Note: Descriptions are shown in the official language in which they were submitted.
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FUNGICIDES
This invention relates to novel quinolinyloxyalkanoic acid amides, processes
for
preparing them, to compositions containing them and to methods of using them
to
combat fungi, especially fungal infections of plants.
Certain quinolinyloxyalkanoic acid amide derivatives and their use as
agricultural and
horticultural bactericides are disclosed, for example, in WO 04/047538 and JP
2001-
89453.
The present invention is concerned with the provision of particular
substituted quinoline-
6-yloxyalkanoic acid amides for use mainly as plant fungicides.
Thus according to the present invention there is provided a compound of the
general
formula I
L
Q N Y-'I 3
12
S(O)n R
N Q3
Q2 R
wherein
Q', Q2 and Q3, independently of each other, are halogen, cyano, nitro, azido,
optionally
substituted C1_6 alkyl, optionally substituted C3.6 cycloalkyl, optionally
substituted C3_6 -
heterocyclyl, which contains at least one heteroatom selected from sulphur,
oxygen or
NR , where R is hydrogen or optionally substituted C1_6alkyl, optionally
substituted C3_6
cycloalkyl(C1.4)alkyl, optionally substituted C2_6 alkenyl, optionally
substituted C2_6
alkynyl, optionally substituted C,_6 alkoxy, optionally substituted C2_6
alkenyloxy,
optionally substituted C2_6 alkynyloxy, optionally substituted aryl,
optionally substituted
aryloxy, optionally substituted aryl(C,_6)alkyl, optionally substituted
aryi(C1_6)alkoxy,
optionally substituted heteroaryl, optionally substituted heteroaryloxy,
optionally
substituted heteroaryl(C,_6)alkyl, optionally substituted
heteroaryl(C1_6)alkoxy, -SF5 or
-S(O)u(C1_6)alkyl, wherein u is 0, 1 or 2 and the alkyl group is optionally
substituted with
halogen, or
Q', Q2 and Q3, independently of each other, are -OS02(Cl_a)alkyl, wherein the
alkyl
group is optionally substituted with halogen, or
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Q', Q2 and Q3, independently of each other, are -CONR'R", -COR', -CO2R',
-CR"=NR", -NRuR", -NRuCOR", -NR"CO2R", -SO2NRuR" or -NRUSO2R', wherein R' is
optionally substituted C,.6 alkyl and Ru and R", independently of each other,
are
hydrogen or C1.6 alkyl optionally substituted with halogen, or, in the case of
-CONRuR" or
-SO2NR"R", R"R" may join to form a 5- or 6-membered carbocyclic or
heterocyclic ring
containing a heteroatom selected from sulfur, oxygen and NR , wherein R is
hydrogen
or optionally substituted C1.6aIkyV, or, in the case of -CRu=NR", R" is
hydraxy or
optionally substituted C1.6alkoxy, optionally substituted aryloxy or
optionally substituted
heteroaryloxy, or
Q' and Q2, independently of each other, additionally denote hydrogen,
R' is optionally substituted C,-4 alkyl, optionally substituted C2_4 alkenyl,
optionally
substituted C2.4 alkynyl or optionally substituted C3.4 cycloalkyl,
R2 is hydrogen, C,$ alkyl, C3_4 cycloalkyl, C2_8 alkenyl, cyano, hydroxy,
alkoxy,
cyano(C,.4)alkyl, C,_4 alkoxy(C,_4)alkyl, C,.4 alkoxy(C1_4)alkoxy(C1_4)alkyl
or
benzyloxy(C,_4)alkyl, wherein the phenyl ring is optionally substituted with
C,_4 alkoxy,
R3 is -(CRaRb)P(CR Rd)q(X)r(CReRf)sR4, wherein
Ra, Rb, Rc, Rd, Re and R, independently of each other, are hydrogen, C,-4
alkyl, halogen,
cyano, hydroxy, C,-4 alkoxy or C,-4 alkoxycarbonyl, or
RaRb, R Rd or ReR' may join to form a 3 to 8 membered carbocyclic or
heterocyclic ring
containing a heteroatom selected from sulfur, oxygen and NR , wherein R is
hydrogen
or optionally substituted C1_6alkyl,
X is (CO), (CO)O, O(CO), 0, S(O)t, wherein t is 0, 1 or 2, or X is NH or
N(C,_6)alkyl,
p, r and s, independently of each other, are 0 or 1,
q is 0, 1 or 2,
R4 is optionally substituted C1_6 alkyl, optionally substituted C2.6 alkenyl, -
CR =NR',
wherein R"" is hydrogen or C,_6 alkyl and R' is hydroxy or optionally
substituted
C1_6alkoxy, optionally substituted aryloxy or optionally substituted
heteroaryloxy, or -
CH2-C=C-RS, wherein
R5 is hydrogen, C,_8 alkyl optionally substituted with halogen, hydroxy, C,_6
alkoxy, C1_3
3o alkoxy(C,_3)alkoxy, cyano, C1_4 alkylcarbonyloxy, aminocarbonyloxy, mono-
or di(C,.4)-
alkylaminocarbonyloxy, tri(C,_4)alkylsilyloxy or -S(O)9(C1_6)alkyl, wherein g
is 0, 1 or 2, or
R5 is C3_6 cycloalkyl optionally substituted with halogen, hydroxy, C,_6
alkoxy, C1_3 alkoxy-
(C1_3)alkoxy, cyano, C1.4 alkylcarbonyloxy, aminocarbonyloxy, mono- or
di(C,_a)alkyl-
aminocarbonyloxy, tri(C,.4)alkylsilyloxy or -S(O)9(C1_6)alkyl, wherein g is 0,
1 or 2, or
R5 is C3_6 cycloalkyl(C,_4)alkyl, wherein the alkyl and/or cycloalkyl moiety
is optionally
substituted with halogen, hydroxy, C1_6 alkoxy, C,_3 alkoxy(C,.3)alkoxy,
cyano, C,.4 alkyl-
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carbonyloxy, aminocarbonyloxy, mono- or di(C,-4)alkylaminocarbonyloxy, tri(C,-
4)a{kyl-
silyloxy or -S(O)9(C,_6)alkyl, wherein g is 0, 1 or 2, or
R5 is optionally substituted aryl, optionally substituted aryl(C,_a)alkyl,
optionally
substituted aryloxy(C,.4)alkyl, optionally substituted heteroaryl or
optionally substituted
heteroaryl(C1_4)alkyl or optionally substituted heteroaryloxy(C,.4)alkyl, or
R 4 is optionally substituted C3_6 cycloalkyl, optionally substituted C5_6
cycloalkenyl,
optionally substituted aryl, optionally substituted heteroaryl or an
optionally substituted
5- to 8-membered ring optionally containing a heteroatom selected from sulfur,
oxygen
or NR , wherein R is hydrogen or optionally substituted C1_6alkyl, or
lo when R3 is -(CRaRb)P(CR Rd)q(X)r(CReRf)sR4, R2 and R3 may join to form a 5-
or 6-
membered ring optionally substituted with halogen, C,-4 alkyl, mono- or di-
(C,_4)alkylaminocarbonyl, and optionally containing a heteroatom selected from
sulphur,
oxygen and NR00, wherein R is C1_4 alkyl optionally substituted with
halogen, C,_6
alkoxy or cyano, or R00 is phenyl optionally substituted with nitro, C,_4
alkyl, halo(C,-4)-
alkyl, C,-4 alkylcarbonyl or heteroaryl, or R2 and R3 may join to form an
optionally
substituted 6,6-membered bicycle,
R3 is -(CR3oR4o)C=CR50, wherein
R30 and R40, independently of each other, are hydrogen, C,_6alkyl, halo(C,-
4)alkyl, C,-4
alkoxy(C1.3)alkyl, C2_3 alkenyl or C2_3alkynyl, or
2o R30 and R40 join with the carbon atom to which they are attached to form a
3 to 6
membered carbocyclic or heterocyclic ring containing a heteroatom selected
from sulfur,
oxygen or NR0 , wherein R is hydrogen or C,_, alkyl, where the carbocyclic
or
heterocyclic ring is optionally substituted with halo or C,-4 alkyl,
R50 is hydrogen, optionally substituted C,_4 alkyl, optionally substituted
C3_6 cycloalkyl,
optionally substituted aryl or optionally substituted heteroaryl containing a
heteroatom
selected from sulphur, oxygen or NRooo wherein Rooo is hydrogen or C,_salkyl,
L is sulfur or oxygen, and
n is 0, 1 or 2, and
salts and N-oxides of the compounds of the formula I.
The compounds of the invention contain at least one asymmetric carbon atom and
may
exist as enantiomers (or as pairs of diastereoisomers) or as mixtures of such.
Further,
when n is 1, the compounds of the invention are sulphoxides, which can exists
in two
enantiomeric forms, and the adjacent carbon can also exists in two
enantiomeric forms.
Compounds of general formula (I) can therefore exist as racemates,
diastereoisomers,
or single enantiomers, and the invention includes all possible isomers or
isomer
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mixtures in all proportions. It is to be expected that for any given compound,
one isomer
may be more fungicidally active than another.
N-oxides of the compounds of the formula I preferably denote the N-oxides
formed by
the quinoline moiety.
The salts which the compounds of the formula I can form are preferably those
formed by
interaction of these compounds with acids. The term "acid" comprises mineral
acids
such as hydrogen halides, sulphuric acid, phosphoric acid etc. as well as
organic acids,
io preferably the commonly used alkanoic acids, for example formic acid,
acetic acid and
propionic acid.
Except where otherwise stated, alkyl groups and alkyl moieties of alkoxy,
alkylthio, etc.,
suitably contain from 1 to 6, typically from 1 to 4, carbon atoms in the form
of straight or
branched chains. Examples are methyl, ethyl, n-and iso-propyl and n-, sec-,
iso- and
tert-butyl. Where alkyl moieties contain 5 or 6 carbon atoms, examples are n-
pentyl and
n-hexyl. Examples of suitable optional substituents of alkyl groups and
moieties include
halo, hydroxy, C,_4 alkoxy and C,_4 alkoxy(C1_4)alkoxy, cyano, optionally
substituted aryl
and optionally substituted heteroaryl. Where the optional substituent is halo,
the
haloalkyl group or moiety is typically monochloromethyl, monofluoromethyl,
dichloromethyl, difluoromethyl, trichloromethyl or trifluoromethyl.
Except where otherwise stated, alkenyl and alkynyl moieties also suitably
contain from 2
to 6, typically from 2 to 4, carbon atoms in the form of straight or branched
chains.
Examples are allyl, ethynyl and propargyl. Optional substituents include halo,
alkoxy,
optionally substituted aryl and optionally substituted heteroaryl.
Halo includes fluoro, chloro, bromo and iodo.
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
sulphur, oxygen or NR moieties as 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, thiazolyl, oxadiazolyl, pyrazolyl,
imidazolyl, triazolyl,
isothiazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl,
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benzofuranyl, benzothienyl, dibenzofuranyl, dibenzothienyl, benzothiazolyl,
benzoxazolyl, benzimidazolyl, indolyl, quinolyl, isoquinolyl, quinazolinyl and
quinoxalinyl
groups and, where appropriate, N-oxides and salts thereof. Any of the aryl or
heteroaryl
values are optionally substituted. Except where otherwise stated, substituents
which
may be present include one or more of the following: halo, hydroxy, mercapto,
C1.6 alkyl
(especially methyl and ethyl), C2_6 alkenyl (especially allyl), C2_6 alkynyl
(especially
propargyl), C1_6 alkoxy (especially methoxy), C2_6 alkenyloxy (especially
allyloxy), C2_6
alkynyloxy (especially propargyloxy), halo(C,-6)alkyl (especially
trifluoromethyl), halo(C,_
6)alkoxy (especially trifluoromethoxy), -S(O)m(C,-6)alkyl wherein m is 0, 1 or
2 and the
1o alkyl is optionally substituted with halo, hydroxy(C1_6)alkyl,
C,.4alkoxy(C,_4)alkyl,
C,_4alkoxy(C,-4)alkoxy, C3_6 cycloalkyl, C3_6 cycloalkyl(C1_4)alkyl,
optionally substituted
aryl (especially optionally substituted phenyl), optionally substituted
heteroaryl
(especially optionally substituted pyridyl or pyrimidinyl), optionally
substituted aryloxy
(especially optionally substituted phenoxy), optionally substituted
heteroaryloxy
(especially optionally substituted pyridyloxy or pyrimidinyloxy), optionally
substituted
-S(O),,aryl wherein m is 0, 1 or 2 (especially optionally substituted
phenylthio), optionally
substituted -S(O)mheteroaryl wherein m is 0, 1 or 2 (especially optionally
substituted
pyridylthio or pyrimidinylthio), optionally substituted aryl(C,_4)alkyl
(especially optionally
substituted benzyl, optionally substituted phenethyl and optionally
substituted phenyl
n-propyl) in which the alkyl moiety is optionally substituted with hydroxy,
optionally
substituted heteroaryl(C,-4)alkyl (especially optionally substituted pyridyl-
or pyrimidinyl-
(C,-4)alkyl), optionally substituted aryl(C2_4)alkenyl (especially optionally
substituted
phenylethenyl), optionally substituted heteroaryl(C2_4)alkenyl (especially
optionally
substituted pyridylethenyl or pyrimidinylethenyl), optionally substituted
aryl(C,_4)alkoxy
(especially optionally substituted benzyloxy and phenethyloxy), optionally
substituted
heteroaryl(C1_4)alkoxy (especially optionally substituted pyridyl(C,_4)alkoxy
or pyrimi-
dinyl(C,_a)alkoxy), optionally substituted aryloxy(C1_4)alkyl (especially
phenoxymethyl),
optionally substituted heteroaryloxy-(C1_4)alkyl (especially optionally
substituted
pyridyloxy or pyrimidinyloxy(C,_4)alkyl), optionally substituted -
S(O)m(C1_4)alkylaryl
wherein m is 0, 1 or 2 (especially optionally substituted benzylthio and
phenethylthio),
optionally substituted -S(O)m(C1_4)alkylheteroaryl wherein m is 0, 1 or 2
(especially
optionally substituted pyridyl(C,_4)alkylthio or pyrimidinyl(C,.4)alkylthio),
optionally
substituted -(C,.a)alkylS(O)maryl wherein m is 0, 1 or 2 (especially
phenylthiomethyl),
optionally substituted -(C,_4)alkyl S(O)mheteroaryl wherein m is 0, 1 or 2
(especially
optionally substituted pyridylthio(C,_4)alkyl or pyrimidinylthio(C1_4)alkyl),
acyloxy,
including C,_4 alkanoyloxy (especially acetyloxy) and benzoyloxy, cyano,
isocyano,
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thiocyanato, isothiocyanato, nitro, NR9Rh, -NHCOR9, -NHCONR9R'', -CONR9Rh, -
C02R9,
-SO2R', -OSO2R', -COR9, -CR9=NRh or -N=CR9Rh in which R' is C, , alkyl,
halo(C,-4)alkyl,
C1_4 alkoxy, halo(C,.4)alkoxy, C,-4 alkylthio, C3.6 cycloalkyl, C3_6
cycloalkyl(C,.4)alkyl,
phenyl or benzyl, the phenyl and benzyl groups being optionally substituted
with
halogen, C,_4 alkyl or C1.4 alkoxy and Rg and R'' are independently hydrogen,
C,_4 alkyl,
halo(C,_,)alkyl, C,-4 alkoxy, halo(C,_4)alkoxy, C,., alkylthio, C3_6
cycloalkyl, C3_6 cyclo-
alkyl(C,.4)alkyl, phenyl or benzyl, the phenyl and benzyl groups being
optionally
substituted with halogen, C,_4 alkyl or C,-4 alkoxy.
Of particular interest are those compounds of the formula (I), wherein Q2 is
hydrogen,
Q' and Q3 are as above.
Another group of preferred compounds of the formula (I) are those, wherein Q'
is
halogen, aryl or heteroaryl, Q2 is hydrogen and Q3 is as above.
Another group of preferred compounds of the formula (I) are those, wherein Q'
is aryl,
Q2 is hydrogen and Q3 is as defined above.
Another group of preferred compounds of the formula (I) are those, wherein Q'
is
heteroaryl, Q2 is hydrogen and Q3 is as defined above.
Another group of preferred compounds of the formula (i) are those, wherein Q'
and Q3
are halogen and QZ is hydrogen.
Another group of preferred compounds of the formula (I) are those, wherein, Q'
is aryl or
heteroaryl, Q2 is hydrogen and Q3 is halogen.
Another group of preferred compounds of the formula (I) are those, wherein Q'
and Q2
are hydrogen and Q3 is halogen or optionally substituted alkyl.
Another group of preferred compounds of the formula (I) are those, wherein Q'
is
halogen, Q2 is hydrogen and Q3 is optionally substituted alkyl.
Another group of preferred compounds of the formula (I) are those, wherein Q'
and Q2
are halogen and Q3 is optionally substituted alkyl.
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Another group of preferred compounds of the formula (I) are those, wherein Q'
is bromo.
Another group of preferred compounds of the formula (I) are those, wherein Q'
is iodo.
Another group of preferred compounds of the formula (I) are those, wherein Q'
is chloro.
Another group of preferred compounds of the formula (I) are those, wherein Q'
is fluoro.
Another group of preferred compounds of the formula (4) are those, wherein Q3
is
io halogen.
Another group of preferred compounds of the formula (I) are those, wherein Q3
is
fluorine.
Another group of preferred compounds of the formula (I) are those, wherein Q'
is bromo,
Q2 is hydrogen and Q3 is fluoro.
Another group of preferred compounds of the formula (I) are those, wherein Q'
is bromo,
Q2 is hydrogen and Q3 is chloro.
Another group of preferred compounds of the formula (I) are those, wherein Q'
is iodo,
Q2 is hydrogen and Q3 is fluoro.
Another group of preferred compounds of the formula (I) are those, wherein Q'
is iodo,
Q2 is hydrogen and Q3 is chloro.
Another group of preferred compounds of the formula (I) are those, wherein Q'
is
hydrogen, halogen, aryl or heteroaryl.
Another group of preferred compounds of the formula (I) are those, wherein R'
is C,_a
alkyl or halo(C,_a)alkyl.
Another group of preferred compounds of the formula (I) are those, wherein R'
is
methyl.
Another group of preferred compounds of the formula (I) are those, wherein R'
is ethyl.
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Another group of preferred compounds of the formula (I) are those, wherein R2
is
hydrogen or methyl.
Another group of preferred compounds of the formula (I) are those, wherein R2
is
hydrogen.
Another group of preferred compounds of the formula (I) are those, wherein Q',
Q2 and
Q3 are halogen.
1o Another group of preferred compounds of the formula (I) are those, wherein
Q'is
halogen, Q2 is C1-4alkyl and Q3 is halogen.
Another group of preferred compounds of the formula (I) are those, wherein
Q'is
halogen, Q2 is C,-4alkyl and Q3 is chloro.
Another group of preferred compounds of the formula (I) are those, wherein
Q'is
halogen, Q2 is C1_4alkyl and Q3 is fluoro.
Another group of preferred compounds of the formula (I) are those, wherein
Q'is
2o halogen, Q2 is methyl and Q3 is halogen.
Another group of preferred compounds of the formula (I) are those, wherein Q'
is
halogen, Q2 is methyl and Q3 is chloro.
Another group of preferred compounds of the formula (I) are those, wherein
Q'is
halogen, Q2 is methyl and Q3 is fluoro.
Another group of preferred compounds of the formula (I) are those, wherein
Q'is bromo,
Q2 is methyl and Q3 is chloro.
Another group of preferred compounds of the formula (I) are those, wherein
Q'is bromo,
Q2 is methyl and Q3 is fluoro.
Another group of preferred compounds of the formula (I) are those, wherein
Q'is iodo,
Q2 is methyl and Q3 is chloro.
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Another group of preferred compounds of the formula (I) are those, wherein
Q'is iodo,
Q2 is methyl and Q3 is fluoro.
Another group of preferred compounds of the formula (I) are those, wherein Q'
is
halogen, QZ and Q3 are C1_4alkyl.
Another group of preferred compounds of the formula (I) are those, wherein R3
is tert-
1o butyl, 1-halo-2-methylprop-2-yl, 1,1-dihalo-2-methylprop-2-yl, 1,1,1-
trihalo-2-methylprop-
2-yl, 1-alkoxy-2-methylprop-2-yl, 1-alkenyloxy-2-methylprop-2-yl, 1-alkynyloxy-
2-
methylprop-2-yl, 1-cyano-2-methyl-prop-2-yl, 1-alkoxyalkoxy-2-methyl-prop-2-
yl, 1-ha1o-
3-methylbut-3-yl, 1,1-dihalo-3-methylbut-3-yl, 1,1,1-trihalo-3-methylbut-3-yl,
1-alkoxy-3-methylbut-3-yl, 1-alkenyloxy-3-methylbut-3-yl, 1-alkynyloxy-3-
methylbut-3-yl,
1-cyano-3-methylbut-3-yl, 2-cyanoprop-2-yl, 2-methoxycarbonylprop-2-yl or 2-
methylaminocarbonylprop-2-yl, 1-alkylthio-2-methylprop-2-yl, 1-alkylsulphinyl-
2-
methylprop-2-yl, 1-alkylsulphonyl-2-methylprop-2-yl,. 2-cyano-l-alkoxyprop-2-
yl, 2-
methyl-1 -[(E and/or Z)-hydroxyimino]-prop-2-yl, 2-methyl-1 -[(E and/or Z)-
alkoxyimino]-
prop-2-yl, 2-methyl-1 -[(E and/or Z)-aryloxyimino]-prop-2-yl, 2-methyl-1 -[(E
and/or Z)-
2o heteroaryloxyimino]-prop-2-yl, 1-alkoxy-prop-2-yl, 1-halo-prop-2-yl, 3-
methyl-but-1-yn-3-
yl, 1-alkyl-3-methyl-but-1-yn-3-yl, 4-methyl-pent-2-yn-4-yl, 1-hydroxy-4-
methyl-pent-2-yn-
4-y1, 1-alkoxy-4-methyl-pent-2-yn-4-yl, 1-alkoxyalkoxy-4-methyl-pent-2-yn-4-
yl, 1-
alkoxyalkoxyalkyl-4-methyl-pent-2-yn-4-yl,l-cyanoalkyl-3-methylbut-3-yl, 1-
haloalkyl-3-
methylbut-3-yl, and more preferably, wherein R3 is tert-butyl, 1-halo-2-
methylprop-2-yl,
1-fluoro-2-methylprop-2-yl, 1-methoxy-2-methylprop-2-yl, 1-ethoxy-2-methylprop-
2-yl, 1-
allyloxy-2-methylprop-2-yl, 1 -(prop-2-ynyloxy)-2-methylprop-2-yl, 2-cyano-1 -
ethoxy-prop-
2-yl, 2-cyano-l-methoxyprop-2-yl, 1-halo-3-methylbut-3-yl, 1-fluoro-3-
methylbut-3-yl, 3-
methylbut-1 -yn-3-yl, 4-methylpent-2-yn-4-yl, 5-methyl-hex-3-yn-5-yl, 1 -
methoxy-4-
methyl-pent-2-yn-4-yl, 1-allyloxy-4-methyl-pent-2-yn-4-yl, 1 -p ropargyloxy-4-
methyl -pent-
2-yn-4-yl, 1 -ethoxy-4-methyl-pent-2-yn-4-yl.
Another group of preferred compounds of the formula (I) are those, wherein R4
is C1.6
alkyl optionally substituted with C,_aalkoxy-(C,_4)alkoxy(C1_4)alkyl, wherein
the alkyl group
optionally substituted with halo, mono- or di-(C,_6)alkylamino or
tri(C,.4)alkylsilyl, or R4 is
C,_6 alkyl optionally substituted with benzyloxy(C1_4)alkyl, wherein the alkyl
group is
optionally substituted with halo, mono- or di-(C,_6)alkylamino or
tri(C,_a)alkylsilyl, or R4 is
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C,_6 alkyl optionally substituted with C2_6 alkenyloxy or -S(O)X(C1_6)alkyl,
wherein x is 0, 1
or 2 and the alkyl group is optionally substituted with halo, mono- or di-
(C,_6)alkylamino, -
NH(C,_a)alkyl=NOR, wherein R is hydrogen or C1_4alkyl, or wherein the alkyl
group is
optionally substituted with tri(C1.4)alkylsilyl, or R 4 is -CR"u=NR'', wherein
R"u is hydrogen
or C,_6 alkyl and R' is hydroxy or optionally substituted C1_6alkoxy.
Another group of preferred compounds of the formula (1) are those, wherein the
optionally substituted aryl and optionally substituted heteroaryl rings or
moieties of the
R5 values are optionally substituted with halogen, cyano, nitro, azido, C,_s
alkyl,
1o halo(C,_6)alkyl, C3-6 cycloalkyl, C3_6 cycloalkyl(C,_4)alkyl, C2.6 alkenyl,
halo(C2_6)alkenyl,
C2_6 alkynyl, halo(C2.6)alkynyl, C1.6 alkoxy, halo(C,_6)alkoxy, C2_6
alkenyloxy, halo(C2_6)-
alkenyloxy, C2_6 alkynyloxy, halo(C2_6)alkynyloxy, aryl, aryloxy,
aryl(C,_6)alkyl, aryl-
(C,_6)alkoxy, heteroaryl, heteroaryloxy, heteroaryl(C,_6)alkyl,
heteroaryl(C1_6)alkoxy, -SF5,
-S(O)9(C,_4)alkyl wherein g is 0, 1 or 2 and the alkyl is optionally
substituted with halo, or
R5 is optionally substituted with -OS02(C,.4)alkyl, wherein the alkyl group is
optionally
substituted with halo, or R5 is optionally substituted with -CONR9Rh, -COR9, -
CO2R9, -
R9=NRh, -NR9Rh4-NR9CORh, -NR9CO2R'', -SO2NR9Rh or -NR9SO2R', wherein R' is
C1.6
alkyl optionally substituted with halogen and R9 and Rh, independently of each
other, are
hydrogen or C1.6 alkyl optionally substituted with halogen, or, in the case of
-CONR9Rh
or -SO2NR9R'', R9Rh may join to form a 5- or 6-membered carbocyclic or
heterocyclic
ring containing a heteroatom selected from sulphur, oxygen or NR , wherein R
is
hydrogen or optionally substituted C1_6alkyl.
Another group of preferred compounds of the formula (I) are those, wherein the
optionally substituted aryl, optionally substituted heteroaryl or optionally
substituted 5- to
8-membered ring R4 is optionally substituted with halogen, cyano, nitro,
azido, C1_6 alkyl,
halo(C,_6)alkyl, C3_6 cycloalkyl, C3_6 cycloalkyl(C1_4)alkyl, C2_6 alkenyl,
halo(C2_6)alkenyl,
C2_6 alkynyl, halo(C2.6)alkynyl, C1.6 alkoxy, halo(C1_6)alkoxy, C2_6
alkenyloxy, halo(C2_6)-
alkenyloxy, C2.6 alkynyloxy, halo(C2_6)alkynyloxy, -SF5, -S(O)x(C1_6)alkyl,
wherein x is 0, 1
or 2 and the alkyl group is optionally substituted with halo, or R4 is
optionally substituted
with -OS02(C1_4)alkyl, wherein the alkyl group is optionally substituted with
halogen,
-CONRxRY, -CON(ORx)Ry, -CORX, -COZRx, -CRx=NRY, -NRXRy, -NRxCORy, -NRXCO2RY,
-SO2NRxRy or -NRXSO2RZ, wherein RZ is C,_$ alkyl optionally substituted with
halogen
and R" and Ry, independently of each other, are hydrogen or C1_6 alkyl
optionally
substituted with halogen.
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Another group of preferred compounds of the formula (I) are those, wherein
R50is
C1_4alkyl optionally substituted with halogen, hydroxy, C1.6alkoxy, C2_6
alkenyl (especially
allyl), C2.6 alkynyl (especially propargyl), C,.a alkoxy(C1.4)alkoxy, cyano,
C,_4
alkylcarbonyloxy, aminocarbonyloxy, mono- or di(C,_4)alkylamino-carbonyloxy,
S(O)P(C,_
6)-alkyl, wherein p is 0, 1 or 2, triazolyl, pyrazolyl, imidazolyl, tri(C,_4)-
alkylsilyloxy,
optionally substituted phenoxy, optionally substituted thienyloxy, optionally
substituted
benzyloxy or optionally substituted thienylmethoxy.
Another group of preferred compounds of the formula (I) are those, wherein R50
is C3_
6cycloalkyl optionally substituted with halogen, hydroxy, C1_6 alkoxy, C1_4
alkoxy(C,_
4)alkoxy, cyano, C,_aalkylcarbonyloxy, aminocarbonyloxy, mono- or
di(C,.4)alkylamino-
carbonyloxy, S(O)P(C1_6)-alkyl, wherein p is 0, 1 or 2, triazolyl, pyrazolyl,
imidazolyl,
tri(C,-4)-alkylsilyloxy, optionally substituted phenoxy, optionally
substituted thienyloxy,
optionally substituted benzyloxy or optionally substituted thienylmethoxy.
Another group of preferred compounds of the formula (I) are those, wherein the
optionally substituted aryl orthe optionally substituted heteroaryl R50 is
optionally
substituted with halogen, hydroxy, mercapto, C1_4 alkyl, C2_4 alkenyl, C2_4
alkynyl, C,-4
alkoxy, C2_4 alkenyloxy, C2_4 alkynyloxy, halo(C,_4)alkyl, hafo(C,,)alkoxy,
C,_4 alkylthio,
halo(C,_a)-alkylthio, hydroxy(C,_4)alkyl, C,-4alkoxy(C,-4)alkyl,
C3_6cycloalkyl, C3_6
cycloalkyl-(C,_4)alkyl, phenoxy, benzyloxy, benzoyloxy, cyano, isocyano,
thiocyanato,
isothiocyanato, nitro, NRpRq, NHCORP, -NHCONRPRq, CONRpR4, -S02R , OS02R ,
CORP, CRP=NR4 or N=CRpRq, wherein R is C1_4alkyl, halo(C,_4)alkyl,
C1.4alkoxy,
halo(C,.4)alkoxy, C1_4alkylthio, C3_6 cycloalkyl, C3_6cycloa4kyl(C1_4)alkyl,
phenyl or benzyl,
the phenyl and benzyl groups being optionally substituted with halogen,
C14alkyl or C,.4
alkoxy, and RP and Rq are independently hydrogen, C,.4alkyl, halo(C,_4)alkyl,
C1_4 alkoxy,
halo(C,-4)alkoxy, C,-4 alkylthio, C3_6cycloalkyl, C3_6cycloalkyl(C,.4)alkyl,
phenyl or benzyl,
the phenyl and benzyl groups being optionally substituted with halogen,
C,_4alkyl or C,_4
alkoxy.
Another group of preferred compounds of the formula (I) are those, wherein L
is oxygen.
Another group of preferred compounds of the formula (I) are those, wherein n
is 0.
Another group of preferred compounds of the formula (I) are the N-oxides
formed by the
quinoline moiety in the compounds of the formula I.
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Compounds that form part of the invention are illustrated in Tables 1 to 192
below.
Melting points (mp) and/or diagnostic molecular ion (eg M+, [M+1 ]+) values
and/or
spectroscopic (1 H NMR) data are provided in Examples 1-5 while biological
activities
are provided in Example 6.
Table 1
The compounds in Table 1 are of the general formula (I) where 01 is chloro, 02
is
hydrogen, 03 is chloro, n is 0, L is 0, R' is methyl, and R2 and R3 have'the
values given
1o in the table.
Compound No. R R
1 H CH3
2 CH3 CH3
3 H C2H5
4 C2H5 C2H5
5 H prop-2-yl
6 CH3 prop-2-yl
7 prop-2-yl prop-2-yl
8 CH3 n-butyl
9 H but-2-yl
H 2-methyl-prop-1 -yl
11 2-methyl-prop-1 -yl 2-methyl-prop-1 -yl
12 H tert-C4H9
13 CH3 tert-C4H9
14 H pent-2-yl
H pent-3-yl
16 H 2-methyl-but-2-yl
17 H 3-methyl-but-1 -yl
18 H 3-methyl-pent-2-yl
19 H 4-methyl-pent-2-yl
H 3,3-dimethyl-but-2-yl
21 H 2-methyl-hex-2-yl
22 H 2,4-dimethyl-pent-2-yl
23 H 2,4,4-trimethy{-but-2-yl
24 H 2,4,4-trimethyl-pent-2-yl
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25 H CI-n-C3H6-
26 H CI-CH2(CH3)2C-
27 H F3C(CH3)2C-
28 H NC-CH2-
29 CH3 NC-CH2-
30 NC-CH2- NC-CH2-
31 H (NC)2CH-
32 H NC-C2H4-
33 CH3 NC-C2H4-
34 NC-C2H4- NC-C2H4-
35 H (CH3)2C(CN)-
36 H C2H5(CH3)C(CN)-
37 H (C2H5)2C(CN)-
38 H (CH3)2CH(CH3)C(CN)-
39 H HO-CH2(CH3)2C-
40 H HO-C2H4(CH3)2C-
41 H 1-hydroxy-2-(hydroxymethyl)-prop-2-
yI
42 H 1 -hydroxy-2-(methoxymethyl)prop-2-
yl
43 H 1 -methoxy-2-(methoxymethyl)prop-
2-yl
44 H 1 -hydroxy-2-(hydroxymethyl)-but-2-yI
45 C2H5OC2H4- C2H50CZH4-
46 CH3 (CH30)2CHCH2-
47 H CH30-CH2(CH3)2C-
48 H CH30-C2H4(CH3)2C-
49 H C2H50-C2H4(CH3)2C-
50 H CH3S-CH2(CH3)2C-
51 H NC-(CH30)CH-
52 H CH30CH2(CH3)C(CN)-
53 H CH3SCH2(CH3)C(CN)-
54 H CH3(CO)(CH3)2C-
55 H CH3CHBr(CO)(CH3)2C-
56 H CH3(CO)(OH)CH(CH3)2C-
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57 H CH3OC2H4(CO)(CH3)2C-
58 H CH3(CO)CH2(CH3)2C-
59 H CH3O(CO)(CH3)CH-
60 H CH3O(CO)(CH3)2C-
61 H C2H5O(CO)C2H4-
62 H CH3NH(CO)(CH3)2C-
63 H (CH3)2N(CO)(CH3)2C-
64 H (CH3)3SiCH2-
65 H tert-C4H9(CH3)2SiO-CH2(CH3)2C-
66 H tert-C4H9(CH3)2SiO-C2H4(CH3)2C-
67 H 4-FPhCH20CH2(CH3)2C-
68 H C2H5OCH2(CH3)2C-
69 H CH3OCH2CH2O(CH3)2C-
70 H CH2=CHCH2-
71 CH2=CHCH2- CH2=CHCH2-
72 H CH2=C(CH3)CH2-
73 H CH2=CH(CH3)CH-
74 H CH2=CH(CH3)2C-
75 H CH3(CO)CH=CH-
76 CH3 CH3(CO)CH=CH-
77 H pent-3-en-2-yl
78 H 2-methyl-hex-3-en-2-yl (E)
79 H 2-methyl-hex-3-en-2-yl (Z)
80 H 2-methyl-pent-4-en-3-on-2-yl
81 H CH3O(CO)CH=(CI)C(CH3)2C-
82 H C6H5-C(CH3)=CH(CH3)2C-
83 CH2=CHCH2- CH2=CHCH2OC2H4-
84 H CH=CCH2-
85 CH3 CH=CCH2-
86 H cycloprop-1-yl
87 NC-C2H4- cycloprop-1 -yl
88 cycloprop-1-yl cycloprop-1 -yl
89 H 1 -cyano-cycloprop-1 -yl
90 H 2-cyano-cycloprop-1 -yl
91 H 1 -methoxycarbonyl-cycloprop-1 -yl
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92 H 1-[N,N-dimethylaminocarbonyl]-
cycloprop-1-yl
93 H 1 -[N-methyl-N-methoxy-
aminocarbonyl]-cycloprop-1-yl
94 H 1-cyano-1-cyclopropyl-eth-1-yl
95 H cyclopent-1-yl
96 H 1 -cyano-cyclopent-1 -yl
97 H cyclohex-1 -yl
98 CH2=CHCH2- cyclohex-l-yl
99 H 4-cyano-cyclohex-1 -yl
100 H 1-cyano-4-methyl-cyclohex-i -yl
101 H 4-tert-butyl-1 -cyano-cyclohex-1 -yl
102 H 2-methyl-3-cyanotetrahydro-
furan-3-yl
103 H 5-methyl-1,3-dioxolan-5-yl
104 H 5-ethyl-1,3-dioxolan-5-yl
105 H 3,5-dimethyl-1,3-dioxolan-5-yl
106 H N-ethoxycarbonyl-piperid-4-yl
107 H morpholino
108 H cyclohex-1-yl-methyl
109 H 4-cyano-cyclopenten-3-yl
110 H 5-tert-butyl-2H-1,3,4-thiadiazin-2-yl
111 H 2-(cyclohexen-1 -yl)-eth-l -yl
112 H fur-2-yl
113 H 5-methoxycarbonyl-fur-2-yl
114 H thien-2-yl
115 H 2-methoxycarbonyl-thien-3-yl
116 H 4-methoxycarbonyl-thien-3-yl
117 H oxazol-2-yl
118 H 5-methyl-isoxazol-3-yl
119 H 4-cyano-3-methyl-isoxazol-5-yl
120 H thiazol-2-yl
121 H 5-ethylthio-1,3,4-thiadiazol-2-yl
122 H fur-2-ylmethyl
123 H cyanofur-1-ylmethyl
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124 H thien-2-ylmethyl
125 H C6H5-
126 H 2-CI-C6H4-
127 H 2-I-C6H4-
128 H 2-NC-C6H4-
129 H 3-CF3-C6H4-
130 H 3-CH3S-C6H4-
131 H 3-CH3O(CO)-C6H4-
132 H 4-CI-C6H4-
133 H 4-F-C6H4-
134 H 4-CF3O-C6H4-
135 H 4-(C2H5)2N-C6H4-
136 H 4-(N-methyl- N-acetyl-amino)-phenyl
137 H 2,4-dichlorophenyl
138 H 4-methoxy-2-methy{phenyl
139 H 3,4-dichlorophenyl
140 H 3-chloro-4-fluorophenyl
141 H 2,5-difluorophenyl
142 H 5-fluoro-2-methylphenyl
143 H 5,6,7,8-tetrahydronaphth-2-yi
144 H 2,3-dihydrobenzofuran-5-yl-methyl
145 H 5-cyano-4,6-dimethoxy-pyrid-2-yI
146 H 2,6-dimethoxy-pyrid-3-yl
147 H 6-chloro-pyridazin-3-yl
148 H 4,6-dimethoxy-pyrimid-2-yl
149 H 2-chloro-5-fluoro-pyrimid-6-yl
150 H C6H5CH2-
151 CH3 C6H5CH2-
152 H 2-F-C6H4CH2-
153 H 2-CI-C6H4CH2-
154 CH3 2-CI-C6H4CH2-
155 H 2-N02-C6H4CH2-
156 H 2-CH3-C6H4CH2-
157 H 2-CH3O-C6H4CH2-
158 H 2-CHF2O-C6H4CH2-
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159 H 2-CH3S-C6H4CH2-
160 H 2-CF3S-C6H4CH2-
161 H 3-CI-C6H4CH2-
162 H 3-1-C6H4CH2-
163 H 3-CH3-C6H4CH2-
164 H 3-CH3O-C6H4CH2-
165 H 4-F-C6H4CH2-
166 H 4-CI-C6H4CH2-
167 H 4-CH3-C6H4CH2-
168 H 4-CF3-C6H4CH2-
169 H 4-CH3O-C6H4CH2-
170 H 4-CF3O-C6H4CH2-
171 H 2,6-di-F-C6H3CH2-
172 3-methyl-but-2-en-1-yl 2,5-di-F-C6H3CH2-
173 H 2-F-4-CI-C6H3CH2-
174 H 2-F-6-CI-C6H3CH2-
175 H 2,6-di-CI-C6H3CH2-
176 4-methyl-pent-2-en-1-yl 3,4-di-CI-C6H3CH2-
177 H 2-F-6-CH3O-C6H3CH2-
178 H 2,4,5-tri-F-C6H2CH2-
179 H 2,4-di-CI-6-CH3-C6H2CH2-
180 H 3,4,5-tri-CH3O-C6H2CH2-
181 H C6H5-CH(CH3)-
182 H 4-F-C6H4-CH(CH3)-
183 H 4-NO2-C6H4-CH(CH3)-
184 H 4-n-pentyl-C6H4-CH(CH3)-
185 H 4-CH3SO2-C6H4-CH(CH3)-
186 H C6H5(CO)CH2-
187 H C6H5-CH(CN)-
188 H C6H5-(CH3O)CH-
189 H C6H5-(CH3)2C-
190 H m-CI-C6H5-(CH3)2C-
191 H 3,5-di-CI-C6H3-(CH3)2C-
192 H C6H5-(C2H50(CO))CH-
193 H phenethyl
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194 H 3-methoxy-4-propargyioxy-phenethyl
195 H 3-methoxy-4-(pent-2-yn-1 -yloxy)-
phenethyl
196 H 2-methyl-3-phenyl-prop-2-yl
197 H C6H50-C2H4-
198 H 4-F-C6H4-CH2OCH2(CH3)2C-
199 H C6H5-CH2O(CO)C2H4-
200 H naphth-2-yl-(CH3)CH-
201 NC-C2H4- pyrid-3-ylmethyl
202 CH3 2-pyrid-2-yleth-1 -yl
203 H 2-(3-chloro-5-trifluoromethyl-pyrid-2-
yI)oxyeth-1-yl
204 H 2-methyl-4-pyrazin-2-yl-but-3-on-2-yI
205 -(CH2)4-
206 -(CH2)5-
207 -(CH2)4CH(C2H5)-
208 - C3H6CH[(CO)N(C2H5)2]CH2-
209 -CH(CH3)CH=CHCH(CH3)-
-CH2
210 0
-C2H4
211 -C2H4OC2Ha-
212 -CH2CH(CH3)OCH(CH3)CH2-
213 -C2H4SCH2-
214 -C2H4SC2H4-
215 -(CH2)2NH(CH2)2-
216 -(CH2)2N(p-NO2-C6H4)(CH2)2-
217 -(CH2)2N(m-CF3-C6H4)(CH2)2-
218 -(CH2)2N(p-CH3CO-C6H4)(CH2)2-
219 -(CH2)2N(pyrid-2-yI)(CH2)2-
220 H (HZC=CHCH20CH2)(CH3)2C-
221 H (HCCHCH20CH2)(CH3)2C-
222 H (CH3CH20CH2)(CH3)2C-
223 H ((CH3 )2CHOCH2)(CH3)2C-
224 H C6H5CH2OCH2(CH3)2C-
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225 H (CH3CH20CH2)(CH3)2C-
226 H 4-F-C6H4-CH2(CH3)C(CN)-
227 H 4-CI-C6H4-CH2(CH3)C(CN)-
228 H 4-CH3O-C6H4-CH2CH2(CH3)C(CN)-
229 H 2-CI-C6H4-CH2(CH3)C(CN)-
230 H (CH3 )2CH-CH2(CH3)C(CN)-
231 H 1 -methoxymethyl-cycloprop-1 -yl
232 H 1-benzyloxymethyl-cycloprop-1-yl
233 H 1 -methoxymethoxy-2- methyl-prop-2-
yl
235 H 1-cyclopropyl-eth-1-yl
236 H 2-fluoro-eth-1-yl
237 H 2,2,2-trifluoro-1-methyl-eth-1-yl
238 H HC=CC(CH3)2-
239 CH3 HC=CC(CH3)2-
240 H HC=CC(CH2CH3)(CH3)-
241 CH3 HC=CC(CH2CH3)(CH3)-
242 H HC=CC(CH2CH2)-
243 CH3 HC=CC(CH2CH2)-
244 H (H3C)C=CC(CH3)2-
245 CH3 (H3C)C=CC(CH3)2-
246 H (H3C)C=CC(CH2CH3)(CH3)-
247 CH3 (H3C)C=CC(CH2CH3)(CH3)-
248 H (H3C)C=CC(CH2CH2)-
249 CH3 (H3C)C=CC(CH2CH2)-
250 H (HOCH2)C=CC(CH3)Z-
251 H (CH30CH2)C=CC(CH3)2-
252 H (HOCH2)C=CC(CH3)(CH2CH3)2-
253 H (CH3CH2OCH2)C=CC(CH3)2-
254 H (CH30CH2)C=CC(CH3)(CH2CH3)2-
255 H (CH30C2H4OC2H4)C=CC(CH3)2-
256 H (CI-n-C3H6)C=CC(CH3)2-
257 H (NC-n-C3H6)C=CC(CH3)2-
258 H (CH3SCH2)C=CC(CH3)2-
259 H (C6H5)C=CC(CH3)2-
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260 H (CH3)Z(CH3O)CC=CC(CH3)2-
261 H (H2C=CHCH2OCH2)(CH3)CH-
262 H (HC=CHCH2OCH2)(CH3)CH-
263 H (CH3CH2OCH2)(CH3)CH-
264 H (CH3OCH2)(CH3)CH-
265 H ((CH3 )2CHOCH2)(CH3)CH-
266 H C6H5CH2OCH2(CH3)CH-
267 H (CH3CH2OCH2)(CH3)CH-
268 H (cC4H7)CH-
269 H (cC4H7)CH3C-
270 H FCH2(CH3)CH-
271 H CICH2(CH3)CH-
272 H FCH2CH2(CH3)CH-
273 H CICH2CH2(CH3)CH-
274 H FCH2(CH3)2C-
275 H FCH2CH2(CH3)2C-
276 H CICH2CH2(CH3)2C-
277 H CH3O(C2H4)C=CC(CH3)2-
278 H tetrahydro-furan-2-ylmethyl
279 H 1 -(tetrahydro-f uran-2-yl)ethyl
280 H 1-methyl-1 -(tetrahydro-furan-2-yl)ethyl
281 H 2-[1,3]dioxolan-2-yl-ethyl
282 H 2-[1,3]dioxolan-2-yl-l-methyl-ethyl
283 H 2-[1,3]dioxolan-2-yl-1,l-dimethyl-ethyl
284 H prop-l-yl
285 CH3 prop-l-yl
286 H thiophen-3-ylmethyl
287 H 1 -(thiophen-3-yl)-eth-1 -yl
289 H 1-methyl-1 -(thiophen-3-yl)-eth-1 -yl
290 H cyclopent-l-yl
291 H 3-F-C6H4-CH2-
292 H 3-F-C6H4-CH(CH3)-
293 H 3-F-C6H4-C(CH3)2-
294 H C2H5C=CC(CH3)2-
294 H nC3H7C=CC(CH2CH3)(CH3)-
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296 H i-C3H7C=CC(CH2CH2)-
297 H n-CaH9C=CC(CH3)2-
298 H sec-C4H9C=CC(CH3)2-
299 H iso-C4H9C=CC(CH3)2-
300 H tert-C4H9C=CC(CH3)2-
301 H HOC2H4C=CC(CH3)2-
302 H CH3(CH3O)(CH)C=CC(CH3)2-
303 H (nC3H7OCH2)C=CC(CH3)2-
304 H (nC3H7OCH2CH2)C=CC(CH3)2-
305 H (tert-C4H9OCH2)C=CC(CH3)2-
306 H (tert-C4H9OCH2CH2)C=CC(CH3)2-
307 H (NCCH2)C=CC(CH3)2-
308 H (NCCH2CH2)C=CC(CH3)2-
309 H (C6H5OCH2)C=CC(CH3)2-
310 H (C6H5OCH2CH2)C=CC(CH3)2-
311 H (4-FC6H5)C=CC(CH3)2-
312 H (4-CIC6H5)C=CC(CH3)2-
313 H (4-BrC6H5)C=CC(CH3)2-
314 H (4-CH3-C6H5)C=CC(CH3)2-
315 H (3-FC6H5)C=CC(CH3)2-
316 H (3-CIC6H5)C=CC(CH3)2-
317 H (3-CH3-C6H5)C=CC(CH3)2-
318 H (2-FC6H5)C=CC(CH3)2-
319 H (2-CIC6H5)C=CC(CH3)2-
320 H (2-BrC6H5)C=CC(CH3)2-
321 H (2-CH3-C6H5)C=CC(CH3)2-
322 H (thien-2-yl)C=CC(CH3)2-
323 H (thien-3-yl)C=CC(CH3)2-
Table 2
The compounds in Table 2 are of the general formula (I) where Q1 is bromo, Q2
is
hydrogen, Q3 is chloro, n is 0, L is 0, R' is methyl, R2 and R3 have the
values 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 Q1 is bromo, 02 is hydrogen, Q3 is chloro.
Similarly,
compounds 2 to 323 of Table 2 are the same as compounds 2 to 323 of Table 1,
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respectively, except that in the compounds of Table 2 Q1 is bromo, 02 is
hydrogen, Q3
is chloro. -
Table 3
The compounds in Table 3 are of the general formula (I) where Q1 is iodo, Q2
is
hydrogen, 03 is chloro, n is 0, L is 0, R' is methyl, R2 and R3 have the
values 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 Q1 is iodo, 02 is hydrogen, Q3 is chloro.
Similarly,
compounds 2 to 323 of Table 3 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 3 01 is iodo, 02 is
hydrogen, 03 is
lo chloro.
Table 4
The compounds in Table 4 are of the general formula (I) where Q1 is flouro, Q2
is
hydrogen, 03 is chloro, n is 0, L is 0, R' is methyl, R2 and R3 have the
values 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 Q1 is fluoro, 02 is hydrogen, Q3 is chloro.
Similarly,
compounds 2 to 323 of Table 4 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 3 01 is fluoro, Q2 is
hydrogen, Q3
is chloro.
Table 5
2o The compounds in Table 5 are of the general formula (I) where Q1 is chloro,
Q2 is
hydrogen, Q3 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the
values 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 01 is chloro, Q2 is hydrogen, 03 is fluoro.
Similarly,
compounds 2 to 323 of Table 5 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 5 Q1 is chloro, Q2 is
hydrogen, 03
is fluoro.
Table 6
The compounds in Table 6 are of the general formula (I) where Q1 is bromo, 02
is
hydrogen, Q3 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 6 is the same as compound 1 of Table 1
except
that in compound 1 of Table 5 Q1 is bromo, Q2 is hydrogen, Q3 is fluoro.
Similarly,
compounds 2 to 323 of Table 6 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 6 01 is bromo, Q2 is
hydrogen,. Q3
is fluoro.
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Table 7
The compounds in Table 7 are of the general formula (I) where 01 is iodo, 02
is
hydrogen, 03 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 7 is the same as compound 1 of Table 1
except
that in compound 1 of Table 7 Q1 is iodo, 02 is hydrogen, 03 is fluoro.
Similarly,
compounds 2 to 323 of Table 7 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 7 01 is iodo, Q2 is
hydrogen, 03 is
fluoro.
Tab1e 8
1o The compounds in Table 8 are of the general formula (I) where Q1 is fluoro,
02 is
hydrogen, Q3 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 8 is the same as compound 1 of Table 1
except
that in compound 1 of Table 8 01 is fluoro, 02 is hydrogen, 03 is fluoro.
Similarly,
compounds 2 to 323 of Table 8 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 8 01 is fluoro, Q2 is
hydrogen, Q3
is fluoro.
Table 9
The compounds in Table 9 are of the general formula (I) where Q1 is hydrogen,
Q2 is
hydrogen, 03 is chloro, n is 0, L is 0, R' is methyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 9 is the same as compound 1 of Table 1
except
that in compound 1 of Table 9 Q1 is hydrogen, Q2 is hydrogen, Q3 is chloro.
Similarly,
compounds 2 to 323 of Table 9 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 9 01 is hydrogen, Q2 is
hydrogen,
Q3 is chloro.
Table 10
The compounds in Table 10 are of the general formula (I) where Q1 is hydrogen,
Q2 is
hydrogen, Q3 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 10 is the same as compound 1 of Table 1
except
that in compound 1 of Table 10 Q1 is hydrogen, Q2 is hydrogen, Q3 is fluoro.
Similarly,
compounds 2 to 323 of Table 10 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 10 Q1 is hydrogen, Q2 is
hydrogen,
Q3 is fluoro.
Table 11
The compounds in Table 11 are of the general formula (I) where Q1 is hydrogen,
Q2 is
hydrogen, Q3 is bromo, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 11 is the same as compound 1 of Table 1
except
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that in compound 1 of Table 11 01 is hydrogen, Q2 is hydrogen, 03 is bromo.
Similarly,
compounds 2 to 323 of Table 11 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 11 Q1 is hydrogen, Q2 is
hydrogen,
Q3 is bromo.
Table 12
The compounds in Table 12 are of the general formula (I) where 01 is chloro,
Q2 is
hydrogen, Q3 is methyl, n is 0, L is 0, R' is methyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 12 is the same as compound 1 of Table 1
except
that in compound 1 of Table 12 01 is chloro, 02 is hydrogen, Q3 is methyl.
Similarly,
1o compounds 2 to 323 of Table 12 are the same as compounds 2 to 323 of Table
1,
respectively, except that in the compounds of Table 12 Q1 is chloro, Q2 is
hydrogen, Q3
is methyl.
Table 13
The compounds in Table 13 are of the general formula (I) where Q1 is bromo, 02
is
hydrogen, Q3 is methyl, n is 0, L is 0, R' is methyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 13 is the same as compound 1 of Table 1
except
that in compound 1 of Table 13 01 is bromo, 02 is hydrogen, Q3 is methyl.
Similarly,
compounds 2 to 323 of Table 13 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 13 Q1 is bromo, Q2 is
hydrogen, 03
is methyl.
Table 14
The compounds in Table 14 are of the general formula (I) where Q1 is iodo, Q2
is
hydrogen, Q3 is methyl, n is 0, L is 0, R' is methyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 14 is the same as compound 1 of Table 1
except
that in compound 1 of Table 14 Q1 is iodo, Q2 is hydrogen, Q3 is methyl.
Similarly,
compounds 2 to 323 of Table 14 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 14 01 is iodo, 02 is
hydrogen, Q3
is methyl.
Table 15
The compounds in Table 15 are of the general formula (I) where Q1 is flouro,
Q2 is
hydrogen, Q3 is methyl, n is 0, L is 0, R' is methyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 15 is the same as compound 1 of Table 1
except
that in compound 1 of Table 15 01 is fluoro, Q2 is hydrogen, Q3 is methyl.
Similarly,
compounds 2 to 323 of Table 15 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 15 Q1 is fluoro, Q2 is
hydrogen, 03
is methyl.
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Table 16
The compounds in Table 16 are of the general formula (I) where Q1 is hydrogen,
Q2 is
hydrogen, Q3 is methyl, n is 0, L is 0, R' is methyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 16 is the same as compound 1 of Table 1
except
that in compound 1 of Table 16 Q1 is hydrogen, Q2 is hydrogen, Q3 is methyl.
Similarly,
compounds 2 to 323 of Table 16 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 16 01 is hydrogen, 02 is
hydrogen,
03 is methyl.
Table 17
io The compounds in Table 17 are of the general formula (1) where Q1 is
chloro, Q2 is
hydrogen, 03 is chloro, n is 0, L is 0, R' is ethyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 17 is the same as compound 1 of Table 1
except
that in compound 1 of Table 17 R' is ethyl, 01 is chloro, 02 is hydrogen, Q3
is chloro.
Similarly, compounds 2 to 323 of Table 17 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 17 R' is ethyl,
Q1 is chloro,
02 is hydrogen, 03 is chloro.
Table 18
The compounds in Table 18 are of the general formula (I) where 01 is bromo, 02
is
hydrogen, 03 is chloro, n is 0, L is 0, R' is ethyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 18 is the same as compound 1 of Table 1
except
that in compound 1 of Table 18 R' is ethyl, 01 is bromo, 02 is hydrogen, Q3 is
chloro.
Similarly, compounds 2 to 323 of Table 18 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 18 R' is ethyl,
Q1 is bromo,
Q2 is hydrogen, 03 is chloro.
Table 19
The compounds in Table 19 are of the general formula (I) where Q1 is iodo, Q2
is
hydrogen, 03 is chloro, n is 0, L is 0, R' is ethyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 19 is the same as compound 1 of Table 1
except
that in compound 1 of Table 19 R' is ethyl, Q1 is iodo, Q2 is hydrogen, Q3 is
chloro.
Similarly, compounds 2 to 323 of Table 19 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 19 R' is ethyl,
01 is iodo,
Q2 is hydrogen, Q3 is chloro.
Table 20
The compounds in Table 20 are of the general formula (I) where Q1 is chloro,
Q2 is
hydrogen, Q3 is fluoro, n is 0, L is 0, R' is ethyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 20 is the same as compound 1 of Table 1
except
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that in compound 1 of Table 20 R' is ethyl, 01 is chloro, 02 is hydrogen, Q3
is fluoro.
Similarly, compounds 2 to 323 of Table 20 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 20 R' is ethyl,
Q1 is chloro,
Q2 is hydrogen, 03 is fluoro.
Table 21
The compounds in Table 21 are of the general formula (I) where Q1 is bromo, Q2
is
hydrogen, Q3 is fluoro, n is 0, L is 0, R' is ethyl, R2 and R3 have the values
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 R' is ethyl, Q1 is bromo, 02 is hydrogen, Q3 is
fluoro.
1o Similarly, compounds 2 to 323 of Table 21 are the same as compounds 2 to
323 of
Table 1, respectively, except that in the compounds of Table 21 R' is ethyl,
01 is bromo,
Q2 is hydrogen, 03 is fluoro.
Table 22
The compounds in Table 22 are of the general formula (I) where Q1 is iodo, Q2
is
hydrogen, 03 is fluoro, n is 0, L is 0, R' is ethyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 22 is the same as compound 1 of Table 1
except
that in compound 1 of Table 22 R' is ethyl, 01 is iodo, Q2 is hydrogen, Q3 is
fluoro.
Similarly, compounds 2 to 323 of Table 22 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 22 R' is ethyl,
Q1 is iodo,
Q2 is hydrogen, Q3 is fluoro.
Table 23
The compounds in Table 23 are of the general formula (I) where Q1 is hydrogen,
02 is
hydrogen, 03 is chloro, n is 0, L is 0, R' is ethyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 23 is the same as compound 1 of Table 1
except
that in compound 1 of Table 23 R' is ethyl, Q1 is hydrogen, 02 is hydrogen, 03
is
chloro. Similarly, compounds 2 to 323 of Table 23 are the same as compounds 2
to 323
of Table 1, respectively, except that in the compounds of Table 23 R' is
ethyl, 01 is
hydrogen, Q2 is hydrogen, Q3 is chloro.
Table 24
The compounds in Table 24 are of the general formula (I) where Q1 is hydrogen,
Q2 is
hydrogen, Q3 is fluoro, n is 0, L is 0, R' is ethyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 24 is the same as compound 1 of Table 1
except
that in compound 1 of Table 24 R' is ethyl, Q1 is hydrogen, Q2 is hydrogen, 03
is fluoro.
Similarly, compounds 2 to 323 of Table 24 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 24 R' is ethyl,
Q1 is
hydrogen, Q2 is hydrogen, Q3 is fluoro.
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Table 25
The compounds in Table 25 are of the general formula (I) where Q1 is chloro,
Q2 is
hydrogen, Q3 is methyl, n is 0, L is 0, R' is ethyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 25 is the same as compound 1 of Table 1
except
that in compound 1 of Table 25 R' is ethyl, Q1 is chloro, Q2 is hydrogen, Q3
is methyl.
Similarly, compounds 2 to 323 of Table 25 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 25 R' is ethyl,
01 is chloro,
Q2 is hydrogen, 03 is methyl.
Table 26
The compounds in Table 26 are of the general formula (I) where Q1 is bromo, Q2
is
hydrogen, 03 is methyl, n is 0, L is 0, R' is ethyl, R2 and R3 have the values
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 R' is ethyl, Q1 is bromo, Q2 is hydrogen, 03 is
methyl.
Similarly, compounds 2 to 323 of Table 26 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 26 R' is ethyl,
Q1 is bromo,
02 is hydrogen, 03 is methyl.
Table 27
The compounds in Table 27 are of the general formula (I) where 01 is iodo, 02
is
hydrogen, Q3 is methyl, n is 0, L is 0, R' is ethyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 27 is the same as compound 1 of Table 1
except
that in compound 1 of Table 27 R' is ethyl, 01 is iodo, Q2 is hydrogen, Q3 is
methyl.
Similarly, compounds 2 to 323 of Table 27 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 27 R' is ethyl,
Q1 is iodo,
Q2 is hydrogen, Q3 is methyl.
Table 28
The compounds in Table 28 are of the general formula (I) where 01 is hydrogen,
Q2 is
hydrogen, Q3 is methyl, n is 0, L is 0, R' is ethyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 28 is the same as compound 1 of Table 1
except
that in compound 1 of Table 28 R' is ethyl, 01 is hydrogen, 02 is hydrogen, Q3
is
methyl. Similarly, compounds 2 to 323 of Table 28 are the same as compounds 2
to 323
of Table 1, respectively, except that in the compounds of Table 28 R' is
ethyl, Q1 is
hydrogen, Q2 is hydrogen, Q3 is methyl.
Table 29
The compounds in Table 29 are of the general formula (I) where Q1 is thiophen-
3-yl, Q2
is hydrogen, Q3 is chloro, n is 0, L is 0, R' is methyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 29 is the same as compound 1 of Table 1
except
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that in compound 1 of Table 29 01 is thiophen-3-yl, Q2 is hydrogen, 03 is
chloro.
Similarly, compounds 2 to 323 of Table 29 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 29 01 is thiophen-
3-yl, 02
is hydrogen, Q3 is chloro.
Table 30
The compounds in Table 30 are of the general formula (I) where Q1 is thiophen-
3-yl, 02
is hydrogen, 03 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 30 is the same as compound 1 of Table 1
except
that in compound 1 of Table 30 01 is thiophen-3-yl, 02 is hydrogen, Q3 is
fluoro.
1o Similarly, compounds 2 to 323 of Table 30 are the same as compounds 2 to
323 of
Table 1, respectively, except that in the compounds of Table 30 Q1 is thiophen-
3-yl, 02
is hydrogen, 03 is fluoro.
Table 31
The compounds in Table 31 are of the general formula (I) where Q1 is thiophen-
2-yl, Q2
is hydrogen, Q3 is chloro, n is 0, L is 0, R' is methyl, R 2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 31 is the same as compound 1 of Table 1
except
that in compound 1 of Table 31 Q1 is thiophen-2-yl, Q2 is hydrogen, 03 is
chloro.
Similarly, compounds 2 to 323 of Table 31 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 31 Q1 is thiophen-
2-yl, Q2
is hydrogen, Q3 is chloro.
Table 32
The compounds in Table 32 are of the general formula (I) where 01 is thiophen-
2-yl, Q2
is hydrogen, Q3 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 32 is the same as compound 1 of Table 1
except
that in compound 1 of Table 32 Q1 is thiophen-2-yl, 02 is hydrogen, 03 is
fluoro.
Similarly, compounds 2 to 323 of Table 32 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 32 Q1 is thiophen-
2-yl, 02
is hydrogen, 03 is fluoro.
Table 33
The compounds in Table 33 are of the general formula (I) where Q1 is thiophen-
3-yl, Q2
is hydrogen, Q3 is chloro, n is 0, L is 0, R' is ethyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 33 is the same as compound 1 of Table 1
except
that in compound 1 of Table 33 Q1 is thiophen-3-yl, Q2 is hydrogen, 03 is
chloro.
Similarly, compounds 2 to 323 of Table 33 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 33 Q1 is thiophen-
3-yl, 02
is hydrogen, Q3 is chloro.
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Table 34
The compounds in Table 34 are of the general formula (I) where Q1 is thiophen-
3-yl, Q2
is hydrogen, Q3 is fluoro, n is 0, L is 0, R' is ethyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 34 is the same as compound 1 of Table 1
except
that in compound 1 of Table 34 Q1 is thiophen-3-yl, 02 is hydrogen, Q3 is
fluoro.
Similarly, compounds 2 to 323 of Table 34 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 34 Q1 is thiophen-
3-yi, Q2
is hydrogen, Q3 is fluoro.
Table 35
1o The compounds in Table 35 are of the general formula (I) where Q1 is
thiophen-2-yl, 02
is hydrogen, 03 is chloro, n is 0, L is 0, R' is ethyl, R2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 35 is the same as compound 1 of Table 1
except
that in compound 1 of Table 35 01 is thiophen-2-yl, Q2 is hydrogen, Q3 is
chloro.
Similarly, compounds 2 to 323 of Table 35 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 35 Q1 is thiophen-
2-yl, Q2
is hydrogen, Q3 is chloro.
Table 36
The compounds in Table 36 are of the general formula (I) where Q1 is thiophen-
2-yl, Q2
is hydrogen, Q3 is fluoro, n is 0, L is 0, R' is ethyl, R2 and R3 have the
values listed in
2o Table 1. Thus, compound 1 of Table 36 is the same as compound 1 of Table 1
except
that in compound 1 of Table 36 01 is thiophen-2-yl, 02 is hydrogen, Q3 is
fluoro.
Similarly, compounds 2 to 323 of Table 36 are the same as compounds 2 to 323
of
Table 1, respectively, except that in the compounds of Table 36 Q1 is thiophen-
2-yl, Q2
is hydrogen, 03 is fluoro.
Table 37
The compounds in Table 37 are of the general formula (I) where Q1 is chloro,
Q2 is
methyl, Q3 is chloro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 37 is the same as compound 1 of Table 1
except
that in compound 1 of Table 37 01 is chloro, Q2 is methyl, Q3 is chloro.
Similarly,
compounds 2 to 323 of Table 37 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 37 Q1 is chloro, Q2 is
methyl, Q3 is
chloro.
Table 38
The compounds in Table 38 are of the general formula (I) where 01 is bromo, Q2
is
methyl, Q3 is chloro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 38 is the same as compound 1 of Table 1
except
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that in compound 1 of Table 38 Q1 is bromo, Q2 is methyl, Q3 is chloro.
Similarly,
compounds 2 to 323 of Table 38 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 38 Q1 is bromo, Q2 is
methyl, Q3 is
chloro.
Table 39
The compounds in Table 39 are of the general formula (I) where Q1 is iodo, Q2
is
methyl, Q3 is chloro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 39 is the same as compound 1 of Table 1
except
that in compound 1 of Table 39 01 is iodo, 02 is methyl, Q3 is chloro.
Similarly,
1o compounds 2 to 323 of Table 39 are the same as compounds 2 to 323 of Table
1,
respectively, except that in the compounds of Table 39 Q1 is iodo, Q2 is
methyl, Q3 is
chloro.
Table 40
The compounds in Table 40 are of the general formula (I) where Q1 is fluoro,
02 is
methyl, Q3 is chloro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 40 is the same as compound 1 of Table 1
except
that in compound 1 of Table 40 01 is fluoro, Q2 is methyl, 03 is chloro.
Similarly,
compounds 2 to 323 of Table 40 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 40 Q1 is fluoro, Q2 is
methyl, Q3 is
chloro.
Table 41
The compounds in Table 41 are of the general formula (I) where 01 is chloro,
Q2 is
methyl, Q3 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 41 is the same as compound 1 of Table 1
except
that in compound 1 of Table 41 01 is chloro, Q2 is methyl, Q3 is fluoro.
Similarly,
compounds 2 to 323 of Table 41 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 41 Q1 is chloro, Q2 is
methyl, Q3 is
fluoro.
Table 42
The compounds in Table 42 are of the general formula (I) where Q1 is bromo, Q2
is
methyl, Q3 is fluoro, n is 0, L is 0, R' is methyl, R 2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 42 is the same as compound 1 of Table 1
except
that in compound 1 of Table 42 01 is bromo, Q2 is methyl, Q3 is fluoro.
Similarly,
compounds 2 to 323 of Table 42 are'the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 42 Q1 is bromo, 02 is
methyl, Q3 is
fluoro.
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Table 43
The compounds in Table 43 are of the general formula (I) where Q1 is iodo, 02
is
methyl, Q3 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 43 is the same as compound 1 of Table 1
except
that in compound 1 of Table 43 01 is iodo, Q2 is methyl, Q3 is fluoro.
Similarly,
compounds 2 to 323 of Table 43 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 43 Q1 is iodo, 02 is
methyl, 03 is
fluoro.
Table 44
1o The compounds in Table 44 are of the general formula (I) where 01 is
fluoro, 02 is
methyl, 03 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 44 is the same as compound 1 of Table 1
except
that in compound 1 of Table 44 01 is fluoro, Q2 is methyl, Q3 is fluoro.
Similarly,
compounds 2 to 323 of Table 44 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 44 Q1 is fluoro, 02 is
methyl, 03 is
fluoro.
Table 45
The compounds in Table 45 are of the general formula (I) where 01 is chloro,
02 is
methyl, Q3 is bromo, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 45 is the same as compound 1 of Table 1
except
that in compound 1 of Table 45 Q1 is chloro, 02 is methyl, 03 is bromo.
Similarly,
compounds 2 to 323 of Table 45 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 45 Q1 is chloro, Q2 is
methyl, Q3 is
bromo.
Table 46
The compounds in Table 46 are of the general formula (I) where 01 is bromo, Q2
is
methyl, Q3 is bromo, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 46 is the same as compound 1 of Table 1
except
that in compound 1 of Table 46 01 is bromo, Q2 is methyl, Q3 is bromo.
Similarly,
compounds 2 to 323 of Table 46 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 46 Q1 is bromo, Q2 is
methyl, Q3 is
bromo.
Table 47
The compounds in Table 47 are of the general formula (I) where Q1 is iodo, Q2
is
methyl, Q3 is bromo, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 47 is the same as compound 1 of Table 1
except
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that in compound 1 of Table 47 01 is iodo, 02 is methyl, Q3 is bromo.
Similarly,
compounds 2 to 323 of Table 47 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 47 Q1 is iodo, 02 is
methyl, 03 is
bromo.
Table 48
The compounds in Table 48 are of the general formula (I) where Q1 is fluoro,
Q2 is
methyl, Q3 is bromo, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in
Table 1. Thus, compound 1 of Table 48 is the same as compound 1 of Table 1
except
that in compound 1 of Table 48 01 is fluoro, 02 is methyl, Q3 is bromo.
Similarly,
io compounds 2 to 323 of Table 48 are the same as compounds 2 to 323 of Table
1,
respectively, except that in the compounds of Table 48 Q1 is fluoro, Q2 is
methyl, Q3 is
bromo.
Table 49
The compounds in Table 49 are of the general formula (I) where 01 is chloro,
Q2 is
chloro, Q3 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in Table
1. Thus, compound 1 of Table 49 is the same as compound 1 of Table 1 except
that in
compound 1 of Table 49 Q1 is chloro, Q2 is chloro, Q3 is fluoro. Similarly,
compounds 2
to 323 of Table 49 are the same as compounds 2 to 323 of Table 1,
respectively, except
that in the compounds of Table 49 Q1 is Q1 is chloro, 02 is chloro, 03 is
fluoro.
2o Table 50
The compounds in Table 50 are of the general formula (I) where 01 is bromo, Q2
is
chloro, Q3 is fluoro, n is 0, L is 0, R' is methyl, R 2 and R3 have the values
listed in Table
1. Thus, compound 1 of Table 50 is the same as compound 1 of Table 1 except
that in
compound 1 of Table 50 01 is bromo, Q2 is chloro, Q3 is fluoro. Similarly,
compounds 2
to 323 of Table 50 are the same as compounds 2 to 323 of Table 1,
respectively, except
that in the compounds of Table 50 Q1 is 01 is bromo, Q2 is chloro, Q3 is
fluoro.
Table 51
The compounds in Table 51 are of the general formula (I) where 01 is flouro,
Q2 is
chloro, Q3 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in Table
1. Thus, compound 1 of Table 51 is the same as compound 1 of Table 1 except
that in
compound 1 of Table 51 Q1 is flouro, Q2 is chloro, Q3 is fluoro. Similarly,
compounds 2
to 323 of Table 51 are the same as compounds 2 to 323 of Table 1,
respectively, except
that in the compounds of Table 51 Q1 is Q1 is flouro, Q2 is chloro, 03 is
fluoro.
Table 52
The compounds in Table 52 are of the general formula (I) where Q1 is iodo, Q2
is
chloro, Q3 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in Table
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1. Thus, compound 1 of Table 52 is the same as compound 1 of Table 1 except
that in
compound 1 of Table 52 Q1 is iodo, Q2 is chloro, Q3 is fluoro. Similarly,
compounds 2 to
323 of Table 52 are the same as compounds 2 to 323 of Table 1, respectively,
except
that in the compounds of Table 52 Q1 is 01 is iodo, 02 is chloro, Q3 is
fluoro.
Table 53
The compounds in Table 53 are of the general formula (I) where Q1 is chloro,
Q2 is
bromo, Q3 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in Table
1. Thus, compound 1 of Table 53 is the same as compound 1 of Table 1 except
that in
compound 1 of Table 53 01 is chloro, Q2 is bromo, Q3 is fluoro. Similarly,
compounds 2
1o to 323 of Table 53 are the same as compounds 2 to 323 of Table 1,
respectively, except
that in the compounds of Table 53 01 is Q1 is chloro, Q2 is bromo, Q3 is
fluoro.
Table 54
The compounds in Table 54 are of the general formula (I) where Q1 is bromo, Q2
is
bromo, 03 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in Table
1. Thus, compound 1 of Table 54 is the same as compound 1 of Table 1 except
that in
compound 1 of Table 54 Q1 is bromo, Q2 is bromo, Q3 is fluoro. Similarly,
compounds 2
to 323 of Table 54 are the same as compounds 2 to 323 of Table 1,
respectively, except
that in the compounds of Table 54 Q1 is 01 is bromo, 02 is bromo, Q3 is
fluoro.
Table 55
The compounds in Table 55 are of the general formula (I) where Q1 is flouro,
Q2 is
bromo, Q3 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in Table
1. Thus, compound 1 of Table 55 is the same as compound 1 of Table 1 except
that in
compound 1 of Table 55 Q1 is flouro, Q2 is bromo, Q3 is fluoro. Similarly,
compounds 2
to 323 of Table 55 are the same as compounds 2 to 323 of Table 1,
respectively, except
that in the compounds of Table 55 Q1 is 01 is flouro, Q2 is bromo, Q3 is
fluoro.
Table 56
The compounds in Table 56 are of the general formula (I) where Q1 is iodo, Q2
is
bromo, Q3 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in Table
1. Thus, compound 1 of Table 56 is the same as compound 1 of Table 1 except
that in
compound 1 of Table 56 Q1 is iodo, Q2 is bromo, Q3 is fluoro. Similarly,
compounds 2
to 323 of Table 56 are the same as compounds 2 to 323 of Table 1,
respectively, except
that in the compounds of Table 56 Q1 is Q1 is iodo, Q2 is bromo, Q3 is fluoro.
Table 57
The compounds in Table 57 are of the general formula (I) where Q1 is chloro,
Q2 is
fluoro, Q3 is fluoro, n is 0, L is 0, R' is methyl, R 2 and R3 have the values
listed in Table
1. Thus, compound 1 of Table 57 is the same as compound 1 of Table 1 except
that in
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compound 1 of Table 57 Q1 is chloro, Q2 is fluoro, 03 is fluoro. Similarly,
compounds 2
to 323 of Table 57 are the same as compounds 2 to 323 of Table 1,
respectively, except
that in the compounds of Table 57 01 is 01 is chloro, Q2 is fluoro, Q3 is
fluoro.
Table 58
The compounds in Table 58 are of the general formula (I) where Q1 is bromo, Q2
is
fluoro, Q3 is fluoro, n is 0, L is 0, R' is methyl, R 2 and R3 have the values
listed in Table
1. Thus, compound 1 of Table 58 is the same as compound 1 of Table 1 except
that in
compound 1 of Table 58 Q1 is bromo, Q2 is fluoro, Q3 is fluoro. Similarly,
compounds 2
to 323 of Table 58 are the same as compounds 2 to 323 of Table 1,
respectively, except
lo that in the compounds of Table 58 01 is Q1 is bromo, Q2 is fluoro, 03 is
fluoro.
Table 59
The compounds in Table 59 are of the general formula (I) where 01 is fluoro,
Q2 is
fluoro, 03 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the values
listed in Table
1. Thus, compound 1 of Table 59 is the same as compound 1 of Table 1 except
that in
compound 1 of Table 59 Q1 is fluoro, Q2 is fluoro, Q3 is fluoro. Similarly,
compounds 2
to 323 of Table 59 are the same as compounds 2 to 323 of Table 1,
respectively, except
that in the compounds of Table 59 Q1 is Q1 is fluoro, 02 is fluoro, 03 is
fluoro.
Table 60
The compounds in Table 60 are of the general formula (I) where Q1 is iodo, Q2
is fluoro,
Q3 is fluoro, n is 0, L is 0, R' is methyl, R2 and R3 have the values listed
in Table 1.
Thus, compound 1 of Table 60 is the same as compound 1 of Table 1 except that
in
compound 1 of Table 60 Q1 is iodo, Q2 is fluoro, Q3 is fluoro. Similarly,
compounds 2 to
323 of Table 60 are the same as compounds 2 to 323 of Table 1, respectively,
except
that in the compounds of Table 60 Q1 is 01 is iodo, Q2 is fluoro, Q3 is
fluoro.
Table 61
The compounds in Table 61 are of the general formula (I) where Q1 is thiophen-
3-yl, Q2
is fluoro, Q3 is fluoro, n is 0, L is 0, R' is methyl, R 2 and R3 have the
values listed in
Table 1. Thus, compound 1 of Table 61 is the same as compound 1 of Table 1
except
that in compound 1 of Table 61 01 is thiophen-3-yl, 02 is fluoro, Q3 is
fluoro. Similarly,
compounds 2 to 323 of Table 61 are the same as compounds 2 to 323 of Table 1,
respectively, except that in the compounds of Table 61 Q1 is Q1 is thiophen-3-
yl, Q2 is
fluoro, Q3 is fluoro.
Tables 62 to 121
Tables 62 to 121 correspond exactly to Tables 1 to 61 (i.e. Table 62
corresponds exactly
to Table 1, Table 63 corresponds exactly to Table 2, and so on) the only
difference
being that in each of Tables 62 to 121, L is S instead of Q.
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Tables 122 to 181
Tables 122 to 181 correspond exactly to Tables 1 to 61 (i.e. Table 122
corresponds
exactly to Table 1, Table 123 corresponds exactly to Table 2, and so on) the
only
difference being that in each of Tables 122 to 181, n is 1 instead of 0.
Tables 182 to 241
Tables 182 to 241 correspond exactly to Tables 1 to 61 (i.e. Table 182
corresponds
exactly to Table 1, Table 183 corresponds exactly to Table 2, and so on) the
only
difference being that in each of Tables 182 to 241, n is 2 instead of 0.
The compounds of general formula (I) may be prepared as outlined in Schemes 1
to 8
1o below, in which 01, Q2, 03, R', R2 and R3 have the meanings given above,
R14 is H or
C,_4 alkyl, as indicated, R10 is C,_6 alkyl, optionally substituted benzyl,
optionally
substituted C2_6 alkenyl, optionally substituted C2.4 alkynyl, R6, R', R8, R9,
R 12 and R73
are independently H or C,-4 alkyl, R9 is H or C,_3 alkyl, Rh is H or C1.3
alkyl, R' is C1_6 alkyl,
optionally substituted benzyl, optionally substituted C2-6 alkenyl, optionally
substituted
C2_4 alkynyl, m is 0, 1 or 2, DMF is N,IV dimethylformamide, NBS is N-
bromosuccinimide, NCS is N-chlorosuccinimide and MCPBA is m-chloroperbenzoic
acid. Other abbreviations are defined in the text.
Where typical or preferred process conditions (reaction temperature, time,
solvent, mole
ratios of reactants) are given, unless otherwise stated other process
conditions can also
2o be used. While optimum reaction conditions may vary with the particular
reactants or
solvents used, such conditions can be determined by routine optimisation
procedures by
one skilled in the art.
Compounds of formula (1), where n is 0 and L is 0, may be prepared as shown in
Scheme 1. Esters of formula (2), where R5 is C1_4 alkyl, may be halogenated to
give
haloesters of formula (3), where Hal is a halogen atom such as bromine,
chlorine or
iodine, by reaction with a halogenating agent such as N-bromosuccinimide, in a
suitable
solvent such as carbon tetrachloride or acetonitrile, in the presence of a
radical initiator
such as AIBN (azo-isobutyronitrile), and a light source, at between ambient
temperature
and the reflux temperature of the solvent. Compounds of general formula (3)
are then
reacted with alkanethiols of general formula R'SH, in the presence of a base
such as
sodium hydride, in a suitable solvent such as DMF, to give compounds of
general
formula (6), or are reacted with alkanethiol salts R'S-M+, where M is a metal
such as
sodium or lithium, in a suitable solvent such as DMF, to give compounds of
general
formula (6).
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Scheme 1
0
~ R'SH/base/
O~ R~a Halagenating O I O O R" soNent
' ~\ \ O/ eg. NBS N ~ O Hal eg. NaH/DMF
N 03 OZ
Oz (2) (3)
O, ( \ ~ OH
O
O~I ::tmn+Q
+.R1/base/ o2 O+ \ O R
O .
r Haf~OIR eg.
R'~ R1iS eg. NaH/DMF N 03 y~R'
(4) (5) (6) 02
M'OH-
solvent
amide coupling 0
0 e.g. HOBT/ 3
EDC O' \ \ O ~R
O' O~OH I i
I I i / S RZ
N 03 SNR H`N~R3 N 03
IZ OZ
Oz R
(7) (8) (1) where n = 0
Alternatively esters of general formula (4) are halogenated to give haloesters
of formula
(5), where Hal is a halogen atom such as bromine, chlorine or iodine, by
reaction with a
halogenating agent such as N-chlorosuccinimide or N-bromosuccinimide, in a
suitable
solvent such as carbon tetrachloride or acetonitrile, at between 0 C and the
reflux
temperature of the solvent. Haloesters of formula (5) are reacted with 6-
hydroxy
quinolines, where Q1, 02 and Q3 are as defined above, in the presence of a
base such
as potassium t-butoxide, potassium carbonate, or sodium hydride in a suitable
solvent
such as t-butanol, 1,4-dioxane or DMF, at between ambient temperature and the
reflux
temperature of the solvent, to give compounds of formula (6). Compounds of
formula (6)
are hydrolysed to acids of formula (7) by reaction with an alkali metal
hydroxide M+OH-,
in a suitable solvent such as aqueous methanol, ethanol, or THF
(tetrahydrofuran) at
between ambient temperature and the reflux temperature of the solvent followed
by
acidification. Acids of formula (7) can be condensed with amines of formula
(8), using
suitable activating agents such as HOBT (1 -hydroxybenzotriazole) and EDC (1 -
ethyl-3-
N,N-dimethylaminopropylcarbodiimide hydrochloride), at between 0 C and ambient
temperature in a suitable solvent such as DMF, to give compounds of general
formula
(1)wherenisOandLisO.
Compounds of general formula (1), where n is 1 or 2, are prepared by oxidation
of
compounds (1) where n = 0 to the sulphoxide (n is 1) or sulphone (n is 2)
oxidation
state, as shown in Scheme 2. For example, esters of the general formula (6)
where R5 is
C1_4 alkyl can be oxidised to sulphoxides of formula (9) with an oxidising
agent such as
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sodium periodate in a suitable solvent such ethanol, between 0 C and ambient
temperature. Sulphones of formula (10) can be made either directly from
compounds of
formula (6) with two or more equivalents of an oxidising agent such as m-
chloro-
perbenzoic acid (MCPBA), in a suitable solvent such as dichloromethane between
0 C
and the reflux temperature of the solvent, or from sulphoxides of formula (9)
with one or
more equivalents of m-chloroperbenzoic acid. Sulphides of formula (6),
sulphoxides of
formula (9) or sulphones of formula (10) can be hydrolysed to the
corresponding acids
(7), (11) or (12) by reaction with an alkali metal hydroxide in a suitable
solvent such as
ethanol at between 0 C and the ref lux temperature of the solvent followed by
io acidification. The acids of formula (7), (11) or (12) can be condensed with
amines of
formula (8), using suitable activating agents such as HOBT and EDC, at between
0 C
and ambient temperature, to give compounds of general formula (1) where n is
0, 1 or 2.
Scheme 2
oxidising agent
e.g. MCPBA
O
O
Q RB o)ddising a ent Ou
I \ \ O O~ e.g. NalO.g 0, \ \ OY \O~R6 B 9disMing CPBA nt Q \ \ O O Ra
~ / g` I SO
N Qs R ~ I N 0, S=0 N 03 7 0
OR
2 R 02
(6) 02 (9) (10)
M'OH-
solvent M-OH- MIOH-
solvent solvent
Q
0 oxidising agent oxidising agent II
Q
Q' i\ \ OH e.g. MCPBA ' I\ \ O OH
O-T'u \QH e.g. NalO.
Q O
~
N Qz 03 S-Ri 1j 03 R, N 3 ~
\\~~ (7) Qz (11) oxidising agent O
z(12) R
e.g. MCPBA
Amide eoupling Amide coupling Amide coupling
H.NR3 e.g.HOBT/EDC H, N~R3 e.g.HOBT/EDC H.N.R3 e.g.HOBT/EDC
Rz Rz Rz
(8) (8) (8)
Q 0
0 oxidising agent oxidisin9 agent
Q' R3 e.g. NalO, Q, i\ \ O N~R3 e.g. MCPBA O' \ \ O R3
z i
I i S. Rz N Q S-0 R I N Q3S;~ Rz
N Q3 R, a R, R,
Q Qz Qa
z (1)wheren=1
(1) where n= 0 oxidising agent (1) where n= 2
e.g. MCPBA
Similarly, sulphoxides of formula (11) and of formula (1) where n is 1 can be
prepared
from sulphides of formula (7) and of formula (1) where n is 0 respectively,
using
oxidising agents such as sodium metaperiodate or m-chloroperbenzoic acid as
described above. Sulphones of formula (12) and of formula (1) where n is 2,
can be
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prepared either from sulphides of formula (7) and of formula (1) where n i.s
0, by using at
least two equivalents of oxidising agents such as m-chloroperbenzoic acid, or
from
sulphoxides of formula (11) and of formula (1) where n is 1, using one or more
equivalents of oxidising agents such as m-chloroperbenzoic acid, as described
above.
Compounds of formula (1) can also be prepared as shown in Scheme 3. Acids of
formula (13) can be condensed with amines of formula (8), using suitable
activating
agents such as HOBT and EDC, at between 0 C and ambient temperature, to give
compounds of formula (14). Compounds of formula (14) can be halogenated to
compounds of formula (16) using a halogenating agent such as N-
chlorosuccinimide, in
1o a suitable solvent such as carbon tetrachloride or acetonitrile, at between
0 C and
ambient temperature. Amides of formula (16) can also be prepared from acid
halides of
formula (15) by reaction with amines of formula (8) in the presence of a base
such as
triethylamine in a suitable solvent such as dichloromethane, at between 0 C
and
ambient temperature.
Scheme 3
amide coupling
O e.g. HOBT/ 0
OH EDC N IR3
H_ IR 3 iz
RN Riis R
(13) RZ (8) (14)
Halogenating
agent Q+ OH
eg. NCS 0 N O base/solvent O /base/ Qz C3 Oi ~ ~ O~NR3
e.g. Et3N/CH2CI2 3
Hal` ~ Hal N IR solvent 03
~ / S, R , RZ
Y ` Hal 11 H- IR3 z e.g. NaH/DMF
R N R i~S R Oz
IZ
R
(15) (8) (16) (1) where n = 0
Halosulphides of formula (16) can be reacted with substituted 6-hydroxy
quinolines, in
the presence of a base such as potassium carbonate or sodium hydride, in a
suitable
solvent such as DMF, at between 0 C and 80 C, to give compounds of formula (1)
where n is 0.
As shown in Scheme 4, amines of the general formula (18) or (20), which are
examples
of amines of the general formula (8) wherein R2 is H, may be prepared by
alkylation of
an aminoalcohol of the general formula (17) or (19) using a suitable base,
such as n-
butyl lithium or sodium hydride, followed by reaction with a suitable
alkylating reagent
R10LG, such as an alkyl iodide, for example, methyl iodide, to form an
alkylated
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compound of the general formula (18) or (20), respectively. A carbonyl
derivative
R12COR13 (21), for example formaldehyde, can be reacted with ammonia, usually
in form
of ammonium chloride, and cyanide, conveniently in form of an aqueous solution
sodium
cyanide, to provide an a-aminoalkyne (22) (Strecker synthesis).
Scheme 4
H Re R base H R6 R
R LG
N OH N OR10
H~ R R m HI R~ R m
(17) (18)
H OH base H OR'o
I N~Ru R LG ,N+R"
H OH H OR'o
(19) (20)
NaCN
Ri2 NH4CI R1\ CN
13~0 R1s/\NHZ
(22)
As shown in Scheme 5, silyl-protected aminoalkynes of the general formula (24)
may be
obtained by reacting amines of general formula (23) with 1,2-bis-
(chlorodimethylsilyl)-
ethane in the presence of a suitable base, such as a tertiary organic amine
base, for
example, triethylamine. Amines of the general formula (26), which are examples
of
amines of the general formula (8) wherein R2 is H and R3 is -(CR30R40)C=CR50,
may be
prepared by alkylation of a silyl-protected aminoalkyne of the general formula
(24) using
a suitable base, such as n-butyl lithium, followed by reaction with a suitable
alkylating
reagent R50LG, such as an alkyl iodide, for example, methyl iodide, to form an
alkylated
compound of the general formula (25). The silyl protecting group may then be
removed
from a compound of the general formula (25) with, for example, an aqueous acid
to form
an aminoalkyne of the general formula (26).
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Scheme 5
si/
30 Si
Si N R 1. base ~N R30
\ Rao\ 2. LG-(CHZ)nCHZCI / Rao \
H CI
(24) (32)
MCN
eg KCN
30 SI/
H2N R H3p+ N R3o
R40~ ~` S
CN Rao -
CN
(34) (33)
MCN
eg KCN
0 0
Q O H MCN o H 30
' \ \ N R30
eg KCN \ N R
40 N Q3 SRti CI N / Q3 SR R " CN
O2 02
(35) (36)
In a similar procedure, a silyl-protected aminoalkyne of the general formula
(24) may be
reacted with a carbonyl derivative RaCORb, for example formaldehyde, using a
suitable
base, such as n-butyl lithium, to provide an aminoalkyne (27) containing a
hydroxyalkyl
moiety. A compound of the general formula (27) may either first be treated
with a base,
such as sodium hydride or potassium bis(trimethylsilyl)amide followed by a
compound
R LG, where LG represents a leaving group such as a halogen, or sulphonate
ester
such as OSO2Me, or OS02-4-tolyl, for example ethyl iodide, to give a compound
of the
general formula (29). After removal of the silyl protecting group, compounds
of general
formula (30) are obtained. Alternatively, the silyl protecting group can first
be removed to
yield compounds of the general formula (28). Aminoalkynes of the general
formula (28)
may be further derivatised by reacting with a silylating agent, for example t-
butyl-
dimethylsilyl chloride, to give a derivative silylated on oxygen of the
general formula
(31).
20
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Scheme 6
H
30 ci~;;s si-ci si- /
1. base Si-
N R ~
H' --- .N R ~,N R3o
Rao \ base S~ Rao\ 2.R50LG S\
H
Rao\ R
so
(23) (24) (25)
1.base H30+
2. RaCORb
H /
H,N R3 H30+ (Si R N H R 30
Ra \ OH \ ao \ H
Ra R OH so
Ra
(28) (27) Rb (26)
R63SiC'
imidazole/ \ 1. base
DMF / \ 2.RcLG
H ~~~lll 11" H Sif
N R3 H~N R3 H30+ N R30
H R OSiR63 Ra OR Rao OR
b Ra Ra b Ra
(31) R (30) R b (29) R
As shown in Scheme 6, silyl-protected aminoalkynes of the general formula (32)
may be
obtained by reacting silyl-protected amines of general formula (24) with
chloroalkanes
bearing a suitable leaving group, for example bromide or iodide, in the
presence of a
suitable base, such as asodium or lithium amide base, for example, sodium
bis(trimethylsilyl)amide or sodium amide. Amines of the general formula (34),
which are
examples of amines of the general formula (8) wherein R2 is H and and R3 is -
to (CR30Ra0)C=CR50 may be prepared by displacement of chloride anion by
cyanide,
followed by removal of the silyl protecting group with, for example, an
aqueous acid, to
form a cyano compound of the general formula (34).
In a similar procedure, an amide of the general formula (35) can be reacted
with, for
example, potassium cyanide yielding a cyano amidoalkyne of the general formula
(36).
As shown in Scheme 7, compounds of the general formula (1), wherein R50 is H,
may be
reacted under Sonogashira conditions with, for example, optionally substituted
aryl or
heteroaryl chlorides, bromides, iodides or triflates to form substituted aryl
or heteroaryl
compounds of general formula (1), wherein R50 is an optionally substituted
aryl or
heteroaryl group. A suitable palladium catalyst is
bis(triphenylphosphine)palladium (II)
chloride.
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Scheme 7
O p
pH so
Q' I\ \ YLNH R3O Ar-L or \ \ N R
p
Rao
, IS\ ' Rao~ ~ Heteroaryl-L I ~ / S,
N Q3 R Cul, Et3N N 03 R (Hetero)aryl
Q2 Palladium catalyst Qz
L = Cl, Br, 1, OSOZCF3 (36)
(1) where R2 = H and
R3 is -(CR3 R4 )CCR50, R50 = H)
Other amines of the general formula (8) are either commercially available or
may be
prepared by standard literature methods or standard modifications.
As shown in Scheme 8, compounds of the general formula (1), wherein 01 is
bromine or
iodine, may be reacted under Suzuki conditions with, for example, optionally
substituted
aryl or heteroaryl boronic acids to form substituted aryl or heteroaryl
compounds of
general formula (1), wherein 01 is an optionally substituted aryl or
heteroaryl group. A
suitable palladium catalyst is tetrakis(triphenylphosphine)palladium(O).
Scheme S
0 0
IN Ar-B(OM: or ArlHeteroaryl QO, ~
Q 0 N.RHeteroaryl-B(OH) TN):: S, R I N R S, R, R
Palladium catalyst
base
(1) where Q 1 = Br, I, n= 1
Thioamides (Compounds of the general formula (1) where L = S) may be prepared
from
the corresponding amides using thionating agents such as phosphous
pentasuiphide,
Lawesson's or Davy's reagents or prepared from the corresponding thionoacids
or
thionoesters using standard literature methods or standard modifications.
The substituted 6-hydroxy quinolines are available, or may be prepared using
straightforward techniques of organic chemistry. When the compounds are not
commercially available, they may be prepared from available precursors using
straightforward transformations that are well known in the art that are well
described in
standard textbooks of heterocyclic chemistry. For example, substituted
aromatic amines
may be readily converted into substituted quinolin-6-ols with appropriate
electrophiles,
such as 2,2,3 tribromopropanal. Examples of such reactions are provided in
Examples
1-3.
The compounds of formula (I) are active fungicides and may be used to control
one or
more of the following pathogens: Pyricularia oryzae (Magnaporthe grisea) on
rice and
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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
io 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 poml) 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
Pythiurn 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
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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
io 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., Ophiostoma piceae, 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 (I) may move acropetally, basipetally or locally in
plant tissue to
be active against one or more fungi. Moreover, a compound of formula (I) 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
phytopathogenic
fungi which comprises applying a fungicidally effective amount of a compound
of formula
(I), or a composition containing a compound of formula (I), 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.
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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 (I) are preferably used for agricultural,
horticultural and
turfgrass purposes in the form of a composition.
In order to apply a compound of formula (I) 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
(I) is
usually formulated into a composition which includes, in addition to the
compound of
formula (I), 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 (I). The composition is generally
used for
the control of fungi such that a compound of formula (I) is applied at a rate
of from 0.1g
to 10kg per hectare, preferably from 1 g to 6kg per hectare, more preferably
from 1 g to
1 kg per hectare.
When used in a seed dressing, a compound of formula (I) is used at a rate of
0.0001g to
lOg (for example 0.001 g or 0.05g), preferably 0.005g to 10g, more preferably
0.005g to
4g, per kilogram of seed.
In another aspect the present invention provides a fungicidal composition
comprising a
fungicidally effective amount of a compound of formula (I) 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 (I).
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
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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 (I).
Dustable powders (DP) may be prepared by mixing a compound of formula (I) with
one
or more solid diluents (for example natural clays, kaolin, pyrophyllite,
bentonite, alumina,
1o 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 (I) 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 (I) 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
(I) 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 (I) (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
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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 (I)
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).
1o Emulsifiable concentrates (EC) or oil-in-water emulsions (EW) may be
prepared by
dissolving a compound of formula (I) 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-alkylpyrrolidones (such as N-methylpyrrolidone or N-
octyl-
pyrrolidone), dimethyl amides of fatty acids (such as C8-C,o fatty 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 (I) either as a liquid (if it is not a liquid at ambient 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 (I) 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
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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 (I). SCs may
be
prepared by ball or bead milling the solid compound of formula (I) 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.
1o Alternatively, a compound of formula (I) 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 (I) and a suitable
propellant (for
example n-butane). A compound of formula (I) 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 (I) 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 dropiet is
encapsulated by a
polymeric shell and contains a compound of formula (I) 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 (I) and they may be
used for
seed treatment. A compound of formula (I) 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 (I)). 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
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oil), and blends of these with other bio-enhancing adjuvants (ingredients
which may aid
or modify the action of a compound of formula (I)).
A compound of formula (I) 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
1o 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
2o dodecylbenzenesulphonate, 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 olefin 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.
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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 (I) 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
1o 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 (I) 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 (I)
(for
example 0.0001 to 10%, by weight) depending upon the purpose for which they
are to
be used.
A compound of formula (I) 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 (I).
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The invention therefore also provides a fertiliser composition comprising a
fertiliser and
a compound of formula (I).
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
1o of activity or a greater level of intrinsic activity than the compound of
formula (I) alone.
Further the other fungicide may have a synergistic effect on the fungicidal
activity of the
compound of formula (I).
The compound of formula (I) 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 (I); 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 (/V-(1-cyano-1,2-dimethylpropyl)-2-(2,4-
dichlorophenoxy) pro-
pionamide), 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,
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dimethomorph, dimoxystrobin, diniconazole, dinocap, dithianon, dodecyl
dimethyl
ammonium chloride, dodemorph, dodine, doguadine, edifenphos, epoxiconazole,
ethaboxam, ethirimol, ethyl (Z)-N-benzyl-N([methyl(methyl-
thioethylideneaminooxy-
carbonyl)amino]thio)-[i-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,
io imibenconazole, iminoctadine, iminoctadine triacetate, ipconazole,
iprobenfos,
iprodione, iprovalicarb, isopropanyl butyl carbamate, isoprothiolane,
kasugamycin,
kresoxim-methyl, LY1 86054, 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-
(thiocyano-
methylthio)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 the compounds of the
formulae:
N^N \ CH3 ~ I CH3
~JL0 F3C .F3C OCH F CH3ON Ol ~~ 3 CH30N
J\
Yl J N-N NHCH3
N, 0 H3c and
The compounds of formula (I) may be mixed with soil, peat or other rooting
media for the
protection of plants against seed-borne, soil-borne or foliar fungal diseases.
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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.
1o The invention is illustrated by the following Examples in which the
following
abbreviations are used:
ml = millilitres m.p. = melting point (uncorrected)
g = grammes b.p. = boiling point
THF = tetrahydrofuran DMSO = dimethylsulphoxide
M+ = mass ion DMF = N, N-
s = singlet dimethylformamide
d = doublet
HOBT = 1 -hydroxybenzotriazole HOAT = 7-aza-1 -hydroxybenzotriazole
bs = broad singlet NMR = nuclear magnetic resonance
t = triplet HPLC = high performance liquid
chromatography
q quartet TLC = thin layer chromatography
m = multiplet glc = gas-liquid
chromatography
ppm = parts per million EDC = 1-ethyl-3-N,N-dimethylamino
M = molar propylcarbodiimide hydrochloride
EXAMPLE 1
This examples illustrates the preparation of 2-(3-Bromo-7-chloro-quinolin-6-
yloxy)-N-tert-
butyl-2-methylsulfanyl-acetamide (Compound No. 12 of Table 2)
Stage 1. Preparation of 3-bromo-7-chloro-quinolin-6-ol
Step 1
3-Chloro-4-methoxy aniline (10g) in acetic acid (100m1) was treated with 2,2,3
tribromopropanal (1 8.8g) and the mixture was stirred at room temperature for
2h after
which it was diluted with water and extracted with ethyl acetate. The organic
phase was
washed with 2N NaOH, dried over sodium sulphate, filtered and evaporated under
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reduced pressure to give the desired product, 3-bromo-7-chloro-6-methoxy-
quinoline, as
a yellow solid after chromatography (silica; hexane/ethyl acetate) (M+274).
'H NMR (CDCI3) Sppm: 8.78 (1 H,d); 8.21 (1 H,d); 8.10 (1 H,s); 7.03 (1 H,s).
Step 2
A mixture of the product from Step 1(1.4g) and hydrobromic acid (48 wt%
solution in
water) (100 ml x2) was refluxed for 62 hours. The mixture was cooled to
ambient
temperature, diluted with water, treated with sodium hydrogen carbonate and
extracted
with ethyl acetate. The extract was dried over magnesium sulfate, filtered and
evaporated under reduced pressure to give the required product, 3-bromo-7-
chloro-
1o quinolin-6-ol (M+ 260).1 H NMR (DMSO) S ppm: 7.34 (1 H, s); 7.07 (1 H, s);
8.60 (1 H, d);
8.73 (1 H, d); 11.12 (1 H, s).
Stage 2: Preparation of (3-Bromo-7-chloro-quinolin-6-yloxy)-methylsulfanyl-
acetic acid
methyl ester
Step 1
To a stirred solution of methyl (methylthio)acetate (10.8 ml) in
dichloromethane (300m1)
cooled to -15 C was added dropwise sulphuryl chloride (8.1 ml). The mixture
was
allowed to warm to room temperature over two hours and then concentrated under
reduced pressure to give crude chloro-methylsulfanyl-acetic acid methyl ester
as a
colourless liquid. The product was used in the next step without further
purification. 'H
NMR (CDCI3) S ppm: 2.33 (3H, s); 3.83 (3H, s); 5.49 (1 H,s).
Step 2
To a stirred solution of 3-bromo-7-chloro-quinolin-6-ol from Stage 1, Step
2(1.1 g) in dry
DMF (17m1) containing anhydrous potassium carbonate (3.1 g) at ambient
temperature
was added chloro-methylsulfanyl-acetic acid methyl ester (0.79g) dropwise. The
mixture
was heated for 1 hour at 60-65 C then cooled to ambient temperature, diluted
with water
and extracted with ethyl acetate. The extracts were combined, washed with
brine, dried
over magnesium sulfate, filtered and evaporated under reduced pressure.
Purification of
the crude material by chromatography (silica; ethyl acetate /hexane 1:4 by
volume)
provided the title compound, 3-bromo-7-chloro-quinolin-6-yloxy)-methylsulfanyl-
acetic
acid methyl ester (M+ 378). 'H NMR (CDC13) S ppm: 2.29 (3H, s); 3.89 (3H, s);
5.74
(1 H, s) 7.18 (1 H,8); 8.16 (1 H, s); 8.23 (1 H, s); 8.82 (1 H, s).
Stage 3: Preparation of (3-Bromo-7-chloro-quinolin-6-yloxy)-methylsulfanyl-
acetic acid
To a stirred solution of the product from Stage 2, Step 2 (1.1 g) in ethanol
(14ml) at
ambient temperature was added a solution of 2N sodium hydroxide in water
(2.2ml). The
mixture was stirred at room temperature for 1 hour and then poured into ice-
water and
acidified with 2M hydrochloric acid. The resulting precipitate was filtered
from solution,
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washed with cold water and dried in vacuo to give (3-bromo-7-chloro-quinolin-6-
yloxy)-
methylsulfanyl-acetic acid (M+ 364).'H NMR (DMSO-d6) S ppm: 2.20 (3H, s); 6.18
(1 H,
s) 7.57 (1 H, s); 8.19 (1 H, s); 8.28 (1 H, d); 8.88 (1 H, d); 13.7 (1 H, bs).
Stage 4: Preparation of 2-(3-Bromo-7-chloro-quinolin-6-yloxy)-N-tert-butyl-2-
methylsulfanyl-acetamide
The product from Stage 3 above, 3-bromo-7-chloro-quinolin-6-yloxy)-
methylsulfanyl-
acetic acid (85 mg) from in dry N,N-dimethylformamide (2ml) was treated with t
butylamine (17 mg), N-(3-dimethylamino-propyl)-N'-ethyl carbodiimide
hydrochloride (45
mg), HOAt (32 mg) and triethylamine (24 mg) at ambient temperature with
stirring for 3
1o hours. The mixture was poured into water, extracted with ethyl acetate
(three times) and
the extracts combined, washed with saturated aqueous sodium carbonate
solution,
water (three times) then dried over magnesium sulfate, filtered and evaporated
under
reduced pressure to give an oil. The oil was fractionated by chromatography
(silica;
hexane/ ethyl acetate, 3:1 by volume) to give the required product as a white
solid (m.p.
172-174 C, M+ 419). 'H NMR (CDCI3) S ppm: 1.46 (9H, s); 2.18 (3H, s); 5.63 (1
H, s);
6.89 (1 H, bs); 7.28 (1 H,s); 7.28 (1 H, s); 8.18 (1 H, s), 8.27 (1 H, d);
8.83 (1 H, d).
The following amides were prepared using a similar procedure.
Compound No. 238 of Table 2: using 1,1-dimethyl-prop-2-ynylamine, m.p. 169-171
C;
'H NMR (CDCI3) S ppm: 1.75 (6H,s); 2.19 (3H, s); 2.41 (1 H, s); 5.69 (1 H, s);
7.16 (1 H,
bs); 7.29 (1 H, s); 8.18 (1 H, s); 8.27 (1 H, d); 8.83 (1 H, d).
Compound No. 52 of Table 2: using 2-amino-3-methoxy-2-methyl-propionitrile,'H
NMR
(CDCI3) S ppm: diastereoisomeric mixture (1/1); 1.82 and 1.84 (3H, 2xs); 2.18
and 2.20
(3H, 2xs); 3.52 and 3.53 (3H, 2xs); 3.64-3.84 (2H, 2xdd); 5.76 and 5.77 (1 H,
2xs); 7.29
and 7.30 (1 H, 2xs); 7.59 and 7.61 (1 H, 2xbs); 8.18 (1 H, s); 8.29 (1 H, d);
8.85 (1 H, s).
Compound No. 244 of Table 2: using 1,1-dimethyl-but-2-ynylamine, m.p. 160-162
C; ' H
NMR (CDCI3) S ppm: 1.71 (6H,s); 1.83 (3H, s); 2.19 (3H, s); 5.66 (1 H, s);
7.15 (1 H, bs);
7.27 (1 H, s); 8.18 (1 H, s); 8.27 (1 H, d); 8.83 (1 H, d).
Compound No. 251 of Table 2: using 4-methoxy-1,1-dimethy4-but-2-ynylamine,
m.p.
124-125 C; 'H NMR (CDCI3) 8 ppm: 1.75 (6H,s); 2.19 (3H, s); 3.39 (3H, s); 4.13
(2H, s);
5.67 (1 H, s); 7.17 (1 H, bs); 7.28 (1 H, s); 8.18 (1 H, s); 8.28 (1 H, d);
8.84 (1 H, d).
EXAMPLE 2
This examples illustrates the preparation of 2-(3-Bromo-7-methyl-quinolin-6-
yloxy)-N-
tert-butyl-2-methylsulfanyl-acetamide (Compound No. 12 of Table 13)
Stage 1. Preparation of 3-bromo-7-methyl-quinolin-6-ol
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4-Amino-2-methyl-phenol (5g) in acetic acid (60ml) was treated with 2,2,3
tribromopropanal (11.9g) and the mixture was stirred at room temperature for
3h after
which it was diluted with water and extracted with ethyl acetate. The organic
phase was
washed with aqueous NH4OH, dried over sodium sulphate, filtered and evaporated
under reduced pressure to give the required product, 3-bromo-7-methyl-6-
quinolin-6-ol
which was used as such in the following step (M+240),'H NMR (DMSO-dQ) S ppm:
2.32
(3H, s); 7.12 (1 H, s); 7.75 (1 H, s); 8.46 (1 H, d); 8.64 (1 H, d); 10.35 (1
H, bs).
Stage 2: Preparation of methyl 3-bromo-7-methyl-quinolinyl-6-oxy-2-
methylthioacetate
In a similar procedure to Stage 2, Step 2 of Example 1, 3-bromo-7-methyl-
quinolin-6-ol
was reacted with methyl 2-bromo-2-methylthioacetate to give methyl 3-bromo-7-
methyl-
quinolinyl-6-oxy-2-methylthio-acetate (M+358). 'H NMR (CDCI3) S ppm: 2.25 (3H,
s);
2.50 (3H, s); 3.88 (3H, s); 5.73 (1 H, s); 6.99 (1 H,s); 7.86 (1 H,s); 8.19 (1
H, d), 8.76 (1 H,
d).
Stage 3: Preparation of (3-Bromo-7-methyl-quinolin-6-yloxy)-methylsulfanyl-
acetic acid
In a similar procedure to Stage 3 of Example 1, methyl 3-bromo-7-methyl-
quinolinyl-6-
oxy-2-methylthio-acetate was hydrolysed to give (3-bromo-7-methyl-quinolin-6-
yloxy)-
methylsulfanyl-acetic acid (M+344). 'H NMR (DMSO) S ppm: 2.19 (3H, s); 2.42
(3H, s);
6.07 (1 H, s); 7.42 (1 H, s); 7.86 (1 H, s); 8.52 (1 H, s), 8.78 (1 H, s),
13.55 (1 H, bs).
Stage 4: Preparation of 2-(3-Bromo-7-methyl-guinolin-6-yloxy)-N-tert-butyl-2-
methylsulfanyl-acetamide
In a similar procedure to Stage 4 of Example 1, 2-(3-bromo-7-methyl-quinolinyl-
6-oxy)-2-
methylthioacetic acid was condensed with t-butylamine to give 2-(3-bromo-7-
methyl-
quinolin-6-yloxy)-N-tert-butyl-2-methylsulfanyl-acetamide (m.p. 132-134 C,
M+344). 'H
NMR (CDCI3) S ppm: 1.44 (9H, s); 2.19 (3H, s); 2.49 (3H, s); 5.60 (1 H, s);
6.48 (1 H, bs);
7.10 (1 H, s); 7.89 (1 H, s); 8.21 (1 H, d), 8.78 (1 H, d).
The following amides were prepared using a similar procedure.
Compound No. 16 of Table 13: using 1,1-dimethyl-propylamine, m.p. 135-137 C;
'H
NMR (CDCI3) S ppm: 0.88 (3H, t); 1.39 (6H, s); 1.79 (2H, q); 2.20 (3H, s);
2.48 (3H, s);
5.59 (1 H, s); 6.39 (1 H, bs); 7.10 (1 H, s); 7.89 (1 H, s); 8.21 (1 H, d);
8.78 (1 H, d).
Compound No. 238 of Table 13: using 1,1-dimethyl-prop-2-ynylamine, m.p. 141-
146 C;
' H NMR (CDC13) 8 ppm: 1.74 (6H,s); 2.19 (3H, s); 2.41 (1 H, s); 2.50 (3H, s);
5.65 (1 H,
s); 6.77 (1 H, bs); 7.10 (1 H, s); 7.89 (1 H, s); 8.21 (1 H, d); 8.78 (1 H,
d).
Compound No. 52 of Table 13: using 2-amino-3-methoxy-2-methyl-propionitrile,'H
NMR
(CDCI3) 8 ppm: diastereoisomeric mixture (1/1); 1.81 and 1.83 (3H, 2xs); 2.20
and 2.21
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(3H, 2xs); 2.48 (3H, s); 3.50 and 3.53 (3H, 2xs); 3.61-3.82 (2H, 2xdd); 5.72
and 5.75
(1 H, 2xs); 7.11 and 7.13 (1 H, 2xs);
7.32 and 7.34 (1 H, 2xbs); 7.90 (1 H, s); 8.23 (1 H, s); 8.79 (1 H, s).
Compound No. 221 of Table 13: using 1,1-dimethyl-2-prop-2-ynyloxy-ethylamine,
m.p.
114-116 C; 'H NMR (CDCI3) 8 ppm: 1.41 (3H,s); 1.44 (3H,s); 2.18 (3H, s); 2.50
(1 H, t);
3.54 (2H, dd); 4.19 (2H, d); 5.61 (1 H, s); 6.92 (1 H, bs); 7.10 (1 H, s);
7.88 (1 H, s); 8.22
(1 H, d); 8.77 (1 H, d).
Compound No. 251 of Table 13: using 4-methoxy-1,1-dimethyl-but-2-ynylamine,
m.p.
129-132 C; 'H NMR (CDCI3) 8 ppm: 1.73 (6H, s); 2.20 (3H, s); 2.49 (3H, s);
3.37 (3H,
lo s); 4.11 (2H, s); 5.63 (1 H, s); 6.76 (1 H, bs); 7.10 (1 H, s); 7.89 (1 H,
s); 8.21 (1 H, d); 8.78
(1 H, d).
EXAMPLE 3
This examples illustrates the preparation of 2-(3-Bromo-7-fluoro-quinolin-6-
yloxy)-N-tert-
butyl-2-methylsulfanyl-acetamide (Compound No. 12 of Table 6)
Stage 1. Preparation of 3-bromo-7-fluoro-quinolin-6-ol
Step 1
In a similar procedure to Step 1, Stage 1 of Example 1, 3-fluoro-4-methoxy-
phenylamine
(2g) in acetic acid (25m1) was treated with 2,2,3 tribromopropanal (4.2g) to
give 3-
bromo-7-fluoro-6-methoxy-quinoline (M+258).'H NMR (CDCI3) S ppm: 4.02 (3H, s);
7.07
(1 H, d); 7.75 (1 H, d); 8.23 (1 H, d); 8.78 (1 H, d).
Step 2
In a similar procedure to Step 1, Stage 2 of Example 1, 3-bromo-7-fluoro-6-
methoxy-
quinoline from the previous step was treated with hydrobromic acid to give 3-
bromo-7-
fluoro-quinolin-6-ol (M+244).'H NMR (DMSO-a6) 8 ppm: 7.35 (1 H, d); 7.77 (1 H,
d);
8.59 (1 H, d); 8.74 (1 H, d), 10.93 (1 H, s).
Stage 2: Preparation of (3-bromo-7-fluoro-quinolin-6-yloxy)-methylsulfanyl-
acetic acid
methyl ester
In a similar procedure to Stage 2, Step 2 of Example 1, 3-bromo-7-fluoro-
quinolin-6-ol
from the previous step was reacted with methyl 2-bromo-2-methylthioacetate
from Stage
2, Step1 of Example 1, to give methyl 3-bromo-7-fluoro-quinolinyl-6-oxy-2-
methylthioacetate (M+362). 'H NMR (CDCI3) 8 ppm: 2.27 (3H, s); 3.89 (3H, s);
5.77
(1 H, s) 7.26 (1 H, d); 7.77 (1 H, s); 8.23 (1 H, s); 8.83 (1 H, s).
Stage 3: Preparation of (3-bromo-7-fluoro-quinolin-6-yloxy)-methylsulfanyl-
acetic acid
In a similar procedure to Stage 3 of Example 1, methyl 3-bromo-7-fluoro-
quinolinyl-6-
oxy-2-methylthio-acetate was hydrolysed to give (3-bromo-7-fluoro-quinolin-6-
yloxy)-
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methylsulfanyl-acetic acid (M+348). 'H NMR (DMSO-d6) S ppm: 6.16 (1 H, s);
7.71 (1 H,
d) 7.90 (1 H, d); 8.62 (1 H, d), 8.88 (1 H, d), 13.69 (1 H, bs).
Stage 4: Preparation of 2-(3-bromo-7-fluoro-quinolin-6-yloxy)-N-tert-butyl-2-
methylsulfanyl-acetamide
In a similar procedure to Stage 4 of Example 1, 2-(3-bromo-7-fluoro-quinolinyl-
6-oxy)-2-
methylthioacetic acid was condensed with t-butylamine to give 2-(3-bromo-7-
fluoro-
quinolin-6-yloxy)-N-tert-butyl-2-methylsulfanyl-acetamide (m.p. 144-145 C, M+
403). ' H
NMR (CDCI3) 8 ppm: 1.45 (9H, s); 2.19 (3H, s); 5.62 (1 H, s); 6.62 (1 H, bs);
7.30 (1 H, d);
7.79 (1 H, d); 8.26 (1 H, d), 8.84 (1 H, d).
The following amides were prepared using a similar procedure.
Compound No. 238 of Table 6: using 1, 1 -dimethyl-prop-2-ynylamine, m.p. 167-
169 C;
'H NMR (CDC13) 8 ppm: 1.75 (6H,s); 2.21 (3H, s); 2.41 (1 H, s); 2.50 (3H, s);
5.68 (1 H,
s); 6.89 (1 H, bs); 7.33 (1 H, d); 7.79 (1 H, d); 8.26 (1 H, d); 8.84 (1 H,
d).
Compound No. 52 of Table 6: using 2-amino-3-methoxy-2-methyl-propionitrile,'H
NMR
(CDCI3) S ppm: diastereoisomeric mixture (1/1); 1.81 and 1.83 (3H, 2xs); 2.21
and 2.22
(3H, 2xs); 3.52 and 3.54 (3H, 2xs); 3.64-3.84 (2H, 2xdd); 5.75 and 5.76 (1 H,
2xs); 7.33-
7.36 (2H, m); 7.80 (1 H, d); 8.28 (1 H, d); 8.85 (1 H, d).
Compound No. 221 of Table 6: using 1, 1 -Dimethyl-2-prop-2-ynyloxy-ethylamine,
m.p.
115-117 C; 'H NMR (CDCI3) S ppm: 1.44 (3H,s); 1.46 (3H,s); 2.20 (3H, s); 2.45
(1H, t);
3.61 (2H, dd); 4.20 (2H, d); 5.63 (1 H, s); 6.90 (1 H, bs); 7.28 (1 H, d);
7.78 (1 H, d); 8.26
(1 H, d); 8.83 (1 H, d).
Compound No. 251 of Table 6: using 4-methoxy-1, 1 -dimethyl-but-2-ynylamine,
m.p.
115-117 C; 'H NMR (CDCI3) S ppm: 1.74 (6H, s); 2.21 (3H, s); 2.49 (3H, s);
3.38 (3H,
s); 4.12 (2H, s); 5.65 (1 H, s); 6.88 (1 H, bs); 7.31 (1 H, d); 7.79 (1 H, d);
8.26 (1 H, d); 8.84
(1 H, d).
Compound No. 244 of Table 6: using 1, 1 -dimethyl-but-2-ynylamine, m.p. 130-
132 C;1 H
NMR (CDCI3) S ppm: 1.70 (6H,s); 1.83 (3H, s); 2.21 (3H, s); 5.65 (1 H, s);
6.86 (1 H, bs);
7.31 (1 H, d); 7.78 (1 H, d); 8.25 (1 H, d); 8.84 (1 H, d).
Compound No. 68 of Table 6: using 2-ethoxy-1, 1 -dimethyl-ethylamine, m.p. 111-
113 C;
'H NMR (CDC13) 5 ppm: 1.21 (3H, t); 1.43 (H,s); 1.46 (3H,s); 2.20 (3H, s);
3.43 (2H, dd);
3.51-3.58 (2H, m), 5.63 (1 H, s); 7.17 (1 H, bs); 7.28 (1 H, d); 7.78 (1 H,
d); 8.25 (1 H, d);
8.83 (1 H, d).
Compound No. 277 of Table 6: using 5-methoxy-1,1-dimethyl-pent-2-ynylamine,
m.p.
104-106 C; 'H NMR (CDCI3) 8 ppm: 1.71 (6H, s); 2.20 (3H, s); 2.48 (2H, t);
3.37 (3H, s);
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3.50 (2H, t); (5.65 (1 H, s); 6.88 (1 H, bs); 7.31 (1 H, d); 7.79 (1 H, d);
8.26 (1 H, d); 8.84
(1 H, d).
Compound No. 256 of Table 6: using 6-chloro-1, 1 -dimethyl-hex-2-ynylamine,
m.p. 95-
97 C; 'H NMR (CDCI3) S ppm: 1.70 (6H, s); 1.96 (2H, quin),2.20 (3H, s); 2.90
(2H, t);
3.68 (2H, t); 3.50 (2H, t); 5.66 (1 H, s); 6.87 (1 H, bs); 7.31 (1 H, d); 7.79
(1 H, d); 8.26 (1 H,
d); 8.84 (1 H, d).
EXAMPLE 4
This exampies illustrates the preparation of 2-(3-iodo-7-fluoro-quinolin-6-
yloxy)-N-tert-
to butyl-2-methylsulfanyl-acetamide (Compound No. 12 of Table 7)
Stage 1: Preparation of 3-iodo-6-hydroxyquinoline
To a stirred mixture of 3-bromo-7-fluoro-6-hydroxyquinoline from Example 3,
Stage 1,
Step 2 (0.50g), sodium iodide (0.62g) and copper iodide (0.08g) in dioxane
(3.Oml) was
added N,N,N',N'-tetramethyl-ethane-l,2-diamine (0.07g) in a sealed tube. The
mixture
was stirred at 120 C for 14h and upon cooling was treated with aqueous ammonia
followed by aqueous hydrochloric acid. Extraction with ethyl acetate, drying
of the
organic phase over magnesium sulphate, filtration and evaporation under
reduced
pressure gave the required product (M+290) as a light brown coloured powder
that was
used as such in the next step. 'H NMR (CDCI3) S ppm: 7.30 (1 H, d); 7.72 (1 H,
d); 8.02
(1 H,d), 8.73 (1 H,d); 8.83 (1 H, d), 10.88 (1 H, s).
Stage 2: Preparation of N-tert-Butyl-2-(3-iodo-7-fluoro-quinolin-6-yloxy)-2-
methylsu Ifanyl-acetamide
In a similar procedure to Stage 2, Step 1 of Example 1, 3-iodo-7-fluoro-6-
hydroxy-
quinoline was reacted with chloromethyfsulfanyl-acetic acid ethyl ester to
give (3-iodo-7-
fluoro-quinolin-6-yloxy)-methylsulfanyl-acetic acid ethyl ester (M+408).
In a similar procedure to Stage 3 of Example 1, (3-iodo-7-fluoror-quinolin-6-
yloxy)-
methylsulfanyl-acetic acid ethyl ester was hydrolysed to give (3-iodo-7-fluoro-
quinolin-6-
yloxy)-methylsulfanyl-acetic acid (M+ 394).
In a similar procedure to Stage 4 of Example 1, (3-iodo-7-fluoro-quinolin-6-
yloxy)-
methylsulfanyl-acetic acid was condensed with t-butylamine to give N-tert-
butyl-2-(3-
iodo-quinolin-6-yloxy)-2-methylsulfanyl-acetamide as a white solid (m.p. 165-
166 C, M+
449).
'H NMR (CDCI3)8 ppm: 1.44 (9H,s); 2.18 (3H,s); 5.60 (1 H,s); 6.62 (1 H, bs);
7.27 (1 H,d);
7.76 (1 H,dd); 8.47 (1 H, d); 8.97 (1 H, d).
The following amides were prepared using a similar procedure.
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Compound No. 238 of Table 7: using 1,1-dimethyl-prop-2-ynylamine, m.p. 150-152
C;
'H NMR (CDCI3) S ppm: 1.75 (6H, s); 2.20 (3H, s); 2.40 (1 H, s); 5.66 (1 H,
s); 6.88 (1 H,
bs); 7.27 (1 H, s); 7.77 (1 H, s); 8.47 (1 H, d); 8.97 (1 H, d).
Compound No. 52 of Table 7: using 2-amino-3-methoxy-2-methyl-propionitrile,'H
NMR
(CDCI3) S ppm: diastereoisomeric mixture (1/1); 1.82 and 1.84 (3H, 2xs); 2.20
and 2.22
(3H, 2xs);
3.53 and 3.54 (3H, 2xs); 3.64-3.84 (2H, 2xdd); 5.73 and 5.75 (1 H, 2xs); 7.27-
7.36 (3H,
m); 7.77 (1 H, d); 8.49 (1 H, d); 8.98 (1 H, s).
Compound No. 244 of Table 7: using 1, 1 -dimethyl-but-2-ynylamine, m.p. 142-
145 C; ' H
1o NMR (CDCI3) S ppm: 1.70 (6H,s); 1.83 (3H, s); 2.20 (3H, s); 5.64 (1 H, s);
6.87 (1 H, bs);
7.27 (1 H, d); 7.76 (1 H, d); 8.47 (1 H, d); 8.96 (1 H, d).
Compound No. 251 of Table 7: using 4-methoxy-1, 1 -dimethyl-but-2-ynylamine,
m.p.
110-112 C; 'H NMR (CDCI3) S ppm: 1.74 (6H,s); 2.20 (3H, s); 3.38 (3H, s); 4.13
(2H, s);
5.65 (1 H, s); 6.89 (1 H, bs); 7.27 (1 H, d); 7.78 (1 H, d); 8.47 (1 H, d);
8.97 (1 H, d).
EXAMPLE 5
This examples illustrates the preparation of N-tert-butyl-2-(7-fluoro-3-
thiophen-3-yl-
quinolin-6-yloxy)-2-methylsulfanyl-acetamide (Compound No. 12 of Table 30).
Stage 1: A stirred mixture of 2-(3-bromo-7-fluoro-quinolin-6-yfoxy)-N-tert-
butyl-2-
methylsulfanyl-acetamide from Example 3, Stage 4 (160mg),
bis(triphenylphosphine)palladium (fI) chloride (1.4 mg), 3-thiophene boronic
acid (56mg)
and sodium hydrogen carbonate (101mg)) in dioxane/water (1:1 mixture, 4.8m1)
was
heated to 70 C for 14h. Upon cooling, the reaction mixture was treated with
saturated
aqueous sodium hydrogen carbonate (5ml). Extraction with ethyl acetate, drying
of the
organic phase over magnesium sulphate, filtration and evaporation under
reduced
pressure gave the crude product which was fractionated by chromatography
(silica;
hexane/ ethyl acetate, 2:1 by volume) to give the required product as a white
solid (m.p.
170-173 C, M+ 405). 'H NMR (CDCI3) 6 ppm: 1.46 (9H, s); 2.20 (3H, s); 5.64 (1
H, s);
6.66 (1 H, bs); 7.42 (1 H, d); 7.51 (2H, m); 7.66 (1 H, m), 7.80 (1 H, d),
8.22 (1 H, d); 9.13
(1 H, d).
The following amide was prepared using a similar procedure. 2-(7-Fluoro-3-
thiophen-3-
yl-quinolin-6-yloxy)-N-(4-methoxy-1,1-dimethyl-but-2-ynyl)-2-methyl-sulfanyl-
acetamide
(Compound No. 251 of Table 30) m.p. 132-134 C; 'H NMR (CDCI3) S ppm: 1.75 (6H,
s);
2.22 (3H, s); 3.39 (3H, s); 4.13 (2H, s); 5.68 (1 H, s); 6.93 (1 H, bs); 7.42
(1 H, d); 7.51
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(2H, m); 7.66 (1 H, m), 7.82 (1 H, d), 8.22 (1 H, d); 9.13 (1 H, d). prepared
from 2-(3-
Bromo-7-fluoro-quinolin-6-yloxy)-N-(4-methoxy-l,1-dimethyl-but-2-ynyl)-2-
methylsulfanyl-acetamide from Example 3, stage 4, above.
EXAMPLE 6
This Example illustrates the fungicidal properties of compounds of formula
(I).
The compounds were tested in a leaf disk assay, with methods described below.
The
test compounds were dissolved in DMSO and diluted into water to 200 ppm. In
the case
of the test on Pythium ultimum, they were dissolved in DMSO and diluted into
water to
20 ppm.
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 biotch): 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.
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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
1o fungus. After appropriate incubation the activity of a compound was
assessed four 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.
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.
Septoria tritici (leaf blotch): Conidia of the fungus from cryogenic storage
were directly
mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO)
solution
of the test compounds into a microtiter plate (96-well format) the nutrient
broth
containing the fungal spores was added. The test plates were incubated at 24 C
and the
inhibition of growth was determined photometrically after 72 hrs.
Fusarium culmorum (root rot): Conidia of the fungus from cryogenic storage
were directly
mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO)
solution
of the test compounds into a microtiter plate (96-well format) the nutrient
broth containing
the fungal spores was added. The test plates were incubated at 24 C and the
inhibition
of growth was determined photometrically after 48 hrs.
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Pythium ultimum (Damping off): Mycelial fragments of the fungus, prepared from
a fresh
liquid culture, were mixed into potato dextrose broth. A solution of the test
compound in
dimethyl sulphoxide was diluted with water to 20ppm then placed into a 96-well
microtiter plate and the nutrient broth containing the fungal spores was
added. The test
plate was incubated at 24 C and the inhibition of growth was determined
photometrically
after 48 hours.
The following compounds (number of compound first, followed by table number in
brackets) gave at least 60% control of the following fungal infection at
200ppm:
i0 Plasmopara viticola, compounds 9 (6), 12 (7), 38 (6), 52 (6), 52 (7), 60
(6), 95 (6), 221
(6), 221 (13), 235 (6), 238 (7), 238 (10), 244 (6), 244 (7), 251 (2), 251 (7),
251 (10), 251
(13), 251 (30), 256 (6), 264 (6), 277 (6), 278 (6), Phytophthora infestans,
compounds 12
(6), 12 (10), 52 (7), 52 (13), 221 (6), 221 (13), 238 (7), 238 (10), 238 (13),
244 (6), 244
(7), 251 (7), 251 (10), 256 (6), 275 (7), 277 (6), 278 (6), Etysiphe graminis
f.sp. tritici,
compounds 9(6), 12 (6), 12 (13), 28 (6), 38 (6), 52 (6), 52 (7), 52 (13), 68
(6), 86 (6),
181 (6),189 (6), 221 (6), 221 (13), 235 (6), 238 (6), 238 (7), 238 (10), 238
(13), 244 (6),
251 (6), 251 (7), 251 (13), 251 (30), 256 (6), 264 (6), 268 (6), 275 (6), 275
(7), 277 (6),
278 (6), 281 (6), 284 (6), Pyricularia oryzae, compounds 9 (6), 52 (6), 52
(7), 68 (6), 221
(6), 238 (6), 244 (7), 251 (6), 251 (7), 275 (7), 277 (6), 278 (6), Puccinia
recondita f.sp.
tritici, compounds 52 (6), 52 (7), 68 (6), 221 (6), 238 (7), 251(2), 264 (6),
Septoria
nodorum, compounds 9(6), 12 (2), 12 (7), 12 (10), 12 (13), 12 (30), 52 (6), 52
(7), 68
(6), 221 (6), 235 (6), 238 (6), 238 (7), 244 (6), 244 (7), 244 (13), 251 (6),
251 (7), 251
(13), 256 (6), 264 (6), 277 (6), 278 (6), 281 (6), Septoria tritici, compounds
9 (6), 12 (6),
12 (7), 12 (13), 16 (13), 38 (6), 52 (2), 52 (6), 52 (7), 52(13), 68 (6), 95
(6), 122 (6), 221
(6), 221 (13), 224 (6), 235 (6), 238 (6), 238 (7), 238 (13), 244 (2), 244 (6),
244 (7), 251
(6), 251 (7), 251 (13), 251 (2), 251 (30), 256 (6), 264 (6), 268 (6), 275 (7),
277 (6), 278
(6), 281 (6), 284 (6), 287 (6), 291 (6), Fusarium culmorum, compounds 9 (6),
12 (6), 12
(7), 221 (6), 238 (6), 238 (7), 244 (6), 244 (7), 251 (6), 251 (7), 251 (13),
284 (6), The
following compounds (number of compound first, followed by table number in
brackets)
gave at least 60% control of the following fungal infection at 20ppm: Pythium
ultimum,
compounds 9(6), 12 (10), 52 (6), 52 (13), 221 (6), 221 (13), 235 (6), 238 (6),
244 (6),
251 (6), 251 (10), 251 (13), 251 (30), 264 (6), 275 (7), 278 (6), 281 (6).
