same as compound 1 of Table 2, etc.) except that in all of the compounds of Table 113 Y is CF instead of CH.

Table 114

Table 114 consists of 3310 compounds. Each of these compounds is exactly the same as the corresponding compound in Tables 1 to 5 (thus, for example, compound 1 of Table 114 is the same as compound 1 of Table 1, compound 663 of Table 114 is the same as compound 1 of Table 2, etc.) except that in all of the compounds of Table 114 Y is CCl instead of CH.

Table 115

Table 115 consists of 3310 compounds. Each of these compounds is exactly the same as the corresponding compound in Tables 1 to 5 (thus, for example, compound 1 of Table 115 is the same as compound 1 of Table 1, compound 663 of Table 115 is the same as compound 1 of Table 2, etc.) except that in all of the compounds of Table 115 Y is CBr instead of CH.

Table 116

Table 116 consists of 3310 compounds. Each of these compounds is exactly the same as the corresponding compound in Tables 1 to 5 (thus, for example, compound 1 of Table 116 is the same as compound 1 of Table 1, compound 663 of Table 116 is the same as compound 1 of Table 2, etc.) except that in all of the compounds of Table 116 Y is CCH₃instead of CH.
Compounds of formula (7) or (8), which are examples of compounds of general formula (1) where one of R and R²is NR³R⁴, can be made as shown in Scheme 1, in which W, X, Y, Z, R¹, R³and R⁴have the meanings given above and R⁷is C_1-4alkyl.
Compounds of general formula (4) can be prepared from compounds of general formula (2), which are either commercially available or made by methods known in the literature, by reaction with acids of general formula (3), using standard coupling methods, for example by conversion to the acid chloride using a chlorinating agent such as thionyl chloride, followed by reaction of the resultant acid chloride optionally in the presence of a base such as triethylamine, in a suitable solvent such as dichloromethane or toluene. Compounds of general formula (5) can be prepared by treating compounds of general formula (4) with a base such as sodium hydride, optionally in the presence of a Lewis acid such as magnesium oxide, in a suitable solvent such as N,N-dimethylformamide (DMF) or toluene, at between room temperature and 150° C., but preferably at 60-90° C. Compounds of general formula (6) can be prepared by reaction of compounds of general formula (5) with a chlorination reagent such as phosphorus oxychloride, either neat or in a suitable solvent such as toluene, at between 50 and 150° C., but preferably between 80 and 110° C., or in a microwave reactor at between 150 and 300° C., but preferably between 200 and 250° C. Compounds of formula (7) and (8) can be prepared by reaction of compounds of general formula (6) with an amine R³R⁴NH, either neat, or in a suitable solvent such as DMF, between room temperature and 150° C., but preferably between 50 and 80° C. If compounds (7) and (8) are produced as a mixture they can be separated by suitable means such as crystallisation or chromatography under normal or reverse phase conditions.
Compounds of the general formulae (5), (6), (7) and (8) may be derivatised, via the chloro or hydroxy substituents, using routine chemical techniques to form other compounds of the general formula (1). Alternatively, other compounds of the general formula (1) may be prepared using a similar methodology to that described for preparing the compounds (5) to (8) and employing preparative techniques known from the chemical literature.
Compounds of formula (7) can also be made as shown in Scheme 2.
Compounds of general formula (10) can be prepared from compounds of general formula (9), which are either commercially available or made by methods known in the literature, by reaction with acids of general formula (3), using standard coupling methods, for example by conversion to the acid chloride using a chlorinating agent such as thionyl chloride, followed by reaction of the resultant acid chloride optionally in the presence of a base such as triethylamine, in a suitable solvent such as dichloromethane or toluene. Compounds of general formula (11) can be prepared by treating compounds of general formula (10) with a base such as sodium hydride, optionally in the presence of a Lewis acid such as magnesium oxide, in a suitable solvent such as N,N-dimethylformamide (DMF) or toluene, at between room temperature and 150° C., but preferably at 60-90° C. Compounds of general formula (12) can be prepared by reaction of compounds of general formula (11) with a chlorination reagent such as phosphorus oxychloride, either neat or in a suitable solvent such as toluene, at between 50 and 150° C., but preferably between 80 and 110° C., or in a microwave reactor at between 150 and 300° C., but preferably between 200 and 250° C. Compounds of formula (7) can be prepared from compounds of formula (12) by reductive amination, for example by reaction with a ketone or aldehyde in a suitable solvent such as ethanol or toluene, at between room temperature and reflux, optionally in the presence of an acid catalyst such as para-toluenesulphonic acid or a drying agent such as molecular sieves, followed by treatment with a suitable reducing agent such as sodium borohydride, at between −20° C. and 40° C., but preferably at room temperature. The aldehyde or ketone is chosen so that the desired groups R³and R⁴are formed after reduction of the product of reaction with the amine (12). For example if compounds of formula (12) are reacted with one equivalent of propionaldehyde and then sodium borohydride, compounds of formula (7) where R³is npropyl, and R⁴is hydrogen are formed. If required, the reaction can be repeated with a different aldehyde or ketone. For example, if acetone is used for the second reaction, then compounds of formula (7) where R³is n-propyl and R⁴is iso-propyl, are formed. Alternatively compounds of formula (7) can be formed from compounds of formula (12) by alkylation with a group R³LG, by treatment with a suitable base such as sodium hydride in a solvent such as DMF, or a base such as potassium carbonate in a solvent such as acetone or DMF, at between −78° C. and 100° C., but preferably between room temperature and 60° C., followed by treatment with R⁴LG in a second step under the same conditions if required.
Compounds of formula (13) can be prepared as shown in Scheme 3 from compounds of formula (6) by reaction with a source of fluoride ion, such as potassium fluoride, in a suitable solvent such as sulpholane, at a temperature between 50° C. and 200° C., but preferably at 80-150° C. Compounds of formula (14) and/or compounds of formula (15) can be prepared from difluoro compounds of formula (13) by reaction with an amine of formula R³R⁴NH in a suitable solvent such as DMF or CH₂Cl₂, at a temperature of 0° C.-100° C., but preferably at room temperature.
Compounds of general formula (16), where Hal¹is chlorine or fluorine, can be converted into compounds of formula (17) as shown in Scheme 4. Compounds of general formula (17) where Hal²is bromine or iodine can be formed by reacting compounds of general formula (16) with a metal halide, for example cuprous bromide, in a suitable solvent, for example DMF, at between room temperature and 155° C., but preferably between 70° C. and 155° C.
Further assistance in the preparation of the compounds of formula (1) may be derived from the following publications: Emilio, Toja, et. al., J. Heterocyclic Chem., 23, 1955 (1986), H. Schafer, et. al., J. f. prakt. Chemie, 321(4), 695 (1970) and H. Bredereck et. al., Chem. Ber. 96, 1868-1872 (1993).
The intermediate chemicals having the general formulae (4), (5), (6) and (13):
wherein W, X, Y, Z, R¹and R⁷are as define above, other than the compound of formula (6) wherein X and Y are N, W and Z are C—Cl and R¹is Cl, are believed to be novel compounds and form a further part of this invention.
It should be noted that the intermediate of general formula (5) may exist in the tautomeric forms (a), (b) and (c) as well as in the form shown in formula (5):
The invention as defined by the general formula (5) embraces all such tautomers.
Of particular interest are the intermediates listed in Tables 128 to 132 below. In Table 128 the compounds have the general formula (4) where R⁷is methyl and W, X, Y, Z and R¹have the values shown in the table.

TABLE 128

Cmpd
No.	R¹	W	X	Y	Z

1	2,4,6-trifluorophenyl	N	CH	CH	N
2	2,5,6-trifluorophenyl	N	CH	CH	N
3	2,3,4,5,6-pentafluorophenyl	N	CH	CH	N
4	2,3,5,6-tetrafluorophenyl	N	CH	CH	N
5	2,6-difluoro-4-methoxyphenyl	N	CH	CH	N
6	2-fluoro-6-chlorophenyl	N	CH	CH	N
7	2,6-difluorophenyl	N	CH	CH	N
8	2,3,5,6-tetrafluorophenyl	N	CH	CH	N
9	2-fluorophenyl	N	CH	CH	N
10	2-chlorophenyl	N	CH	CH	N
11	2-bromophenyl	N	CH	CH	N
12	2,4-dichlorophenyl	N	CH	CH	N
13	2,4,6-trifluorophenyl	N	N	CH	CH
14	2,5,6-trifluorophenyl	N	N	CH	CH
15	2,3,4,5,6-pentafluorophenyl	N	N	CH	CH
16	2,3,5,6-tetrafluorophenyl	N	N	CH	CH
17	2,6-difluoro-4-methoxyphenyl	N	N	CH	CH
18	2-fluoro-6-chlorophenyl	N	N	CH	CH
19	2,6-difluorophenyl	N	N	CH	CH
20	2,3,5,6-tetrafluorophenyl	N	N	CH	CH
21	2-fluorophenyl	N	N	CH	CH
22	2-chlorophenyl	N	N	CH	CH
23	2-bromophenyl	N	N	CH	CH
24	2,4-dichlorophenyl	N	N	CH	CH
25	2,4,6-trifluorophenyl	CH	N	N	CH
26	2,5,6-trifluorophenyl	CH	N	N	CH
27	2,3,4,5,6-pentafluorophenyl	CH	N	N	CH
28	2,3,5,6-tetrafluorophenyl	CH	N	N	CH
29	2,6-difluoro-4-methoxyphenyl	CH	N	N	CH
30	2-fluoro-6-chlorophenyl	CH	N	N	CH
31	2,6-difluorophenyl	CH	N	N	CH
32	2,3,5,6-tetrafluorophenyl	CH	N	N	CH
33	2-fluorophenyl	CH	N	N	CH
34	2-chlorophenyl	CH	N	N	CH
35	2-bromophenyl	CH	N	N	CH
36	2,4-dichlorophenyl	CH	N	N	CH
37	2,4,6-trifluorophenyl	CH	CH	N	N
38	2,5,6-trifluorophenyl	CH	CH	N	N
39	2,3,4,5,6-pentafluorophenyl	CH	CH	N	N
40	2,3,5,6-tetrafluorophenyl	CH	CH	N	N
41	2,6-difluoro-4-methoxyphenyl	CH	CH	N	N
42	2-fluoro-6-chlorophenyl	CH	CH	N	N
43	2,6-difluorophenyl	CH	CH	N	N
44	2,3,5,6-tetrafluorophenyl	CH	CH	N	N
45	2-fluorophenyl	CH	CH	N	N
46	2-chlorophenyl	CH	CH	N	N
47	2-bromophenyl	CH	CH	N	N
48	2,4-dichlorophenyl	CH	CH	N	N

Table 129

Table 129 consists of 48 compounds of the general formula (5), where W, X, Y, Z and R¹have the values given in Table 128. Thus, compound 1 of Table 129 has the same W, X, Y, Z and R¹values as compound 1 of Table 128, etc.

Table 130

Table 130 consists of 48 compounds of the general formula (6), where W, X, Y, Z and R¹have the values given in Table 128. Thus, compound 1 of Table 130 has the same W, X, Y, Z and R¹values as compound 1 of Table 128, etc.

Table 131

Table 131 consists of 48 compounds of the general formula (13), where W, X, Y, Z and R¹have the values given in Table 128. Thus, compound 1 of Table 131 has the same W, X, Y, Z and R¹values as compound 1 of Table 128, etc.

Table 132

Table 132 consists of 48 compounds of the general formula (4), where W, X, Y, Z and R¹have the values given in Table 128 and R⁷is ethyl. Thus, compound 1 of Table 132 is the same as compound 1 of Table 128 except that in compound 1 of Table 132, K⁷is ethyl instead of methyl. Similarly, compounds 2 to 48 of Table 132 are the same as compounds 2 to 48 of Table 128 except that in the compounds of Table 132, K⁷is ethyl.
The compounds of formula (1) are active fungicides and may be used to control one or more of the following pathogens: Pyricularia oryzae (Magnaporthe grisea) on rice and wheat and other Pyricularia spp. on other hosts; Puccinia triticina (or recondita), Puccinia striiformis and other rusts on wheat, Puccinia hordei, Puccinia striiformis and other rusts on barley, and rusts on other hosts (for example turf, rye, coffee, pears, apples, peanuts, sugar beet, vegetables and ornamental plants); Erysiphe cichoracearum on cucurbits (for example melon); Blumeria (or Erysiphe) graminis (powdery mildew) on barley, wheat, rye and turf and other powdery mildews on various hosts, such as Sphaerotheca macularis on hops, Sphaerotheca fusca (Sphaerotheca fuliginea) on cucurbits (for example cucumber), Leveillula taurica on tomatoes, aubergine and green pepper, Podosphaera leucotricha on apples and Uncinula necator on vines; Cochliobolus spp., Helminthosporium spp., Drechslera spp. (Pyrenophora spp.), Rhynchosporium spp., Mycosphaerella graminicola (Septoria tritici) and Phaeosphaeria nodorum (Stagonospora nodorum or Septoria nodorum), Pseudocercosporella herpotrichoides and Gaeumannomyces graminis on cereals (for example wheat, barley, rye), turf and other hosts; Cercospora arachidicola and Cercosporidium personatum on peanuts and other Cercospora spp. on other hosts, for example sugar beet, bananas, soya beans and rice; Botrytis cinerea (grey mould) on tomatoes, strawberries, vegetables, vines and other hosts and other Botrytis spp. on other hosts; Alternaria spp. on vegetables (for example carrots), oil-seed rape, apples, tomatoes, potatoes, cereals (for example wheat) and other hosts; Venturia spp. (including Venturia inaequalis (scab)) on apples, pears, stone fruit, tree nuts and other hosts; Cladosporium spp. on a range of hosts including cereals (for example wheat) and tomatoes; Monilinia spp. on stone fruit, tree nuts and other hosts; Didymella spp. on tomatoes, turf, wheat, cucurbits and other hosts; Phoma spp. on oil-seed rape, turf, rice, potatoes, wheat and other hosts; Aspergillus spp. and Aureobasidium spp. on wheat, lumber and other hosts; Ascochyta spp. on peas, wheat, barley and other hosts; Stemphylium spp. (Pleospora spp.) on apples, pears, onions and other hosts; summer diseases (for example bitter rot (Glomerella cingulata), black rot or frogeye leaf spot (Botryosphaeria obtusa), Brooks fruit spot (Mycosphaerella pomi), Cedar apple rust (Gymnosporangium juniperi-virginianae), sooty blotch (Gloeodes pomigena), flyspeck (Schizothyrium pomi) and white rot (Botryosphaeria dothidea)) on apples and pears; Plasmopara viticola on vines; other downy mildews, such as Bremia lactucae on lettuce, Peronospora spp. on soybeans, tobacco, onions and other hosts, Pseudoperonospora humuli on hops and Pseudoperonospora cubensis on cucurbits; Pythium spp. (including Pythium ultimum) on turf and other hosts; Phytophthora infestans on potatoes and tomatoes and other Phytophthora spp. on vegetables, strawberries, avocado, pepper, ornamentals, tobacco, cocoa and other hosts; Thanatephorus cucumeris on rice and turf and other Rhizoctonia spp. on various hosts such as wheat and barley, peanuts, vegetables, cotton and turf, Sclerotinia spp. on turf, peanuts, potatoes, oil-seed rape and other hosts; Sclerotium spp. on turf, peanuts and other hosts; Gibberella fujikuroi on rice; Colletotrichum spp. on a range of hosts including turf, coffee and vegetables; Laetisaria fuciformis on turf, Mycosphaerella spp. on bananas, peanuts, citrus, pecans, papaya and other hosts; Diaporthe spp. on citrus, soybean, melon, pears, lupin and other hosts; Elsinoe spp. on citrus, vines, olives, pecans, roses and other hosts; Verticillium spp. on a range of hosts including hops, potatoes and tomatoes; Pyrenopeziza spp. on oil-seed rape and other hosts; Oncobasidium theobromae on cocoa causing vascular streak dieback; Fusarium spp., Typhula spp., Microdochium nivale, Ustilago spp., Urocystis spp., Tilletia spp. and Claviceps purpurea on a variety of hosts but particularly wheat, barley, turf and maize; Ramularia spp. on sugar beet, barley and other hosts; post-harvest diseases particularly of fruit (for example Penicillium digitatum, Penicillium italicum and Trichoderma viride on oranges, Colletotrichum musae and Gloeosporium musarum on bananas and Botrytis cinerea on grapes); other pathogens on vines, notably Eutypa lata, Guignardia bidwellii, Phellinus igniarus, Phomopsis viticola, Pseudopeziza tracheiphila and Stereum hirsutum; other pathogens on trees (for example Lophodermium seditiosum) or lumber, notably Cephaloascus fragrans, Ceratocystis spp., Ophiostomapiceae, Penicillium spp., Trichoderma pseudokoningii, Trichoderma viride, Trichoderma harzianum, Aspergillus niger, Leptographium lindbergi and Aureobasidium pullulans; and fungal vectors of viral diseases (for example Polymyxa graminis on cereals as the vector of barley yellow mosaic virus (BYMV) and Polymyxa betae on sugar beet as the vector of rhizomania).
A compound of formula (1) may move acropetally, basipetally or locally in plant tissue to be active against one or more fungi. Moreover, a compound of formula (1) may be volatile enough to be active in the vapour phase against one or more fungi on the plant.
The invention therefore provides a method of combating or controlling phytopatho-genic fungi which comprises applying a fungicidally effective amount of a compound of formula (1), or a composition containing a compound of formula (1), to a plant, to a seed of a plant, to the locus of the plant or seed or to soil or any other plant growth medium, e.g. nutrient solution.
The term “plant” as used herein includes seedlings, bushes and trees. Furthermore, the fungicidal method of the invention includes protectant, curative, systemic, eradicant and antisporulant treatments.
The compounds of formula (1) are preferably used for agricultural, horticultural and turfgrass purposes in the form of a composition.
In order to apply a compound of formula (1) to a plant, to a seed of a plant, to the locus of the plant or seed or to soil or any other growth medium, a compound of formula (1) is usually formulated into a composition which includes, in addition to the compound of formula (1), a suitable inert diluent or carrier and, optionally, a surface active agent (SFA). SFAs are chemicals that are able to modify the properties of an interface (for example, liquid/solid, liquid/air or liquid/liquid interfaces) by lowering the interfacial tension and thereby leading to changes in other properties (for example dispersion, emulsification and wetting). It is preferred that all compositions (both solid and liquid formulations) comprise, by weight, 0.0001 to 95%, more preferably 1 to 85%, for example 5 to 60%, of a compound of formula (1). The composition is generally used for the control of fungi such that a compound of formula (1) is applied at a rate of from 0.1 g to 10 kg per hectare, preferably from 1 g to 6 kg per hectare, more preferably from 1 g to 1 kg per hectare.
When used in a seed dressing, a compound of formula (1) is used at a rate of 0.0001 g to 10 g (for example 0.001 g or 0.05 g), preferably 0.005 g to 10 g, more preferably 0.005 g to 4 g, per kilogram of seed.
In another aspect the present invention provides a fungicidal composition comprising a fungicidally effective amount of a compound of formula (1) and a suitable carrier or diluent therefor.
In a still further aspect the invention provides a method of combating and controlling fungi at a locus, which comprises treating the fungi, or the locus of the fungi with a fungicidally effective amount of a composition comprising a compound of formula (1).
The compositions can be chosen from a number of formulation types, including dustable powders (DP), soluble powders (SP), water soluble granules (SG), water dispersible granules (WG), wettable powders (WP), granules (GR) (slow or fast release), soluble concentrates (SL), oil miscible liquids (OL), ultra low volume liquids (UL), emulsifiable concentrates (EC), dispersible concentrates (DC), emulsions (both oil in water (EW) and water in oil (EO)), micro-emulsions (ME), suspension concentrates (SC), aerosols, fogging/smoke formulations, capsule suspensions (CS) and seed treatment formulations. The formulation type chosen in any instance will depend upon the particular purpose envisaged and the physical, chemical and biological properties of the compound of formula (1).
Dustable powders (DP) may be prepared by mixing a compound of formula (1) with one or more solid diluents (for example natural clays, kaolin, pyrophillite, bentonite, alumina, montmorillonite, kieselguhr, chalk, diatomaceous earths, calcium phosphates, calcium and magnesium carbonates, sulphur, lime, flours, talc and other organic and inorganic solid carriers) and mechanically grinding the mixture to a fine powder.
Soluble powders (SP) may be prepared by mixing a compound of formula (1) with one or more water-soluble inorganic salts (such as sodium bicarbonate, sodium carbonate or magnesium sulphate) or one or more water-soluble organic solids (such as a polysaccharide) and, optionally, one or more wetting agents, one or more dispersing agents or a mixture of said agents to improve water dispersibility/solubility. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water soluble granules (SG).
Wettable powders (WP) may be prepared by mixing a compound of formula (1) with one or more solid diluents or carriers, one or more wetting agents and, preferably, one or more dispersing agents and, optionally, one or more suspending agents to facilitate the dispersion in liquids. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water dispersible granules (WG).
Granules (GR) may be formed either by granulating a mixture of a compound of formula (1) and one or more powdered solid diluents or carriers, or from pre-formed blank granules by absorbing a compound of formula (1) (or a solution thereof, in a suitable agent) in a porous granular material (such as pumice, attapulgite clays, fuller's earth, kieselguhr, diatomaceous earths or ground corn cobs) or by adsorbing a compound of formula (1) (or a solution thereof, in a suitable agent) on to a hard core material (such as sands, silicates, mineral carbonates, sulphates or phosphates) and drying if necessary. Agents which are commonly used to aid absorption or adsorption include solvents (such as aliphatic and aromatic petroleum solvents, alcohols, ethers, ketones and esters) and sticking agents (such as polyvinyl acetates, polyvinyl alcohols, dextrins, sugars and vegetable oils). One or more other additives may also be included in granules (for example an emulsifying agent, wetting agent or dispersing agent).
Dispersible Concentrates (DC) may be prepared by dissolving a compound of formula (1) in water or an organic solvent, such as a ketone, alcohol or glycol ether. These solutions may contain a surface active agent (for example to improve water dilution or prevent crystallisation in a spray tank).
Emulsifiable concentrates (EC) or oil-in-water emulsions (EW) may be prepared by dissolving a compound of formula (1) in an organic solvent (optionally containing one or more wetting agents, one or more emulsifying agents or a mixture of said agents). Suitable organic solvents for use in ECs include aromatic hydrocarbons (such as alkylbenzenes or alkylnaphthalenes, exemplified by SOLVESSO 100, SOLVESSO 150 and SOLVESSO 200; SOLVESSO is a Registered Trade Mark), ketones (such as cyclohexanone or methylcyclohexanone), alcohols (such as benzyl alcohol, furfuryl alcohol or butanol), N-alkypyrrolidones (such as N-methylpyrrolidone or N-octylpyrrolidone), dimethyl amides of fatty acids (such as C₈-C₁₀fatty acid dimethylamide) and chlorinated hydrocarbons. An EC product may spontaneously emulsify on addition to water, to produce an emulsion with sufficient stability to allow spray application through appropriate equipment. Preparation of an EW involves obtaining a compound of formula (1) either as a liquid (if it is not a liquid at room temperature, it may be melted at a reasonable temperature, typically below 70° C.) or in solution (by dissolving it in an appropriate solvent) and then emulsifying the resultant liquid or solution into water containing one or more SFAs, under high shear, to produce an emulsion. Suitable solvents for use in EWs include vegetable oils, chlorinated hydrocarbons (such as chlorobenzenes), aromatic solvents (such as alkylbenzenes or alkylnaphthalenes) and other appropriate organic solvents that have a low solubility in water.
Microemulsions (ME) may be prepared by mixing water with a blend of one or more solvents with one or more SFAs, to produce spontaneously a thermodynamically stable isotropic liquid formulation. A compound of formula (1) is present initially in either the water or the solvent/SFA blend. Suitable solvents for use in MEs include those hereinbefore described for use in ECs or in EWs. An ME may be either an oil-in-water or a water-in-oil system (which system is present may be determined by conductivity measurements) and may be suitable for mixing water-soluble and oil-soluble pesticides in the same formulation. An ME is suitable for dilution into water, either remaining as a microemulsion or forming a conventional oil-in-water emulsion.
Suspension concentrates (SC) may comprise aqueous or non-aqueous suspensions of finely divided insoluble solid particles of a compound of formula (1). SCs may be prepared by ball or bead milling the solid compound of formula (1) in a suitable medium, optionally with one or more dispersing agents, to produce a fine particle suspension of the compound. One or more wetting agents may be included in the composition and a suspending agent may be included to reduce the rate at which the particles settle. Alternatively, a compound of formula (1) may be dry milled and added to water, containing agents hereinbefore described, to produce the desired end product.
Aerosol formulations comprise a compound of formula (1) and a suitable propellant (for example n-butane). A compound of formula (1) may also be dissolved or dispersed in a suitable medium (for example water or a water miscible liquid, such as n-propanol) to provide compositions for use in non-pressurised, hand-actuated spray pumps.
A compound of formula (1) may be mixed in the dry state with a pyrotechnic mixture to form a composition suitable for generating, in an enclosed space, a smoke containing the compound.
Capsule suspensions (CS) may be prepared in a manner similar to the preparation of EW formulations but with an additional polymerisation stage such that an aqueous dispersion of oil droplets is obtained, in which each oil droplet is encapsulated by a polymeric shell and contains a compound of formula (1) and, optionally, a carrier or diluent therefor. The polymeric shell may be produced by either an interfacial polycondensation reaction or by a coacervation procedure. The compositions may provide for controlled release of the compound of formula (1) and they may be used for seed treatment. A compound of formula (1) may also be formulated in a biodegradable polymeric matrix to provide a slow, controlled release of the compound.
A composition may include one or more additives to improve the biological performance of the composition (for example by improving wetting, retention or distribution on surfaces; resistance to rain on treated surfaces; or uptake or mobility of a compound of formula (1)). Such additives include surface active agents, spray additives based on oils, for example certain mineral oils or natural plant oils (such as soy bean and rape seed oil), and blends of these with other bio-enhancing adjuvants (ingredients which may aid or modify the action of a compound of formula (1)).
A compound of formula (1) may also be formulated for use as a seed treatment, for example as a powder composition, including a powder for dry seed treatment (DS), a water soluble powder (SS) or a water dispersible powder for slurry treatment (WS), or as a liquid composition, including a flowable concentrate (FS), a solution (LS) or a capsule suspension (CS). The preparations of DS, SS, WS, FS and LS compositions are very similar to those of, respectively, DP, SP, WP, SC and DC compositions described above. Compositions for treating seed may include an agent for assisting the adhesion of the composition to the seed (for example a mineral oil or a film-forming barrier).
Wetting agents, dispersing agents and emulsifying agents may be SFAs of the cationic, anionic, amphoteric or non-ionic type.
Suitable SFAs of the cationic type include quaternary ammonium compounds (for example cetyltrimethyl ammonium bromide), imidazolines and amine salts.
Suitable anionic SFAs include alkali metals salts of fatty acids, salts of aliphatic monoesters of sulphuric acid (for example sodium lauryl sulphate), salts of sulphonated aromatic compounds (for example sodium dodecylbenzenesulphonate, calcium dodecyl-benzenesulphonate, butylnaphthalene sulphonate and mixtures of sodium di-isopropyl- and tri-isopropyl-naphthalene sulphonates), ether sulphates, alcohol ether sulphates (for example sodium laureth-3-sulphate), ether carboxylates (for example sodium laureth-3-carboxylate), phosphate esters (products from the reaction between one or more fatty alcohols and phosphoric acid (predominately mono-esters) or phosphorus pentoxide (predominately di-esters), for example the reaction between lauryl alcohol and tetraphosphoric acid; additionally these products may be ethoxylated), sulphosuccinamates, paraffin or olefine sulphonates, taurates and lignosulphonates.
Suitable SFAs of the amphoteric type include betaines, propionates and glycinates.
Suitable SFAs of the non-ionic type include condensation products of alkylene oxides, such as ethylene oxide, propylene oxide, butylene oxide or mixtures thereof, with fatty alcohols (such as oleyl alcohol or cetyl alcohol) or with alkylphenols (such as octylphenol, nonylphenol or octylcresol); partial esters derived from long chain fatty acids or hexitol anhydrides; condensation products of said partial esters with ethylene oxide; block polymers (comprising ethylene oxide and propylene oxide); alkanolamides; simple esters (for example fatty acid polyethylene glycol esters); amine oxides (for example lauryl dimethyl amine oxide); and lecithins.
Suitable suspending agents include hydrophilic colloids (such as polysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose) and swelling clays (such as bentonite or attapulgite).
A compound of formula (1) may be applied by any of the known means of applying fungicidal compounds. For example, it may be applied, formulated or unformulated, to any part of the plant, including the foliage, stems, branches or roots, to the seed before it is planted or to other media in which plants are growing or are to be planted (such as soil surrounding the roots, the soil generally, paddy water or hydroponic culture systems), directly or it may be sprayed on, dusted on, applied by dipping, applied as a cream or paste formulation, applied as a vapour or applied through distribution or incorporation of a composition (such as a granular composition or a composition packed in a water-soluble bag) in soil or an aqueous environment.
A compound of formula (1) may also be injected into plants or sprayed onto vegetation using electrodynamic spraying techniques or other low volume methods, or applied by land or aerial irrigation systems.
Compositions for use as aqueous preparations (aqueous solutions or dispersions) are generally supplied in the form of a concentrate containing a high proportion of the active ingredient, the concentrate being added to water before use. These concentrates, which may include DCs, SCs, ECs, EWs, MEs SGs, SPs, WPs, WGs and CSs, are often required to withstand storage for prolonged periods and, after such storage, to be capable of addition to water to form aqueous preparations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment. Such aqueous preparations may contain varying amounts of a compound of formula (1) (for example 0.0001 to 10%, by weight) depending upon the purpose for which they are to be used.
A compound of formula (1) may be used in mixtures with fertilisers (for example nitrogen-, potassium- or phosphorus-containing fertilisers). Suitable formulation types include granules of fertiliser. The mixtures suitably contain up to 25% by weight of the compound of formula (1).
The invention therefore also provides a fertiliser composition comprising a fertiliser and a compound of formula (1).
The compositions of this invention may contain other compounds having biological activity, for example micronutrients or compounds having similar or complementary fungicidal activity or which possess plant growth regulating, herbicidal, insecticidal, nematicidal or acaricidal activity.
By including another fungicide, the resulting composition may have a broader spectrum of activity or a greater level of intrinsic activity than the compound of formula (1) alone. Further the other fungicide may have a synergistic effect on the fungicidal activity of the compound of formula (1).
The compound of formula (1) may be the sole active ingredient of the composition or it may be admixed with one or more additional active ingredients such as a pesticide, fungicide, synergist, herbicide or plant growth regulator where appropriate. An additional active ingredient may: provide a composition having a broader spectrum of activity or increased persistence at a locus; synergise the activity or complement the activity (for example by increasing the speed of effect or overcoming repellency) of the compound of formula (1); or help to overcome or prevent the development of resistance to individual components. The particular additional active ingredient will depend upon the intended utility of the composition.
Examples of fungicidal compounds which may be included in the composition of the invention are AC 382042 (N-(1-cyano-1,2-dimethylpropyl)-2-(2,4-dichlorophenoxy) propionamide), acibenzolar-S-methyl, alanycarb, aldimorph, anilazine, azaconazole, azafenidin, azoxystrobin, benalaxyl, benomyl, benthiavalicarb, biloxazol, bitertanol, blasticidin S, boscalid (new name for nicobifen), bromuconazole, bupirimate, captafol, captan, carbendazim, carbendazim chlorhydrate, carboxin, carpropamid, carvone, CGA 41396, CGA 41397, chinomethionate, chlorbenzthiazone, chlorothalonil, chlorozolinate, clozylacon, copper containing compounds such as copper oxychloride, copper oxyquinolate, copper sulphate, copper tallate, and Bordeaux mixture, cyamidazosulfamid, cyazofamid (IKF-916), cyflufenamid, cymoxanil, cyproconazole, cyprodinil, debacarb, di-2-pyridyl disulphide 1,1′-dioxide, dichlofluanid, diclocymet, diclomezine, dicloran, diethofencarb, difenoconazole, difenzoquat, diflumetorim, O,O-di-iso-propyl-S-benzyl thiophosphate, dimefluazole, dimetconazole, dimethirimol, dimethomorph, dimoxystrobin, diniconazole, dinocap, dithianon, dodecyl dimethyl ammonium chloride, dodemorph, dodine, doguadine, edifenphos, epoxiconazole, ethaboxam, ethirimol, ethyl (Z)-N-benzyl-N([methyl(methyl-thioethylideneaminooxycarbonyl)amino]thio)-β-alaninate, etridiazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenoxanil (AC 382042), fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumetover, flumorph, fluoroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutolanil, flutriafol, folpet, fosetyl-aluminium, fuberidazole, furalaxyl, furametpyr, guazatine, hexaconazole, hydroxyisoxazole, hymexazole, imazalil, imibenconazole, iminoctadine, iminoctadine triacetate, ipconazole, iprobenfos, iprodione, iprovalicarb, isopropanyl butyl carbamate, isoprothiolane, kasugamycin, kresoxim-methyl, LY186054, LY211795, LY 248908, mancozeb, maneb, mefenoxam, mepanipyrim, mepronil, metalaxyl, metalaxyl M, metconazole, metiram, metiram-zinc, metominostrobin, metrafenone, MON65500 (N-allyl-4,5-dimethyl-2-trimethylsilylthiophene-3-carboxamide), myclobutanil, NTN0301, neoasozin, nickel dimethyldithiocarbamate, nitrothale-isopropyl, nuarimol, ofurace, organomercury compounds, orysastrobin, oxadixyl, oxasulfuron, oxolinic acid, oxpoconazole, oxycarboxin, pefurazoate, penconazole, pencycuron, phenazin oxide, phosphorus acids, phthalide, picoxystrobin, polyoxin D, polyram, probenazole, prochloraz, procymidone, propamocarb, propamocarb hydrochloride, propiconazole, propineb, propionic acid, proquinazid, prothioconazole, pyraclostrobin, pyrazophos, pyrifenox, pyrimethanil, pyroquilon, pyroxyfur, pyrrolnitrin, quaternary ammonium compounds, quinomethionate, quinoxyfen, quintozene, silthiofam (MON 65500), S-imazalil, simeconazole, sipconazole, sodium pentachlorophenate, spiroxamine, streptomycin, sulphur, tebuconazole, tecloftalam, tecnazene, tetraconazole, thiabendazole, thifluzamide, 2-(thiocyanomethylthio)-benzothiazole, thiophanate-methyl, thiram, tiadinil, timibenconazole, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triazbutil, triazoxide, tricyclazole, tridemorph, trifloxystrobin, triflumizole, triforine, triticonazole, validamycin A, vapam, vinclozolin, XRD-563, zineb, ziram, zoxamide and compounds of the formulae:
The compounds of formula (1) may be mixed with soil, peat or other rooting media for the protection of plants against seed-borne, soil-borne or foliar fungal diseases.
Some mixtures may comprise active ingredients, which have significantly different physical, chemical or biological properties such that they do not easily lend themselves to the same conventional formulation type. In these circumstances other formulation types may be prepared. For example, where one active ingredient is a water insoluble solid and the other a water insoluble liquid, it may nevertheless be possible to disperse each active ingredient in the same continuous aqueous phase by dispersing the solid active ingredient as a suspension (using a preparation analogous to that of an SC) but dispersing the liquid active ingredient as an emulsion (using a preparation analogous to that of an EW). The resultant composition is a suspoemulsion (SE) formulation.
The invention is illustrated by the following Examples in which the following abbreviations are used:
ml=millilitres f=fine
g=grammes THF=tetrahydrofuran
ppm=parts per million DCM=dichloromethane
s=singlet DMF═N,N-dimethylformamide
d=doublet DMSO=dimethylsulphoxide
t=triplet DMAP=4-dimethylaminopyridine
q=quartet NMR=nuclear magnetic resonance
m=multiplet HPLC=high performance liquid
b=broad chromatography

EXAMPLE 1

This Example illustrates the preparation of [6-chloro-7-(2,4,6-trifluorophenyl)-pyrido[2,3-b]pyrazin-8-yl]-isopropylamine (Compound No. 3, Table 1).

Step 1

Methyl 2-amino-3-pyrazine carboxylate (2.2 g) was dissolved in dry DCM (20 ml) to give a cloudy pale yellow solution, and pyridine (2 ml) in dry DCM (12 ml) was added. The stirred suspension was cooled in an ice bath, and 2,4,6-trifluorophenylacetyl chloride (3.0 g) in dry DCM (13 ml) was added dropwise. The reaction gradually became a deep orange, and then went clear. It was stirred for 6 hours and stood overnight. The reaction mixture was washed with water, brine, and then dilute hydrochloric acid, and the DCM layer was dried over magnesium sulphate. The solvent was evaporated to yield an orange solid which was triturated with ether, to give methyl 2-[2,4,6-trifluorophenylacetylamino]-3-pyrazine carboxylate as a yellow solid (1.5 g).

¹H NMR (CDCl₃) δ ppm: 4.03 (s, 5H), 6.74 (t, 2H), 8.43 (d, 1H), 8.61 (d, 1H) 10.9 (s, 1H).

Step 2

The product of Step 1 (3.25 g) was dissolved in DMF (10 ml) and added dropwise to a stirred suspension of sodium hydride (0.60 g of an 80% dispersion in mineral oil) in DMF (80 ml). There was an immediate reaction, and the mixture was stirred at room temperature for 2 hours, and at 80° C. for 8 hours. The reaction mixture was cooled and evaporated to give a yellow solid (3 g), which was then acidified with dilute hydrochloric acid. The resultant white suspension was filtered and collected, washed with ether and dried to give 6,8-dihydroxy-7-(2,4,6-trifluorophenyl)pyrido[2,3-b]pyrazine (1.8 g).
¹H NMR (d⁶-DMSO) δ ppm: 7.25 (t, 2H), 8.6 (fd, 1H), 8.7 (fd, 1H), 12.6 (s, 1H).

Step 3

The product from Step 2 (0.90 g) was added portion-wise to phosphorus oxychloride (10 ml) with stirring. The reaction was exothermic. The mixture became brown with a fine suspension, and was then refluxed for 6 hours. Excess phosphorus oxychloride was evaporated, the mixture was diluted with DCM, and then washed with water to give a black oil, which was purified by flash column chromatography on silica gel (40-60) eluting with diethyl ether, to give 6,8-dichloro-7-(2,4,6-trifluorophenyl)pyrido[2,3-b]pyrazine as a dark oil (0.40 g).
¹H NMR (CDCl₃) δ ppm: 6.9 (t, 2H), 9.1 (d, 1H), 9.2 (d, 1H).

Alternative Procedure for Step 3

Phosphorus oxychloride (20.90 g) was added over 15 minutes to a suspension of the product from Step 2 (10.0 g), in 1,2-dichloroethane (80 ml) containing DMF (5.0 g) maintained at a temperature between 79°-81° C. Stirring was continued at this temperature for 3 hours, and the reaction was then cooled. The mixture was poured carefully into saturated sodium bicarbonate solution (500 ml) keeping the temperature below 30° C. After stirring for 20 minutes the product was extracted with ethyl acetate, washed with water and brine and dried over sodium sulphate. The solvent was evaporated to yield a dark red oil, which was purified by flash chromatography eluting with cyclohexane:ethyl acetate, 4:1 to give 6,8-dichloro-7-(2,4,6-trifluorophenyl)pyrido[2,3-b]pyrazine as a light brown solid (7.5 g), m.p. 139-141° C.

Step 4

The product from Step 3 (0.20 g), isopropylamine (1.0 ml) and N-ethyl-diisopropylamine (0.20 g) were refluxed in a sealed tube at 90° C. for 17 hours. The dark coloured reaction mixture was evaporated to give an oil, which was purified by flash column chromatography on silica gel (40-60) in diethyl ether.
A fraction containing a mixture of isomers (0.080 g), was obtained, and a portion of this mixture (0.020 g) was purified by reverse phase HPLC on a Kromasil 100-5C18 column, eluting with methanol:water (65:35) to give [6-chloro-7-(2,4,6-trifluorophenyl)-pyrido[2,3-b]pyrazin-8-yl]-isopropylamine as a frothy solid (0.013 g).
¹H NMR (CDCl₃) δ ppm: 1.1 (d, 6H), 3.26 (m, 1H), 6.84 (m, 2H), 6.95 (bd, 1H), 8.67 (d, 1H), 9.0 (d, 1H).

EXAMPLE 2

This Example illustrates the preparation of [6-fluoro-7-(2,4,6-trifluorophenyl)-pyrido[2,3-b]pyrazin-8-yl]-isopropylamine (Compound No. 3, Table 103)

Step 1

6,8-Dichloro-7-(2,4,6-trifluorophenyl)-pyrido[2,3-b]pyrazine (1.25 g) and potassium fluoride (0.66 g, spray dried) in dry sulpholane (5 ml) were heated to 130° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine and dried over sodium sulphate. After evaporation of the solvent, the remaining oil was purified by flash chromatography on silica gel eluting with cyclohexane:ethyl acetate, 3:1 to yield 6,8-difluoro-7-(2,4,6-trifluorophenyl)-pyrido[2,3-b]-pyrazine as a slightly brownish solid (0.79 g), m.p. 120-121° C.

Step 2

The product from Step 1 (0.30 g) was added to a suspension of isopropylamine (0.090 g), potassium carbonate (0.21 g) and a catalytic amount of DMAP in DMF (3 ml), and the mixture was stirred at room temperature for 19 hours. After addition of ethyl acetate, the mixture was washed with water and brine, dried over sodium sulphate, filtered and the solvent evaporated. The residue was purified by flash chromatography eluting with toluene:ethyl acetate, 9:1 to give [6-fluoro-7-(2,4,6-trifluorophenyl)-pyrido[2,3-b]pyrazin-8-yl]-isopropylamine as a yellow powder (0.20 g), m.p. 127-128° C.

EXAMPLE 3

This Example illustrates the preparation of [6-chloro-7-(2,4,6-trifluorophenyl)-pyrido[3,2-c]pyridazin-8-yl]-isopropylamine (Compound No. 3, Table 11).

Step 1

A solution of 4-aminopyridazine-3-carbonitrile (0.248 g, prepared as in J. Het. Chem. (1970), 3, 467-473) in absolute ethanol (30 ml) was saturated with hydrogen chloride gas, the flask being cooled in an ice bath. The ice bath was then removed and the resulting solution was refluxed for 18 hours. It was then cooled, the solvent evaporated, and cold, saturated aqueous sodium bicarbonate was added. The aqueous phase was then extracted with DCM, the organic phases were combined, dried over magnesium sulphate, filtered and evaporated to give 4-aminopyridazine-3-carboxylic acid ethyl ester as a white solid (0.229 g). The aqueous phase was evaporated, DCM was added, the organic phase was isolated, dried over magnesium sulphate, filtered and evaporated under vacuo to give further ester as a white solid (0.010 g), m.p. 149-150° C.
¹H NMR (CDCl₃) δ ppm: 1.48 (t, 3H), 4.52 (q, 2H), 6.73 (d, 1H), 8.75 (d, 1H).

Step 2

A mixture of the product from Step 1 (0.239 g) and DMAP (0.175 g) in dry toluene (1 ml) was added to 2,4,6-trifluorophenylacetyl chloride (crude product from reaction of 0.275 g 2,4,6-trifluorophenylacetic acid and oxalyl chloride) and a few drops of DMF in toluene (1 ml) at room temperature, giving a thick yellow precipitate. The stirred suspension was heated for 3 hours at reflux, becoming dark brown/green with a green precipitate. It was left to stand overnight for 18 hours. The solid was collected and washed with diethyl ether. The dark green filtrate was evaporated to give a dark green liquid which was purified by flash column chromatography on silica gel (40-60) eluting with ethyl acetate to give 4-[2-(2,4,6-trifluorophenyl)-acetylamino]-pyridazine-3-carboxylic acid ethyl ester as green/yellow oil that solidified on standing (0.307 g).
¹H NMR (CDCl₃) δ ppm: 1.50 (t, 3H), 3.87 (s, 2H), 4.55 (q, 2H), 6.77 (t, 2H), 8.78 (d, 1H), 9.15 (d, 1H), 11.20 (bs, 1H).

Step 3

The product from Step 2 (0.307 g) and potassium carbonate (0.25 g) were stirred in dry DMF (10 ml) at 110° C. for 2 hours and then cooled and stood for 18 hours. The DMF was evaporated and the resulting brown solid was triturated with diethyl ether and the organic phase decanted. The solid was dissolved in water then acidified with dilute hydrochloric acid to neutrality. Most of the aqueous phase was then evaporated, leading to precipitation of a black solid that was filtered, and the yellow/brown aqueous phase was evaporated to dryness, affording a residue that was dissolved in methanol, the insoluble inorganic salts were filtered and the organic phase was evaporated to dryness to give 7-(2,4,6-trifluorophenyl)-5H-pyrido[3,2-c]pyridazine-6,8-dione as a light brown/beige solid (0.258 g).
¹H NMR (CD₃OD) δ ppm: 6.83 (2d, 2H), 7.44 (d, 1H), 9.00 (d, 1H).

Step 4

Phosphorus oxychloride (0.048 ml) was added to the product from Step 3 (0.05 g) in 1,2-dichloroethane (2 ml) containing a catalytic amount of DMF. The suspension was stirred and refluxed for 1 hour and then stood for 18 hours, and then refluxed for a further hour and then allowed to cool. The excess phosphorus oxychloride was evaporated to give a brown oil, which was dissolved in DCM and washed with cold water. The organic layer was separated and dried over magnesium sulphate, filtered and evaporated to give a brown oil, which was purified by flash column chromatography on silica gel (40-60) eluting with diethyl ether to give 6,8-dichloro-7-(2,4,6-trifluorophenyl)-pyrido[3,2-c]pyridazine as a yellow oil (0.015 g).
¹H NMR (CDCl₃) δ ppm: 6.92 (m, 2H), 8.11 (d, 1H), 9.71 (d, 1H).

Step 5

Isopropylamine (0.5 ml) was added to the product from Step 4 (0.015 g) dissolved in DCM (1 ml) containing dimethylacetamide (0.3 ml) in a sealed tube. The yellow solution became yellow/greenish. The vessel was then sealed and stirred at room temperature. The solvents were evaporated and the crude residue was purified using preparative thin layer chromatography silica gel plates eluting with ethyl acetate:hexane 1:1 to give [6-Chloro-7-(2,4,6-trifluorophenyl)-pyrido[3,2-c]pyridazin-8-yl]-isopropylamine (0.003 g).
¹H NMR (CDCl₃) δ ppm: 1.16 (d, 6H), 3.41 (m, 1H), 6.85 (dd, 2H), 7.79 (bs, 1H), 7.84 (d, 1H). 9.40 (d, 1H).

EXAMPLE 4

This Example illustrates the preparation of [2-chloro-3-(2,4,6-trifluorophenyl)-pyrido[2,3-d]pyridazin-4-yl]-isopropylamine (Compound No. 3, Table 21).

Step 1

5-Aminopyridazine-4-carboxylic acid ethyl ester (1.26 g, prepared according to J. Het. Chem., (1968), 5, 845) was dissolved in dry toluene (125 ml) at 90° C., and DMAP (0.92 g) was added. 2,4,6-Trifluorophenylacetyl chloride (1.75 g of 95% purity material) was added dropwise with stirring at 70° C., and a white solid precipitated. The reaction was stirred at reflux for 5 hours and then filtered hot. The filtrate was evaporated to give 5-[2-(2,4,6-trifluorophenyl)-acetylamino]-pyridazine-4-carboxylic acid ethyl ester as a white solid (2.6 g), m.p. 143-144° C.
¹H NMR (CDCl₃) δ ppm: 1.45 (t, 3H), 3.90 (s, 2H), (4.45 (q, 2H), 6.75 (m, 2H), 9.45 (s1H), 10.60 (s, 1H), 11.1 (bs, 1H).

Step 2

The product from Step 1 (2.5 g) was dissolved in dry THF (50 ml) and the flask purged with nitrogen. Sodium bis-trimethylsilylamide (22.1 ml of a 1M solution in THF) was added dropwise with stirring at 0° C. A yellow precipitate appeared, and the reaction was stirred for 3 hours at 0° C. The reaction was quenched with concentrated hydrochloric acid (5 ml) at 0° C. and then poured onto ice water, extracted with DCM and dried over magnesium sulphate. The solvent was evaporated to give 3-(2,4,6-trifluorophenyl)-1H-pyrido[2,3-d]pyridazine-2,4-dione as a yellow solid. Further product crystallised out of the aqueous solution overnight, to give a total yield of 1.29 g, m.p. >300° C.
¹H NMR (d⁶-DMSO) δ ppm: 7.25 (m, 2H), 9.17 (s, 1H), 9.47 (s, 1H), 12.30 (bs, 1H).

Step 3

The product from Step 2 (0.10 g) was heated to 90° C. with phosphorus oxychloride (1.6 ml) with stirring. After 1 hour a clear yellow solution was obtained and the excess solvent was evaporated and ice water was added, giving a yellow solid. This was extracted with DCM, and the solution dried over magnesium sulphate and evaporated to give 2,4-dichloro-3-(2,4,6-trifluorophenyl)-pyrido[2,3-d]pyridazine as a yellow foamy glass (0.11 g).
¹H NMR (CDCl₃) δ ppm: 6.90 (m, 2H), 9.80 (s, 1H), 10.0 (s, H).

Step 4

Isopropylamine (1.5 ml) was added to the product from Step 3 (0.020 g) in DCM and the tube stoppered and the reaction stirred overnight at room temperature. The DCM was evaporated and water added to the residue, which was then extracted with DCM. The extract was dried over magnesium sulphate and evaporated to give an orange oil, which was purified by HPLC eluting with ethyl acetate:hexane 4:1 to give [2-Chloro-3-(2,4,6-trifluorophenyl)-pyrido[2,3-d]pyridazin-4-yl]-isopropylamine (0.007 g)
¹H NMR (CDCl₃) δ ppm: 1.27 (d, 6H), 4.05 (m, 1H), 4.90 (bs, 1H), 6.92 (m, 2H), 9.55 (s, 1H), 9.90 (s, 1H).

EXAMPLE 5

This Example illustrates the preparation of [7-chloro-6-(2,4,6-trifluorophenyl)-pyrido[2,3-c]pyridazin-5-yl]-isopropylamine (Compound No. 3, Table 26).

Step 1

3-Aminopyridazine-4-carboxylic acid (1.68 g, prepared as in JOC, (1985), 50, 346) was refluxed in ethanol (170 ml) with concentrated hydrochloric acid (2 ml) and p-toluene-sulphonyl chloride (0.1 g) for 55 hours. The solvent was evaporated and ice water added to the residue, which was then neutralised with solid sodium bicarbonate. The mixture was extracted with chloroform, insoluble material filtered, the organic extract dried over magnesium sulphate and evaporated to give 3-aminopyridazine-4-carboxylic acid ethyl ester (1.02 g) as a white solid.
¹H NMR (CDCl₃) δ ppm: 1.40 (t, 3H), 4.40 (q, 2H), 6.50 (bs, 2H), 7.74 (d, 1H), 8.72 (d, 1H).

Step 2

The product from Step 1 (0.36 g) was dissolved in dry toluene (25 ml) and DMAP (0.262 g) was added. A solution of 2,4,6-trifluorophenylacetyl chloride (0.45 g) in dry toluene (1 ml) was added dropwise with stirring, and a white precipitate formed. After stirring at room temperature for 10 minutes the reaction was stirred under reflux for 4.5 hours, and then allowed to stand overnight at room temperature. The white solid was filtered and washed with toluene, and the filtrate evaporated to give a brown oil, which was purified by HPLC eluting with ethyl acetate:hexane 4:1 to give 3-[2-(2,4,6-trifluorophenyl)-acetylamino]-pyridazine-4-carboxylic acid ethyl ester as a pale yellow solid (0.57 g), m.p. 135° C.
¹H NMR (CDCl₃) δ ppm: 1.40 (t, 3H), 4.22 (s, 2H), 4.41 (q, 2H), 6.70 (m, 2H), 7.94 (d, 1H), 9.15 (d, 1H), 10.30 (bs, 1H).

Step 3

The product from Step 2 (2.0 g) was dissolved in dry THF (50 ml), and sodium bistrimethylsilylamide (17.7 ml of a 1.0M solution in THF) was added dropwise with stirring under nitrogen at 0° C. The reaction was stirred for 3 hours at 0° C. and a yellow precipitate was formed. The reaction was quenched with concentrated hydrochloric acid and then poured into ice water. The solid was filtered, washed with water and air dried to give 6-(2,4,6-trifluorophenyl)-8H-pyrido[2,3-c]pyridazine-5,7-dione as a yellow solid (1.92 g), m.p. >330° C., still containing some THF, which was used without further purification.
¹H NMR (D₆-DMSO) δ ppm: 7.30 (m, 2H), 8.10 (d, 1H), 9.20 (d, 1H), 11.90 (bs, 1H), 12.60 (s, 1H).

Step 4

The product from Step 3 (0.060 g) was heated to 90° C. in phosphorus oxychloride (1 ml) for 1 hour to give a clear black solution. The mixture was cooled and the excess in phosphorus oxychloride evaporated. The residue was quenched with ice and aqueous sodium bicarbonate, extracted with ethyl acetate, the extract dried over magnesium sulphate and evaporated to give 5,7-dichloro-6-(2,4,6-trifluorophenyl)-pyrido[2,3-c]pyridazine as a black solid (0.087 g).
¹H NMR (CDCl₃) δ ppm: 6.90 (m, 2H), 8.30 (d, 1H), 9.75 (d, 1H).

Step 4

The product from Step 3 (0.080 g) was stirred with isopropylamine (2 ml) in DCM (5 ml) at room temperature overnight and then heated to 40° C. in a sealed tube for 4 hours. The volatiles were evaporated, water was added and the mixture extracted with DCM. The extracts were dried over magnesium sulphate and evaporated to give a dark brown tar, which was purified by preparative TLC on silica gel plates eluting with ethyl acetate:hexane 3:2 to give [7-Chloro-6-(2,4,6-trifluorophenyl)-pyrido[2,3-c]pyridazin-5-yl]-isopropylamine (0.008 g),
¹H NMR (CDCl₃) δ ppm: 1.20 (d, 6H), 3.71 (m, 1H), 4.45 (bs, 1H), 6.87-6.92 (m, 2H), 7.97 (d, 1H), 9.37 (d, 1H).

TABLE 133

			NMR data (ppm,
			in CDCl₃,
Compound	Table	Compound	unless otherwise
No.	No.	Structure	stated) or Mpt.

3	1		1.1 (d, 6 H), 3.26 (m, 1 H), 6.84 (m, 2 H),6.95 (bd, 1 H), 8.67 (d, 1 H), 9.0 (d, 1 H).

4	1		0.8 (t, 3 H), 1.27 (m, 2 H), 1.55 (m, 2 H),2.87 (m, 2 H), 6.8, 6.85 (ABd, 2 H); 8.66,8.99 (ABd, 2 H).

14	1		129-131° C.

15	1		149-150° C.

16	1		175-177° C.

17	1		153-155° C.

22	1		0.92 (m) + 1.22 (m) + 1.55 (m)(total = 8 H), 2.9 (m, 2 H), 6.85 (m, 2 H),8.78, 8.96 (ABd, 2 H).

23	1		151-153° C.

58	1		102-104° C.

108	1		1.12 (d, 3 H), 3.27 (m, 2 H), 3.3 (s, 3 H),3.5 (m, 1 H), 6.8 (m, 2 H), 8.67 (d) + 8.97 (ABd)(total = 2 H)

161	1		138-140° C.

162	1		140-141° C.

219	1		3.0 (s, 6 H), 6.85 (m, 2 H), 8.65,8.87 (ABd, 2 H)

3	5		157-159° C.

4	5		0.82 (m, 3 H), 1.22 m + 1.5 m (total = 4 H),2.82 (m, 2 H), 7.1-7.47 (m, 3 H), 8.67 + 9.05(ABd, 2 H).

17	5		159-160° C.

20	5		166-168° C.

22	5		163-165° C.

23	5		163-165° C.

28	5		71-73° C.

108	5		1.05 (d) + 1.12 (d) (total = 3 H), 3.1-3.5(m, 3 H), 3.25 (d) + 3.32 (d) (total = 3 H),7.1 (m) + 7.4 (m) (total = 4 H), 8.67(d, 1 H), 9.06 (d, 1 H)

161	5		0.82 (m, 4 H), 3.65 (m, 4 H), 7.12-7.35(m, 3 H), 8.66 + 8.87 (ABd, 2 H).

162	5		1.52 (m, 6 H), 3.3 (m, 4 H), 7.25 (m) + 7.4 (m)(total = 3 H), 8.78 + 8.95 (ABd, 2 H).

171	5		2.3 (s, 3 H), 2.5 (m, 4 H), 7.15 (m, 1 H),7.37 (m, 2 H), 8.75 (d, 1 H), 8.92 (d, 1 H).

3	11		1.16 (d, 6 H), 3.41 (m, 1 H), 6.85 (dd, 2 H),7.79 (bs, 1 H), 7.84 (d, 1 H). 9.40 (d, 1 H).

23	11		0.79 (t, 3 H), 1.11 (d, 3 H), 1.47 (m, 2 H),3.13 (m, 1 H), 6.86 (dd, 2 H), 7.79 (bs,1 H), 7.84 (d, 1 H), 9.40 (d, 1 H).

3	21		1.27 (d, 6 H), 4.05 (m, 1 H), 4.90 (bs, 1 H),6.92 (m, 2 H), 9.55 (s, 1 H), 9.90 (s, 1 H).

3	26		1.20 (d, 6 H), 3.71 (m, 1 H), 4.45 (bs, 1 H),6.87-6.92 (m, 2 H), 7.97 (d, 1 H), 9.37 (d, 1 H).

3	31		1.25 (d, 6 H), 4.5 (bd, 1 H), 4.6 (m, 1 H),7.15 (t, 2 H), 7.6 (m, 1 H), 8.625 (fd, 1 H),8.85 (fd, 1 H).

3	32		1.10 (d, 6 H), 4.52 (m, 2 H), 7.28 (m, 3 H),7.47 (m, 1 H), 8.52 (d, 1 H), 8.76 (d, 1 H)

23	32		0.78 (m, 3 H), 1.07 (m, 3 H), 1.45 (m, 2 H),4.48 (m, 2 H), 7.25 (m, 3 H), 7.50 (m, 1 H),8.51 (d, 1 H), 8.71 (d, 1 H)

3	37		160-161° C.

16	37		181-183° C.

171	37		2.3 (s, 3 H), 2.5 (m, 3 H), 3.2-3.5 (m, 4 H),7.27 (m) + 7.4 (m) + 7.62 (m) (total = 3 H), 8.77(d, 1 H), 8.92 (d, 1 H).

3	43		1.10 (d, 6 H), 4.32 (d, 1 H), 4.57 (m,1 H), 7.22 (m, 1 H), 7.35 (m, 1 H), 7.48(m, 1 H), 7.78 (m, H), 8.53 (d, 1 H), 8.71(d, 1 H)

23	43		0.81 (m, 3 H), 1.10 (m, 3 H), 1.40 (m,2 H), 4.26 (m, 1 H), 4.45 (m, 1 H), 7.25 (m,1 H), 7.38 (m, 1 H), 7.50 (m, 1 H), 7.76(m, 1 H), 8.52 (d, 1 H), 8.74 (d, 1 H)

3	103		127-128° C.

5	103		138-140° C.

12	103		106-108° C.

14	103		120-121° C.

15	103		153-154° C.

23	103		101-102° C.

58	103		99-100° C.

92	103		1.07 (t, 3 H), 1.57 (s, 3 H), 3.52 (s, 2 H), 3.72(q, 2 H), 4.85 (m, 2 H), 6.85 (m, 2 H), 8.8 (d,1 H), 9.0 (d, 1 H).

161	103		148-150° C.

171	103		167-160° C.

2651	103		100-101° C.

2660	103		1.3 (d, 3 H), 1.4 (d, 3 H), 3.9 (m, 1 H), 6.95-7.6(m, 4 H), 8.75 (m, 1 H), 9.05 (m, 1 H).

2671	103		123-124° C.

2706	103		0.8 (m, 6 H), 1.72 (m, 1 H), 2.6 (m, 2 H), 7.02-7.47 (m, 4 H), 8.6 (d, 1 H), 8.92 (d, 1 H).

43704	103		133-135° C.(diastereoisomer 1)

43704	103		137-139° C.(diastereoisomer 2)

43715	103		118-119° C.

43750	103		0.80 (d) + 0.83 (d) (total = 6 H), 1.72 (m, 1 H),2.65 (m, 2 H), 7.1-7.3 (m) + 7.35, 7.6 (d)(total = 3 H), 8.6 (d, 1 H), 8.92 (d, 1 H).

1	128		4.03 (s, 5 H), 6.74 (t, 2 H), 8.43 (d, 1 H), 8.61(d, 1 H), 10.9 (s, 1 H).

6	128		162-163° C.

12	128		158-159° C.

13	128		1.48 (t, 3 H), 4.52 (q, 2 H), 6.73 (d, 1 H),8.75 (d, 1 H).

25	128		1.45 (t, 3 H), 3.90 (s, 2 H), (4.45 (q, 2 H), 6.75(m, 2 H), 9.45 (s1 H), 10.60 (s, 1 H), 11.1 (bs,1 H).

37	128		1.40 (t, 3 H), 4.22 (s, 2 H), 4.41 (q, 2 H),6.70 (m, 2 H), 7.94 (d, 1 H), 9.15 (d, 1 H), 10.30(bs, 1 H).

1	129		(d⁶-DMSO) 7.25(t, 2 H), 8.6(fd, 1 H), 8.7(fd,1 H), 12.6(s, 1 H).

6	129		>220° C.

9	129		250-252° C.

11	129		258° C.

12	129		>200° C.

13	129		(CD₃OD) 6.83 (2d, 2 H), 7.44 (d, 1 H),9.00 (d, 1 H).

25	129		(D⁶-DMSO) 7.25 (m, 2 H), 9.17 (s, 1 H),9.47 (s, 1 H), 12.30 (bs, 1 H).

37	129		(D₆-DMSO) 7.30 (m, 2 H), 8.10 (d, 1 H),9.20 (d, 1 H), 11.90 (bs, 1 H), 12.60 (s, 1 H).

1	130		139-141° C.

6	130		154-155° C.

9	130		7.21 (m, 1 H), 7.28(m, 2 H), 7.48(m, 1 H),8.95(d, 1 H), 9.08(d, 1 H).

11	130		7.18(d, 1 H), 7.29(m, 1 H), 7.41(t, 1 H),7.69(dd, 1 H), 9.00(d, 1 H), 9.09(d, 1 H).

12	130		159-160° C.

13	130		6.92 (m, 2 H), 8.11 (d, 1 H), 9.71 (d, 1 H).

25	130		6.90 (m, 2 H), 9.80 (s, 1 H), 10.0 (s, 1 H).

37	130		6.90 (m, 2 H), 8.30 (d, 1 H), 9.75 (d, 1 H).

1	131		120-121° C.

6	131		7.27 (m) + 7.55 (m) (total = 3 H), 9.07 (d, 1 H),9.2 (d, 1 H).

12	131		7.45 (m) + 7.67 (d) (total = 3 H), 9.07 (d, 1 H),9.2 (d, 1 H).

EXAMPLE 6

This Example illustrates the fungicidal properties of the compounds of the general formula (1).
Compounds were tested in a leaf disk assay, with methods described below. Test compounds were dissolved in DMSO, and diluted into water to 200 ppm.
Plasmopara viticola (downy mildew of grapevine): grapevine leaf disks were placed on agar in a 24-well plate and sprayed a solution of the test compound. After allowing to dry completely, for between 12 and 24 hours, the leaf disks were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed seven days after inoculation as preventive fungicidal activity.
Phytophthora infestans (late blight of potato on tomato): tomato leaf disks were placed on water agar in a 24-well plate and sprayed with a solution of the test compound. After allowing to dry completely, for between 12 and 24 hours, the leaf disks were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed four days after inoculation as preventive fungicidal activity.
Erysiphe graminis f.sp. hordei (barley powdery mildew): barley leaf segments were placed on agar in a 24-well plate and sprayed with a solution of the test compound. After allowing to dry completely, for between 12 and 24 hours, the leaf disks were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed four days after inoculation as preventive fungicidal activity.
Erysiphe graminis f.sp. tritici (wheat powdery mildew): wheat leaf segments were placed on agar in a 24-well plate and sprayed with a solution of the test compound. After allowing to dry completely, for between 12 and 24 hours, the leaf disks were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed four days after inoculation as preventive fungicidal activity.
Puccinia recondita f.sp. tritici (wheat brown rust): wheat leaf segments were placed on agar in a 24-well plate and sprayed with a solution of the test compound. After allowing to dry completely, for between 12 and 24 hours, the leaf disks were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed nine days after inoculation as preventive fungicidal activity.
Septoria nodorum (wheat glume blotch): wheat leaf segments were placed on agar in a 24-well plate and sprayed with a solution of the test compound. After allowing to dry completely, for between 12 and 24 hours, the leaf disks were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed four days after inoculation as preventive fungicidal activity.
Pyrenophora teres (barley net blotch): barley leaf segments were placed on agar in a 24-well plate and sprayed with a solution of the test compound. After allowing to dry completely, for between 12 and 24 hours, the leaf disks were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed four days after inoculation as preventive fungicidal activity.
Pyricularia oryzae (rice blast): rice leaf segments were placed on agar in a 24-well plate and sprayed with a solution of the test compound. After allowing to dry completely, for between 12 and 24 hours, the leaf disks were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed four days after inoculation as preventive fungicidal activity.
Botrytis cinerea (grey mould): bean leaf disks were placed on agar in a 24-well plate and sprayed with a solution of the test compound. After allowing to dry completely, for between 12 and 24 hours, the leaf disks were inoculated with a spore suspension of the fungus. After appropriate incubation the activity of a compound was assessed four days after inoculation as preventive fungicidal activity.
The following compounds gave greater than 60% control of disease:
Plasmopara viticola, Compounds 4 (1), 20 (1), 23 (5);
Phytophthora infestans, Compounds 3 (1), 58 (5), 3 (103);
Erysiphe graminis f.sp. hordei, Compounds 3 (1), 14 (1), 15 (1), 16 (1), 17 (1), 22 (1), 23 (1), 58 (1), 108 (1), 161 (1), 162 (1), 3 (5), 4 (5), 17 (5), 20 (5), 22 (5), 23 (5), 28 (5), 58 (5), 108 (5), 162 (5), 171 (5), 665 (31), 23 (32), 3 (37), 16 (37), 171 (37), 665 (37), 678 (37), 3 (43), 23 (43), 685 (43), 3 (103), 12 (103), 23 (103), 58 (103), 92 (103), 2651 (103), 2660 (103), 2671 (103), 23844 (103) diastereoisomer 1, 23844 (103) diastereoisomer 2, 23855 (103), 23890 (103;
Erysiphe graminis f.sp. tritici, Compounds 3 (1), 4 (1), 15 (1), 16 (1), 2291), 23 (1), 58 (1), 108 (1), 162 (1), 219 (1), δ 95), 161 (5), 3 (31), 16 (37), 665 (37), 3 (103), 12 (103), 23 (103), 58 (103), 92 (103), 2651 (103), 2660 (103), 2671 (103), 23844 (103) diastereoisomer 1, 23844 (103) diastereoisomer 2, 23855 (103), 23890 (103);
Puccinia recondita f.sp. tritici, Compounds 3 (1), 14 (1), 15 (1), 16 (1), 17 (1), 23 (1), 58 (1), 108 (1), 161 (1), 162 (1), 4 (5), 17 (5), 23 (5), 28 (5), 58 (5), 108 (5), 3 (31), 16 (37), 665 (37), 678 (37), 3 (103), 12 (103), 23 (103), 58 (103), 92 (103), 2651 (103), 2660 (103), 2671 (103), 23844 (103) diastereoisomer 1, 23855 (103), 23890 (103);
Septoria nodorum, Compounds 391), 15 (1), 16 (1), 17 (1), 23 (1), 58 (1), 5895), 161 (5), 22 (6), 665 (37), 685 (43), 12 (103), 23 (103), 58 (103), 2660 (103), 2671 (103), 23844 (103) diastereoisomer 1, 23855 (103), 23890 (103);
Pyrenophora teres, Compounds 3 (1), 14 (1), 15 (1), 16 (1), 17 (1), 23 (1), 58 (1), 161 (1), 3 (5), 20 (5), 16 (37), 665 (37), 3 (103), 12 (103), 23 (103), 58 (103), 2651 (103), 2660 (103), 2671 (103), 23844 (103) diastereoisomer 1, 23855 (103), 23890 (103);
Pyricularia oryzae, Compounds 3 (1), 4 (1), 14 (1), 15 (1), 16 (1), 17 (1), 20 (1), 23 (1), 58 (1), 108 (1), 161 (1), 3 (5), 4 (5), 20 (5), 23 (5), 58 (5), 108 (5), 3 (32), 3 (37), 16 (37), 678 (37), 3 (43), 3 (103), 12 (103), 23 (103), 58 (103), 92 (103), 171 (103), 2651 (103), 2669 (103), 2671 (103), 23844 (103) diastereoisomer 1, 23844 (103) diastereoisomer 2, 23855 (103), 23890 (103);
Botrytis cinerea, Compounds 4 (1), 14 (1), 15 (1), 16 (1), 17 (1), 22 (1), 58 (1), 108 (1), 4 (5), 22 (5), 28 (5), 58 (5), 108 (5), 162 (5), 16 (37), 678 (37), 23 (103), 92 (103), 2651 (103), 2660 (103), 23844 (103) diastereoisomer 2, 23855 (103), 23890 (103).

Claims

1. The compound of the general formula (1):

wherein

W and X, X and Y or Y and Z are N and the other two are CR⁸;

R⁸is H, halo, C_1-4alkyl, C_1-4alkoxy or halo(C_1-4)alkyl;

R is halo;

R¹is halo, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_3-8cycloalkyl, C_3-8cycloalkyl(C_1-6)alkyl, C_1-8alkoxy, C_1-8alkylthio, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, aryl(C_1-4)alkyl, aryl(C_1-4)alkoxy, heteroaryl(C_1-4)alkyl, heteroaryl(C_1-4)alkoxy, aryl(C_1-4)alkylthio, heteroaryl(C_1-4)alkylthio, morpholino, piperidino or pyrrolidino;

R²is NR³R⁴;

R³and R⁴are independently H, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, aryl, aryl(C_1-8)alkyl, C_3-8cycloalkyl, C_3-8cycloalkyl(C_1-6)alkyl, heteroaryl, heteroaryl(C_1-8)alkyl, NR⁵R⁶, provided that not both R³and R⁴are H or NR⁵R⁶, or

R³and R⁴together form a C_3-7alkylene or C_3-7alkenylene chain optionally substituted with one or more C_1-4alkyl or C_1-4alkoxy groups, or,

together with the nitrogen atom to which they are attached, R³and R⁴form a morpholine, thiomorpholine, thiomorpholine S-oxide or thiomorpholine S-dioxide ring or a piperazine or piperazine N—(C_1-4)alkyl ring; and

R⁵and R⁶are independently H, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, aryl, aryl(C_1-8)alkyl, C_3-8cycloalkyl, C_3-8cycloalkyl (C_1-6)alkyl, heteroaryl or heteroaryl(C_1-8)alkyl;

any of the foregoing alkyl, alkenyl, alkynyl or cycloalkyl groups or moieties (other than for R⁸) being optionally substituted with halogen, cyano, C_1-6alkoxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6haloalkoxy, C_1-6alkylthio, tri(C_1-4)alkylsilyl, C_1-6alkylamino or C_1-6dialkylamino,

any of the foregoing morpholine, thiomorpholine, piperidine, piperazine and pyrrolidine rings being optionally substituted with C_1-4alkyl, and

any of the foregoing aryl or heteroaryl groups or moieties being optionally substituted with one or more substituents selected from halo, hydroxy, mercapto, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_2-6alkenyloxy, C_2-6alkynyloxy, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, C_1-6alkylthio, halo(C_1-6)alkylthio, hydroxy(C_1-6)alkyl, C_1-4alkoxy(C_1-6)alkyl, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl, phenoxy, benzyloxy, benzoyloxy, cyano, isocyano, thiocyanato, isothiocyanato, nitro, —NR′″R″″, —NHCOR′″, —NHCONR′″R″″, —CONR′″R″″, —SO₂R′″, —OSO₂R′″, —COR′″, —CR′″═NR″″ or —N═CR′″R″″, in which R′″ and R″″ are independently hydrogen, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy, halo(C_1-4)alkoxy, C_1-4alkylthio,

C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl, phenyl or benzyl, the phenyl and benzyl groups being optionally substituted with halogen, C_1-4alkyl or C_1-4alkoxy.

2. A compound according to claim 1 wherein

R³is C_1-8alkyl, halo(C_1-8)alkyl, hydroxy(C_1-8)alkyl, C_1-4alkoxy(C_1-8)alkyl, C_1-4alkoxyhalo-(C_1-8)alkyl, tri(C_1-4)alkylsilyl(C_1-6)alkyl, C_1-4alkylcarbonyl(C_1-8)alkyl, C_1-4alkylcarbonyl-halo(C_1-8)alkyl, phenyl(1-4)alkyl, C_2-8alkenyl, halo(C_2-8)alkenyl, C_2-8alkynyl, C_3-8cycloalkyl optionally substituted with chloro, fluoro or methyl, C_3-8cycloalkyl(C_1-4)alkyl, phenylamino, piperidino or morpholino, the phenyl ring of phenylalkyl or phenylamino being optionally substituted with one, two or three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy and halo(C_1-4)alkoxy; and

R⁴is H, C_1-4alkyl, halo(C_1-4)alkyl or amino, or

R³and R⁴together form a C_3-7alkylene or alkenylene chain optionally substituted with methyl, or,

together with the nitrogen atom to which they are attached, R³and R⁴form a morpholine, thiomorpholine, thiomorpholine S-oxide or thiomorpholine S-dioxide ring or a piperazine or piperazine N—(C_1-4)alkyl ring, in which the morpholine or piperazine rings are optionally substituted with methyl.

3. A compound according to claim 1 wherein

R¹is phenyl optionally substituted with from one to five halogen atoms or with from one to three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy or halo(C_1-4)alkoxy, pyridyl optionally substituted with from one to four halogen atoms or with from one to three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy or halo(C_1-4)alkoxy, 2- or 3-thienyl optionally substituted with from one to three halogen atoms or with from one to three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl,

C_1-4alkoxy or halo(C_1-4)alkoxy, or piperidino or morpholino both optionally substituted with one or two methyl groups.

4. A compound according to claim 4 wherein R¹is 2,6-difluorophenyl, 2-fluoro-6-chlorophenyl, 2,5,6-trifluorophenyl, 2,4,6-trifluorophenyl, 2,6-difluoro-4-methoxyphenyl or pentafluorophenyl.

5. A compound according to claim 1 wherein

R⁸is H, halo, C_1-4alkyl, C_1-4alkoxy or halo(C_1-4)alkyl;

R is halo;

R¹is halo, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_3-8cycloalkyl, C_3-8cycloalkyl(C_1-6)alkyl, C_1-8alkoxy, C_1-8alkylthio, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, aryl(C_1-4)alkyl, aryl(C_1-4)alkoxy, heteroaryl(C_1-4)alkyl, heteroaryl(C_1-4)alkoxy, aryl(C_1-4)-alkylthio, heteroaryl(C_1-4)alkylthio, morpholino, piperidino or pyrrolidino;

R²is NR³R⁴;

together with the nitrogen atom to which they are attached, R³and R⁴form a morpholine, thiomorpholine, thiomorpholine S-oxide or thiomorpholine S-dioxide ring or a piperazine or piperazine N—(C_1-14)alkyl ring; and

R⁵and R⁶are independently H, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, aryl, aryl(C_1-8)alkyl, C_3-8cycloalkyl, C_3-8cycloalkyl(C_1-6)alkyl, heteroaryl or heteroaryl(C_1-8)alkyl;

any of the aryl, heteroaryl, aryloxy or heteroaryl groups being optionally substituted with one or more substituents selected from halo, hydroxy, mercapto, C_1-6alkyl, C_2-6alkenyl,

C_2-6alkynyl, C_1-6alkoxy, C_2-6alkenyloxy, C_2-6alkynyloxy, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, C_1-6alkylthio, halo(C_1-6)alkylthio, hydroxy(C_1-6)alkyl, C_1-4alkoxy(C_1-6)alkyl, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl, phenoxy, benzyloxy, benzoyloxy, cyano, isocyano, thiocyanato, isothiocyanato, nitro, —NR′″R″″, —NHCOR′″, —NHCONR′″R″″, —CONR′″R″″, —SO₂R′″, —OSO₂R′″, —COR′″, —CR′″═NR″″ or —N═CR′″R″″, in which R′″ and R″″ are independently hydrogen, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy, halo(C_1-4)alkoxy, C_1-4alkylthio,

6. A compound according to claim 1 wherein

R⁸is H, halo, C_1-4alkyl, C_1-4alkoxy or halo(C_1-4)alkyl;

R is halo;

R²is NR³⁴;

R³is C_1-4alkyl, halo(C_1-4)alkyl, C_2-4alkenyl, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl or phenylamino in which the phenyl ring is optionally substituted with one, two or three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy and halo(C_1-4)alkoxy; and

R⁴is H, C_1-4alkyl or amino, or

R³and R⁴together form a C_4-6alkylene chain optionally substituted with C_1-4alkyl or C_1-4alkoxy, or,

together with the nitrogen atom to which they are attached, R³and R⁴form a morpholine, thiomorpholine, thiomorpholine S-oxide or thiomorpholine S-dioxide ring or a piperazine or piperazine N—(C_1-4)alkyl ring;

any of the alkyl, alkenyl, alkynyl or cycloalkyl groups or moieties (other than for R⁸) being optionally substituted with halogen, cyano, C_1-6alkoxy, C_1-6alkylcarbonyl,

C_1-6alkoxycarbonyl, C_1-6haloalkoxy, C_1-6alkylthio, tri(C_1-4)alkylsilyl, C_1-6alkylamino or

C_1-6dialkylamino,

any of the aryl or heteroaryl groups or moieties being optionally substituted with one or more substituents selected from halo, hydroxy, mercapto, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl,

C_1-6alkoxy, C_2-6alkenyloxy, C_2-6alkynyloxy, halo(C_1-6)alkyl, halo(C_1-6)alkoxy,

C_1-6alkylthio, halo(C_1-6)alkylthio, hydroxy(C_1-6)alkyl, C_1-4alkoxy(C_1-6)alkyl, C_3-6cycloalkyl,

C_3-6cycloalkyl(C_1-4)alkyl, phenoxy, benzyloxy, benzoyloxy, cyano, isocyano, thiocyanato, isothiocyanato, nitro, —NR′″R″″, —NHCOR′″, —NHCONR′″R″″, —CONR′″R″″, —SO₂R′″, —OSO₂R′″, —COR′″, —CR′″═NR″″ or —N═CR′″R″″, in which R′″ and R″″ are independently hydrogen, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy, halo(C_1-4)alkoxy, C_1-4alkylthio,

7. A compound according to claim 1 wherein

R⁸is H, halo, C_1-4alkyl, C_1-4alkoxy or halo(C_1-4)alkyl;

R is halo;

R¹is optionally substituted phenyl;

R²is NR³R⁴;

any of the alkyl, alkenyl, alkynyl or cycloalkyl groups or moieties (other than for R⁸) being optionally substituted with halogen, cyano, C_1-6alkoxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6haloalkoxy, C_1-6alkylthio, tri(C_1-4)alkylsilyl, C_1-6alkylamino or C_1-6dialkylamino,

any of the aryl or heteroaryl groups or moieties, including the phenyl group of R¹, being optionally substituted with one or more substituents selected from halo, hydroxy, mercapto, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, C_2-6alkenyloxy, C_2-6alkynyloxy, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, C_1-6alkylthio, halo(C_1-6)alkylthio, hydroxy(C_1-6)alkyl, C_1-4alkoxy(C_1-6)alkyl, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-14)alkyl, phenoxy, benzyloxy, benzoyloxy, cyano, isocyano, thiocyanato, isothiocyanato, nitro, —NR′″R″″, —NHCOR′″, —NHCONR′″R″″, —CONR′″R″″, —SO₂R′″, —OSO₂R′″, —COR′″, —CR′″═NR″″ or —N═CR′″R″″, in which R′″ and R″″ are independently hydrogen, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy, halo(C_1-4)alkoxy, C_1-4alkylthio, C_3-6cycloalkyl, C_3-6cycloalkyl(C_1-4)alkyl, phenyl or benzyl, the phenyl and benzyl groups being optionally substituted with halogen, C_1-4alkyl or

C_1-4alkoxy.

8. A compound according to claim 1 wherein

R⁸is H, halo, C_1-4alkyl, C_1-4alkoxy or halo(C_1-4)alkyl;

R is halo;

R¹is phenyl optionally substituted with from one to five halogen atoms or with from one to three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy or halo(C_1-4)alkoxy, pyridyl optionally substituted with from one to four halogen atoms or with from one to three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy or halo(C_1-4)alkoxy, 2- or 3-thienyl optionally substituted with from one to three halogen atoms or with from one to three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy or halo(C_1-4)alkoxy, or piperidino or morpholino both optionally substituted with one or two methyl groups;

R²is NR³R⁴;

R³is C_1-8alkyl, halo(C_1-8)alkyl, hydroxy(C_1-8)alkyl, C_1-4alkoxy(C_1-8)alkyl, C_1-4alkoxyhalo-(C_1-8)alkyl, tri(C_1-4)alkylsilyl(C_1-6)alkyl, C_1-4alkylcarbonyl(C_1-8)alkyl, C_1-4alkylcarbonyl-halo(C_1-8)alkyl, phenyl(_1-4)alkyl, C_2-8alkenyl, halo(C_2-8)alkenyl, C_2-8alkynyl, C_3-8cycloalkyl optionally substituted with chloro, fluoro or methyl, C_3-8cycloalkyl(C_1-4)alkyl, phenylamino, piperidino or morpholino, the phenyl ring of phenylalkyl or phenylamino being optionally substituted with one, two or three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy and halo(C_1-4)alkoxy; and

R⁴is H, C_1-4alkyl, halo(C_1-4)alkyl or amino, or

R³and K⁴together form a C_3-7alkylene or C_3-7alkenylene chain optionally substituted with methyl, or,

9. A compound according to claim 1 wherein

R⁸is H, halo, C_1-4alkyl, C_1-4alkoxy or halo(C_1-4)alkyl;

R is halo;

R¹is phenyl optionally substituted with from one to five halogen atoms or with from one to three substituents selected from halo, C_1-4alkyl, halo(C_1-4)alkyl, C_1-4alkoxy or

halo(C_1-4)alkoxy;

R²is NR³R⁴;

R⁴is H, C_1-4alkyl or amino, or R³and R⁴together form a C_4-6alkylene chain optionally substituted with methyl, or, together with the nitrogen atom to which they are attached, R³and R⁴form a morpholine ring.

10. A process for preparing a compound of the general formula (1) according to claim 1 wherein R is chloro or fluoro and R²is NR³R⁴and W, X, Y, Z, R¹, R³and R⁴are as defined in claim 1, which comprises reacting an amine of the general formula NR³R⁴with a compound of the general formula (6) or (13)

11. The intermediate chemicals having the general formulae (4), (5), (6) and (13):

wherein W, X, Y, Z and R¹are as defined in claim 1 and R⁷is C_1-4alkyl, other than the compound of formula (6) wherein X and Y are N, W and Z are C—Cl and R¹is Cl.

12. A plant fungicidal composition comprising a fungicidally effective amount of a compound as defined in claim 1 and a suitable carrier or diluent therefor.

13. A method of combating or controlling phytopathogenic fungi which comprises applying to a plant, to a seed of a plant, to the locus of the plant or seed or to soil or to any other plant growth medium, a fungicidally effective amount of a compound according to claim 1 or a composition according to claim 13.