U.S. patent application number 17/162352 was filed with the patent office on 2021-05-27 for microbiocidal heterobicyclic derivatives.
This patent application is currently assigned to SYNGENTA PARTICIPATIONS AG. The applicant listed for this patent is SYNGENTA PARTICIPATIONS AG. Invention is credited to Farhan BOU HAMDAN, Laura QUARANTA, Stephan TRAH, Matthias WEISS.
Application Number | 20210155619 17/162352 |
Document ID | / |
Family ID | 1000005380970 |
Filed Date | 2021-05-27 |
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United States Patent
Application |
20210155619 |
Kind Code |
A1 |
QUARANTA; Laura ; et
al. |
May 27, 2021 |
MICROBIOCIDAL HETEROBICYCLIC DERIVATIVES
Abstract
Intermediates for compounds of the formula (I): ##STR00001##
Inventors: |
QUARANTA; Laura; (Stein,
CH) ; TRAH; Stephan; (Stein, CH) ; WEISS;
Matthias; (Stein, CH) ; BOU HAMDAN; Farhan;
(Stein, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SYNGENTA PARTICIPATIONS AG |
Basel |
|
CH |
|
|
Assignee: |
SYNGENTA PARTICIPATIONS AG
Basel
CH
|
Family ID: |
1000005380970 |
Appl. No.: |
17/162352 |
Filed: |
January 29, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15751976 |
Feb 12, 2018 |
10906897 |
|
|
PCT/EP2016/068890 |
Aug 8, 2016 |
|
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17162352 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/04 20130101;
A01N 43/56 20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; A01N 43/56 20060101 A01N043/56 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 12, 2015 |
EP |
15180771.6 |
Claims
1. A compound of formula (XA): ##STR00145## wherein R.sub.5a is
fluoro or hydrogen; and R.sub.5b fluoro or hydrogen; or a compound
of formula (XB): ##STR00146## wherein R.sub.5a is fluoro or
hydrogen; and R.sub.5b is fluoro or hydrogen; or a compound of
formula (XC): ##STR00147## wherein R.sub.5a is fluoro or hydrogen;
and R.sub.5b is fluoro or hydrogen; or a compound of formula (XD):
##STR00148## wherein R.sub.5a is fluoro or hydrogen; and R.sub.5b
is fluoro or hydrogen.
2. The compound of claim 1, wherein the compound is the compound of
formula (XA).
3. The compound of claim 2, wherein R.sub.5a is fluoro; and
R.sub.5b is fluoro.
4. The compound of claim 2, wherein R.sub.5a is hydrogen; and
R.sub.5b is hydrogen.
5. The compound of claim 2, wherein R.sub.5a is fluoro; and
R.sub.5b is hydrogen.
6. The compound of claim 2, wherein R.sub.5a is hydrogen; and
R.sub.5b is fluoro.
7. The compound of claim 1, wherein the compound is the compound of
formula (XB).
8. The compound of claim 7, wherein R.sub.5a is fluoro; and
R.sub.5b is fluoro.
9. The compound of claim 7, wherein R.sub.5a is hydrogen; and
R.sub.5b is hydrogen.
10. The compound of claim 7, wherein R.sub.5a is fluoro; and
R.sub.5b is hydrogen.
11. The compound of claim 7, wherein R.sub.5a is hydrogen; and
R.sub.5b is fluoro.
12. The compound of claim 1, wherein the compound is the compound
of formula (XC).
13. The compound of claim 12, wherein R.sub.5a is fluoro; and
R.sub.5b is fluoro.
14. The compound of claim 12, wherein R.sub.5a is hydrogen; and
R.sub.5b is hydrogen.
15. The compound of claim 12, wherein R.sub.5a is fluoro; and
R.sub.5b is hydrogen.
16. The compound of claim 12, wherein R.sub.5a is hydrogen; and
R.sub.5b is fluoro.
17. The compound of claim 1, wherein the compound is the compound
of formula (XD).
18. The compound of claim 17, wherein R.sub.5a is fluoro; and
R.sub.5b is fluoro.
19. The compound of claim 17, wherein R.sub.5a is hydrogen; and
R.sub.5b is hydrogen.
20. The compound of claim 17, wherein R.sub.5a is fluoro; and
R.sub.5b is hydrogen.
21. The compound of claim 17, wherein R.sub.5a is hydrogen; and
R.sub.5b is fluoro.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 15/751,976, filed Feb. 12, 2018, which is a 371 of
International Application No. PCT/EP2016/068890, filed Aug. 8,
2016, which claims priority to EP Application No. 15180771.6 filed
Aug. 12, 2015, the contents of which are incorporated herein by
reference herein.
[0002] The present invention relates to microbiocidal
heterobicyclic derivatives, e.g. as active ingredients, which have
microbiocidal activity, in particular fungicidal activity. The
invention also relates to preparation of these heterobicyclic
derivatives, to intermediates useful in the preparation of these
heterobicyclic derivatives, to the preparation of these
intermediates, to agrochemical compositions which comprise at least
one of the heterobicyclic derivatives, to preparation of these
compositions and to the use of the heterobicyclic derivatives or
compositions in agriculture or horticulture for controlling or
preventing infestation of plants, harvested food crops, seeds or
non-living materials by phytopathogenic microorganisms, in
particular fungi.
[0003] Certain fungicidal heterobicyclic compounds are described in
WO05070917. It has now surprisingly been found that certain novel
heterobicyclic derivatives have favourable fungicidal
properties.
[0004] The present invention therefore provides compounds of
formula (I)
##STR00002##
[0005] Wherein
[0006] Q.sub.1 is a nitrogen atom and Q.sub.2 is a carbon atom;
or
[0007] Q.sub.1 is a carbon atom and Q.sub.2 is a nitrogen atom;
[0008] Y--X represents a radical selected from G1, G2, G3 and
G4:
##STR00003##
[0009] R.sub.1 and R.sub.2 are each independently selected from
hydrogen, cyano, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.2-C.sub.6 alkenyl and C.sub.2-C.sub.6 alkynyl, in which the
alkyl, cycloalkyl, alkenyl and alkynyl groups may be optionally
substituted with 1 to 3 substituents independently selected from
halogen, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio;
or
[0010] R.sub.1 and R.sub.2 together with the carbon atom to which
they are attached represent a C.sub.3-C.sub.10 cycloalkyl group
(which may be optionally substituted with 1 to 3 substituents
independently selected from the group consisting of halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6
alkylthio);
[0011] R.sub.3 and R.sub.4 are each independently selected from
hydrogen, halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.3-C.sub.7 cycloalkyl, C.sub.2-C.sub.6 alkenyl and
C.sub.2-C.sub.6 alkynyl, in which the alkyl, alkoxy, cycloalkyl,
alkenyl and alkynyl groups may be optionally substituted with 1 to
3 substituents independently selected from halogen, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkylthio; or
[0012] R.sub.3 and R.sub.4 together with the carbon atom to which
they are attached represent C.dbd.O, C.dbd.NOR.sub.d,
C.dbd.C(R.sub.b)(R.sub.c) or C.sub.3-C.sub.10 cycloalkyl (which may
be optionally substituted with 1 to 3 substituents independently
selected from the group consisting of a halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio); where
R.sub.b and R.sub.c are each independently selected from hydrogen,
halogen, cyano, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkylthio, in which the alkyl,
cycloalkyl, alkenyl and alkynyl groups may be optionally
substituted with 1 to 3 substituents independently selected from
halogen, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio, and
where R.sub.d is selected from hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.6 alkenyl and
C.sub.3-C.sub.6 alkynyl, in which the alkyl, cycloalkyl, alkenyl
and alkynyl groups may be optionally substituted with 1 to 3
substituents independently selected from halogen, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkylthio; or
[0013] R.sub.2 and R.sub.3 together with the carbon atoms to which
they are attached represent a C.sub.3-C.sub.10 cycloalkyl (which
may be optionally substituted with 1 to 3 substituents
independently selected from the group consisting of halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6
alkylthio, and, additionally, a ring carbon unit may be replaced by
an oxygen or sulphur atom);
[0014] each R.sub.5 independently represents halogen, hydroxyl,
mercapto, nitro, cyano, formyl, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.7
cycloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 alkenyloxy,
C.sub.3-C.sub.6 alkynyloxy, C.sub.1-C.sub.6 alkylthio,
--C(.dbd.NOR.sub.a)C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6
alkylcarbonyl, aryl, heteroraryl, aryloxy or heteroraryloxy, in
which the alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkenyloxy,
alkynyloxy, aryl and heteroaryl groups may be optionally
substituted with 1 to 5 substituents independently selected from
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, cyano and
C.sub.1-C.sub.6 alkylthio; n is 0, 1, 2, 3 or 4:
[0015] R.sub.6 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy or hydroxyl;
[0016] each R.sub.7 independently represents hydroxyl, mercapto,
cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6
haloalkenyl, C.sub.3-C.sub.6 haloalkynyl, C.sub.1-C.sub.6
alkylthio, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6
haloalkylthio, C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6
alkylcarbonyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.3-C.sub.6 alkenyloxy or C.sub.3-C.sub.6 alkynyloxy; m is 0,
1, 2, 3 or 4; and
[0017] R.sub.a is hydrogen, C.sub.1-C.sub.6 alkylcarbonyl or
C.sub.1-C.sub.6 alkyl, which may be optionally substituted with 1
to 3 substituents independently selected from the group consisting
of halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio and
phenoxy; or a salt or N-oxide thereof.
[0018] In a second aspect the present invention provides an
agrochemical composition comprising a compound of formula (I).
[0019] Compounds of formula (I) may be used to control
phytopathogenic microorganisms. Thus, in order to control a
phytopathogen a compound of formula (I), or a composition
comprising a compound of formula (I), according to the invention
may be applied directly to the phytopathogen, or to the locus of a
phytopathogen, in particular to a plant susceptible to attack by
phytopathogens.
[0020] Thus, in a third aspect the present invention provides the
use of a compound of formula (I), or a composition comprising a
compound of formula (I), as described herein to control a
phytopathogen.
[0021] In a further aspect the present invention provides a method
of controlling phytopathogens, comprising applying a compound of
formula (I), or a composition comprising a compound of formula (I),
as described herein to said phytopathogen, or to the locus of said
phytopathogen, in particular to a plant susceptible to attack by a
phytopathogen.
[0022] Compounds of formula (I) are particularly effective in the
control of phytopathogenic fungi.
[0023] Thus, in a yet further aspect the present invention provides
the use of a compound of formula (I), or a composition comprising a
compound of formula (I), as described herein to control
phytopathogenic fungi.
[0024] In a further aspect the present invention provides a method
of controlling phytopathogenic fungi, comprising applying a
compound of formula (I), or a composition comprising a compound of
formula (I), as described herein to said phytopathogenic fungi, or
to the locus of said phytopathogenic fungi, in particular to a
plant susceptible to attack by phytopathogenic fungi.
[0025] Where substituents are indicated as being optionally
substituted, this means that they may or may not carry one or more
identical or different substituents, e.g. one to three
substituents. Normally not more than three such optional
substituents are present at the same time. Where a group is
indicated as being substituted, e.g. alkyl, this includes those
groups that are part of other groups, e.g. the alkyl in
alkylthio.
[0026] The term "halogen" refers to fluorine, chlorine, bromine or
iodine, preferably fluorine, chlorine or bromine.
[0027] Alkyl substituents may be straight-chained or branched.
Alkyl on its own or as part of another substituent is, depending
upon the number of carbon atoms mentioned, for example, methyl,
ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and the isomers
thereof, for example, isopropyl, iso-butyl, sec-butyl, tert-butyl
or iso-amyl.
[0028] Alkenyl substituents (either alone or as part of a larger
group, eg. alkenyloxy) can be in the form of straight or branched
chains, and the alkenyl moieties, where appropriate, can be of
either the (E)- or (Z)-configuration. Examples are vinyl and allyl.
The alkenyl groups are preferably C.sub.2-C.sub.6, more preferably
C.sub.2-C.sub.4 and most preferably C.sub.2-C.sub.3 alkenyl
groups.
[0029] Alkynyl substituents (either alone or as part of a larger
group, eg. alkynyloxy) can be in the form of straight or branched
chains. Examples are ethynyl and propargyl. The alkynyl groups are
preferably C.sub.2-C.sub.6, more preferably C.sub.2-C.sub.4 and
most preferably C.sub.2-C.sub.3 alkynyl groups.
[0030] Haloalkyl groups (either alone or as part of a larger group,
eg. haloalkyloxy) may contain one or more identical or different
halogen atoms and, for example, may stand for CH.sub.2Cl,
CHCl.sub.2, CCl.sub.3, CH.sub.2F, CH.sub.2F.sub.2, CF.sub.3,
CF.sub.3CH.sub.2, CH.sub.3CF.sub.2, CF.sub.3CF.sub.2 or
CCl.sub.3CCl.sub.2.
[0031] Haloalkenyl groups (either alone or as part of a larger
group, eg. haloalkenyloxy) are alkenyl groups, respectively, which
are substituted with one or more of the same or different halogen
atoms and are, for example, 2,2-difluorovinyl or
1,2-dichloro-2-fluoro-vinyl.
[0032] Haloalkynyl groups (either alone or as part of a larger
group, eg. haloalkynyloxy) are alkynyl groups, respectively, which
are substituted with one or more of the same or different halogen
atoms and are, for example, 1-chloro-prop-2-ynyl.
[0033] Alkoxy means a radical --OR, where R is alkyl, e.g. as
defined above. Alkoxy groups include, but are not limited to,
methoxy, ethoxy, 1-methylethoxy, propoxy, butoxy, 1-methylpropoxy
and 2-methylpropoxy.
[0034] Cyano means a --CN group.
[0035] Amino means an --NH.sub.2 group.
[0036] Hydroxyl or hydroxy stands for a --OH group.
[0037] Aryl groups (either alone or as part of a larger group, such
as e.g. aryloxy, aryl-alkyl) are aromatic ring systems which can be
in mono-, bi- or tricyclic form. Examples of such rings include
phenyl, naphthyl, anthracenyl, indenyl or phenanthrenyl. Preferred
aryl groups are phenyl and naphthyl, phenyl being most preferred.
Where an aryl moiety is said to be substituted, the aryl moiety is
preferably substituted by one to four substituents, most preferably
by one to three substituents.
[0038] Heteroaryl groups (either alone or as part of a larger
group, such as e.g. heteroaryloxy, heteroaryl-alkyl) are aromatic
ring systems containing at least one heteroatom and consisting
either of a single ring or of two or more fused rings. Preferably,
single rings will contain up to three heteroatoms and bicyclic
systems up to four heteroatoms which will preferably be chosen from
nitrogen, oxygen and sulfur. Examples of monocyclic groups include
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl,
imidazolyl, triazolyl (e.g. [1,2,4] triazolyl), furanyl,
thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,
isothiazolyl and thiadiazolyl. Examples of bicyclic groups include
purinyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl,
benzimidazolyl, benzothiophenyl and benzothiazolyl. Monocyclic
heteroaryl groups are preferred, pyridyl being most preferred.
Where a heteroaryl moiety is said to be substituted, the heteroaryl
moiety is preferably substituted by one to four substituents, most
preferably by one to three substituents.
[0039] Heterocyclyl groups or heterocyclic rings (either alone or
as part of a larger group, such as heterocyclyl-alkyl) are
non-aromatic ring structures containing up to 10 atoms including
one or more (preferably one, two or three) heteroatoms selected
from O, S and N. Examples of monocyclic groups include, oxetanyl,
4,5-dihydro-isoxazolyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl,
[1,3]dioxolanyl, piperidinyl, piperazinyl, [1,4]dioxanyl,
imidazolidinyl, [1,3,5]oxadiazinanyl, hexahydro-pyrimidinyl,
[1,3,5]triazinanyl and morpholinyl or their oxidised versions such
as 1-oxo-thietanyl and 1,1-dioxo-thietanyl. Examples of bicyclic
groups include 2,3-dihydro-benzofuranyl, benzo[1,4]dioxolanyl,
benzo[1,3]dioxolanyl, chromenyl, and
2,3-dihydro-benzo[1,4]dioxinyl. Where a heterocyclyl moiety is said
to be substituted, the heterocyclyl moiety is preferably
substituted by one to four substituents, most preferably by one to
three substituents.
[0040] The presence of one or more possible asymmetric carbon atoms
in a compound of formula (I) means that the compounds may occur in
optically isomeric forms, i.e. enantiomeric or diastereomeric
forms. Also atropisomers may occur as a result of restricted
rotation about a single bond. Formula (I) is intended to include
all those possible isomeric forms and mixtures thereof. The present
invention includes all those possible isomeric forms and mixtures
thereof for a compound of formula (I). Likewise, formula (I) is
intended to include all possible tautomers. The present invention
includes all possible tautomeric forms for a compound of formula
(I).
[0041] In each case, the compounds of formula (I) according to the
invention are in free form, in oxidized form as a N-oxide or in
salt form, e.g. an agronomically usable salt form.
[0042] N-oxides are oxidized forms of tertiary amines or oxidized
forms of nitrogen containing heteroaromatic compounds. They are
described for instance in the book "Heterocyclic N-oxides" by A.
Albini and S. Pietra, CRC Press, Boca Raton 1991.
[0043] Preferred values of Y--X, R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.b, R.sub.c, R.sub.d, R.sub.5, R.sub.6, R.sub.7,
R.sub.a, m, n, Q.sub.1 and Q.sub.2 are, in any combination thereof,
as set out below:
[0044] Preferably Y--X represents the radical G1.
[0045] Preferably R.sub.1 and R.sub.2 are each independently
selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7
cycloalkyl, in which the alkyl and cycloalkyl groups may be
optionally substituted with 1 to 3 substituents independently
selected from halogen, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6
alkylthio; or R.sub.1 and R.sub.2 together with the carbon atom to
which they are attached represent a C.sub.3-C.sub.6 cycloalkyl
group (which may be optionally substituted with 1 to 3 substituents
independently selected from the group consisting of halogen,
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy).
[0046] More preferably R.sub.1 and R.sub.2 are each independently a
hydrogen or C.sub.1-C.sub.4 alkyl group, in which the alkyl group
may be optionally substituted with 1 to 3 substituents
independently selected from halogen, and C.sub.1-C.sub.6 alkoxy; or
R.sup.1 and R.sup.2 together with the carbon atom to which they are
attached represent a C.sub.3-C.sub.5 cycloalkyl group.
[0047] Even more preferably R.sub.1 and R.sub.2 are each
independently a C.sub.1-C.sub.3 alkyl; or R.sub.1 and R.sub.2
together with the carbon atom to which they are attached represent
a C.sub.3-C.sub.4 cycloalkyl group.
[0048] Most preferably R.sub.1 and R.sub.2 are each independently a
C.sub.1-C.sub.2 alkyl group (especially most preferred is when both
are methyl).
[0049] Preferably R.sub.3 and R.sub.4 are each independently
selected from hydrogen, halogen, hydroxyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy and C.sub.3-C.sub.7 cycloalkyl, in which the
alkyl, alkoxy and cycloalkyl groups may be optionally substituted
with 1 to 3 substituents independently selected from halogen,
C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio; or R.sub.3
and R.sub.4 together with the carbon atom to which they are
attached represent C.dbd.O, C.dbd.NOR.sub.d,
C.dbd.C(R.sub.b)(R.sub.c) or C.sub.3-C.sub.6 cycloalkyl (which may
be optionally substituted with 1 to 3 substituents independently
selected from the group consisting of a halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio), where
R.sub.b and R.sub.c are each independently selected from hydrogen,
halogen, cyano, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkylthio, in which the alkyl,
cycloalkyl, alkenyl and alkynyl groups may be optionally
substituted with 1 to 3 substituents independently selected from
halogen, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio, and
where R.sub.d is selected from hydrogen, C.sub.1-C.sub.6 alkyl.
C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.6 alkenyl and
C.sub.3-C.sub.6 alkynyl, in which the alkyl, cycloalkyl, alkenyl
and alkynyl groups may be optionally substituted with 1 to 3
substituents independently selected from halogen, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkylthio; or R.sub.2 and R.sub.3
together with the carbon atoms to which they are attached represent
a C.sub.3-C.sub.7 cycloalkyl (which may be optionally substituted
with 1 to 3 substituents independently selected from the group
consisting of halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkylthio, and, additionally, a ring
carbon unit may be replaced by an oxygen or sulphur atom).
[0050] More preferably R.sub.3 and R.sub.4 are each independently
selected from hydrogen, halogen, C.sub.1-C.sub.4 alkyl and
C.sub.3-C.sub.4 cycloalkyl, in which the alkyl and cycloalkyl
groups may be optionally substituted with 1 to 3 substituents
independently selected from halogen, C.sub.1-C.sub.3 alkoxy and
C.sub.1-C.sub.3 alkylthio; or R.sub.3 and R.sub.4 together with the
carbon atom to which they are attached represent C.dbd.O,
C.dbd.NOR.sub.d, or C.sub.3-C.sub.6 cycloalkyl (which may be
optionally substituted with 1 to 3 substituents independently
selected from the group consisting of a halogen, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkylthio), where
R.sub.d is selected from hydrogen, C.sub.1-C.sub.4 alkyl and
C.sub.3-C.sub.5 cycloalkyl, in which the alkyl and cycloalkyl
groups may be optionally substituted with 1 to 3 substituents
independently selected from halogen, C.sub.1-C.sub.3 alkoxy and
C.sub.1-C.sub.3 alkylthio (preferably R.sub.d is selected from
hydrogen and C.sub.1-C.sub.3 alkyl, in which the alkyl group may be
optionally substituted with 1 to 3 halogen atoms (preferably fluoro
atoms)).
[0051] Even more preferably R.sub.3 and R.sub.4 are each
independently selected from hydrogen, halogen and C.sub.1-C.sub.4
alkyl; or R.sub.3 and R.sub.4 together with the carbon atom to
which they are attached represent C.dbd.O or C.sub.3-C.sub.4
cycloalkyl.
[0052] Most preferably R.sub.3 and R.sub.4 are each independently
selected from hydrogen, fluoro and C.sub.1-C.sub.2 alkyl
(especially most preferred is if both are methyl or both are
fluoro); or R.sub.3 and R.sub.4 together with the carbon atom to
which they are attached represent C.sub.3-C.sub.4 cycloalkyl.
[0053] Preferably each R.sub.5 independently represents halogen,
cyano, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 alkenyloxy, C.sub.3-C.sub.6
alkynyloxy, C.sub.1-C.sub.6 alkylthio,
--C(.dbd.NOR.sub.a)C.sub.1-C.sub.6alkyl, phenyl, heteroraryl
(wherein heteroaryl is pyridyl, thiophenyl, thiazolyl, imidazolyl
or oxazolyl), phenoxy or heteroraryloxy (wherein heteroaryl is
pyridyl, thiophenyl, thiazolyl, imidazolyl or oxazolyl), in which
the alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkenyloxy,
alkynyloxy, phenyl and heteroaryl groups may be optionally
substituted with 1 to 5 substituents independently selected from
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, cyano and
C.sub.1-C.sub.6 alkylthio; n is 0, 1, 2, 3 or 4.
[0054] More preferably each R.sub.5 independently represents
halogen, cyano, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.4 cycloalkyl,
C.sub.1-C.sub.3 alkoxy, C.sub.3-C.sub.6 alkenyloxy, C.sub.3-C.sub.6
alkynyloxy, phenyl, heteroraryl (wherein heteroaryl is pyridyl,
thiazolyl or oxazolyl), in which the alkyl, cycloalkyl, alkoxy,
alkenyloxy, alkynyloxy, phenyl and heteroaryl groups may be
optionally substituted with 1 to 3 substituents independently
selected from halogen, C.sub.1-C.sub.3 alkyl and C.sub.1-C.sub.3
alkoxy; n is 0, 1 or 2.
[0055] Even more preferably each R.sub.5 independently represents
halogen, cyano, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.4 cycloalkyl;
n is 0, 1 or 2.
[0056] Most preferably each R.sub.5 independently represents
fluoro, chloro, bromo, cyano, or C.sub.1-C.sub.2 alkyl (especially
most preferred is fluoro); n is 0, 1 or 2 (preferably 0 or 1).
[0057] Preferably R.sub.6 is hydrogen, halogen, or C.sub.1-C.sub.2
alkyl.
[0058] More preferably R.sub.6 is hydrogen, fluoro, chloro, or
methyl.
[0059] Most preferably R.sub.6 is hydrogen.
[0060] Preferably each R.sub.7 independently represents cyano,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6
haloalkenyl, C.sub.3-C.sub.6 haloalkynyl, C.sub.1-C.sub.6
alkylthio, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6
haloalkylthio, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.3-C.sub.6alkenyloxy or C.sub.3-C.sub.6 alkynyloxy; m is 0, 1,
2, 3 or 4.
[0061] More preferably each R.sub.7 independently represents cyano,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.4 alkylthio or
C.sub.3-C.sub.4 cycloalkyl; m is 0, 1 or 2.
[0062] Even more preferably each R.sub.7 independently represents
cyano, halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or
C.sub.3-C.sub.4 cycloalkyl; m is 0, 1 or 2.
[0063] Most preferably each R.sub.7 independently represents
fluoro, chloro or C.sub.1-C.sub.3 alkyl (especially most preferred
is fluoro or methyl); m is 1 or 2.
[0064] Preferably R.sub.a is hydrogen or C.sub.1-C.sub.2 alkyl.
[0065] The preferences above apply both when Q.sub.1 is a nitrogen
atom and when Q.sub.2 is a carbon atom, and when Q.sub.1 is a
carbon atom and Q.sub.2 is a nitrogen atom.
[0066] Preferably Q.sub.1 is a carbon atom and Q.sub.2 is a
nitrogen atom.
Embodiments according to the invention are provided as set out
below.
[0067] Embodiment 1 provides compounds of formula (I), and a salt
or N-oxide thereof, as defined above.
[0068] Embodiment 2 provides compounds according to embodiment 1
wherein R.sub.1 and R.sub.2 are each independently selected from
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, in
which the alkyl and cycloalkyl groups may be optionally substituted
with 1 to 3 substituents independently selected from halogen,
C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio; or
[0069] R.sub.1 and R.sub.2 together with the carbon atom to which
they are attached represent a C.sub.3-C.sub.6 cycloalkyl group
(which may be optionally substituted with 1 to 3 substituents
independently selected from the group consisting of halogen,
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy).
[0070] Embodiment 3 provides compounds according to embodiment 1 or
2 wherein R.sub.3 and R.sub.4 are each independently selected from
hydrogen, halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy and C.sub.3-C.sub.7 cycloalkyl, in which the alkyl, alkoxy
and cycloalkyl groups may be optionally substituted with 1 to 3
substituents independently selected from halogen, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkylthio; or R.sub.3 and R.sub.4
together with the carbon atom to which they are attached represent
C.dbd.O, C.dbd.NOR.sub.d, C.dbd.C(R.sub.b)(R.sub.c) or
C.sub.3-C.sub.6 cycloalkyl (which may be optionally substituted
with 1 to 3 substituents independently selected from the group
consisting of a halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkylthio), where R.sub.b and R.sub.c
are each independently selected from hydrogen, halogen, cyano,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy and
C.sub.1-C.sub.6 alkylthio, in which the alkyl, cycloalkyl, alkenyl
and alkynyl groups may be optionally substituted with 1 to 3
substituents independently selected from halogen, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkylthio, and where R.sub.d is selected
from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.3-C.sub.6 alkenyl and C.sub.3-C.sub.6 alkynyl, in which the
alkyl, cycloalkyl, alkenyl and alkynyl groups may be optionally
substituted with 1 to 3 substituents independently selected from
halogen, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio; or
R.sub.2 and R.sub.3 together with the carbon atoms to which they
are attached represent a C.sub.3-C.sub.7 cycloalkyl (which may be
optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio, and,
additionally, a ring carbon unit may be replaced by an oxygen or
sulphur atom).
[0071] Embodiment 4 provides compounds according to any one of
embodiments 1, 2 or 3 wherein each R.sub.6 independently represents
halogen, cyano, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6 alkenyloxy, C.sub.3-C.sub.6
alkynyloxy, C.sub.1-C.sub.6 alkylthio,
--C(.dbd.NOR.sub.a)C.sub.1-C.sub.6alkyl, phenyl, heteroraryl
(wherein heteroaryl is pyridyl, thiophenyl, thiazolyl, imidazolyl
or oxazolyl), phenoxy or heteroraryloxy (wherein heteroaryl is
pyridyl, thiophenyl, thiazolyl, imidazolyl or oxazolyl), in which
the alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, alkenyloxy,
alkynyloxy, phenyl and heteroaryl groups may be optionally
substituted with 1 to 5 substituents independently selected from
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, cyano and
C.sub.1-C.sub.6 alkylthio; n is 0, 1, 2, 3 or 4.
[0072] Embodiment 5 provides compounds according to any one of
embodiments 1, 2, 3 or 4 wherein R.sub.6 is hydrogen, halogen, or
C.sub.1-C.sub.2 alkyl.
[0073] Embodiment 6 provides compounds according to any one of
embodiments 1, 2, 3, 4, or 5 wherein each R.sub.7 independently
represents cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 haloalkynyl, C.sub.3-C.sub.6 haloalkynyl,
C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 haloalkylthio, C.sub.3-C.sub.7 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6alkenyloxy or
C.sub.3-C.sub.6 alkynyloxy; m is 0, 1, 2, 3 or 4.
[0074] Embodiment 7 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, or 6 wherein R.sub.1 and R.sub.2 are
each independently a hydrogen or C.sub.1-C.sub.4 alkyl group, in
which the alkyl group may be optionally substituted with 1 to 3
substituents independently selected from halogen, and
C.sub.1-C.sub.6 alkoxy; or R.sup.1 and R.sup.2 together with the
carbon atom to which they are attached represent a C.sub.3-C.sub.6
cycloalkyl group.
[0075] Embodiment 8 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, or 7 wherein R.sub.3 and R.sub.4 are
each independently selected from hydrogen, halogen, C.sub.1-C.sub.4
alkyl and C.sub.3-C.sub.4 cycloalkyl, in which the alkyl and
cycloalkyl groups may be optionally substituted with 1 to 3
substituents independently selected from halogen, C.sub.1-C.sub.3
alkoxy and C.sub.1-C.sub.3 alkylthio; or R.sub.3 and R.sub.4
together with the carbon atom to which they are attached represent
C.dbd.O, C.dbd.NOR.sub.d, or C.sub.3-C.sub.6 cycloalkyl (which may
be optionally substituted with 1 to 3 substituents independently
selected from the group consisting of a halogen, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkylthio), where
R.sub.d is selected from hydrogen, C.sub.1-C.sub.4 alkyl and
C.sub.3-C.sub.6 cycloalkyl, in which the alkyl and cycloalkyl
groups may be optionally substituted with 1 to 3 substituents
independently selected from halogen, C.sub.1-C.sub.3 alkoxy and
C.sub.1-C.sub.3 alkylthio (preferably R.sub.d is selected from
hydrogen and C.sub.1-C.sub.3 alkyl, in which the alkyl group may be
optionally substituted with 1 to 3 halogen atoms (preferably fluoro
atoms)).
[0076] Embodiment 9 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, or 8 wherein each R.sub.5
independently represents halogen, cyano, C.sub.1-C.sub.4 alkyl,
C.sub.3-C.sub.4 cycloalkyl, C.sub.1-C.sub.3 alkoxy, C.sub.3-C.sub.6
alkenyloxy, C.sub.3-C.sub.6 alkynyloxy, phenyl, heteroraryl
(wherein heteroaryl is pyridyl, thiazolyl or oxazolyl), in which
the alkyl, cycloalkyl, alkoxy, alkenyloxy, alkynyloxy, phenyl and
heteroaryl groups may be optionally substituted with 1 to 3
substituents independently selected from halogen, C.sub.1-C.sub.3
alkyl and C.sub.1-C.sub.3 alkoxy; n is 0, 1 or 2.
[0077] Embodiment 10 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, 8, or 9 wherein R.sub.6 is
hydrogen, fluoro, chloro, or methyl.
[0078] Embodiment 11 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 wherein each R.sub.7
independently represents cyano, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.4
alkylthio or C.sub.3-C.sub.4 cycloalkyl; m is 0, 1 or 2.
[0079] Embodiment 12 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 wherein R.sub.1 and
R.sub.2 are each independently a C.sub.1-C.sub.3 alkyl; or R.sub.1
and R.sub.2 together with the carbon atom to which they are
attached represent a C.sub.3-C.sub.4 cycloalkyl group.
[0080] Embodiment 13 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 wherein R.sub.3
and R.sub.4 are each independently selected from hydrogen, halogen
and C.sub.1-C.sub.4 alkyl; or R.sub.3 and R.sub.4 together with the
carbon atom to which they are attached represent C.dbd.O or
C.sub.3-C.sub.4 cycloalkyl.
[0081] Embodiment 14 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 wherein
each R.sub.5 independently represents halogen, cyano,
C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.4 cycloalkyl; n is 0, 1 or
2.
[0082] Embodiment 15 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 wherein
R.sub.6 is hydrogen.
[0083] Embodiment 16 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15
wherein each R.sub.7 independently represents cyano, halogen,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.3-C.sub.4
cycloalkyl; m is 0, 1 or 2.
[0084] Embodiment 17 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16
wherein R.sub.1 and R.sub.2 are each independently a
C.sub.1-C.sub.2 alkyl group (preferably both are methyl).
[0085] Embodiment 18 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16
or 17 wherein R.sub.3 and R.sub.4 are each independently selected
from hydrogen, fluoro and C.sub.1-C.sub.2 alkyl (preferably both
are methyl or both are fluoro); or R.sub.3 and R.sub.4 together
with the carbon atom to which they are attached represent
C.sub.3-C.sub.4 cycloalkyl.
[0086] Embodiment 19 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17 or 18 wherein each R.sub.5 independently represents fluoro,
chloro, bromo, cyano, or C.sub.1-C.sub.2 alkyl (preferably fluoro);
n is 0, 1 or 2 (preferably 0 or 1).
[0087] Embodiment 20 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18 or 19 wherein each R.sub.7 independently represents fluoro,
chloro or C.sub.1-C.sub.3 alkyl (preferably fluoro or methyl); m is
1 or 2.
[0088] Embodiment 21 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19 or 20 wherein Y--X represents the radical G1.
[0089] Embodiment 22 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20 or 21 wherein Q.sub.1 is a nitrogen atom and when
Q.sub.2 is a carbon atom
[0090] Embodiment 23 provides compounds according to any one of
embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20 or 21 wherein Q.sub.1 is a carbon atom and
[0091] Q.sub.2 is a nitrogen atom.
[0092] One group of compounds according to the invention are those
of formula (I'):
##STR00004##
wherein Y--X, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, m and n are as defined for compounds of formula (I), or a
salt or N-oxide thereof. Preferred definitions of Y--X, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m and n are as defined
for compounds of formula (I).
[0093] Another group of compounds according to the invention are
those of formula (I''):
##STR00005##
wherein Y--X, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, m and n are as defined for compounds of formula (I), or a
salt or N-oxide thereof. Preferred definitions of Y--X, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m and n are
as defined for compounds of formula (I).
[0094] A preferred group of compounds according to the invention
are those of formula (I-1):
##STR00006##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, m and n are as defined for compounds of formula (I), or a
salt or N-oxide thereof. Preferred definitions of R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m and n are as defined
for compounds of formula (I).
[0095] Another preferred group of compounds according to the
invention are those of formula (I-2):
##STR00007##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, m and n are as defined for compounds of formula (I), or a
salt or N-oxide thereof. Preferred definitions of R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sub.3, m and n are
as defined for compounds of formula (I).
[0096] Another preferred group of compounds according to the
invention are those of formula (I-3):
##STR00008##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, m and n are as defined for compounds of formula (I). or a
salt or N-oxide thereof. Preferred definitions of R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m and n are as defined
for compounds of formula (I).
[0097] Another preferred group of compounds according to the
invention are those of formula (I-4):
##STR00009##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.8,
R.sup.7, m and n are as defined for compounds of formula (I), or a
salt or N-oxide thereof. Preferred definitions of R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m and n are as defined
for compounds of formula (I).
[0098] Another preferred group of compounds according to the
invention are those of formula (I-5):
##STR00010##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, m and n are as defined for compounds of formula (I), or a
salt or N-oxide thereof. Preferred definitions of R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m and n are as defined
for compounds of formula (I).
[0099] Another preferred group of compounds according to the
invention are those of formula (I-6):
##STR00011##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sub.a, m and n are as defined for compounds of formula
(I), or a salt or N-oxide thereof. Preferred definitions of
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sub.a, m and n are as defined for compounds of formula (I).
[0100] Another preferred group of compounds according to the
invention are those of formula (I-7):
##STR00012##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, m and n are as defined for compounds of formula (I), or a
salt or N-oxide thereof. Preferred definitions of R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m and n are as defined
for compounds of formula (I).
[0101] Another preferred group of compounds according to the
invention are those of formula (I-8):
##STR00013##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5. R.sup.6,
R.sup.7, m and n are as defined for compounds of formula (I), or a
salt or N-oxide thereof. Preferred definitions of R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m and n are as defined
for compounds of formula (I).
[0102] A further preferred group of compounds according to the
invention are those of formula (I-9) which are compounds of formula
(I) wherein Y--X is as defined for compounds of formula (I);
R.sub.1 and R.sub.2 are each independently selected from hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, in which the
alkyl and cycloalkyl groups may be optionally substituted with 1 to
3 substituents independently selected from halogen, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkylthio; or R.sub.1 and R.sub.2
together with the carbon atom to which they are attached represent
a C.sub.3-C.sub.6 cycloalkyl group (which may be optionally
substituted with 1 to 3 substituents independently selected from
the group consisting of halogen, C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy); R.sub.3 and R.sub.4 are each independently
selected from hydrogen, halogen, hydroxyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy and C.sub.3-C.sub.7 cycloalkyl, in which the
alkyl, alkoxy and cycloalkyl groups may be optionally substituted
with 1 to 3 substituents independently selected from halogen,
C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio; or R.sub.3
and R.sub.4 together with the carbon atom to which they are
attached represent C.dbd.O, C.dbd.NOR.sub.d,
C.dbd.C(R.sub.b)(R.sub.c) or C.sub.3-C.sub.6 cycloalkyl (which may
be optionally substituted with 1 to 3 substituents independently
selected from the group consisting of a halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio), where
R.sub.b and R.sub.c are each independently selected from hydrogen,
halogen, cyano, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkylthio, in which the alkyl,
cycloalkyl, alkenyl and alkynyl groups may be optionally
substituted with 1 to 3 substituents independently selected from
halogen, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkylthio, and
where R.sub.d is selected from hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.6 alkenyl and
C.sub.3-C.sub.6 alkynyl, in which the alkyl, cycloalkyl, alkenyl
and alkynyl groups may be optionally substituted with 1 to 3
substituents independently selected from halogen, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkylthio; or R.sub.2 and R.sub.3
together with the carbon atoms to which they are attached represent
a C.sub.3-C.sub.7 cycloalkyl (which may be optionally substituted
with 1 to 3 substituents independently selected from the group
consisting of halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkylthio, and, additionally, a ring
carbon unit may be replaced by an oxygen or sulphur atom); each
R.sub.5 independently represents halogen, cyano, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.3-C.sub.6 alkenyloxy, C.sub.3-C.sub.6 alkynyloxy,
C.sub.1-C.sub.6 alkylthio, C(.dbd.NOR.sub.a)C.sub.1-C.sub.5alkyl,
phenyl, heteroraryl (wherein heteroaryl is pyridyl, thiophenyl,
thiazolyl, imidazolyl or oxazolyl), phenoxy or heteroraryloxy
(wherein heteroaryl is pyridyl, thiophenyl, thiazolyl, imidazolyl
or oxazolyl), in which the alkyl, cycloalkyl, alkenyl, alkynyl,
alkoxy, alkenyloxy, alkynyloxy, phenyl and heteroaryl groups may be
optionally substituted with 1 to substituents independently
selected from halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, cyano and C.sub.1-C.sub.6 alkylthio; n is 0, 1, 2, 3 or 4;
R.sub.6 is hydrogen, halogen, or C.sub.1-C.sub.2 alkyl; each
R.sub.7 independently represents cyano, halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.3-C.sub.6 haloalkynyl, C.sub.1-C.sub.6 alkylthio,
C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkylthio,
C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.6
alkenyloxy or C.sub.3-C.sub.6alkynyloxy; m is 0, 1, 2, 3 or 4; and
R.sub.a is hydrogen or C.sub.1-C.sub.2 alkyl; or a salt or N-oxide
thereof.
[0103] One group of compounds according to this embodiment are
compounds of formula (I-9a) which are compounds of formula (I-9)
wherein Q.sub.1 is a nitrogen atom and Q.sub.2 is a carbon
atom.
[0104] A preferred group of compounds according to this embodiment
are compounds of formula (I-9b) which are compounds of formula
(I-9) wherein Q.sub.1 is a carbon atom and Q.sub.2 is a nitrogen
atom.
[0105] A further preferred group of compounds according to the
invention are those of formula (I-10) which are compounds of
formula (I) wherein Y--X represents the radical G1; R.sub.1 and
R.sub.2 are each independently a hydrogen or C.sub.1-C.sub.4 alkyl
group, in which the alkyl group may be optionally substituted with
1 to 3 substituents independently selected from halogen, and
C.sub.1-C.sub.6 alkoxy; or R.sup.1 and R.sup.2 together with the
carbon atom to which they are attached represent a C.sub.3-C.sub.5
cycloalkyl group; R.sub.3 and R.sub.4 are each independently
selected from hydrogen, halogen, C.sub.1-C.sub.4 alkyl and
C.sub.3-C.sub.4 cycloalkyl, in which the alkyl and cycloalkyl
groups may be optionally substituted with 1 to 3 substituents
independently selected from halogen, C.sub.1-C.sub.3 alkoxy and
C.sub.1-C.sub.3 alkylthio; or R.sub.3 and R.sub.4 together with the
carbon atom to which they are attached represent C.dbd.O,
C.dbd.NOR.sub.d, or C.sub.3-C.sub.6 cycloalkyl (which may be
optionally substituted with 1 to 3 substituents independently
selected from the group consisting of a halogen, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkylthio), where
R.sub.d is selected from hydrogen, C.sub.1-C.sub.4 alkyl and
C.sub.3-C.sub.5 cycloalkyl, in which the alkyl and cycloalkyl
groups may be optionally substituted with 1 to 3 substituents
independently selected from halogen, C.sub.1-C.sub.3 alkoxy and
C.sub.1-C.sub.3 alkylthio (preferably R.sub.d is selected from
hydrogen and C.sub.1-C.sub.3 alkyl, in which the alkyl group may be
optionally substituted with 1 to 3 halogen atoms (preferably fluoro
atoms)); each R.sub.5 independently represents halogen, cyano,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.4 cycloalkyl, C.sub.1-C.sub.3
alkoxy, C.sub.3-C.sub.6 alkenyloxy, C.sub.3-C.sub.6 alkynyloxy,
phenyl, heteroraryl (wherein heteroaryl is pyridyl, thiazolyl or
oxazolyl), in which the alkyl, cycloalkyl, alkoxy, alkenyloxy,
alkynyloxy, phenyl and heteroaryl groups may be optionally
substituted with 1 to 3 substituents independently selected from
halogen, C.sub.1-C.sub.3 alkyl and C.sub.1-C.sub.3 alkoxy; n is 0,
1 or 2; R.sub.6 is hydrogen, fluoro, chloro, or methyl; each
R.sub.7 independently represents cyano, halogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.2-C.sub.3 alkynyl,
C.sub.1-C.sub.4 alkylthio or C.sub.3-C.sub.4 cycloalkyl; and m is
0, 1 or 2; or a salt or N-oxide thereof.
[0106] One group of compounds according to this embodiment are
compounds of formula (I-10a) which are compounds of formula (I-10)
wherein Q.sub.1 is a nitrogen atom and Q.sub.2 is a carbon
atom.
[0107] A preferred group of compounds according to this embodiment
are compounds of formula (I-10b) which are compounds of formula
(I-10) wherein Q.sub.1 is a carbon atom and Q.sub.2 is a nitrogen
atom.
[0108] A further preferred group of compounds according to the
invention are those of formula (I-11) which are compounds of
formula (I) wherein Y--X represents the radical G1; R.sub.1 and
R.sub.2 are each independently a C.sub.1-C.sub.3 alkyl; or R.sub.1
and R.sub.2 together with the carbon atom to which they are
attached represent a C.sub.3-C.sub.4 cycloalkyl group; R.sub.3 and
R.sub.4 are each independently selected from hydrogen, halogen and
C.sub.1-C.sub.4 alkyl; or R.sub.3 and R.sub.4 together with the
carbon atom to which they are attached represent C.dbd.O or
C.sub.3-C.sub.4 cycloalkyl; each R.sub.6 independently represents
halogen, cyano, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.4 cycloalkyl;
n is 0, 1 or 2; R.sub.6 is hydrogen, fluoro, chloro, or methyl;
each R.sub.7 independently represents cyano, halogen,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.3-C.sub.4
cycloalkyl; and m is 0, 1 or 2; or a salt or N-oxide thereof.
[0109] One group of compounds according to this embodiment are
compounds of formula (I-11a) which are compounds of formula (I-11)
wherein Q.sub.1 is a nitrogen atom and Q.sub.2 is a carbon
atom.
[0110] A preferred group of compounds according to this embodiment
are compounds of formula (I-11b) which are compounds of formula
(I-11) wherein Q.sub.1 is a carbon atom and Q.sub.2 is a nitrogen
atom.
[0111] A further preferred group of compounds according to the
invention are those of formula (I-12) which are compounds of
formula (I) wherein Y--X represents the radical G1; R.sub.1 and
R.sub.2 are each independently a C.sub.1-C.sub.2 alkyl group
(preferably both are methyl); R.sub.3 and R.sub.4 are each
independently selected from hydrogen, fluoro and C.sub.1-C.sub.2
alkyl (preferably both are methyl or both are fluoro); or R.sub.3
and R.sub.4 together with the carbon atom to which they are
attached represent C.sub.3-C.sub.4 cycloalkyl; each R.sub.5
independently represents fluoro, chloro, bromo, cyano, or
C.sub.1-C.sub.2 alkyl (preferably fluoro); n is 0, 1 or 2
(preferably 0 or 1); R.sub.6 is hydrogen; each R.sub.7
independently represents fluoro, chloro or C.sub.1-C.sub.3 alkyl
(preferably fluoro or methyl); and m is 1 or 2; or a salt or
N-oxide thereof.
[0112] One group of compounds according to this embodiment are
compounds of formula (I-12a) which are compounds of formula (I-12)
wherein Q.sub.1 is a nitrogen atom and Q.sub.2 is a carbon
atom.
[0113] A preferred group of compounds according to this embodiment
are compounds of formula (I-12b) which are compounds of formula
(I-12) wherein Q.sub.1 is a carbon atom and Q.sub.2 is a nitrogen
atom.
[0114] A particularly preferred group of compounds are compounds of
formula (IK):
##STR00014##
wherein R.sub.1 is methyl; R.sub.2 is methyl; R.sub.3 is methyl or
fluoro; R.sub.4 is methyl or fluoro; R.sub.5a is fluoro or
hydrogen; R.sub.5b is fluoro or hydrogen; R.sub.6 is hydrogen;
R.sub.7a is methyl or hydrogen; and R.sub.7b is methyl, fluoro or
hydrogen; or a salt or N-oxide thereof.
[0115] In compounds of formula (IK) special preference is given to
compounds wherein R.sub.1 is methyl, R.sub.2 is methyl, R.sub.6 is
hydrogen and R.sub.3, R.sub.4, R.sub.5a, R.sub.5b, R.sub.7a and
R.sub.7b are as defined below:
TABLE-US-00001 Com- pound R.sub.3 R.sub.4 R.sub.5a R.sub.5b
R.sub.7a R.sub.7b IK-1 methyl methyl fluoro hydrogen methyl methyl
IK-2 fluoro fluoro fluoro hydrogen methyl methyl IK-3 fluoro fluoro
hydrogen fluoro methyl methyl IK-4 fluoro fluoro hydrogen hydrogen
methyl methyl IK-5 fluoro fluoro hydrogen hydrogen methyl fluoro
IK-6 fluoro fluoro hydrogen hydrogen methyl hydrogen IK-7 fluoro
fluoro hydrogen hydrogen hydrogen methyl IK-8 methyl methyl fluoro
hydrogen methyl hydrogen IK-9 fluoro fluoro hydrogen fluoro methyl
hydrogen IK-10 fluoro fluoro hydrogen fluoro hydrogen methyl
[0116] Compounds according to the invention may possess any number
of benefits including, inter alia, advantageous levels of
biological activity for protecting plants against diseases that are
caused by fungi or superior properties for use as agrochemical
active ingredients (for example, greater biological activity, an
advantageous spectrum of activity, an increased safety profile,
improved physicochemical properties, or increased
biodegradability).
[0117] Specific examples of compounds of formula (I) are
illustrated in the Tables A1 to A17 and B1 to B17 below:
Table A1 provides 195 compounds of formula Ia
##STR00015##
wherein R.sub.6, R.sub.7a and R.sub.7b are all H and wherein the
values of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the
radical Y--X (and when Y--X is G2 the corresponding Ra) are as
defined in Table Z below:
TABLE-US-00002 TABLE Z Entry R.sub.1 R.sub.2 R.sub.3 R.sub.4
R.sub.5 Y-X* Ra 1 CH.sub.3 CH.sub.3 H H H [n = 0] G1 -- 2 CH.sub.3
CH.sub.3 H H 5-F G1 -- 3 CH.sub.3 CH.sub.3 H H 6-F G1 -- 4 CH.sub.3
CH.sub.3 H H 7-F G1 -- 5 CH.sub.3 CH.sub.3 H H 8-F G1 -- 6 CH.sub.3
CH.sub.3 H H 5-Cl G1 -- 7 CH.sub.3 CH.sub.3 H H 6-Cl G1 -- 8
CH.sub.3 CH.sub.3 H H 7-Cl G1 -- 9 CH.sub.3 CH.sub.3 H H 8-Cl G1 --
10 CH.sub.3 CH.sub.3 H H 5-Br G1 -- 11 CH.sub.3 CH.sub.3 H H 6-Br
G1 -- 12 CH.sub.3 CH.sub.3 H H 5-I G1 -- 13 CH.sub.3 CH.sub.3 H H
5,6-F.sub.2 G1 -- 14 CH.sub.3 CH.sub.3 H H 5,6-Cl.sub.2 G1 -- 15
CH.sub.3 CH.sub.3 H H 5-F-6-Cl G1 -- 16 CH.sub.3 CH.sub.3 H H
5-CH.sub.3 G1 -- 17 CH.sub.3 CH.sub.3 H H 6-CH.sub.3 G1 -- 18
CH.sub.3 CH.sub.3 H H 7-CH.sub.3 G1 -- 19 CH.sub.3 CH.sub.3 H H
5-CH.sub.2CH.sub.3 G1 -- 20 CH.sub.3 CH.sub.3 H H 5-cyclopropyl G1
-- 21 CH.sub.3 CH.sub.3 H H 5-CN G1 -- 22 CH.sub.3 CH.sub.3 H H
5-OCH.sub.3 G1 -- 23 CH.sub.3 CH.sub.3 H H 5-OC.sub.6H.sub.5 G1 --
24 CH.sub.3 CH.sub.3 H H 5-O-(pyrid-2-yl) G1 -- 25 CH.sub.3
CH.sub.3 H H 5-CF.sub.3 G1 -- 26 CH.sub.3 CH.sub.3 H H
5-C.sub.6H.sub.6 G1 -- 27 CH.sub.3 CH.sub.3 H H
5-(2-F-C.sub.6H.sub.5) G1 -- 28 CH.sub.3 CH.sub.3 H H
5-(thiazol-2-yl) G1 -- 29 CH.sub.3 CH.sub.3 H H H [n = 0] G2 H 30
CH.sub.3 CH.sub.3 H H 5-F G2 H 31 CH.sub.3 CH.sub.3 H H H [n = 0]
G2 CH.sub.3 32 CH.sub.3 CH.sub.3 H H 5-F G2 CH.sub.3 33 CH.sub.3
CH.sub.3 H H H [n = 0] G3 -- 34 CH.sub.3 CH.sub.3 H H 5-F G3 -- 35
CH.sub.3 CH.sub.3 H H H [n = 0] G4 -- 36 CH.sub.3 CH.sub.3 H H 5-F
G4 -- 37 CH.sub.3 CH.sub.3 H CH.sub.3 H [n = 0] G1 -- 38 CH.sub.3
CH.sub.3 H CH.sub.3 5-F G1 -- 39 CH.sub.3 CH.sub.3 H OH H [n = 0]
G1 -- 40 CH.sub.3 CH.sub.3 H OH 5-F G1 -- 41 CH.sub.3 CH.sub.3 H
OCH.sub.3 H [n = 0] G1 -- 42 CH.sub.3 CH.sub.3 H OCH.sub.3 5-F G1
-- 43 CH.sub.3 CH.sub.3 H F H [n = 0] G1 -- 44 CH.sub.3 CH.sub.3 H
F 5-F G1 -- 45 CH.sub.3 CH.sub.3 H F 6-F G1 -- 46 CH.sub.3 CH.sub.3
H F 5-Cl G1 -- 47 CH.sub.3 CH.sub.3 H F 6-Cl G1 -- 48 CH.sub.3
CH.sub.3 H F 5-CH.sub.3 G1 -- 49 CH.sub.3 CH.sub.3 CH.sub.3
CH.sub.3 H [n = 0] G1 -- 50 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 5-F
G1 -- 51 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 6-F G1 -- 52 CH.sub.3
CH.sub.3 CH.sub.3 CH.sub.3 7-F G1 -- 53 CH.sub.3 CH.sub.3 CH.sub.3
CH.sub.3 8-F G1 -- 54 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 5-Cl G1
-- 55 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 6-Cl G1 -- 56 CH.sub.3
CH.sub.3 CH.sub.3 CH.sub.3 5-Br G1 -- 57 CH.sub.3 CH.sub.3 CH.sub.3
CH.sub.3 5,6-F.sub.2 G1 -- 58 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3
5,6-Cl.sub.2 G1 -- 59 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 5-F-6-Cl
G1 -- 60 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 5-CH.sub.3 G1 -- 61
CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 5-CH.sub.2CH.sub.3 G1 -- 62
CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 5-cyclopropyl G1 -- 63 CH.sub.3
CH.sub.3 CH.sub.3 CH.sub.3 5-CN G1 -- 64 CH.sub.3 CH.sub.3 CH.sub.3
CH.sub.3 5-OC.sub.6H.sub.5 G1 -- 65 CH.sub.3 CH.sub.3 CH.sub.3
CH.sub.3 5-O-(pyrid-2-yl) G1 -- 66 CH.sub.3 CH.sub.3 CH.sub.3
CH.sub.3 5-C.sub.6H.sub.6 G1 -- 67 CH.sub.3 CH.sub.3 CH.sub.3
CH.sub.3 5-(2-F-C.sub.6H.sub.5) G1 -- 68 CH.sub.3 CH.sub.3 CH.sub.3
CH.sub.3 5-(thiazol-2-yl) G1 -- 69 CH.sub.3 CH.sub.3 CH.sub.3
CH.sub.3 H [n = 0] G2 H 70 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 5-F
G2 H 71 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 H [n = 0] G2 CH.sub.3
72 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 5-F G2 CH.sub.3 73 CH.sub.3
CH.sub.3 CH.sub.3 CH.sub.3 H [n = 0] G3 -- 74 CH.sub.3 CH.sub.3
CH.sub.3 CH.sub.3 5-F G3 -- 75 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3
H [n = 0] G4 -- 76 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 5-F G4 -- 77
CH.sub.3 CH.sub.3 .dbd.O H [n = 0] G1 -- 78 CH.sub.3 CH.sub.3
.dbd.O 5-F G1 79 CH.sub.3 CH.sub.3 .dbd.O 6-F G1 -- 80 CH.sub.3
CH.sub.3 .dbd.O 5-Cl G1 -- 81 CH.sub.3 CH.sub.3 .dbd.O 6-Cl G1 --
82 CH.sub.3 CH.sub.3 .dbd.O 5-Br G1 -- 83 CH.sub.3 CH.sub.3 .dbd.O
5-CN G1 -- 84 CH.sub.3 CH.sub.3 .dbd.O 5-CH.sub.3 G1 -- 85 CH.sub.3
CH.sub.3 .dbd.O 5-CH2CH3 G1 -- 86 CH.sub.3 CH.sub.3 .dbd.NOH H [n =
0] G1 -- 87 CH.sub.3 CH.sub.3 .dbd.NOH 5-F G1 88 CH.sub.3 CH.sub.3
.dbd.NOH 5-CH.sub.3 G1 -- 89 CH.sub.3 CH.sub.3 .dbd.NOCH.sub.3 H [n
= 0] G1 -- 90 CH.sub.3 CH.sub.3 .dbd.NOCH.sub.3 5-F G1 -- 91
CH.sub.3 CH.sub.3 .dbd.NOCH.sub.3 5-CH.sub.3 G1 -- 92 CH.sub.3
CH.sub.3 .dbd.NOCH.sub.3 5-Cl G1 -- 93 CH.sub.3 CH.sub.3 F F H [n =
0] G1 -- 94 CH.sub.3 CH.sub.3 F F 5-F G1 -- 95 CH.sub.3 CH.sub.3 F
F 6-F G1 96 CH.sub.3 CH.sub.3 F F 5-Cl G1 -- 97 CH.sub.3 CH.sub.3 F
F 6-Cl G1 -- 98 CH.sub.3 CH.sub.3 F F 5-Br G1 -- 99 CH.sub.3
CH.sub.3 F F 5,6-F2 G1 -- 100 CH.sub.3 CH.sub.3 F F 5-F-6-Cl G1 --
101 CH.sub.3 CH.sub.3 F F 5-CN G1 -- 102 CH.sub.3 CH.sub.3 F F
5-CH.sub.3 G1 -- 103 CH.sub.3 CH.sub.3 cyclopropyl H [n = 0] G1 --
104 CH.sub.3 CH.sub.3 cyclopropyl 5-F G1 -- 105 CH.sub.3 CH.sub.3
cyclopropyl 5-Cl G1 -- 106 CH.sub.3 CH.sub.3 cyclopropyl 5-CN G1 --
107 CH.sub.3 CH.sub.3 cyclopropyl 5-CH.sub.3 G1 -- 108 CH.sub.3
CH.sub.3 cyclobutyl H [n = 0] G1 -- 109 CH.sub.3 CH.sub.3
cyclobutyl 5-F G1 -- 110 CH.sub.3 CH.sub.3 cyclopentyl H [n = 0] G1
-- 111 CH.sub.3 CH.sub.3 cyclopentyl 5-F G1 -- 112 H H CH.sub.3
CH.sub.3 H [n = 0] G1 -- 113 H H cyclopropyl H [n = 0] G1 -- 114 H
H cyclopropyl 5-F G1 -- 115 H H cyclobutyl H [n = 0] G1 -- 116 H H
cyclobutyl 5-F G1 -- 117 H H cyclopentyl H [n = 0] G1 -- 118 H H
cyclopentyl 5-F G1 -- 119 CH.sub.3 CH.sub.2CH.sub.3 H H H [n = 0]
G1 -- 120 CH.sub.3 CH.sub.2CH.sub.3 H H 5-F G1 -- 121 CH.sub.3
CH.sub.2CH.sub.3 H H 5-Cl G1 -- 122 CH.sub.3 CH.sub.2CH.sub.3 H H
5-Br G1 -- 123 CH.sub.3 CH.sub.2CH.sub.3 H H 5-CH.sub.3 G1 -- 124
CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 H H H [n = 0] G1 -- 125
CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 H H 5-F G1 -- 126
CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 H H 5-Cl G1 -- 127
CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 H H 5-Br G1 -- 128
CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 H H 5-CH.sub.3 G1 -- 129 CH.sub.3
CH.sub.2Cl H H H [n = 0] G1 -- 130 CH.sub.3 CH.sub.2Cl H H 5-F G1
-- 131 CH.sub.3 CH.sub.2Cl CH.sub.3 CH.sub.3 H [n = 0] G1 -- 132
CH.sub.3 CH.sub.2Cl CH.sub.3 CH.sub.3 5-F G1 -- 133 CH.sub.3
CH.sub.2OCH.sub.3 H H H [n = 0] G1 -- 134 CH.sub.3
CH.sub.2OCH.sub.3 H H 5-F G1 -- 135 CH.sub.3 CH.sub.2OCH.sub.3
CH.sub.3 CH.sub.3 H [n = 0] G1 -- 136 CH.sub.3 CH.sub.2OCH.sub.3
CH.sub.3 CH.sub.3 5-F G1 -- 137 CH.sub.3 H H H H [n = 0] G1 -- 138
CH.sub.3 H H H 5-F G1 -- 139 CH.sub.3 CH(CH.sub.3).sub.2 H H H [n =
0] G1 -- 140 CH.sub.3 CH(CH.sub.3).sub.2 H H 5-F G1 -- 141 CH.sub.3
CH.sub.2CH.sub.2CH.sub.3 H H H [n = 0] G1 -- 142 CH.sub.3
CH.sub.2CH.sub.2CH.sub.3 H H 5-F G1 -- 143 cyclopropyl H H H [n =
0] G1 -- 144 cyclopropyl CH.sub.3 CH.sub.3 H [n = 0] G1 -- 145
cyclopropyl .dbd.O H [n = 0] G1 -- 146 cyclopropyl F F H [n = 0] G1
-- 147 cyclopropyl cyclopropyl H [n = 0] G1 -- 148 cyclopropyl H H
5-F G1 -- 149 cyclopropyl CH.sub.3 CH.sub.3 5-F G1 -- 150
cyclopropyl .dbd.O 5-F G1 -- 151 cyclopropyl F F 5-F G1 -- 152
cyclopropyl cyclopropyl 5-F G1 -- 153 cyclopropyl H H 5-Cl G1 --
154 cyclopropyl H H 5-Br G1 -- 155 cyclobutyl H H H [n = 0] G1 --
156 cyclobutyl .dbd.O H [n = 0] G1 -- 157 cyclobutyl F F H [n = 0]
G1 -- 158 cyclobutyl H H 5-F G1 -- 159 cyclobutyl .dbd.O 5-F G1 --
160 cyclobutyl F F 5-F G1 -- 161 cyclobutyl H H 5-Br G1 -- 162
cyclopentyl H H H [n = 0] G1 -- 163 cyclopentyl .dbd.O H [n = 0] G1
-- 164 cyclopentyl F F H [n = 0] G1 -- 165 cyclopentyl H H 5-F G1
-- 166 cyclopentyl .dbd.O 5-F G1 -- 167 cyclopentyl F F 5-F G1 --
168 cyclopentyl H H 5-Br G1 -- 169 cyclohexyl H H H [n = 0] G1 --
170 cyclohexyl .dbd.O H [n = 0] G1 -- 171 cyclohexyl F F H [n = 0]
G1 -- 172 cyclohexyl H H 5-F G1 -- 173 cyclohexyl .dbd.O 5-F G1 --
174 cyclohexyl F F 5-F G1 -- 175 cyclohexyl H H 5-Br G1 -- 176 H
cyclopropyl H H [n = 0] G1 -- 177 CH.sub.3 cyclopropyl H H [n = 0]
G1 -- 178 CH.sub.3 cyclopropyl CH.sub.3 H [n = 0] G1 -- 179
CH.sub.3 cyclopropyl F H [n = 0] G1 -- 180 H cyclopropyl H 5-F G1
-- 181 CH.sub.3 cyclopropyl H 5-F G1 -- 182 CH.sub.3 cyclopropyl
CH.sub.3 5-F G1 -- 183 H cyclobutyl H H [n = 0] G1 -- 184 CH.sub.3
cyclobutyl H H [n = 0] G1 -- 185 CH.sub.3 cyclobutyl CH.sub.3 H [n
= 0] G1 -- 186 CH.sub.3 cyclobutyl F H [n = 0] G1 -- 187 H
cyclobutyl H 5-F G1 -- 188 CH.sub.3 cyclobutyl H 5-F G1 -- 189
CH.sub.3 cyclobutyl CH.sub.3 5-F G1 -- 190 H cyclopentyl H H [n =
0] G1 -- 191 CH.sub.3 cyclopentyl H H [n = 0] G1 -- 192 CH.sub.3
cyclopentyl CH.sub.3 H [n = 0] G1 -- 193 H cyclohexyl H H [n = 0]
G1 -- 194 CH.sub.3 cyclohexyl H H [n = 0] G1 -- 195 CH.sub.3
cyclohexyl CH.sub.3 H [n = 0] G1 -- *Radicals G1, G2, G3 and G4 are
as defined for compounds of formula (I).
Table A2 provides 195 compounds of formula Ia wherein R.sub.7a and
R.sub.7b are H, R.sub.6 is methyl and wherein the values of
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the radical Y--X
(and when Y--X is G2 the corresponding Ra) are as defined in Table
Z above. Table A3 provides 195 compounds of formula Ia wherein
R.sub.7a and R.sub.7b are H, R.sub.6 is chloro and wherein the
values of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the
radical Y--X (and when Y--X is G2 the corresponding Ra) are as
defined in Table Z above. Table A4 provides 195 compounds of
formula Ia wherein R.sub.6 and R.sub.7a are H, R.sub.7b is methyl
and wherein the values of R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5 and the radical Y--X (and when Y--X is G2 the corresponding
Ra) are as defined in Table Z above. Table A5 provides 195
compounds of formula Ia wherein R.sub.6 and R.sub.7b are H,
R.sub.7a is fluoro and wherein the values of R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and the radical Y--X (and when Y--X is G2
the corresponding Ra) are as defined in Table Z above. Table A6
provides 195 compounds of formula Ia wherein R.sub.6 and R.sub.7b
are H, R.sub.7a is methyl and wherein the values of R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the radical Y--X (and when
Y--X is G2 the corresponding Ra) are as defined in Table Z above.
Table A7 provides 195 compounds of formula Ia wherein R.sub.6 and
R.sub.7b are H, R.sub.7a is chloro and wherein the values of
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the radical Y--X
(and when Y--X is G2 the corresponding Ra) are as defined in Table
Z above. Table A8 provides 195 compounds of formula Ia wherein
R.sub.6 and R.sub.7b are H, R.sub.7a is bromo and wherein the
values of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the
radical Y--X (and when Y--X is G2 the corresponding Ra) are as
defined in Table Z above. Table A9 provides 195 compounds of
formula Ia wherein R.sub.6 and R.sub.7b are H, R.sub.7a is ethyl
and wherein the values of R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5 and the radical Y--X (and when Y--X is G2 the corresponding
Ra) are as defined in Table Z above. Table A10 provides 195
compounds of formula Ia wherein R.sub.6 and R.sub.7b are H,
R.sub.7a is cyclopropyl and wherein the values of R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and the radical Y--X (and when Y--X is G2
the corresponding Ra) are as defined in Table Z above. Table A11
provides 195 compounds of formula Ia wherein R.sub.6 is H, R.sub.7b
is methyl, R.sub.7a is fluoro and wherein the values of R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the radical Y--X (and when
Y--X is G2 the corresponding Ra) are as defined in Table Z above.
Table A12 provides 195 compounds of formula Ia wherein R.sub.6 is
H, R.sub.7b is chloro, R.sub.7a is chloro and wherein the values of
R.sub.1, R.sub.2, R.sub.3. R.sub.4, R.sub.5 and the radical Y--X
(and when Y--X is G2 the corresponding Ra) are as defined in Table
Z above. Table A13 provides 195 compounds of formula Ia wherein
R.sub.6 is H, R.sub.7b is fluoro, R.sub.7a is methyl and wherein
the values of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the
radical Y--X (and when Y--X is G2 the corresponding Ra) are as
defined in Table Z above. Table A14 provides 195 compounds of
formula Ia wherein R.sub.6 is H, R.sub.7b is methyl, R.sub.7a is
methyl and wherein the values of R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and the radical Y--X (and when Y--X is G2 the
corresponding Ra) are as defined in Table Z above. Table A15
provides 195 compounds of formula Ia wherein R.sub.6 is H, R.sub.7b
is chloro, R.sub.7a is methyl and wherein the values of R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the radical Y--X (and when
Y--X is G2 the corresponding Ra) are as defined in Table Z above.
Table A16 provides 195 compounds of formula Ia wherein R.sub.6 is
H, R.sub.7b is methyl, R.sub.7a is chloro and wherein the values of
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the radical Y--X
(and when Y--X is G2 the corresponding Ra) are as defined in Table
Z above. Table A17 provides 195 compounds of formula Ia wherein
R.sub.6 is H, R.sub.7b is fluoro, R.sub.7a is cyclopropyl and
wherein the values of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
and the radical Y--X (and when Y--X is G2 the corresponding Ra) are
as defined in Table Z above. Table B1 discloses 195 compounds of
formula Ib
##STR00016##
wherein R.sub.6, R.sub.7a and R.sub.7b are H and wherein the values
of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the radical Y--X
(and when Y--X is G2 the corresponding Ra) are as defined in Table
Z above. Table B2 provides 195 compounds of formula Ib wherein
R.sub.7a and R.sub.7b are H, R.sub.6 is methyl and wherein the
values of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the
radical Y--X (and when Y--X is G2 the corresponding Ra) are as
defined in Table Z above. Table B3 provides 195 compounds of
formula Ib wherein R.sub.7a and R.sub.7b are H, R.sub.6 is chloro
and wherein the values of R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5 and the radical Y--X (and when Y--X is G2 the corresponding
Ra) are as defined in Table Z above. Table B4 provides 195
compounds of formula Ib wherein R.sub.6 and R.sub.7a are H,
R.sub.7b is methyl and wherein the values of R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and the radical Y--X (and when Y--X is G2
the corresponding Ra) are as defined in Table Z above. Table B5
provides 195 compounds of formula Ib wherein R.sub.6 and R.sub.7b
are H, R.sub.7a is fluoro and wherein the values of R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the radical Y--X (and when
Y--X is G2 the corresponding Ra) are as defined in Table Z above.
Table B6 provides 195 compounds of formula Ib wherein R.sub.6 and
R.sub.7b are H, R.sub.7a is methyl and wherein the values of
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the radical Y--X
(and when Y--X is G2 the corresponding Ra) are as defined in Table
Z above. Table B7 provides 195 compounds of formula Ib wherein
R.sub.6 and R.sub.7b are H, R.sub.7a is chloro and wherein the
values of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the
radical Y--X (and when Y--X is G2 the corresponding Ra) are as
defined in Table Z above. Table B8 provides 195 compounds of
formula Ib wherein R.sub.6 and R.sub.7b are H, R.sub.7a is bromo
and wherein the values of R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5 and the radical Y--X (and when Y--X is G2 the corresponding
Ra) are as defined in Table Z above. Table B9 provides 195
compounds of formula Ib wherein R.sub.6 and R.sub.7b are H,
R.sub.7a is ethyl and wherein the values of R.sub.1, R.sub.2.
R.sub.3, R.sub.4, R.sub.5 and the radical Y--X (and when Y--X is G2
the corresponding Ra) are as defined in Table Z above. Table B10
provides 195 compounds of formula Ib wherein R.sub.6 and R.sub.7b
are H, R.sub.7a is cyclopropyl and wherein the values of R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the radical Y--X (and when
Y--X is G2 the corresponding Ra) are as defined in Table Z above.
Table B11 provides 195 compounds of formula Ib wherein R.sub.6 is
H, R.sub.7b is methyl, R.sub.7a is fluoro and wherein the values of
R.sub.1, R.sub.2, R.sub.3, R.sub.4. R.sub.5 and the radical Y--X
(and when Y--X is G2 the corresponding Ra) are as defined in Table
Z above. Table B12 provides 195 compounds of formula Ib wherein
R.sub.6 is H, R.sub.7b is chloro, R.sub.7a is chloro and wherein
the values of R.sub.1, R.sub.2. R.sub.3, R.sub.4, R.sub.5 and the
radical Y--X (and when Y--X is G2 the corresponding Ra) are as
defined in Table Z above. Table B13 provides 195 compounds of
formula Ib wherein R.sub.6 is H, R.sub.7b is fluoro, R.sub.7a is
methyl and wherein the values of R.sub.1, R.sub.2, R.sub.3.
R.sub.4, R.sub.5 and the radical Y--X (and when Y--X is G2 the
corresponding Ra) are as defined in Table Z above. Table B14
provides 195 compounds of formula Ib wherein R.sub.6 is H, R.sub.7b
is methyl, R.sub.7a is methyl and wherein the values of R.sub.1.
R.sub.2, R.sub.3, R.sub.4. R.sub.5 and the radical Y--X (and when
Y--X is G2 the corresponding Ra) are as defined in Table Z above.
Table B15 provides 195 compounds of formula Ib wherein R.sub.6 is
H, R.sub.7b is chloro, R.sub.7a is methyl and wherein the values of
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the radical Y--X
(and when Y--X is G2 the corresponding Ra) are as defined in Table
Z above. Table B16 provides 195 compounds of formula Ib wherein
R.sub.6 is H, R.sub.7b is methyl, R.sub.7a is chloro and wherein
the values of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and the
radical Y--X (and when Y--X is G2 the corresponding Ra) are as
defined in Table Z above. Table B17 provides 195 compounds of
formula Ib wherein R.sub.6 is H, R.sub.7b is fluoro, R.sub.7a is
cyclopropyl and wherein the values of R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and the radical Y--X (and when Y--X is G2 the
corresponding Ra) are as defined in Table Z above.
[0118] Compounds of the present invention can be made as shown in
the following schemes, in which, unless otherwise stated, the
definition of each variable is as defined above for a compound of
formula (I).
[0119] The compounds of formula I-1, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, m and n are as defined
for compounds of formula (I), can be obtained by transformation of
a compound of formula II, wherein R.sub.6, R.sub.7 and m are as
defined for compounds of formula (I), with a compound of formula
III, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are
as defined for compounds of formula (I), under acidic conditions,
e.g. with sulphuric acid, trifluoroacetic acid or
trifluoromethansulfonic acid. This is shown in Scheme 1.
[0120] Compounds of formula III can be obtained by a variety of
known methods, e.g. by addition of a Grignard reagent onto the
corresponding phenyl acetic esters (see for example: Journal of the
American Chemical Society, 1989, 111(12), 4392-8).
##STR00017##
[0121] The compounds of formula II, wherein R.sub.6, R.sub.7 and m
are as defined for compounds of formula I, can be obtained by
transformation of an aminopyridine of formula IV (which are
commercially available or obtainable by a variety of known
methods), wherein R.sub.7 and m are as defined for compounds of
formula I, with a compound of formula V (which are commercially
available or obtainable by a variety of known methods), wherein
R.sub.6 is as defined for compounds of formula I, under oxidative
conditions, e.g. with Iodobenzene 1,1-diacetate. Alternatively, the
compounds of formula II, wherein R.sub.6 is H and R.sub.7 and m are
as defined for compounds of formula I, can be obtained by
transformation of an amidine of formula VI (which are commercially
available or obtainable by a variety of known methods), wherein
R.sup.7 and m are as defined for compounds of formula I, with a
compound of formula VII (which are commercially available or
obtainable by a variety of known methods), wherein Hal is a
halogen, preferably chloro or bromo, under basic conditions, e.g.
with sodium carbonate. This is shown in Scheme 2.
##STR00018##
[0122] The compounds of formula I-1, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, m and n are as defined
for compounds of formula I, can also be obtained by transformation
of a compound of formula VIII, wherein R.sub.6, R.sub.7 and m are
as defined for compounds of formula (I) and R.sub.8 is hydroxyl or
two R.sup.8 together with the interjacent boron atom form a five-
or six membered saturated heterocyclic ring, with a compound of
formula IX, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and
n are as defined for compounds of formula (I) and Hal is halogen,
preferably chloro or bromo, under conditions of the Suzuki-Miyaura
reaction. This is shown in Scheme 3.
[0123] Compounds of formula VIII can be prepared by known methods
(see for example: Eur. J. Org. Chem. 2011, 24, 4654 or in
Tetrahedron 2008, 64, 4596).
##STR00019##
[0124] The compounds of formula IX, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and n are as defined for compounds of
formula (I) and Hal is halogen, preferably chloro or bromo, can be
obtained by transformation of a compound of formula X, wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are as defined
for compounds of formula I, with a halogenation reagent, such as
phosphorus oxychloride phosphorus oxybromide, thionyl chloride,
thionyl bromide or Vilsmeier reagent. This is shown in Scheme
4.
##STR00020##
[0125] The compounds of formula X, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4. R.sub.5 and n are as defined for compounds of
formula I, can be obtained by several transformation known to the
person skilled in the art, for instance they can be prepared by
transformation of a compound of formula XI, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are as defined for
compounds of formula (I) and R.sub.9 is C.sub.1-C.sub.6 alkyl, with
sodium acetate in acetic acid as described in the literature (Yu.
B. Vikharev et al. Pharmaceutical Chemistry Journal, 2005, 39,
405-408). This is shown in Scheme 5.
##STR00021##
[0126] The compounds of formula XI, wherein R.sub.1, R.sub.2.
R.sub.3, R.sub.4, R.sub.5 and n are as defined for compounds of
formula (I) and R.sub.9 is C.sub.1-C.sub.6 alkyl, can be obtained
by transformation of a compound of formula III-a, III-b or III-c,
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are as
defined for compounds of formula (I) and R' is either H or
C.sub.1-C.sub.6 alkyl, with a C.sub.1-C.sub.6 alkyl thiocyanate
under acidic conditions, e.g. with sulfuric acid as described in
the literature (Yu. B. Vikharev et al. Pharmaceutical Chemistry
Journal, 2005, 39, 405-408). This is shown in Scheme 6.
##STR00022##
[0127] Alternatively, the compounds of formula I-1, wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, m
and n are as defined for compounds of formula I, can be obtained by
transformation of a compound of formula XII, wherein R.sub.6,
R.sub.7 and m are as defined for formula (I) and R.sub.10 is
C.sub.1-C.sub.6 alkyl, with a compound of formula IX, wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are as defined
for compounds of formula (I) and Hal is halogen, preferably chloro
or bromo, under conditions of the Stille reaction. This is shown in
Scheme 7.
[0128] Compounds of formula XII can be prepared by known methods
(see for example: Bioorg. Med. Chem. Lett. 2013, 23, 2793).
##STR00023##
[0129] The compounds of formula III-a, III-b or III-c, wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are as defined
for compounds of formula (I) and R' is either H or C.sub.1-C.sub.6
alkyl, are either commercially available or easily prepared using
the methods known by persons who are skilled in the art.
[0130] Alternatively, the compounds of formula X, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are as defined for
compounds of formula I, can be obtained by transformation of a
compound of formula XIII, wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and n are as defined for compounds of formula I,
under acidic conditions, e.g. with sulfuric acid or polyphosphoric
acid as described in the literature (Jun-ichi Minamikawa,
Bioorganic & Medicinal Chemistry, 2003, 11, 2205-2209). This is
shown in Scheme 8.
##STR00024##
[0131] The compounds of formula XIII, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and n are as defined for compounds of
formula I, can be obtained by transformation of a compound of
formula XIV, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
and n are as defined for compounds of formula I, upon treatment
with hydroxylamine or hydroxylamine hydrochloride in a solvent such
as ethanol or pyridine in the presence or absence of a base such as
sodium acetate at temperatures ranging from ambient temperature to
heating. This is shown in Scheme 9.
##STR00025##
[0132] The compounds of formula XIV, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and n are as defined for compounds of
formula I, are either commercially available or easily prepared
using the methods known by persons who are skilled in the art.
[0133] Alternatively, the compounds of formula X, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are as defined for
compounds of formula I, can be obtained by transformation of a
compound of formula XV-a, wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and n are as defined for compounds of formula I,
upon treatment with carbonylating agents such as phosgene,
triphosgene or carbonyl diimidazole and subsequent heating or
utilizing directed catalytic C--H activation--carbonylation in the
presence of carbon monoxide gas, a palladium catalyst such as
palladium acetate and an oxidant such benzoquinone as reported in
the literature (Jaume Granell et al. Chem. Commun., 2011, 47,
1054-1056). This is shown in Scheme 10.
##STR00026##
[0134] Alternatively, the compounds of formula X, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are as defined for
compounds of formula I, can be obtained by transformation of a
compound of formula XV-b, wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and n are as defined for compounds of formula (I)
and Hal is halogen, preferably chloro, bromo, or iodo, utilizing an
intramolecular aminocarbonylation in the presence of carbon
monoxide gas, a palladium catalyst such as
Dichlorobis(tricyclohexylphosphine)palladium(II) or
Dichlorobis(triphenylphosphine) palladium(II) and an organic base
such as triethyl amine, pyrrolidine or an inorganic base such
cesium carbonate or potassium carbonate as reported in the
literature (Ruimao Hua et al. Tetrahedron Letters; 2013, 54,
5159-5161). This is shown in Scheme 11.
##STR00027##
Alternatively, the compounds of formula X, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are as defined for
compounds of formula I, can be obtained by transformation of a
compound of formula XVI, wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and n are as defined for compounds of formula (I)
and R.sub.9 is C.sub.1-C.sub.6 alkyl, under acid conditions e.g.
sulfuric acid or triflic acid as described in the literature
(Tomohiko Ohwada et al. Journal of Organic Chemistry, 2012, 77,
9313). This is shown in Scheme 12.
##STR00028##
[0135] The compounds of formula I-5, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and m and n are as
defined for compounds of formula I, can be obtained by
transformation of a compound of formula XVII, wherein R.sub.6,
R.sub.7 and m are as defined for compounds of formula I, with a
compound of formula III, wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and n are as defined for compounds of formula I,
under acidic conditions, e.g. with sulphuric acid, trifluoroacetic
acid or trifluoromethansulfonic acid. This is shown in Scheme
13.
##STR00029##
[0136] The compounds of formula XVII wherein R.sub.6, R.sub.7 and m
are as defined for compounds of formula (I) can be obtained by
known methods (see, for example: A. Kakehi et al Chemical &
Pharmaceutical Bulletin, 1987, 35, 156-169; P. Gmeiner and J.
Schunemann Archiv de Pharmazie 1988, 321, 517-20). As an example,
compounds XVII can be prepared by reaction of
3-methoxyprop-2-enenitrile with N-amino pyridinium salts of formula
XVIII (which are commercially available or can be obtained by known
methods) wherein R.sup.7 and m are as defined for formula (I) and
the anion A.sup.- can be of different nature (e. g. iodide or
2,4,6-trimethylbenzenesulfonate), in the presence of a base, e. g.
with potassium carbonate. This is shown in Scheme 14.
##STR00030##
[0137] The compounds of formula I-5, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and m and n are as
defined for compounds of formula I, can be obtained by
transformation of a compound of formula XIX, wherein R.sub.6,
R.sub.7 and m are as defined for compounds of formula (I) and
R.sub.8 is hydroxyl or two R.sup.8 together with the interjacent
boron atom form a five- or six membered saturated heterocyclic
ring, with a compound of formula IX, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and n are as defined for compounds of
formula (I) and Hal is halogen, preferably chloro or bromo, under
conditions of the Suzuki-Miyaura reaction. This is shown in Scheme
15.
##STR00031##
[0138] Alternatively, the compounds of formula I-5, wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and m
and n are as defined for compounds of formula I, can be obtained by
transformation of a compound of formula XX, wherein R.sub.6,
R.sub.7 and m are as defined for compounds of formula (I) and
R.sub.10 is C.sub.3-C.sub.6 alkyl, with a compound of formula IX,
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are as
defined for compounds of formula (I) and Hal is halogen, preferably
chloro or bromo, under conditions of the Stille reaction. This is
shown in Scheme 16.
##STR00032##
[0139] Alternatively, the compounds of formula I-5, wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and m
and n are as defined for compounds of formula I, can be obtained by
treatment of a compound of formula IX-c, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6 and n are as defined for
compounds of formula I, with a compound of formula XVIII, wherein
A.sup.- is as defined in scheme 14, R.sub.7 and m are as defined
for compounds of formula I, in the presence of a base such as
potassium carbonate in inert solvent such as dimethylformamide.
This is shown in Scheme 17.
##STR00033##
[0140] The compounds of formula IX-c, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6 and n are as defined for
compounds of formula I, can be obtained by treatment of a compound
of formula IX, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
and n are as defined for compounds of formula (I) and Hal is
halogen, preferably chloro or bromo, with a compound of formula
XXI, wherein R.sub.6 is as defined for compounds of formula (I)
under conditions of the Sonogashira reaction. For compounds of
formula IX-c, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
and n are as defined for compounds of formula (I) and R.sub.6 is H.
the Sonogashira reaction described above is preferably performed
with compounds of formula XXII, wherein R.sub.10 is C.sub.1-C.sub.6
alkyl, to yield compounds of formula IX-d, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are as defined for
compounds of formula (I) and R.sub.10 is C.sub.1-C.sub.6 alkyl,
followed by desilylation under conditions well known to a person
skilled in the art such as potassium carbonate in an alcohol
solvents such as methanol. This is shown in Scheme 18.
##STR00034##
[0141] The compounds of formula I-c, wherein R.sub.3 and R.sub.4
are fluoro and Q.sub.1, Q.sub.2, R.sub.1, R.sub.2, R.sub.5,
R.sub.6, R.sub.7, m and n are as defined for compounds of formula
I, can be obtained by transformation of a compound of formula I-d
wherein R.sub.3 and R.sub.4 together with the carbon atom to which
they are attached represent C.dbd.O and Q.sub.1, Q.sub.2, R.sub.1,
R.sub.2, R.sub.5, R.sub.6, R.sub.7, m and n are as defined for
formula (I) with a fluorinating agent such as diethylaminosulfur
trifluoride (DAST) or 2,2-difluoro-1,3-dimethyl-imidazolidine (DFI)
neat or in the presence of a solvent while heating. This is shown
in Scheme 19.
##STR00035##
[0142] The compounds of formula I-d wherein R.sub.3 and R.sub.4
together with the carbon atom to which they are attached represent
C.dbd.O and Q.sub.1, Q.sub.2, R.sub.1, R.sub.2, R.sub.5, R.sub.6,
R.sub.7, m and n are as defined for formula I, can be obtained by
transformation of a compound of formula I-e wherein R.sup.3 is
hydrogen and R.sup.4 is hydroxy and Q.sub.1, Q.sub.2, R.sub.1,
R.sub.2, R.sub.5, R.sub.6, R.sub.7, m and n are as defined for
formula (I) with an oxidizing agent such as
1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol3(1H)-one (Dess-Martin
periodinane) or using oxalyl chloride, dimethyl sulfoxide (DMSO)
and an organic base, such as triethylamine (Swern oxidation). This
is shown in Scheme 20.
##STR00036##
[0143] The compounds of formula I-e wherein R.sub.3 is hydrogen and
R.sub.4 is hydroxy and Q.sub.1, Q.sub.2, R.sub.1, R.sub.2, R.sub.5,
R.sub.6, R.sub.7, m and n are as defined for formula I, can be
obtained by transformation of a compound of formula I-f wherein
R.sub.3 is hydrogen and R.sub.4 is halogen (hal) such as bromo or
chloro and Q.sub.1, Q.sub.2, R.sub.1, R.sub.2, R.sub.5, R.sub.6,
R.sub.7, m and n are as defined for formula (I) under hydrolysis
condition such as aqueous K.sub.2CO.sub.3. This is shown in Scheme
21.
##STR00037##
[0144] The compound of formula I-f wherein R.sub.3 is hydrogen and
R.sub.4 is halogen (hal) such as bromo or chloro and Q.sub.1,
Q.sub.2, R.sup.1, R.sub.2, R.sub.5, R.sub.6, R.sub.7, m and n are
as defined for formula I, can be obtained by transformation of a
compound of formula I-g wherein R.sup.3 and R.sup.4 are hydrogen
and Q.sub.1, Q.sub.2, R.sub.1, R.sub.2, R.sub.5, R.sub.6, m and n
are as defined for formula (I) with an halogenating agent such as
N-bromo succinimide (NBS) or N-chloro succinimide or
1,3-dibromo-5,5-dimethylhydantoin in the presence of a radical
initiator such as azobisisobutyronitrile (AIM). This is shown in
Scheme 22.
##STR00038##
[0145] The compounds of formula I-g can be obtained according to
the method described in Schemes 1, 3, 4, 12, 14 and 15.
[0146] Alternatively, the compounds of formula I-d wherein R.sub.3
and R.sub.4 together with the carbon atom to which they are
attached represent C.dbd.O and Q.sub.1, Q.sub.2, R.sub.1, R.sub.2,
R.sub.5, R.sub.6, R.sub.7, m and n are as defined for formula I,
can be obtained by transformation of a compound of formula VIII or
XII or XIX or XX wherein R.sub.6, R.sub.7 and m are as defined for
compounds of formula (I) and R.sub.8 is hydroxyl or two R.sub.8
together with the interjacent boron atom form a five- or six
membered saturated heterocyclic ring or R.sub.10 is C.sub.1-C.sub.6
alkyl, with a compound of formula IX-a, wherein R.sub.3 and R.sub.4
together with the carbon atom to which they are attached represent
C.dbd.O and R.sub.1, R.sub.2, R.sub.5 and n are as defined for
compounds of formula (I) and Hal is halogen, preferably chloro or
bromo, under conditions of the Suzuki-Miyaura reaction or Stille
reaction. This is shown in scheme 23.
##STR00039##
[0147] Alternatively, the compounds of formula I-c wherein R.sub.3
and R.sub.4 are fluoro and Q.sub.1, Q.sub.2, R.sup.1, R.sub.2,
R.sub.5, R.sub.6, R.sub.7, m and n are as defined for compounds of
formula I, can be obtained by transformation of a compound of
formula VIII or XII or XIX or XX wherein R.sub.6, R.sub.7 and m are
as defined for compounds of formula (I) and R.sub.8 is hydroxyl or
two R.sub.8 together with the interjacent boron atom form a five-
or six membered saturated heterocyclic ring or R.sub.10 is
C.sub.1-C.sub.6 alkyl, with a compound of formula IX-b, wherein
R.sub.3 and R.sub.4 are fluoro and R.sub.1, R.sub.2, R.sub.5 and n
are as defined for compounds of formula (I) and Hal is halogen,
preferably chloro or bromo, under conditions of the Suzuki-Miyaura
reaction or Stille reaction. This is shown in scheme 24.
##STR00040##
[0148] The compound of formula IX-a and IX-b can be prepared by
analogy to schemes 20, 21 and 22 starting from a compound of
formula X wherein R.sub.3 and R.sub.4 are hydrogen and R.sub.1,
R.sub.2, R.sub.5 and n are as defined for compounds of formula
I.
[0149] Alternatively, the compounds of formula I, wherein Q.sub.1,
Q.sub.2, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, m and n are as defined for compounds of formula I, can be
obtained by transformation of a compound of formula I-h, wherein
Q.sub.1, Q.sub.2, R.sup.1, R.sub.2, R.sub.3, R.sub.4, R.sub.6,
R.sub.7, m and n are as defined for formula (I) and Z represents
chlorine, bromine or iodine in a solvent, in the presence of or
absence of a base, and in the presence of a coupling reagent and a
metal catalyst. There are no particular limitations on the coupling
agent, catalyst, solvent and bases, provided it is used in ordinary
coupling reactions, such as those described in "Cross-Coupling
Reactions: A Practical Guide (Topics in Current Chemistry)", edited
by Norio Miyaura and S. L. Buchwald (editions Springer), or
"Metal-Catalyzed Cross-Coupling Reactions", edited by Armin de
Meijere and Francois Diederich (editions WILEY-VCH). This is shown
in Scheme 25.
##STR00041##
[0150] Alternatively, the compounds of formula I, wherein Q.sub.1,
Q.sub.2, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, m and n are as defined for compounds of formula I, can be
obtained by transformation of a compound of formula I-i, wherein
Q.sub.1, Q.sub.2, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, m and n are as defined for compounds of formula (I) and Y
represents chlorine, bromine or iodine in a solvent, in the
presence of or absence of a base, and in the presence of a coupling
reagent and a metal catalyst. There are no particular limitations
on the coupling agent, catalyst, solvent and bases, provided it is
used in ordinary coupling reactions, such as those described in
"Cross-Coupling Reactions: A Practical Guide (Topics in Current
Chemistry)", edited by Norio Miyaura and S. L. Buchwald (editions
Springer), or "Metal-Catalyzed Cross-Coupling Reactions", edited by
Armin de Meijere and Francois Diederich (editions WILEY-VCH). This
is shown in Scheme 26.
##STR00042##
[0151] Alternatively, the compounds of formula (I) wherein Q.sub.1,
Q.sub.2, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, m and n are as defined above, can be obtained by
transformation of another, closely related, compound of formula (I)
(or an analogue thereof) using standard synthesis techniques known
to the person skilled in the art. Non-exhaustive examples include
oxidation reactions, reduction reactions, hydrolysis reactions,
coupling reactions, aromatic nucleophilic or electrophilic
substitution reactions, nucleophilic substitution reactions,
nucleophilic addition reactions, and halogenation reactions.
[0152] The compounds of formula I-2 and I-6, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.a, m
and n are as defined for compounds of formula I, can be obtained by
transformation of a compound of formula I-1 or I-5, wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, m
and n are as defined for compounds of formula I, under reductive
reaction conditions, e.g. with hydrogen and a catalyst. The ring
nitrogen of the tetrahydroisoquinoline in the compounds of formulas
I-2 and I-6 (when R.sup.a.dbd.H) can further be alkylated (to give
R.sup.a.dbd.C.sub.1-C.sub.6 alkyl) by reaction with a
C.sub.1-C.sub.6 alkylhalide and a base, or acylated (to give
R.sup.a.dbd.C.sub.1-C.sub.6 alkylcarbonyl) by transformation with a
C.sub.1-C.sub.6 alkylcarbonylhalide and a base. This is shown in
Scheme 27.
##STR00043##
[0153] The compounds of formula I-3 and I-7, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, m and n are
as defined for compounds of formula I, can be obtained by
transformation of a compound of formula I-1 or I-5, wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, m
and n are as defined for compounds of formula I, under oxidative
reaction conditions, e.g. with meta-chloroperbenzoic acid. This is
shown in Scheme 28.
##STR00044##
[0154] The compounds of formula I-4 and I-8, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, m and n are
as defined for compounds of formula I, can be obtained by
transformation of a compound of formula I-1 or I-5, wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, m
and n are as defined for compounds of formula I, under oxidative
reaction conditions, e.g. with methyltrioxorhenium and urea
hydrogen peroxide. This is shown in Scheme 29.
##STR00045##
[0155] Alternatively, the compounds of formula I-4 and I-8, wherein
R R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, m
and n are as defined for compounds of formula I, can be obtained by
transformation of a compound of formula I-3 and I-7, wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, m
and n are as defined for compounds of formula I, under acidic
conditions, e.g. with methanesulfonic acid. This is shown in Scheme
30.
##STR00046##
[0156] Certain intermediates described in the above schemes are
novel and as such form a further aspect of the invention.
[0157] One group of novel intermediates are compounds of formula
(XA):
##STR00047## [0158] wherein R.sub.5a is fluoro or hydrogen; and
R.sub.5b is fluoro or hydrogen; and compounds of formula (XB):
[0158] ##STR00048## [0159] wherein R.sub.5a is fluoro or hydrogen;
and R.sub.5b is fluoro or hydrogen; and compounds of formula
(XC):
[0159] ##STR00049## [0160] wherein R.sub.5a is fluoro or hydrogen;
and R.sub.5b is fluoro or hydrogen; and compounds of formula
(XD):
[0160] ##STR00050## [0161] wherein R.sub.5a is fluoro or hydrogen;
and R.sub.5b is fluoro or hydrogen.
[0162] Particularly preferred novel intermediates are:
##STR00051##
[0163] The compounds of formula (I) can be used in the agricultural
sector and related fields of use e.g. as active ingredients for
controlling plant pests or on non-living materials for control of
spoilage microorganisms or organisms potentially harmful to man.
The novel compounds are distinguished by excellent activity at low
rates of application. by being well tolerated by plants and by
being environmentally safe. They have very useful curative,
preventive and systemic properties and may be used for protecting
numerous cultivated plants. The compounds of formula (I) can be
used to inhibit or destroy the pests that occur on plants or parts
of plants (fruit, blossoms, leaves, stems, tubers, roots) of
different crops of useful plants, while at the same time protecting
also those parts of the plants that grow later e.g. from
phytopathogenic microorganisms.
[0164] It is also possible to use compounds of formula (I) as
fungicide. The term "fungicide" as used herein means a compound
that controls, modifies, or prevents the growth of fungi. The term
"fungicidally effective amount" means the quantity of such a
compound or combination of such compounds that is capable of
producing an effect on the growth of fungi. Controlling or
modifying effects include all deviation from natural development,
such as killing, retardation and the like, and prevention includes
barrier or other defensive formation in or on a plant to prevent
fungal infection.
[0165] It is also possible to use compounds of formula (I) as
dressing agents for the treatment of plant propagation material,
e.g., seed, such as fruits, tubers or grains, or plant cuttings
(for example rice), for the protection against fungal infections as
well as against phytopathogenic fungi occurring in the soil. The
propagation material can be treated with a composition comprising a
compound of formula (I) before planting: seed, for example, can be
dressed before being sown. The compounds of formula (I) can also be
applied to grains (coating), either by impregnating the seeds in a
liquid formulation or by coating them with a solid formulation. The
composition can also be applied to the planting site when the
propagation material is being planted, for example, to the seed
furrow during sowing. The invention relates also to such methods of
treating plant propagation material and to the plant propagation
material so treated.
[0166] Furthermore the compounds according to present invention can
be used for controlling fungi in related areas, for example in the
protection of technical materials, including wood and wood related
technical products, in food storage, in hygiene management.
[0167] In addition, the invention could be used to protect
non-living materials from fungal attack, e.g. lumber, wall boards
and paint.
[0168] Compounds of formula (I) and fungicidal compositions
containing them may be used to control plant diseases caused by a
broad spectrum of fungal plant pathogens. They are effective in
controlling a broad spectrum of plant diseases, such as foliar
pathogens of ornamental, turf, vegetable, field, cereal, and fruit
crops.
[0169] These fungi and fungal vectors of disease, as well as
phytopathogenic bacteria and viruses, which may be controlled are
for example:
[0170] Absidia corymbifera, Alternaria spp, Aphanomyces spp,
Ascochyta spp, Aspergillus spp. including A. flavus, A. fumigatus,
A. nidulans, A. niger, A. terrus, Aureobasidium spp. including A.
pullulans, Blastomyces dermatitidis, Blumeria graminis, Bremia
lactucae, Botryosphaeria spp. including B. dothidea, B. obtusa,
Botrytis spp. inclusing B. cinerea, Candida spp. including C.
albicans, C. glabrata, C. krusei, C. lusitaniae, C. parapsilosis,
C. tropicalis, Cephaloascus fragrans, Ceratocystis spp, Cercospora
spp. including C. arachidicola, Cercosporidium personatum,
Cladosporium spp, Claviceps purpurea,
[0171] Coccidioides immitis, Cochliobolus spp, Colletotrichum spp.
including C. musae,
[0172] Cryptococcus neoformans, Diaporthe spp, Didymella spp,
Drechslera spp, Elsinoe spp,
[0173] Epidermophyton spp, Erwinia amylovora, Erysiphe spp.
including E. cichoracearum, Eutypa lata, Fusarium spp. including F.
culmorum, F. graminearum, F. langsethiae, F. moniliforme, F.
oxysporum, F. proliferatum, F. subglutinans, F. solani,
Gaeumannomyces graminis, Gibberella fujikuroi, Gloeodes pomigena,
Gloeosporium musarum, Glomerella cingulate. Guignardia bidwellii,
Gymnosporangium juniperi-virginianae, Helminthosporium spp,
Hemileia spp, Histoplasma spp. including H. capsulatum, Laetisaria
fuciformis, Leptographium lindbergi, Leveillula taurica,
Lophodermium seditiosum, Microdochium nivale, Microsporum spp,
Monilinia spp, Mucor spp, Mycosphaerella spp, including M.
graminicola, M. pomi, Oncobasidium theobromaeon, Ophiostoma piceae,
Paracoccidioides spp, Penicillium spp. including P. digitatum, P.
italicum, Petriellidium spp, Peronosclerospora spp. Including P.
maydis, P. philippinensis and P. sorghi, Peronospora spp,
Phaeosphaeria nodorum, Phakopsora pachyrhizi, Phellinus igniarus,
Phialophora spp, Phoma spp, Phomopsis viticola, Phytophthora spp,
including P. infestans, Plasmopara spp, including P. halstedii, P.
viticola, Pleospora spp., Podosphaera spp. including P.
leucotricha, Polymyxa graminis, Polymyxa betae, Pseudocercosporella
herpotrichoides, Pseudomonas spp, Pseudoperonospora spp. including
P. cubensis, P. humuli, Pseudopeziza tracheiphila, Puccinia Spp.
including P. hordei, P, recondita, P. striiformis, P. triticina,
Pyrenopeziza spp, Pyrenophora spp, Pyricularia spp. including P.
oryzae, Pythium spp. including P. ultimum, Ramularia spp,
Rhizoctonia spp, Rhizomucor pusillus, Rhizopus arrhizus,
Rhynchosporium spp, Scedosporium spp. including S. apiospermum and
S. prolificans, Schizothyrium pomi,
[0174] Sclerotinia spp. Sclerotium spp, Septoria spp, including S.
nodorum, S. tritici, Sphaerotheca macularis, Sphaerotheca fusca
(Sphaerotheca fuliginea), Sporothorix spp, Stagonospora nodorum,
Stemphylium spp., Stereum hirsutum, Thanatephorus cucumeris,
Thielaviopsis basicola, Tilletia spp, Trichoderma spp. including T.
harzianum, T. pseudokoningii, T. viride,
[0175] Trichophyton spp, Typhula spp, Uncinula necator, Urocystis
spp, Ustilago spp, Venturia spp, including V. inaequalis,
Verticillium spp, and Xanthomonas spp.
[0176] In particular, compounds of formula (I) and fungicidal
compositions containing them may be used to control plant diseases
caused by a broad spectrum of fungal plant pathogens in the
Basidiomycete, Ascomycete, Oomycete and/or Deuteromycete,
Blasocladiomycete, Chrytidiomycete, Glomeromycete and/or
Mucoromycete classes.
[0177] These pathogens may include:
[0178] Oomycetes, including Phytophthora diseases such as those
caused by Phytophthora capsici, Phytophthora infestans,
Phytophthora sojae, Phytophthora fragariae, Phytophthora
nicotianae, Phytophthora cinnamomi, Phytophthora citricola,
Phytophthora citrophthora and Phytophthora erythroseptica; Pythium
diseases such as those caused by Pythium aphanidermatum, Pythium
arrhenomanes, Pythium graminicola, Pythium irregulare and Pythium
ultimum; diseases caused by Peronosporales such as Peronospora
destructor, Peronospora parasitica, Plasmopara viticola, Plasmopara
halstedii, Pseudoperonospora cubensis, Albugo candida,
Sclerophthora macrospora and Brernia lactucae; and others such as
Aphanomyces cochlioides, Labyrinthula zosterae, Peronosclerospora
sorghi and Sclerospora graminicola.
[0179] Ascomycetes, including blotch, spot, blast or blight
diseases and/or rots for example those caused by Pleosporales such
as Stemphylium solani, Stagonospora tainanensis, Spilocaea
oleaginea, Setosphaeria turcica, Pyrenochaeta lycoperisici,
Pleospora herbarum, Phoma destructiva, Phaeosphaeria
herpotrichoides, Phaeocryptocus gaeumannii, Ophiosphaerella
graminicola, Ophiobolus graminis, Leptosphaeria maculans,
Hendersonia creberrima, Helminthosporium triticirepentis,
Setosphaeria turcica, Drechslera glycines, Didymella bryoniae,
Cycloconium oleagineum, Corynespora cassficola, Cochliobolus
sativus, Bipolaris cactivora, Venturia inaequalis, Pyrenophora
teres, Pyrenophora tritici-repentis, Alternaria alternata,
Alternaria brassicicola, Alternaria solani and Alternaria
tomatophila, Capnodiales such as Septoria tritici, Septoria
nodorum, Septoria glycines, Cercospora arachidicola, Cercospora
sojina, Cercospora zeae-maydis, Cercosporella capsellae and
Cercosporella herpotrichoides, Cladosporium carpophilum,
Cladosporium effusum, Passalora fulva, Cladosporium oxysporum,
Dothistroma septosporum, Isariopsis clavispora, Mycosphaerella
fijiensis, Mycosphaerella graminicola, Mycovellosiella koepkeii,
Phaeoisariopsis bataticola, Pseudocercospora vitis,
Pseudocercosporella herpotrichoides, Ramularia beticola, Ramularia
collo-cygni, Magnaporthales such as Gaeumannomyces graminis,
Magnaporthe grisea, Pyricularia oryzae, Diaporthales such as
Anisogramma anomala, Apiognomonia errabunda, Cytospora platani,
Diaporthe phaseolorum, Discula destructiva, Gnomonia fructicola,
Greeneria uvicola, Melanconium juglandinum, Phomopsis viticola,
Sirococcus clavigignenti-juglandacearum, Tubakia dryina, Dicarpella
spp., Valsa ceratosperma, and others such as Actinothyrium
graminis, Ascochyta pisi, Aspergillus flavus, Aspergillus
fumigatus, Aspergillus nidulans, Asperisporium caricae, Blumeriella
jaapii, Candida spp., Capnodium ramosum, Cephaloascus spp.,
Cephalosporium gramineum, Ceratocystis paradoxa, Chaetomium spp.,
Hymenoscyphus pseudoalbidus, Coccidioides spp., Cylindrosporium
padi, Diplocarpon malae, Drepanopeziza campestris, Elsinoe
ampelina, Epicoccum nigrum, Epidermophyton spp., Eutypa lata,
Geotrichum candidum, Gibellina cerealis, Gloeocercospora sorghi,
Gloeodes pomigena, Gloeosporium perennans; Gloeotinia temulenta,
Griphospaeria corticola, Kabatiella lini, Leptographium
microsporum, Leptosphaerulinia crassiasca, Lophodermium seditiosum,
Marssonina graminicola, Microdochium nivale, Monilinia fructicola,
Monographella albescens, Monosporascus cannonballus, Naemacyclus
spp., Ophiostorna novo-ulmi, Paracoccidioides brasiliensis,
Penicillium expansum, Pestalotia rhododendri, Petriellidium spp.,
Pezicula spp., Phialophora gregata, Phyllachora pomigena,
Phymatotrichum omnivore, Physalospora abdita, Plectosporium
tabacinum, Polyscytalum pustulans, Pseudopeziza medicaginis,
Pyrenopeziza brassicae, Remulispora sorghi, Rhabdocline
pseudotsugae, Rhynchosporium secalis, Sacrocladium oryzae,
Scedosporium spp., Schizothyrium pomi, Sclerotinia scterotiorum,
Sclerotinia minor; Sclerotium spp., Typhula ishikariensis,
Seimatosporium mariae, Lepteutypa cupressi, Septocyta ruborurn,
Sphaceloma perseae, Sporonema phacidioides, Stigmina palmivora,
Tapesia yallundae, Taphrina bullata, Thielviopsis basicola,
Trichoseptoria fructigena, Zygophiala jarnaicensis; powdery mildew
diseases for example those caused by Erysiphales such as Blumeria
graminis, Erysiphe polygoni, Uncinula necator, Sphaerotheca
fuligena, Podosphaera leucotricha, Podospaera macularis
Gotovinomyces cichoracearum, Leveillula taurica, Microsphaera
diffusa, Oidiopsis gossypii, Phyllactinia guttata and Oidium
arachidis; molds for example those caused by Botryosphaeriales such
as Dothiorella aromatica, Diplodia seriata, Guignardia bidwellii,
Botrytis cinerea, Botryotinia allii, Botryotinia fabae, Fusicoccum
amygdali, Laslodiplodia theobromae, Macrophoma theicola,
Macrophomina phaseolina, Phyllosticta cucurbitacearum; anthracnoses
for example those caused by Glommerelales such as Colletotrichum
gloeosporioides, Colletotrichum lagenarium, Colletotrichum
gossypii, Glomerella cingulata, and Colletotrichum graminicola; and
wilts or blights for example those caused by Hypocreales such as
Acremonium strictum, Claviceps purpurea, Fusarium culmorum,
Fusarium graminearum, Fusarium virguliforme, Fusarium oxysporum,
Fusarium subglutinans, Fusarium oxysporum f.sp. cubense, Gerlachia
nivale, Gibberella fujikurol, Gibberella zeae, Gliocladium spp.,
Myrothecium verrucaria, Nectria ramulariae, Trichoderma viride,
Trichothecium roseum, and Verticillium theobromae.
[0180] Basidiomycetes, including smuts for example those caused by
Ustilaginales such as Ustilaginoidea vixens, Ustilago nuda,
Ustilago tritici, Ustilago zeae, rusts for example those caused by
Pucciniales such as Cerotelium fici, Chtysornyxa arctostaphyli,
Coleosporium ipomoeae, Hemileia vastatrix, Puccinia arachidis,
Puccinia cacabata, Puccinia graminis, Puccinia recondita, Puccinia
sorghi, Puccinia hordel, Puccinia striiformis f.sp. Hordei,
Puccinia striiformis f.sp. Secalis, Pucciniastrum coryli, or
Uredinales such as Cronartium ribicola, Gymnosporangium
juniperi-viginianae, Melampsora medusae, Phakopsora pachyrhizi,
Phragmidium mucronatum, Physopella ampelosidis, Tranzschelia
discolor and Uromyces viciae-fabae; and other rots and diseases
such as those caused by Cryptococcus spp., Exobasidium vexans,
Marasmiellus inoderma, Mycelia spp., Sphacelotheca reiliana,
Typhula ishikariensis, Urocystis agropyri, Itersonilia perplexans,
Corticium invisum, Laetisaria fuciformis, Waitea circinata,
Rhizoctonia solani, Thanetephorus cucurmeris, Entyloma dahliae,
Entylomelle microspore, Neovossia motiniae and Tilletia caries,
[0181] Blastocladiomycetes, such as Physoderma maydis.
[0182] Mucoromycetes, such as Choanephora cucurbitarum; Mucor spp.;
Rhizopus arrhizus,
[0183] As well as diseases caused by other species and genera
closely related to those listed above.
[0184] In addition to their fungicidal activity, the compounds and
compositions comprising them may also have activity against
bacteria such as Erwinia amylovora, Erwinia caratovora, Xanthomonas
campestris, Pseudomonas syringae, Strptomyces scabies and other
related species as well as certain protozoa.
[0185] Within the scope of present invention, target crops and/or
useful plants to be protected typically comprise perennial and
annual crops, such as berry plants for example blackberries,
blueberries, cranberries, raspberries and strawberries; cereals for
example barley, maize (corn), millet, oats, rice, rye, sorghum
triticale and wheat; fibre plants for example cotton, flax, hemp,
jute and sisal; field crops for example sugar and fodder beet,
coffee, hops, mustard, oilseed rape (canola), poppy, sugar cane,
sunflower, tea and tobacco; fruit trees for example apple, apricot,
avocado, banana, cherry, citrus, nectarine, peach, pear and plum;
grasses for example Bermuda grass, bluegrass, bentgrass, centipede
grass, fescue, ryegrass, St. Augustine grass and Zoysia grass;
herbs such as basil, borage, chives, coriander, lavender, lovage,
mint, oregano, parsley, rosemary, sage and thyme; legumes for
example beans, lentils, peas and soya beans; nuts for example
almond, cashew, ground nut, hazelnut, peanut, pecan, pistachio and
walnut; palms for example oil palm; ornamentals for example
flowers, shrubs and trees; other trees, for example cacao, coconut,
olive and rubber; vegetables for example asparagus, aubergine,
broccoli, cabbage, carrot, cucumber, garlic, lettuce, marrow,
melon, okra, onion, pepper, potato, pumpkin, rhubarb, spinach and
tomato; and vines for example grapes.
[0186] The useful plants and/or target crops in accordance with the
invention include conventional as well as genetically enhanced or
engineered varieties such as, for example, insect resistant (e.g.
Bt. and VIP varieties) as well as disease resistant, herbicide
tolerant (e.g. glyphosate- and glufosinate-resistant maize
varieties commercially available under the trade names
RoundupReady.RTM. and LibertyLink.RTM.) and nematode tolerant
varieties. By way of example, suitable genetically enhanced or
engineered crop varieties include the Stoneville 5599BR cotton and
Stoneville 4892BR cotton varieties.
[0187] The term "useful plants" and/or "target crops" is to be
understood as including also useful plants that have been rendered
tolerant to herbicides like bromoxynil or classes of herbicides
(such as, for example, HPPD inhibitors, ALS inhibitors, for example
primisulfuron, prosulfuron and trifloxysulfuron, EPSPS
(5-enol-pyrovyl-shikimate-3-phosphate-synthase) inhibitors, GS
(glutamine synthetase) inhibitors or PPO
(protoporphyrinogen-oxidase) inhibitors) as a result of
conventional methods of breeding or genetic engineering. An example
of a crop that has been rendered tolerant to imidazolinones, e.g.
imazamox, by conventional methods of breeding (mutagenesis) is
Clearfield.RTM. summer rape (Canola). Examples of crops that have
been rendered tolerant to herbicides or classes of herbicides by
genetic engineering methods include glyphosate- and
glufosinate-resistant maize varieties commercially available under
the trade names RoundupReady.RTM., Herculex I.RTM. and
LibertyLink.RTM..
[0188] The term "useful plants" and/or "target crops" is to be
understood as including those which naturally are or have been
rendered resistant to harmful insects. This includes plants
transformed by the use of recombinant DNA techniques, for example,
to be capable of synthesising one or more selectively acting
toxins, such as are known, for example, from toxin-producing
bacteria. Examples of toxins which can be expressed include
.delta.-endotoxins, vegetative insecticidal proteins (Vip),
insecticidal proteins of bacteria colonising nematodes, and toxins
produced by scorpions, arachnids, wasps and fungi. An example of a
crop that has been modified to express the Bacillus thuringiensis
toxin is the Bt maize KnockOut.RTM. (Syngenta Seeds). An example of
a crop comprising more than one gene that codes for insecticidal
resistance and thus expresses more than one toxin is VipCot.RTM.
(Syngenta Seeds). Crops or seed material thereof can also be
resistant to multiple types of pests (so-called stacked transgenic
events when created by genetic modification). For example, a plant
can have the ability to express an insecticidal protein while at
the same time being herbicide tolerant, for example Herculex I.RTM.
(Dow AgroSciences, Pioneer Hi-Bred International).
[0189] The term "useful plants" and/or "target crops" is to be
understood as including also useful plants which have been so
transformed by the use of recombinant DNA techniques that they are
capable of synthesising antipathogenic substances having a
selective action, such as, for example, the so-called
"pathogenesis-related proteins" (PRPs, see e.g. EP-A-0 392 225).
Examples of such antipathogenic substances and transgenic plants
capable of synthesising such antipathogenic substances are known,
for example, from EP-A-0 392 225, WO 95/33818, and EP-A-0 353 191.
The methods of producing such transgenic plants are generally known
to the person skilled in the art and are described, for example, in
the publications mentioned above.
[0190] Toxins that can be expressed by transgenic plants include,
for example, insecticidal proteins from Bacillus cereus or Bacillus
popilliae; or insecticidal proteins from Bacillus thuringiensis,
such as .delta.-endotoxins, e.g. Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2,
Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal
proteins (Vip), e.g. Vip1, Vip2, Vip3 or Vip3A; or insecticidal
proteins of bacteria colonising nematodes, for example Photorhabdus
spp. or Xenorhabdus spp., such as Photorhabdus luminescens,
Xenorhabdus nematophilus; toxins produced by animals, such as
scorpion toxins, arachnid toxins, wasp toxins and other
insect-specific neurotoxins; toxins produced by fungi, such as
Streptomycetes toxins, plant lectins, such as pea lectins, barley
lectins or snowdrop lectins; agglutinins; proteinase inhibitors,
such as trypsin inhibitors, serine protease inhibitors, patatin,
cystatin, papain inhibitors; ribosome-inactivating proteins (RIP),
such as ricin, maize-RIP, abrin, luffin, saporin or bryodin;
steroid metabolism enzymes, such as 3-hydroxysteroidoxidase,
ecdysteroid-UDP-glycosyl-transferase, cholesterol oxidases,
ecdysone inhibitors, HMG-COA-reductase, ion channel blockers, such
as blockers of sodium or calcium channels, juvenile hormone
esterase, diuretic hormone receptors, stilbene synthase, bibenzyl
synthase, chitinases and glucanases.
[0191] Further, in the context of the present invention there are
to be understood by 3-endotoxins, for example Cry1Ab, Cry1Ac,
Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative
insecticidal proteins (Vip), for example Vip1, Vip2, Vip3 or Vip3A,
expressly also hybrid toxins, truncated toxins and modified toxins.
Hybrid toxins are produced recombinantly by a new combination of
different domains of those proteins (see, for example, WO
02/15701). Truncated toxins, for example a truncated Cry1Ab, are
known. In the case of modified toxins, one or more amino acids of
the naturally occurring toxin are replaced. In such amino acid
replacements, preferably non-naturally present protease recognition
sequences are inserted into the toxin, such as, for example, in the
case of Cry3A055, a cathepsin-G-recognition sequence is inserted
into a Cry3A toxin (see WO03/018810).
[0192] More examples of such toxins or transgenic plants capable of
synthesising such toxins are disclosed, for example, in EP-A-0 374
753, WO93/07278, WO95/34656, EP-A-0 427 529, EP-A-451 878 and
WO03/052073.
[0193] The processes for the preparation of such transgenic plants
are generally known to the person skilled in the art and are
described, for example, in the publications mentioned above.
Cryl-type deoxyribonucleic acids and their preparation are known,
for example, from WO 95/34656, EP-A-0 367 474, EP-A-0 401 979 and
WO 90/13651.
[0194] The toxin contained in the transgenic plants imparts to the
plants tolerance to harmful insects. Such insects can occur in any
taxonomic group of insects, but are especially commonly found in
the beetles (Coleoptera), two-winged insects (Diptera) and
butterflies (Lepidoptera).
[0195] Transgenic plants containing one or more genes that code for
an insecticidal resistance and express one or more toxins are known
and some of them are commercially available. Examples of such
plants are: YieldGard.RTM. (maize variety that expresses a Cry1Ab
toxin); YieldGard Rootworm.RTM. (maize variety that expresses a
Cry3Bb1 toxin); YieldGard Plus.RTM. (maize variety that expresses a
Cry1Ab and a Cry38b1 toxin); Starlink.RTM. (maize variety that
expresses a Cry9C toxin); Herculex I.RTM. (maize variety that
expresses a Cry1Fa2 toxin and the enzyme phosphinothricine
N-acetyltransferase (PAT) to achieve tolerance to the herbicide
glufosinate ammonium); NuCOTN 33B.RTM. (cotton variety that
expresses a Cry1Ac toxin); Bollgard I.RTM. (cotton variety that
expresses a Cry1Ac toxin); Bollgard II.RTM. (cotton variety that
expresses a Cry1Ac and a Cry2Ab toxin); VipCot.RTM. (cotton variety
that expresses a Vip3A and a Cry1Ab toxin); NewLeaf.RTM. (potato
variety that expresses a Cry3A toxin); NatureGard.RTM.,
Agrisure.RTM. GT Advantage (GA21 glyphosate-tolerant trait),
Agrisure.RTM. CB Advantage (Bt11 corn borer (CB) trait) and
Protecta.RTM..
[0196] Further examples of such transgenic crops are:
[0197] 1. Bt11 Maize from Syngenta Seeds SAS, Chemin de l'Hobit 27,
F-31 790 St. Sauveur, France, registration number C/FR/96/05/10.
Genetically modified Zea mays which has been rendered resistant to
attack by the European corn borer (Ostrinia nubilalis and Sesamia
nonagrioides) by transgenic expression of a truncated Cry1Ab toxin.
Bt11 maize also transgenically expresses the enzyme PAT to achieve
tolerance to the herbicide glufosinate ammonium.
[0198] 2. Bt176 Maize from Syngenta Seeds SAS, Chemin de l'Hobit
27, F-31 790 St. Sauveur, France, registration number
C/FR/96/05/10. Genetically modified Zea mays which has been
rendered resistant to attack by the European corn borer (Ostrinia
nubilalis and Sesamia nonagrioides) by transgenic expression of a
Cry1Ab toxin. Bt176 maize also transgenically expresses the enzyme
PAT to achieve tolerance to the herbicide glufosinate ammonium.
[0199] 3. MIR604 Maize from Syngenta Seeds SAS, Chemin de l'Hobit
27, F-31 790 St. Sauveur, France, registration number
C/FR/96/05/10. Maize which has been rendered insect-resistant by
transgenic expression of a modified Cry3A toxin. This toxin is
Cry3A055 modified by insertion of a cathepsin-G-protease
recognition sequence. The preparation of such transgenic maize
plants is described in WO 03/018810.
[0200] 4, MON 863 Maize from Monsanto Europe S.A. 270-272 Avenue de
Tervuren, B-1150 Brussels, Belgium, registration number C/DE/02/9.
MON 863 expresses a Cry3Bb1 toxin and has resistance to certain
Coleoptera insects.
[0201] 5. IPC 531 Cotton from Monsanto Europe S.A. 270-272 Avenue
de Tervuren, B-1150 Brussels, Belgium, registration number
C/ES/96/02.
[0202] 6. 1507 Maize from Pioneer Overseas Corporation, Avenue
Tedesco, 7 B-1160 Brussels, Belgium, registration number
C/NL/00/10. Genetically modified maize for the expression of the
protein Cry1F for achieving resistance to certain Lepidoptera
insects and of the PAT protein for achieving tolerance to the
herbicide glufosinate ammonium.
[0203] 7. NK603.times.MON 810 Maize from Monsanto Europe S.A.
270-272 Avenue de Tervuren, 8-1150 Brussels, Belgium, registration
number C/GB/02/M3/03. Consists of conventionally bred hybrid maize
varieties by crossing the genetically modified varieties NK603 and
MON 810. NK603.times.MON 810 Maize transgenically expresses the
protein CP4 EPSPS, obtained from Agrobacterium sp. strain CP4,
which imparts tolerance to the herbicide Roundup.RTM. (contains
glyphosate), and also a Cry1Ab toxin obtained from Bacillus
thuringiensis subsp. kurstaki which brings about tolerance to
certain Lepidoptera, include the European corn borer.
[0204] The term "locus" as used herein means fields in or on which
plants are growing, or where seeds of cultivated plants are sown,
or where seed will be placed into the soil. It includes soil,
seeds, and seedlings, as well as established vegetation.
[0205] The term "plants" refers to all physical parts of a plant,
including seeds, seedlings, saplings, roots, tubers, stems, stalks,
foliage, and fruits.
[0206] The term "plant propagation material" is understood to
denote generative parts of the plant, such as seeds, which can be
used for the multiplication of the latter, and vegetative material,
such as cuttings or tubers, for example potatoes. There may be
mentioned for example seeds (in the strict sense), roots, fruits,
tubers, bulbs, rhizomes and parts of plants. Germinated plants and
young plants which are to be transplanted after germination or
after emergence from the soil, may also be mentioned. These young
plants may be protected before transplantation by a total or
partial treatment by immersion. Preferably "plant propagation
material" is understood to denote seeds.
[0207] Pesticidal agents referred to herein using their common name
are known, for example, from "The Pesticide Manual", 15th Ed.,
British Crop Protection Council 2009.
[0208] The compounds of formula (I) may be used in unmodified form
or, preferably, together with the adjuvants conventionally employed
in the art of formulation. To this end they may be conveniently
formulated in known manner to emulsifiable concentrates, coatable
pastes, directly sprayable or dilutable solutions or suspensions,
dilute emulsions, wettable powders, soluble powders, dusts,
granulates, and also encapsulations e.g. in polymeric substances.
As with the type of the compositions, the methods of application,
such as spraying, atomising, dusting, scattering, coating or
pouring, are chosen in accordance with the intended objectives and
the prevailing circumstances. The compositions may also contain
further adjuvants such as stabilizers, antifoams, viscosity
regulators, binders or tackifiers as well as fertilizers,
micronutrient donors or other formulations for obtaining special
effects.
[0209] Suitable carriers and adjuvants, e.g. for agricultural use,
can be solid or liquid and are substances useful in formulation
technology, e.g. natural or regenerated mineral substances,
solvents, dispersants, wetting agents, tackifiers, thickeners,
binders or fertilizers. Such carriers are for example described in
WO 97/33890.
[0210] Suspension concentrates are aqueous formulations in which
finely divided solid particles of the active compound are
suspended. Such formulations include anti-settling agents and
dispersing agents and may further include a wetting agent to
enhance activity as well an anti-foam and a crystal growth
inhibitor. In use, these concentrates are diluted in water and
normally applied as a spray to the area to be treated. The amount
of active ingredient may range from 0.5% to 95% of the
concentrate.
[0211] Wettable powders are in the form of finely divided particles
which disperse readily in water or other liquid carriers. The
particles contain the active ingredient retained in a solid matrix.
Typical solid matrices include fuller's earth, kaolin clays,
silicas and other readily wet organic or inorganic solids. Wettable
powders normally contain from 5% to 95% of the active ingredient
plus a small amount of wetting, dispersing or emulsifying
agent.
[0212] Emulsifiable concentrates are homogeneous liquid
compositions dispersible in water or other liquid and may consist
entirely of the active compound with a liquid or solid emulsifying
agent, or may also contain a liquid carrier, such as xylene, heavy
aromatic naphthas, isophorone and other non-volatile organic
solvents. In use, these concentrates are dispersed in water or
other liquid and normally applied as a spray to the area to be
treated. The amount of active ingredient may range from 0.5% to 95%
of the concentrate.
[0213] Granular formulations include both extrudates and relatively
coarse particles and are usually applied without dilution to the
area in which treatment is required. Typical carriers for granular
formulations include sand, fuller's earth, attapulgite clay,
bentonite clays, montmorillonite clay, vermiculite, perlite,
calcium carbonate, brick, pumice, pyrophillite, kaolin, dolomite,
plaster, wood flour, ground corn cobs, ground peanut hulls, sugars,
sodium chloride, sodium sulphate, sodium silicate, sodium borate,
magnesia, mica, iron oxide, zinc oxide, titanium oxide, antimony
oxide, cryolite, gypsum, diatomaceous earth, calcium sulphate and
other organic or inorganic materials which absorb or which can be
coated with the active compound. Granular formulations normally
contain 5% to 25% of active ingredients which may include
surface-active agents such as heavy aromatic naphthas, kerosene and
other petroleum fractions, or vegetable oils; and/or stickers such
as dextrins, glue or synthetic resins.
[0214] Dusts are free-flowing admixtures of the active ingredient
with finely divided solids such as talc, clays, flours and other
organic and inorganic solids which act as dispersants and
carriers.
[0215] Microcapsules are typically droplets or granules of the
active ingredient enclosed in an inert porous shell which allows
escape of the enclosed material to the surroundings at controlled
rates. Encapsulated droplets are typically 1 to 50 microns in
diameter. The enclosed liquid typically constitutes 50 to 95% of
the weight of the capsule and may include solvent in addition to
the active compound. Encapsulated granules are generally porous
granules with porous membranes sealing the granule pore openings,
retaining the active species in liquid form inside the granule
pores. Granules typically range from 1 millimetre to 1 centimetre
and preferably 1 to 2 millimetres in diameter. Granules are formed
by extrusion, agglomeration or prilling, or are naturally
occurring. Examples of such materials are vermiculite, sintered
clay, kaolin, attapulgite clay, sawdust and granular carbon. Shell
or membrane materials include natural and synthetic rubbers,
cellulosic materials, styrene-butadiene copolymers,
polyacrylonitriles, polyacrylates, polyesters, polyamides,
polyureas, polyurethanes and starch xanthates.
[0216] Other useful formulations for agrochemical applications
include simple solutions of the active ingredient in a solvent in
which it is completely soluble at the desired concentration, such
as acetone, alkylated naphthalenes, xylene and other organic
solvents. Pressurised sprayers, wherein the active ingredient is
dispersed in finely-divided form as a result of vaporisation of a
low boiling dispersant solvent carrier, may also be used.
[0217] Suitable agricultural adjuvants and carriers that are useful
in formulating the compositions of the invention in the formulation
types described above are well known to those skilled in the
art.
[0218] Liquid carriers that can be employed include, for example,
water, toluene, xylene, petroleum naphtha, crop oil, acetone,
methyl ethyl ketone, cyclohexanone, acetic anhydride, acetonitrile,
acetophenone, amyl acetate, 2-butanone, chlorobenzene, cyclohexane,
cyclohexanol, alkyl acetates, diacetonalcohol, 1,2-dichloropropane,
diethanolamine, p-diethylbenzene, diethylene glycol, diethylene
glycol abietate, diethylene glycol butyl ether, diethylene glycol
ethyl ether, diethylene glycol methyl ether, N,N-dimethyl
formamide, dimethyl sulfoxide, 1,4-dioxane, dipropylene glycol,
dipropylene glycol methyl ether, dipropylene glycol dibenzoate,
diproxitol, alkyl pyrrolidinone, ethyl acetate, 2-ethyl hexanol,
ethylene carbonate, 1,1,1-trichloroethane, 2-heptanone, alpha
pinene, d-limonene, ethylene glycol, ethylene glycol butyl ether,
ethylene glycol methyl ether, gamma-butyrolactone, glycerol,
glycerol diacetate, glycerol monoacetate, glycerol triacetate,
hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate,
isooctane, isophorone, isopropyl benzene, isopropyl myristate,
lactic acid, laurylamine, mesityl oxide, methoxy-propanol, methyl
isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl
octanoate, methyl oleate, methylene chloride, m-xylene, n-hexane,
n-octylamine, octadecanoic acid, octyl amine acetate, oleic acid,
oleylamine, o-xylene, phenol, polyethylene glycol (PEG400),
propionic acid, propylene glycol, propylene glycol monomethyl
ether, p-xylene, toluene, triethyl phosphate, triethylene glycol,
xylene sulfonic acid, paraffin, mineral oil, trichloroethylene,
perchloroethylene, ethyl acetate, amyl acetate, butyl acetate,
methanol, ethanol, isopropanol, and higher molecular weight
alcohols such as amyl alcohol, tetrahydrofurfuryl alcohol, hexanol,
octanol, etc., ethylene glycol, propylene glycol, glycerine and
N-methyl-2-pyrrolidinone. Water is generally the carrier of choice
for the dilution of concentrates.
[0219] Suitable solid carriers include, for example, talc, titanium
dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr,
chalk, diatomaxeous earth, lime, calcium carbonate, bentonite clay,
fuller's earth, cotton seed hulls, wheat flour, soybean flour,
pumice, wood flour, walnut shell flour and lignin.
[0220] A broad range of surface-active agents are advantageously
employed in both said liquid and solid compositions, especially
those designed to be diluted with carrier before application. These
agents, when used, normally comprise from 0.1% to 15% by weight of
the formulation. They can be anionic, cationic, non-ionic or
polymeric in character and can be employed as emulsifying agents,
wetting agents, suspending agents or for other purposes. Typical
surface active agents include salts of alkyl sulfates, such as
diethanolammonium lauryl sulphate; alkylarylsulfonate salts, such
as calcium dodecylbenzenesulfonate; alkylphenol-alkylene oxide
addition products, such as nonylphenol-C.sub. 18 ethoxylate;
alcohol-alkylene oxide addition products, such as tridecyl
alcohol-C.sub. 16 ethoxylate; soaps, such as sodium stearate;
alkylnaphthalenesulfonate salts, such as sodium
dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate
salts, such as sodium di(2-ethylhexyl) sulfosuccinate; sorbitol
esters, such as sorbitol oleate; quaternary amines, such as lauryl
trimethylammonium chloride; polyethylene glycol esters of fatty
acids, such as polyethylene glycol stearate; block copolymers of
ethylene oxide and propylene oxide; and salts of mono and dialkyl
phosphate esters.
[0221] Other adjuvants commonly utilized in agricultural
compositions include crystallisation inhibitors, viscosity
modifiers, suspending agents, spray droplet modifiers, pigments,
antioxidants, foaming agents, anti-foaming agents, light-blocking
agents, compatibilizing agents, antifoam agents, sequestering
agents, neutralising agents and buffers, corrosion inhibitors,
dyes, odorants, spreading agents, penetration aids, micronutrients,
emollients, lubricants and sticking agents.
[0222] In addition, further, other biocidally active ingredients or
compositions may be combined with the compositions of the invention
and used in the methods of the invention and applied simultaneously
or sequentially with the compositions of the invention. When
applied simultaneously, these further active ingredients may be
formulated together with the compositions of the invention or mixed
in, for example, the spray tank. These further biocidally active
ingredients may be fungicides, herbicides, insecticides,
bactericides, acaricides, nematicides and/or plant growth
regulators.
[0223] In addition, the compositions of the invention may also be
applied with one or more systemically acquired resistance inducers
("SAR" inducer). SAR inducers are known and described in, for
example, U.S. Pat. No. 6,919,298 and include, for example,
salicylates and the commercial SAR inducer
acibenzolar-S-methyl.
[0224] The compounds of formula (I) are normally used in the form
of compositions and can be applied to the crop area or plant to be
treated, simultaneously or in succession with further compounds.
These further compounds can be e.g. fertilizers or micronutrient
donors or other preparations, which influence the growth of plants.
They can also be selective herbicides or non-selective herbicides
as well as insecticides, fungicides, bactericides, nematicides,
molluscicides or mixtures of several of these preparations, if
desired together with further carriers, surfactants or application
promoting adjuvants customarily employed in the art of
formulation.
[0225] The compounds of formula (I) may be used in the form of
(fungicidal) compositions for controlling or protecting against
phytopathogenic microorganisms, comprising as active ingredient at
least one compound of formula (I) or of at least one preferred
individual compound as above-defined, in free form or in
agrochemically usable salt form, and at least one of the
above-mentioned adjuvants.
[0226] Normally, in the management of a crop a grower would use one
or more other agronomic chemicals in addition to the compound of
the present invention. Examples of agronomic chemicals include
pesticides, such as acaricides, bactericides, fungicides,
herbicides, insecticides, nematicides, as well as plant nutrients
and plant fertilizers.
[0227] Accordingly, the present invention provides a composition
comprising a compound of formula (I) according to the present
invention together with one or more pesticides, plant nutrients or
plant fertilizers. The combination may also encompass specific
plant traits incorporated into the plant using any means, for
example conventional breeding or genetic modification. Such
compositions may also contain one or more inert carriers as
described above.
[0228] The invention also provides for the use of a composition
comprising a compound of formula (I) according to the present
invention together with one or more pesticides, plant nutrients or
plant fertilizers. The combination may also encompass specific
plant traits incorporated into the plant using any means, for
example conventional breeding or genetic modification.
[0229] Suitable examples of plant nutrients or plant fertilizers
are calcium sulfate (CaSO.sub.4), calcium nitrate
(Ca(NO.sub.3).sub.2.4H.sub.2O), calcium carbonate (CaCO.sub.3),
potassium nitrate (KNO.sub.3), magnesium sulfate (MgSO.sub.4),
potassium hydrogen phosphate (KH.sub.2PO.sub.4), manganese sulfate
(MnSO.sub.4), copper sulfate (CuSO.sub.4), zinc sulfate
(ZnSO.sub.4), nickel chloride (NiCl.sub.2), cobalt sulfate
(CoSO.sub.4), potassium hydroxide (KOH), sodium chloride (NaCl),
boric acid (H.sub.3BO.sub.3) and metal salts thereof
(Na.sub.2MoO.sub.4). The nutrients may be present in an amount of
5% to 50% by weight, preferably of 10% to 25% by weight or of 15%
to 20% by weight each. Preferred additional nutrients are urea
((NH.sub.2).sub.2CO), melamine (C.sub.3H.sub.6N.sub.6), potassium
oxide (K.sub.2O), and inorganic nitrates. The most preferred
additional plant nutrient is potassium oxide. Where the preferred
additional nutrient is urea, it is present in an amount of
generally 1% to 20% by weight, preferably 2% to 10% by weight or of
3% to 7% by weight.
[0230] Suitable examples of pesticides are acycloamino acid
fungicides, aliphatic nitrogen fungicides, amide fungicides,
anilide fungicides, antibiotic fungicides, aromatic fungicides,
arsenical fungicides, aryl phenyl ketone fungicides, benzamide
fungicides, benzanilide fungicides, benzimidazole fungicides,
benzothiazole fungicides, botanical fungicides, bridged diphenyl
fungicides, carbamate fungicides, carbanilate fungicides, conazole
fungicides, copper fungicides, dicarboximide fungicides,
dinitrophenol fungicides, dithiocarbamate fungicides, dithiolane
fungicides, furamide fungicides, furanilide fungicides, hydrazide
fungicides, imidazole fungicides, mercury fungicides, morpholine
fungicides, organophosphorous fungicides, organotin fungicides,
oxathiin fungicides, oxazole fungicides, phenylsulfamide
fungicides, polysulfide fungicides, pyrazole fungicides, pyridine
fungicides, pyrimidine fungicides, pyrrole fungicides, quaternary
ammonium fungicides, quinoline fungicides, quinone fungicides,
quinoxaline fungicides, strobilurin fungicides, sulfonanilide
fungicides, thiadiazole fungicides, thiazole fungicides,
thiazolidine fungicides, thiocarbamate fungicides, thiophene
fungicides, triazine fungicides, triazole fungicides,
triazolopyrimidine fungicides, urea fungicides, valinamide
fungicides, zinc fungicides, Benzoylureas, carbamates,
chloronicotinyls, diacylhydrazines, diamides, fiproles, macrolides,
nitroimines, nitromethylenes, organochlorines, organophosphates,
organosilicons, organotins, phenylpyrazoles, phosphoric esters,
pyrethroids, spinosyns, tetramic acid derivatives, tetronic acid
derivatives, Antibiotic nematicides, avermectin nematicides,
botanical nematicides, carbamate nematicides, oxime carbamate
nematicides, organophosphorus nematicides, nematophagous fungi or
bacteria, amide herbicides, anilide herbicides, arsenical
herbicides, arylalanine herbicides, aryloxyphenoxypropionic
herbicides, benzofuranyl herbicides, benzoic acid herbicides,
benzothiazole herbicides, benzoylcyclohexanedione herbicides,
carbamate herbicides, carbanilate herbicides, chloroacetanilide
herbicides, chlorotriazine herbicides, cyclohexene oxmie
herbicides, cyclopropylisoxazole herbicides, dicarboximide
herbicides, dinitroaniline herbicides, dinitrophenol herbicides,
diphenyl ether herbicides, dithiocarbamate herbicides,
fluoroalkyltriazine herbicides, halogenated aliphatic herbicides,
imidazolinone herbicides, inorganic herbicides, methoxytriazine
herbicides, methylthiotriazine herbicides, nitrile herbicides,
nitrophenyl ether herbicides, organophosphorous herbicides,
oxadiazolone herbicides, oxazole herbicides, phenoxy herbicides,
phenoxyacetic herbicides, phenoxybutyric herbicides,
phenoxypropionic herbicides, phenylenediamine herbicides,
phenylurea herbicides, phthalic acid herbicides, picolinic acid
herbicides, pyrazole herbicides, pyridazine herbicides,
pyridazinone herbicides, pyridine herbicides, pyrimidinediamine
herbicides, pyrimidinyloxybenzylamine herbicides,
pyrimidinylsulfonylurea herbicides, quaternary ammonium herbicides,
quinolinecarboxylic acid herbicides, sulfonamide herbicides,
sulfonanilide herbicides, sulfonylurea herbicides, thiadiazolylurea
herbicides, thioamide herbicides, thiocarbamate herbicides,
thiocarbonate herbicides, thiourea herbicides, triazine herbicides,
triazinone herbicides, triazinylsulfonylurea herbicides, triazole
herbicides, triazolone herbicides, triazolopyrimidine herbicides,
uracil herbicides, urea herbicides, microbials, plant extracts,
pheromones, macrobials and other biologicals.
[0231] A further aspect of invention is related to a method of
controlling or preventing an infestation of plants, e.g. useful
plants such as crop plants, propagation material thereof, e.g.
seeds, harvested crops, e.g. harvested food crops, or of non-living
materials by insects or by phytopathogenic or spoilage
microorganisms or organisms potentially harmful to man, especially
fungal organisms, which comprises the application of a compound of
formula (I) or of a preferred individual compound as above-defined
as active ingredient to the plants, to parts of the plants or to
the locus thereof, to the propagation material thereof, or to any
part of the non-living materials.
[0232] Controlling or preventing means reducing infestation by
insects or by phytopathogenic or spoilage microorganisms or
organisms potentially harmful to man, especially fungal organisms,
to such a level that an improvement is demonstrated.
[0233] A preferred method of controlling or preventing an
infestation of crop plants by phytopathogenic microorganisms,
especially fungal organisms, or insects which comprises the
application of a compound of formula (I), or an agrochemical
composition which contains at least one of said compounds, is
foliar application. The frequency of application and the rate of
application will depend on the risk of infestation by the
corresponding pathogen or insect. However, the compounds of formula
(I) can also penetrate the plant through the roots via the soil
(systemic action) by drenching the locus of the plant with a liquid
formulation, or by applying the compounds in solid form to the
soil, e.g. in granular form (soil application). In crops of water
rice such granulates can be applied to the flooded rice field. The
compounds of formula (I) may also be applied to seeds (coating) by
impregnating the seeds or tubers either with a liquid formulation
of the fungicide or coating them with a solid formulation.
[0234] A formulation. e.g. a composition containing the compound of
formula (I), and, if desired, a solid or liquid adjuvant or
monomers for encapsulating the compound of formula (I), may be
prepared in a known manner, typically by intimately mixing and/or
grinding the compound with extenders, for example solvents, solid
carriers and, optionally, surface active compounds
(surfactants).
[0235] The application methods for the compositions, that is the
methods of controlling pests of the abovementioned type, such as
spraying, atomizing, dusting, brushing on, dressing, scattering or
pouring--which are to be selected to suit the intended aims of the
prevailing circumstances--and the use of the compositions for
controlling pests of the abovementioned type are other subjects of
the invention. Typical rates of concentration are between 0.1 and
1000 ppm, preferably between 0.1 and 500 ppm, of active ingredient.
The rate of application per hectare is preferably 1 g to 2000 g of
active ingredient per hectare, more preferably 10 to 1000 g/ha,
most preferably 10 to 600 g/ha. When used as seed drenching agent,
convenient dosages are from 10 mg to 1 g of active substance per kg
of seeds.
[0236] When the combinations of the present invention are used for
treating seed, rates of 0.001 to 50 g of a compound of formula (I)
per kg of seed, preferably from 0.01 to 10 g per kg of seed are
generally sufficient.
[0237] Suitably, a composition comprising a compound of formula (I)
according to the present invention is applied either preventative,
meaning prior to disease development or curative, meaning after
disease development.
[0238] The compositions of the invention may be employed in any
conventional form, for example in the form of a twin pack, a powder
for dry seed treatment (DS), an emulsion for seed treatment (ES), a
flowable concentrate for seed treatment (FS), a solution for seed
treatment (LS), a water dispersible powder for seed treatment (WS),
a capsule suspension for seed treatment (CF), a gel for seed
treatment (GF), an emulsion concentrate (EC). a suspension
concentrate (SC), a suspo-emulsion (SE), a capsule suspension (CS),
a water dispersible granule (WG), an emulsifiable granule (ES), an
emulsion, water in oil (EO), an emulsion, oil in water (EW), a
micro-emulsion (ME), an oil dispersion (OD), an oil miscible
flowable (OF), an oil miscible liquid (OL), a soluble concentrate
(SL), an ultra-low volume suspension (SU), an ultra-low volume
liquid (UL), a technical concentrate (TK), a dispersible
concentrate (DC), a wettable powder (WP) or any technically
feasible formulation in combination with agriculturally acceptable
adjuvants.
[0239] Such compositions may be produced in conventional manner,
e.g. by mixing the active ingredients with appropriate formulation
inerts (diluents, solvents, fillers and optionally other
formulating ingredients such as surfactants, biocides, anti-freeze,
stickers, thickeners and compounds that provide adjuvancy effects).
Also conventional slow release formulations may be employed where
long lasting efficacy is intended. Particularly formulations to be
applied in spraying forms, such as water dispersible concentrates
(e.g. EC, SC, DC, OD, SE, EW, EO and the like), wettable powders
and granules, may contain surfactants such as wetting and
dispersing agents and other compounds that provide adjuvancy
effects, e.g. the condensation product of formaldehyde with
naphthalene sulphonate, an alkylarylsulphonate, a lignin
sulphonate, a fatty alkyl sulphate, and ethoxylated alkylphenol and
an ethoxylated fatty alcohol.
[0240] A seed dressing formulation is applied in a manner known per
se to the seeds employing the combination of the invention and a
diluent in suitable seed dressing formulation form, e.g. as an
aqueous suspension or in a dry powder form having good adherence to
the seeds. Such seed dressing formulations are known in the art.
Seed dressing formulations may contain the single active
ingredients or the combination of active ingredients in
encapsulated form, e.g. as slow release capsules or
microcapsules.
[0241] In general, the formulations include from 0.01 to 90% by
weight of active agent, from 0 to 20% agriculturally acceptable
surfactant and 10 to 99.99% solid or liquid formulation inerts and
adjuvant(s), the active agent consisting of at least the compound
of formula (I) together with component (B) and (C), and optionally
other active agents, particularly microbicides or conservatives or
the like. Concentrated forms of compositions generally contain in
between about 2 and 80%, preferably between about 5 and 70% by
weight of active agent. Application forms of formulation may for
example contain from 0.01 to 20% by weight, preferably from 0.01 to
5% by weight of active agent. Whereas commercial products will
preferably be formulated as concentrates, the end user will
normally employ diluted formulations.
[0242] Whereas it is preferred to formulate commercial products as
concentrates, the end user will normally use dilute
formulations.
EXAMPLES
[0243] The Examples which follow serve to illustrate the invention.
Certain compounds of the invention can be distinguished from known
compounds by virtue of greater efficacy at low application rates,
which can be verified by the person skilled in the art using the
experimental procedures outlined in the Examples, using lower
application rates if necessary, for example 50 ppm, 12.5 ppm, 6
ppm, 3 ppm, 1.5 ppm, 0.8 ppm or 0.2 ppm.
[0244] Throughout this description, temperatures are given in
degrees Celsius and "m.p." means melting point. LC/MS means Liquid
Chromatography Mass Spectroscopy and the description of the
apparatus and the methods are:
[0245] Method G:
[0246] Spectra were recorded on a Mass Spectrometer (ACQUITY UPLC)
from Waters (SQD, SQDII or ZQ Single quadrupole mass spectrometer)
equipped with an electrospray source (Polarity: positive or
negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor:
2.00 V, Source Temperature: 150.degree. C., Desolvation
Temperature: 350.degree. C., Cone Gas Flow: 0 L/Hr, Desolvation Gas
Flow: 650 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from
Waters: Binary pump, heated column compartment and diode-array
detector. Solvent degasser, binary pump, heated column compartment
and diode-array detector. Column: Waters UPLC HSS T3, 1.8 .mu.m,
30.times.2.1 mm, Temp: 60.degree. C., DAD Wavelength range (nm):
210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH,
B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 1.2 min; Flow
(ml/min) 0.85
[0247] Method H:
[0248] Spectra were recorded on a Mass Spectrometer (ACQUITY UPLC)
from Waters (SQD, SQDII or ZQ Single quadrupole mass spectrometer)
equipped with an electrospray source (Polarity: positive or
negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor:
2.00 V, Source Temperature: 150.degree. C., Desolvation
Temperature: 350.degree. C., Cone Gas Flow: 0 L/Hr, Desolvation Gas
Flow: 650 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from
Waters: Binary pump, heated column compartment and diode-array
detector. Solvent degasser, binary pump, heated column compartment
and diode-array detector. Column: Waters UPLC HSS T3, 1.8 .mu.m,
30.times.2.1 mm, Temp: 60.degree. C., DAD Wavelength range (nm):
210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH,
B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 2.7 min; Flow
(ml/min) 0.85
FORMULATION EXAMPLES
TABLE-US-00003 [0249] Wettable powders a) b) c) active ingredient
[compound of formula (I)] 25% 50% 75% sodium lignosulfonate 5% 5%
-- sodium lauryl sulfate 3% -- 5% sodium
diisobutylnaphthalenesulfonate -- 6% 10% phenol polyethylene glycol
ether -- 2% -- (7-8 mol of ethylene oxide) highly dispersed silicic
acid 5% 10% 10% Kaolin 62% 27% --
[0250] The active ingredient is thoroughly mixed with the adjuvants
and the mixture is thoroughly ground in a suitable mill, affording
wettable powders that can be diluted with water to give suspensions
of the desired concentration.
TABLE-US-00004 Powders for dry seed treatment a) b) c) active
ingredient [compound of formula (I)] 25% 50% 75% light mineral oil
5% 5% 5% highly dispersed silicic acid 5% 5% -- Kaolin 65% 40% --
Talcum -- 20
[0251] The active ingredient is thoroughly mixed with the adjuvants
and the mixture is thoroughly ground in a suitable mill, affording
powders that can be used directly for seed treatment.
TABLE-US-00005 Emulsifiable concentrate active ingredient [compound
of formula (I)] 10% octylphenol polyethylene glycol ether 3% (4-5
mol of ethylene oxide) calcium dodecylbenzenesulfonate 3% castor
oil polyglycol ether (35 mol of ethylene oxide) 4% Cyclohexanone
30% xylene mixture 50%
[0252] Emulsions of any required dilution, which can be used in
plant protection, can be obtained from this concentrate by dilution
with water.
TABLE-US-00006 Dusts a) b) c) Active ingredient [compound of
formula (I)] 5% 6% 4% talcum 95% -- -- Kaolin -- 94% -- mineral
filler -- -- 96%
[0253] Ready-for-use dusts are obtained by mixing the active
ingredient with the carrier and grinding the mixture in a suitable
mill. Such powders can also be used for dry dressings for seed.
TABLE-US-00007 Extruder granules Active ingredient [compound of
formula (I)] 15% sodium lignosulfonate 2% carboxymethylcellulose 1%
Kaolin 82%
[0254] The active ingredient is mixed and ground with the
adjuvants, and the mixture is moistened with water. The mixture is
extruded and then dried in a stream of air.
TABLE-US-00008 Coated granules Active ingredient [compound of
formula (I)] 8% polyethylene glycol (mol. wt. 200) 3% Kaolin
89%
[0255] The finely ground active ingredient is uniformly applied, in
a mixer, to the kaolin moistened with polyethylene glycol.
Non-dusty coated granules are obtained in this manner.
TABLE-US-00009 Suspension concentrate active ingredient [compound
of formula (I)] 40% propylene glycol 10% nonylphenol polyethylene
glycol ether (15 mol of ethylene oxide) 6% Sodium lignosulfonate
10% carboxymethylcellulose 1% silicone oil (in the form of a 75%
emulsion in water) 1% Water 32%
[0256] The finely ground active ingredient is intimately mixed with
the adjuvants, giving a suspension concentrate from which
suspensions of any desired dilution can be obtained by dilution
with water. Using such dilutions, living plants as well as plant
propagation material can be treated and protected against
infestation by microorganisms, by spraying, pouring or
immersion.
TABLE-US-00010 Flowable concentrate for seed treatment active
ingredient [compound of formula (I)] 40% propylene glycol 5%
copolymer butanol PO/EO 2% tristyrenephenole with 10-20 moles EO 2%
1,2-benzisothiazolin-3-one (in the form of a 20% solution 0.5%.sup.
in water) monoazo-pigment calcium salt 5% Silicone oil (in the form
of a 75% emulsion in water) 0.2%.sup. Water 45.3%
[0257] The finely ground active ingredient is intimately mixed with
the adjuvants, giving a suspension concentrate from which
suspensions of any desired dilution can be obtained by dilution
with water. Using such dilutions, living plants as well as plant
propagation material can be treated and protected against
infestation by microorganisms, by spraying, pouring or
immersion.
Slow Release Capsule Suspension
[0258] 28 parts of a combination of the compound of formula (I) are
mixed with 2 parts of an aromatic solvent and 7 parts of toluene
diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This
mixture is emulsified in a mixture of 1.2 parts of
polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water
until the desired particle size is achieved. To this emulsion a
mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is
added. The mixture is agitated until the polymerization reaction is
completed.
[0259] The obtained capsule suspension is stabilized by adding 0.25
parts of a thickener and 3 parts of a dispersing agent. The capsule
suspension formulation contains 28% of the active ingredients. The
medium capsule diameter is 8-15 microns.
[0260] The resulting formulation is applied to seeds as an aqueous
suspension in an apparatus suitable for that purpose.
PREPARATION EXAMPLES
[0261] Using the techniques described both above and below
compounds of formula (I) may be prepared.
Example 1: This Example Illustrates the Preparation of
5-fluoro-1-[8-fluoroimidazo(1,2-a)pyrimidin-3-yl]-3,3,4,4-tetramethyl-iso-
quinoline
Step 1: N'-(3-fluoro-2-pyridyl)-N,N-dimethyl-formamidine
[0262] 1.50 g (13.4 mmol) 2-amino-3-fluoro-pyridine and 1.99 g
(16.2 mmol) N,N-dimethylformamide dimethylacetal in 15 ml methanol
were heated under reflux during 2 h. The reaction mixture was
concentrated under reduced pressure and the residue was purified by
flash chromatography (heptane/ethylacetate=1:1) to give
N'-(3-fluoro-2-pyridyl)-N,N-dimethyl-formamidine as a colourless
oil.
Step 2: 8-fluoroimidazo(1,2-a)pyrimidin-3-carbonitrile
[0263] To 2.11 g (12.6 mmol)
N'-(3-fluoro-2-pyridyl)-N,N-dimethyl-formamidine in 30 ml
isopropanol was added 1.54 g (18.3 mmol) sodium bicarbonate and 1.1
ml (14.9 mmol) bromoacetonitrile and the mixture was stirred at
80.degree. C. overnight. The reaction mixture was concentrated,
extracted with water/ethylacetate, dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
flash chromatography (heptane/ethylacetate=1:1) to give
8-fluoroimidazo(1,2-a)pyrimidin-3-carbonitrile as an oil, which
crystallised from tert-butylmethylether/heptane (1:2) as a beige
powder, m.p. 157-158.degree. C.
Step 3:
5-fluoro-1-(8-fluoroimidazo(1,2-a)pyrimidin-3-yl)-3,3,4,4-tetramet-
hyl-isoquinoline
[0264] To a cooled suspension (0.degree. C.) of 0.13 g (0.80 mmol)
8-fluoroimidazo(1,2-a)pyrimidin-3-carbonitrile in 1.8 ml conc.
sulfuric acid, 0.17 g (0.89 mmol)
3-(2-fluorophenyl)-2,3-dimethyl-butan-2-ol was added within 20 min.
and the mixture was stirred for 1 h at this temperature. The
reaction mixture was poured into ice-water and the pH was adjusted
to 8 using sodium hydroxide. The aqueous phase was extracted with
ethylacetate, dried over sodium sulfate and concentrated under
reduced pressure. The residue was purified by flash chromatography
(heptane/ethylacetate=4:1) to give
5-fluoro-1-(8-fluoroimidazo(1,2-a)pyrimidin-3-yl)-3,3,4,4-tetramethyl-iso-
quinoline as a beige powder, m.p. 156-157.degree. C.
Preparation of 3-(2-fluorophenyl)-2,3-dimethyl-butan-2-ol
Step 1: ethyl-2-(2-fluorophenyl)-2-methyl-propanoate
[0265] To the suspension of 27.4 g (0.69 mol) sodium hydride in 220
ml tetrahydrofuran was added dropwise a mixture of 50.0 g (0.27
mol) ethyl-2-(2-fluorophenyl)acetate and 117.9 g (0.82 mmol)
iodomethane in 60 ml tetrahydrofuran at room temperature. After
stirring overnight 70 ml saturated ammoniumchloride solution was
slowly added. The reaction mixture was poured into 300 ml ice-water
and extracted with ethylacetate, dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
flash chromatography (heptane/ethylacetate=19:1) to give
ethyl-2-(2-fluorophenyl)-2-methyl-propanoate as a yellowish
oil.
Step 2: 3-(2-fluorophenyl)-2,3-dimethyl-butan-2-ol
[0266] 52.1 g (0.25 mol)
ethyl-2-(2-fluorophenyl)-2-methyl-propanoate and 207 ml (0.12 mol)
lanthanum(III) chloride bis(lithium chloride) complex solution (0.6
M in THF) were stirred for 1.5 h at room temperature. Then 248 ml
(0.74 mol) methylmagnesium bromide solution (3.0 M in diethyl
ether) was added dropwise at 0.degree. C. After stirring overnight
at room temperature 60 ml saturated ammoniumchloride solution was
slowly added under cooling. 200 ml water was added and stirring
continued for 30 min. The reaction mixture was extracted with
tert-butyl methylether, filtered over Celite, the phases separated
and the waterphase extracted with tert-butyl methylether. The
organic phases were washed with brine, dried over sodium sulfate
and concentrated under reduced pressure to give
3-(2-fluorophenyl)-2,3-dimethyl-butan-2-ol as a yellowish solid,
m.p. 42-43.degree. C.
Example 2: This Example Illustrates the Preparation of
5-fluoro-3,3,4,4-tetramethyl-1-pyrazolo[1,5-a]pyridin-3-yl-isoquinoline
Step 1: pyrazolo[1,5-a]pyridine-3-carbonitrile
[0267] To a solution of 0.2 g (0.8967 mmol) pyridin-1-ium-1-amine
hydroiodide and 0.18 g (1.3003 mmol) potassium carbonate in 2 mL
N,N-dimethylformamide, 0.085 mL (0.9869 mmol, 0.082 g)
(E)-3-methoxyprop-2-enenitrile at room temperature were added
dropwise. The reaction mixture was stirred over night at 80.degree.
C. The reaction mixture was concentrated under reduced pressure and
the residue was extracted with diethylether/water. The combined
organic phase was washed with brine, dried with sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by flash chromatography (cyclohexane/ethyl acetate=1:1) to
give 0.07 g (0.489 mmol) pyrazolo[1,5-a]pyridine-3-carbonitrile as
beige solid, m.p. 124-127.degree. C.
Step 2:
5-fluoro-3,3,4,4-tetramethyl-1-pyrazolo[1,5-a]pyridin-3-yl-isoquin-
oline
[0268] To a solution of 0.07 g (0.489 mmol)
pyrazolo[1,5-a]pyridine-3-carbonitrile in 0.8 mL sulfuric acid
0.115 g (0.5868 mmol) 3-(2-fluorophenyl)-2,3-dimethyl-butan-2-ol
was added dropwise at 0.degree. C. The reaction mixture was stirred
at 0.degree. C. for three hours then it was poured on cold water,
basified with 8M NaOH to pH 10 and washed three times with
dichloromethane. The organic phase was washed with brine, dried
over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography
(cyclohexane/ethyl acetate=3:1) to give 0.0573 g (0.169 mmol)
5-fluoro-3,3,4,4-tetramethyl-1-pyrazolo[1,5-a]pyridin-3-yl-isoquino-
line as beige solid, m.p. 105-108.degree. C.
Example 3: This Example Illustrates the Preparation of
4,4-difluoro-3,3-dimethyl-1-(8-methylimidazol[1,2-a]pyridin-3-yl)isoquino-
line
Step 1:
1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3,3-dimethyl-4H-isoquinoline
[0269] To an ice cooled (0.degree. C.) solution of 1.00 g (4.50
mmol) 8-bromoimidazo[1,2-a]pyridine-3-carbonitrile in 9.8 mL conc.
sulfuric acid was slowly added 1.01 g (6.76 mmol)
2-methyl-1-phenyl-propan-2-ol over 15 min and the resulting
solution was stirred for additional 60 min at 0-5.degree. C. The
reaction mixture was poured into ice-water and the pH was adjusted
to 9 with 4 N sodium hydroxide solution. The aqueous phase was
extracted with ethyl acetate, dried over sodium sulfate, filtrated
and concentrated under reduced pressure. The residue was purified
by flash chromatography (heptane/ethyl acetate=3:1) to give 1.04 g
(2.94 mmol)
1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3,3-dimethyl-4H-isoquinoline
as light yellow powder.
Step 2:
1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3,3-dimethyl-isoquinolin-4-o-
ne
[0270] To a solution of 0.625 g (1.77 mmol)
1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3,3-dimethyl-4H-isoquinoline
in 50 mL carbon tetrachloride was added 0.661 g (3.52 mmol)
N-bromosuccinimide and 0.076 g (0.44 mmol) azoisobutyronitrile at
RT. The resulting mixture was warmed to 77.degree. C. and stirred
for 120 min at this temperature. After cooling to RT, the reaction
was diluted with dichloromethane, successively washed with water
and brine, dried over sodium sulfate, filtrated and concentrated
under reduced pressure. The residue was purified by flash
chromatography (heptane/ethyl acetate=2:1) to give 0.634 g (1.73
mmol)
1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3,3-dimethyl-isoquinolin-4-one
as off-white solid, m.p. 204-208.degree. C.
Step 3:
1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-4,4-difluoro-3,3-dimethyl-is-
oquinoline
[0271] 0.33 g (0.81 mmol)
1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3,3-dimethyl-isoquinolin-4-one
was suspended in 0.51 mL 2,2-difluoro-1,3-dimethylimidazoline at
RT, warmed to 100.degree. C. and stirred over night at this
temperature. The resulting solution was cooled to RT and slowly
added into ice-cold, saturated bicarbonate solution. This mixture
was extracted with ethyl acetate; the organic layer was washed with
brine, dried over sodium sulfate, filtrated and concentrated under
reduced pressure. The residue was purified by flash chromatography
(toluene/ethyl acetate=1:0-9:1) to afford 0.136 g (0.35 mmol)
1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-4,4-difluoro-3,3-dimethyl-isoquinol-
ine as white solid, m.p. 173.degree. C.
Step 4:
4,4-difluoro-3,3-dimethyl-1-(8-methylimidazo[1,2-a]pyridin-3-yl)is-
oquinoline
[0272] To a solution of 0.09 g (0.23 mmol)
1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-4,4-difluoro-3,3-dimethyl-isoquinol-
ine in 3 mL dioxane (degased) was added 0.072 mL (0.25 mmol)
trimethylboroxine (3.5 M in THF), 0.307 g (0.92 mmol) cesium
carbonate and 0.020 g (0.02 mmol) [Pd(dppf)Cl.sub.2] at RT. The
resulting suspension was warmed to 95.degree. C. and maintained for
90 min at this temperature. After cooling to RT, the reaction was
diluted with water and extracted with ethyl acetate. The organic
layer was washed with brine, dried over sodium sulfate, filtrated
and concentrated under reduced pressure. The residue was purified
by flash chromatography (heptane/ethyl acetate=3:2-2:1) to afford
0.073 g (0.22 mmol)
4,4-difluoro-3,3-dimethyl-1-(8-methylimidazo[1,2-a]pyridin-3-yl)isoquinol-
ine as light brown oil.
Example 4: This example illustrates the preparation of
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4-difluoro-3,3-dimethyl-iso-
quinoline
Step 1: Preparation of 3,3-dimethyl-2H-isoquinoline-1,4-dione
[0273] 1) To a solution of
3,3-dimethyl-2,4-dihydroisoquinolin-1-one (57.1 mmol, 10.0 g) in
CCl4 (285 mL) at room temperature was added N-bromosuccinimide (171
mmol, 30.5 g) and AlBN (8.5 mmol, 1.43 g) and the reaction mixture
was stirred at 70.degree. C. for 3 hours. The reaction mixture was
allowed to cool down to room temperature, concentrated under vacuo
and diluted with EtOAc, washed with water and brine, dried over
Na2SO4, filtered and concentrated to give
4,4-dibromo-3,3-dimethyl-2H-isoquinolin-1-one (25.2 g) as a light
yellow solid which was used directly in the next step without
further purification: LC-MS (Method H) UV Detection: 220 nm,
Rt=1.34; MS: (M+1)=332-334-336; .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.57 (s, 6H) 7.21 (br. s, 1H) 7.70-7.77 (m, 1H)
7.78-7.85 (m, 1H) 8.06-8.14 (m, 1H) 8.23-8.30 (m, 1H).
[0274] 2) To a solution of
4,4-dibromo-3,3-dimethyl-2H-isoquinolin-1-one (20.0 g) in a mixture
of water (450 mL) and tetrahydrofuran (225 mL) was added sodium
carbonate (135 mmol, 14.3 g) and the mixture was stirred at room
temperature for 12 h and at 70.degree. C. for 4 h 30 min. The
reaction mixture was allowed to cool down to room temperature,
diluted with water, acidified to pH 3-4 with 90 mL of a 2 M
solution of hydrochloric acid and extracted with dichloromethane.
The combined organic extracts were dried over Na2SO4, filtered and
concentrated to give 3,3-dimethyl-2H-isoquinoline-1,4-dione (9.95
g) as a yellow solid: LC-MS (Method H) UV Detection: 220 nm,
Rt=0.81; MS: (M+1)=190; .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 1.77 (s, 3H) 1.97 (s, 3H) 7.39 (s, 1H) 7.46-7.58 (m, 1H)
7.60-7.71 (m, 1H) 7.98-8.22 (m, 2H).
Step 2: Preparation of 1-chloro-3,3-dimethyl-isoquinolin-4-one
[0275] To a solution of N,N-dimethylformamide (2.3 mL, 30 mmol) in
dichloromethane (52 mL) at room temperature was added oxalyl
chloride (20 mmol, 1.8 mL) dropwise over a period of 35 min and the
white suspension was vigorously stirred for 15 min until the gas
evolution stopped. A solution of
3,3-dimethyl-2H-isoquinoline-1,4-diose (2.5 g, 13 mmol) in
dichloromethane (25 mL) was then added dropwise and the mixture was
stirred at room temperature for 1 h. The reaction mixture was
poured into an ice-cooled mixture of saturated aqueous NaHCO.sub.3
solution and pentane, and the organic phase was separated. The
aqueous phase was then extracted with pentane, and the combined
organic phases were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated to give
1-chloro-3,3-dimethyl-isoquinolin-4-one (2.5 g) as a yellow solid:
LC-MS (Method H) UV Detection: 220 nm, Rt=1.34; MS: (M+1)=208-210;
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.47 (s, 6H)
7.62-7.69 (m, 1H) 7.73-7.81 (m, 1H) 7.90 (dd, J=8.07, 0.73 Hz, 1H)
8.04 (dd, J=7.50, 0.90 Hz, 1H).
Step 3: Preparation of
3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one
[0276] To a solution of 1-chloro-3,3-dimethyl-isoquinolin-4-one
(2.10 g, 9.1 mmol) in triethylamine (20 mL) was added at room
temperature CuI (0.17 g, 0.9 mmol), bis-triphenylphosphine
Palladium(II) dichloride (320 mg, 0.46 mmol) followed by dropwise
addition of ethynyltrimethylsilane (1.9 mL, 14 mmol). The black
solution was stirred at room temperature for 1 hour. The reaction
mixture was quenched with saturated aqueous NH.sub.4Cl and the
extracted twice with ethyl acetate. The organic phase was washed
with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated. Purification by flash chromatography gave
3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one (2.35 g)
as a dark yellow oil: LC-MS (Method G), Rt=1.21 UV Detection: 220
nm; MS: (M+1)=270; .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
0.32 (s, 9H) 1.51 (s, 6H) 7.63-7.69 (m, 1H) 7.79-7.83 (m, 1H) 7.98
(dd, 2H) 8.05 (dd, 1H).
Step 4: Preparation of 1-ethynyl-3,3-dimethyl-isoquinolin-4-one
[0277] To a solution of
3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one (1.0 g,
3.7 mmol) in methanol (7.5 mL) was added at room temperature
K.sub.2CO.sub.3 (570 mg, 4.1 mmol). The reaction mixture was
stirred at room temperature for 1 h, quenched with water (pH 8/9),
and extracted twice with ethyl acetate. The combined organic phases
were washed with brine, dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated. Purification by flash chromatography
gave 1-ethynyl-3,3-dimethyl-isoquinolin-4-one (700 mg) as a brown
oil: LC-MS (Method G), Rt=0.84, UV Detection: 220 nm; MS:
(M+1)=198; .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.50 (s,
6H) 3.28 (s, 1H) 7.65-7.70 (m, 1H) 7.79-7.85 (m, 1H) 7.98-8.04 (m,
1H) 8.06-8.12 (s, 1H).
Step 5: Preparation of
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-3,3-dimethyl-isoquinolin-4-on-
e
[0278] To a white suspension of 2,3-dimethylpyridin-1-ium-1-amine
iodide (1.0 g, 4.1 mmol) in dichloromethane (20 mL) was added
diazabicycloundecene (623 mg, 4.1 mmol) followed by dropwise
addition of 1-ethynyl-3,3-dimethyl-isoquinolin-4-one (700 mg, 3.2
mmol) dissolved in dichloromethane (10 mL), over a period of 30
min. The resulting brown mixture was stirred at room temperature
for 1 hour, till disappearance of the
1-ethynyl-3,3-dimethyl-isoquinolin-4-one starting material. The
reaction mixture was quenched with water, the organic phase was
separated and washed with saturated aqueous NH.sub.4Cl. The water
phase was extracted with dichloromethane. The combined organic
phases were washed with water and brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash
chromatography gave
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-3,3-dimethyl-isoquinolin-4-on-
e (410 mg) as orange solid: mp=152.degree.-153.degree. C., LC-MS
(Method G), Rt=0.86, UV Detection: 220 nm; MS: (M+1)=318; .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.57 (s, 6H) 2.42 (s, 3H)
2.72 (s, 3H) 7.15 (d, 1H) 7.62-7.85 (m, 3H) 8.15 (d, 1H) 8.35 (s,
1H).
Step 6: Preparation of
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4-difluoro-3,3-dimethyl-iso-
quinoline
[0279] A solution of
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-3,3-dimethyl-isoquinolin-4-on-
e (370 mg, 1.2 mmol) in 2,2-difluoro-1,3-dimethylimidazolidine (14
mmol, 1.8 ml) was stirred at 105.degree. C. for 24 hours. The
reaction mixture was allowed to cool down to room temperature,
diluted with dichloromethane then quenched by slow addition to an
ice cooled saturated aqueous NaHCO.sub.3 solution. The 2 phases
were separated, and the aqueous phase was extracted with DCM. The
combined organic phases were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash chromatography to give
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4-difluoro-3,3-dimethyl-iso-
quinoline (328 mg) as a beige solid: mp=160-161.degree. C., LC-MS
(Method G) UV Detection: 220 nm, Rt=1.03, MS: (M+1)=340; .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.42 (s, 6H) 2.40 (s, 3H)
2.79 (s, 3H) 7.15 (d, 1H) 7.57-7.68 (m, 2H) 7.72 (d, 1H) 7.85 (d,
1H) 7.94 (d, 1H) 8.21 (s, 1H). .sup.19F NMR (400 MHz, CHLOROFORM-d)
.delta. ppm -112.
Example 5: This Example Illustrate the Preparation of
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4,6-trifluoro-3,3-dimethyl--
isoquinoline
Step 1: Preparation of
6-fluoro-3,3-dimethyl-2H-isoquinoline-1,4-dione
[0280] Preparation was performed via an analogous synthetic route
to that described for 3,3-dimethyl-2H-isoquinoline-1,4-dione
6-fluoro-3,3-dimethyl-2H-isoquinoline-1,4-dione (example 4, step
1):
[0281] LC-MS (Method H) UV Detection: 220 nm, Rt=0.94; MS:
(M+1)=208; 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.56 (s, 6H)
7.35 (br. s, 1H) 7.43-7.50 (m, 1H) 7.68-7.74 (m, 1H) 8.25-8.30 (m,
1H). 19F (400 MHz, CHLOROFORM-d) .delta. ppm -103
Step 2: Preparation of
1-chloro-6-fluoro-3,3-dimethyl-isoquinolin-4-one
[0282] To a solution of N,N-dimethylformamide (1.6 mL, 21 mmol) in
dichloromethane (36 mL) at room temperature was added oxalyl
chloride (14 mmol, 1.6 mL) dropwise over a period of 30 min and the
white suspension was vigorously stirred for 25 min until the gas
evolution stopped. A solution of
6-fluoro-3,3-dimethyl-2H-isoquinoline-1,4-dione (2.0 g, 9.7 mmol)
in dichloromethane (20 mL) was then added dropwise at 0.degree. C.
The mixture was allowed to warm to ambient temperature and stirred
for 1 hour. The reaction mixture was poured into an ice-cooled
mixture of saturated aqueous NaHCO.sub.3 solution and pentane, and
the organic phase was separated. The aqueous phase was then
extracted with pentane, and the combined organic phases were washed
with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
to give 1-chloro-6-fluoro-3,3-dimethyl-isoquinolin-4-one (1.95 g)
as a dark yellow oil, that was used without purification in the
next synthetic step: LC-MS (Method H) UV Detection: 220 nm,
Rt=1.42; MS: (M+1)=226-228
Step 3: Preparation of
6-fluoro-3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one
[0283] To a solution of
1-chloro-6-fluoro-3,3-dimethyl-isoquinolin-4-one (1.4 g, 6.0 mmol)
in triethylamine (12 mL) was added at room temperature CuI (116 mg,
0.6 mmol), bis-triphenylphosphine Palladium(II) dichloride (214 mg,
0.3 mmol) followed by dropwise addition of ethynyltrimethylsilane
(1.3 mL, 9.1 mmol). The black solution was stirred at room
temperature overnight. The reaction mixture was quenched with
saturated aqueous NH.sub.4Cl and the extracted twice with ethyl
acetate. The organic phase was washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated. Purification
by flash chromatography gave
6-fluoro-3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one
(1.25 g) as a orange solid: LC-MS (Method G), Rt=1.22 UV Detection:
220 nm; MS: (M+1)=288; .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 0.32 (s, 9H) 1.52 (s, 6H) 7.47-7.52 (m, 1H) 7.70-7.76 (m, 1H)
8.0-8.05 (m, 1H). .sup.19F (400 MHz, CHLOROFORM-d) .delta. ppm
-104.
Step 4: Preparation of
1-ethynyl-6-fluoro-3,3-dimethyl-isoquinolin-4-one
[0284] To a solution of
6-fluoro-3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one
(1.25, 4.3 mmol) in dichloromethane (17 mL) was added at room
temperature potassium fluoride (0.56 g, 9.6 mmol) and 18-crown-6
(1.2 g, 4.3 mmol). The reaction mixture was stirred at room
temperature for 30 min, quenched with saturated aqueous
NaHCO.sub.3, and extracted twice with dichloromethane. The combined
organic phases were washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash
chromatography gave
1-ethynyl-6-fluoro-3,3-dimethyl-isoquinolin-4-one. (610 mg) as a
brown oil: LC-MS (Method G), Rt=0.90, UV Detection: 220 nm; MS:
(M+1)=216; .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.53 (s,
6H) 3.31 (s, 1H) 7.46-7.52 (m, 1H) 7.70-7.75 (m, 1H) 8.02-8.07 (m,
1H). .sup.19F (400 MHz, CHLOROFORM-d) .delta. ppm -103
Step 5: Preparation of
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-6-fluoro-3,3-dimethyl-isoquin-
olin-4-one
[0285] To a solution of 2,3-dimethylpyridin-1-ium-1-amine
2,4,6-trimethylbenzenesulfonate (750 mg, 2.3 mmol) in
dimethylformamide (8 mL) was first added potassium carbonate (490
mg, 3.5 mmol) followed by dropwise addition of
1-ethynyl-6-fluoro-3,3-dimethyl-isoquinolin-4-one (600 mg, 2.8
mmol) dissolved in dimethylformamide (4 mL), over a period of 30
min. The resulting brown mixture was stirred at room temperature
for 2 days, till disappearance of the
1-ethynyl-5-fluoro-3,3-dimethyl-isoquinolin-4-one starting
material. The reaction mixture was quenched with water, and
extracted twice with ethyl acetate. The combined organic phases
were washed with water and brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash
chromatography gave
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-6-fluoro-3,3-dimethyl-isoquin-
olin-4-one (295 mg) as a brown solid: mp=168-170.degree. C., LC-MS
(Method G), Rt=0.92, UV Detection: 220 nm; MS: (M+1)=336; .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.60 (s, 6H) 2.45 (s, 3H)
2.80 (s, 3H) 7.18 (d, 1H) 7.39-7.48 (m, 1H) 7.73-7.95 (m, 3H) 8.23
(br s, 1H). .sup.19F NMR (400 MHz, CHLOROFORM-d) .delta. ppm
-106
Step 6: Preparation of
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4,6-trifluoro-3,3-dimethyl--
isoquinoline
[0286] A solution of
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-6-fluoro-3,3-dimethyl-isoquin-
olin-4-one (280 mg, 0.84 mmol) in
2,2-difluoro-1,3-dimethylimidazolidine (1.3 ml) was stirred at
105.degree. C. for 24 hours. The reaction mixture was allowed to
cool down to room temperature, diluted with dichloromethane then
quenched by slow addition to an ice cooled saturated aqueous
NaHCO.sub.3 solution. The two phases were separated, and the
aqueous phase was extracted with DCM. The combined organic phases
were washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by flash chromatography to
give
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4,6-trifluoro-3,3-dimethyl--
isoquinoline (235 mg) as a beige solid: mp=183-185.degree. C.,
LC-MS (Method G) UV Detection: 220 nm, Rt=1.09, MS: (M+1)=358;
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.45 (s, 6H) 2.45
(s, 3H) 2.80 (s, 3H) 7.19 (d, 1H) 7.22-7.27 (m, 1H) 7.55 (dd, 1H)
7.72-7.77 (m, 1H) 7.95 (d, 1H) 8.21 (br s, 1H). .sup.19F NMR (400
MHz, CHLOROFORM-d) .delta. ppm -106, -113.
Example 6: This Example Illustrates the
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4,5-trifluoro-3,3-dimethyl--
isoquinoline
Step 1: Preparation of
5-fluoro-3,3-dimethyl-2H-isoquinoline-1,4-dione
[0287] 1) To a solution of
5-fluoro-3,3-dimethyl-2,4-dihydroisoquinolin-1-one (5.0 g, 25.9
mmol) in CCl4 (100 mL) at room temperature was added
N-bromosuccinimide (44 mmol, 7.9 g) and AlBN (2.6 mmol, 0.43 g) and
the reaction mixture was stirred at 70.degree. C. for 2 hours,
until starting material has disappeared. The reaction mixture was
allowed to cool down to room temperature, concentrated under vacuo
and diluted with ethyl acetate, washed with water and brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated to give
4-bromo-5-fluoro-3,3-dimethyl-2,4-dihydroisoquinolin-1-one (6.6 g)
as a light yellow solid which was used directly in the next step
without further purification: LC-MS (Method G) UV Detection: 220
nm, Rt=0.83; MS: (M+1)=272-274; .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.30 (s, 3H) 1.55 (s, 3H) 5.30 (s, 1H) 6.15 (br. s, 1H)
7.24-7.30 (m, 1H) 7.40-7.50 (m, 1H) 7.90 (d, 1H). .sup.19F NMR (400
MHz, CHLOROFORM-d) .delta. ppm -119
[0288] 2) A solution of
4-bromo-5-fluoro-3,3-dimethyl-2,4-dihydroisoquinolin-1-one (6.6 g)
in a mixture of water (120 mL) and tetrahydrofuran (120 mL) was
stirred at 90.degree. C. overnight. The reaction mixture was
allowed to cool down to room temperature, diluted with saturated
aqueous NaHCO.sub.3 to pH 7-8 and extracted with ethyl acetate. The
combined organic extracts were dried over Na2SO4, filtered and
concentrated. Purification by flash chromatography gave
5-fluoro-4-hydroxy-3,3-dimethyl-2,4-dihydroisoquinolin-1-one (3.54
g) as a white solid: LC-MS (Method G) UV Detection: 220 nm,
Rt=0.60; MS: (M+1)=210; .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 1.20 (s, 3H) 1.50 (s, 3H) 2.5 (br. d, 1H) 4.7 (d, 1H) 5.75 (br.
s, 1H) 7.27-7.30 (m, 1H) 7.40-7.48 (m, 1H) 7.85 (d, 1H). .sup.19F
NMR (400 MHz, CHLOROFORM-d) .delta. ppm -113
[0289] 3) To a solution of
5-fluoro-4-hydroxy-3,3-dimethyl-2,4-dihydroisoquinolin-1-one (3.54
g, 16.9 mmol) in dichloromethane (200 ml) was added Dess-Martin
periodinane (18.6 mmol, 8.15 g) at 0.degree. C. The reaction
mixture was stirred for 2 hour at temperature between 0 and
10.degree. C. and quenched with saturated aqueous NaHCO.sub.3. The
organic phase was separated and washed with sodium thiosulfate
solution and brine, dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The residue was purified by flash
chromatography to give
5-fluoro-3,3-dimethyl-2H-isoquinoline-1,4-dione (3.08 g) as a white
solid: LC-MS (Method G) UV Detection: 220 nm, Rt=0.68; MS:
(M+1)=208; .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.53 (s,
6H) 2.5 (br. d, 1H) 4.7 (d, 1H) 6.52 (br. s, 1H) 7.38-7.43 (m, 1H)
7.72-7.8 (m, 1H) 8.10 (d, 1H).
Step 2: Preparation of
1-chloro-5-fluoro-3,3-dimethyl-isoquinolin-4-one
[0290] To a solution of dimethylformamide (1.0 mL, 13.5 mmol) in
dichloromethane (25 mL), at room temperature, was added oxalyl
chloride (1.2 mL, 13.5 mmol) dropwise over a period of 30 min the
white suspension was vigorously stirred at the same temperature for
1 hour until the gas evolution stopped. A solution of
5-fluoro-3,3-dimethyl-2H-isoquinoline-1,4-dione (2.0 g, 9.65 mmol)
in dichloromethane (25 mL) was then added dropwise and the mixture
was stirred at room temperature for 1 hour. The reaction mixture
was poured into an ice-cooled saturated aqueous NaHCO.sub.3
solution and pentane, and the organic phase was separated. The
aqueous phase was then extracted with pentane, and the combined
organic phases were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated to give
1-chloro-5-fluoro-3,3-dimethyl-isoquinolin-4-one (2.05 g) as a
yellow solid: LC-MS (Method G), Rt=0.91 UV Detection: 220 nm; MS:
(M+1)=226-228; .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.52
(s, 6H) 7.36-7.44 (m, 1H) 7.77-7.81 (m, 2H).
Step 3: Preparation of
5-fluoro-3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one
[0291] To a solution of
1-chloro-5-fluoro-3,3-dimethyl-isoquinolin-4-one (2.04 g, 9.0 mmol)
in triethylamine (18 mL) was added at room temperature CuI (174 mg,
0.90 mmol), bis-triphenylphosphine Palladium(II) dichloride (0.32
g, 0.45 mmol) followed by dropwise addition of
ethynyltrimethylsilane (1.9 mL, 13.6 mmol). The black solution was
stirred at room temperature for 1 hour. The reaction mixture was
quenched with saturated aqueous NH.sub.4Cl and the extracted twice
with ethyl acetate. The organic phase was washed with brine, dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated.
Purification by flash chromatography gave
5-fluoro-3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one
(2.25 g) as a yellow solid: LC-MS (Method G), Rt=1.16 UV Detection:
220 nm; MS: (M+1)=288; .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 0.30 (s, 9H) 1.51 (s, 6H) 7.29-7.34 (m, 1H) 7.75-7.81 (m, 2H).
.sup.19F (400 MHz, CHLOROFORM-d) .delta. ppm -108.
Step 4: Preparation of
1-ethynyl-5-fluoro-3,3-dimethyl-isoquinolin-4-one
[0292] To a solution of
5-fluoro-3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one
(2.25 g, 7.8 mmol) in dichloromethane (31 mL) was added at room
temperature potassium fluoride (2.2eq, 1.0 g, 17.2 mmol) and
18-crown-6 (2.09 g, 7.8 mmol). The reaction mixture was stirred at
room temperature for 30 min, quenched with saturated aqueous
NaHCO.sub.3, and extracted twice with dichloromethane. The combined
organic phases were washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash
chromatography gave
1-ethynyl-5-fluoro-3,3-dimethyl-isoquinolin-4-one (1.46 g) as a
yellow solid: LC-MS (Method G), Rt=0.83, UV Detection: 220 nm; MS:
(M+1)=216; .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.50 (s,
6H) 3.28 (s, 1H) 7.32-7.37 (m, 1H) 7.75-7.83 (m, 2H).
Step 5: Preparation of
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-5-fluoro-3,3-dimethyl-isoquin-
olin-4-one
[0293] To a solution of 2,3-dimethylpyridin-1-ium-1-amine
2,4,6-trimethylbenzenesulfonate (1.0 g, 3.1 mmol) in
dimethylformamide (16 mL) was first added potassium carbonate (650
mg, 4.6 mmol) followed by dropwise addition of
1-ethynyl-5-fluoro-3,3-dimethyl-isoquinolin-4-one (1.0 g, 4.65
mmol) dissolved in dimethylformamide (6 mL), over a period of 30
min. The resulting brown mixture was stirred at room temperature
for 16 hours, till disappearance of the
1-ethynyl-5-fluoro-3,3-dimethyl-isoquinolin-4-one starting
material. The reaction mixture was quenched with water, and
extracted twice with ethyl acetate. The combined organic phases
were washed with water and brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash
chromatography gave
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-5-fluoro-3,3-dimethyl-Isoquin-
olin-4-one (380 mg) as a brown solid: mp=139-141.degree. C., LC-MS
(Method G), Rt=0.95, UV Detection: 220 nm; MS: (M+1)=336; .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.54 (s, 6H) 2.38 (s, 3H)
2.75 (s, 3H) 7.15 (d, 1H) 7.32 (t, 1H) 7.58 (d, 1H) 7.68-7.71 (m,
1H) 7.78 (d, 1H) 8.16 (s, 1H). .sup.19F NMR (400 MHz, CHLOROFORM-d)
.delta. ppm -112.
Step 6: Preparation of
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4,5-trifluoro-3,3-dimethyl--
isoquinoline
[0294] A solution of
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-5-fluoro-3,3-dimethyl-isoquin-
olin-4-one (360 mg, 1.1 mmol) in
2,2-difluoro-1,3-dimethylimidazolidine (1.7 ml) was stirred at
105.degree. C. for 24 hours. The reaction mixture was allowed to
cool down to room temperature, diluted with dichloromethane then
quenched by slow addition to an ice cooled saturated aqueous
NaHCO.sub.3 solution. The two phases were separated, and the
aqueous phase was extracted with DCM. The combined organic phases
were washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by flash chromatography to
give
1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4,5-trifluoro-3,3-dimethyl--
isoquinoline (310 mg) as a beige solid: mp=185-187.degree. C.,
LC-MS (Method G) UV Detection: 220 nm, Rt=1.14, MS: (M+1)=358;
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.45 (s, 6H) 2.40
(s, 3H) 2.78 (s, 3H) 7.17 (d, 1H) 7.31 (t, 1H) 7.51-7.60 (m, 2H)
7.90 (d, 1H) 8.15 (s, 1H). .sup.19F NMR (400 MHz, CHLOROFORM-d)
.delta. ppm -110, -113.
[0295] The following table gives analytical data for compounds of
formula (I) prepared using synthetic techniques described
above.
TABLE-US-00011 TABLE E Physical data of compounds of formula (I) RT
[M + H] No. Compound name STRUCTURE (min) (measured) Method MP
.degree. C. E-1 5-fluoro-1-imidazo[1,2- a]pyridin-3-yl-3,3,4,4-
tetramethyl-isoquinoline ##STR00052## 0.91 322 G 129- 130 E-2
7-fluoro-1-imidazo[1,2- a]pyridin-3-yl-3,3,4,4-
tetramethyl-isoquinoline ##STR00053## 0.89 322 G E-3
5-chloro-1-imidazo[1,2- a]pyridin-3-yl-3,3-
dimethyl-4H-isoquinoline ##STR00054## 0.92 310 G E-4 5-fluoro-1-(6-
fluoroimidazo[1.2- a]pyridin-3-yl)-3,3,4,4-
tetramethyl-isoquinoline ##STR00055## 1.13 340 G 200- 202 E-5
5-chloro-1-(6- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3-
dimethyl-4H-isoquinoline ##STR00056## 1.11 328 G 142- 143 E-6
5-fluoro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3,4,4-
tetramethyl-isoquinoline ##STR00057## 1.10 340 G 156- 157 E-7 1-[8-
(difluoromethoxy)imidazo [1,2-a]pyridin-3-yl]-5-
fluoro-3,3,4,4-tetramethyl- isoquinoline ##STR00058## 1.15 388 G
121- 122 E-8 1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-5-fluoro-
3,3,4,4-tetramethyl- isoquinoline ##STR00059## 1.15 402 G E-9
5-fluoro-3,3,4,4- tetramethyl-1-(8- methylimidazo[1,2-
a]pyridin-3-yl)isoquinoline ##STR00060## 0.95 336 G 160- 161 E-10
5-fluoro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3-
dimethyl-4H-isoquinoline ##STR00061## 0.99 312 G E-11
5-chloro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3-
dimethyl-4H-isoquinoline ##STR00062## 1.09 328 G 122- 123 E-12
4-bromo-5-chloro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3-
dimethyl-4H-isoquinoline ##STR00063## 1.12 408 G 213- 214 E-13
4-bromo-5-fluoro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3-
dimethyl-4H-isoquinoline ##STR00064## 1.06 392 G 211- 212 E-14
5-fluoro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3-
dimethyl-4H-isoquinolin- 4-ol ##STR00065## 0.77 328 G 219- 219 E-15
5-chloro-1-[8- (difluoromethoxy)imidazo [1,2-a]pyridin-3-yl]-3,3-
dimethyl-4H-isoquinoline ##STR00066## 1.14 376 G 114- 115 E-16
1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-5-fluoro- 3,3-dimethyl-4H-
isoquinoline ##STR00067## 374 1.05 G 179- 181 E-17
5-fluoro-3,3-dimethyl-1- (8- methylsulfanylimidazo[1,2-
a]pyridin-3-yl)-4H- isoquinoline ##STR00068## 340 0.96 G 119- 120
E-18 5-fluoro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3-
dimethyl-isoquinolin-4- one ##STR00069## 0.90 326 G 160- 161 E-19
4,4,5-trifluoro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3-
dimethyl-isoquinoline ##STR00070## 1.06 348 G 145- 146 E-20
5-fluoro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-N-methoxy-
3,3-dimethyl-isoquinolin- 4-imine ##STR00071## 1.08 355 G E-21
1-(8-ethylimidazo[1,2- a]pyridin-3-yl)-5-fluoro-
3,3,4,4-tetramethyl- isoquinoline ##STR00072## 1.02 350 G E-22
1-(8- cyclopropylimidazo[1,2- a]pyridin-3-yl)-5-fluoro-
3,3,4,4-tetramethyl- isoquinoline ##STR00073## 1.03 362 G E-23
1-(8-ethynylimidazo[1,2- a]pyridin-3-yl)-5-fluoro-
3,3,4,4-tetramethyl- isoquinoline ##STR00074## 1.06 346 G 169- 170
E-24 5-fluoro-1-(8- methoxyimidazo[1,2- a]pyridin-3-yl)-3,3,4,4-
tetramethyl-isoquinoline ##STR00075## 0.92 352 G 130- 130 E-25
5-fluoro-1-(6- methoxyimidazo[1,2- a]pyridin-3-yl)-3,3,4,4-
tetramethyl-isoquinoline ##STR00076## 1.05 352 G 214- 215 E-26
3-(5-fluoro-3,3,4,4- tetramethyl-1- isoquinolyl)imidazo[1,2-
a]pyridin-6-ol ##STR00077## 0.85 338 G 321- 322 E-27
3-(5-fluoro-3,3,4,4- tetramethyl-1- isoquinolyl)imidazo[1,2-
a]pyridin-8-ol ##STR00078## 0.91 338 G 271- 272 E-28
5-fluoro-3,3,4,4- tetramethyl-1-(8-prop-2- ynoxyimidazo[1,2-
a]pyridin-3-yl)isoquinoline ##STR00079## 1.01 376 G E-29
5-fluoro-3,3,4,4- tetramethyl-1-[8- (trifluoromethyl)imidazo[1,
2-a]pyridin-3- yl]isoquinoline ##STR00080## 1.22 390 G 141- 142
E-30 5-fluoro-3,3,4,4- tetramethyl-1-(5- methylimidazo[1,2-
a]pyridin-3-yl)isoquinoline ##STR00081## 0.87 336 G 139- 140 E-31
5-fluoro-3,3,4,4- tetramethyl-1-(7- methylimidazo[1,2-
a]pyridin-3-yl)isoquinoline ##STR00082## 1.02 336 G E-32
1-(8-chloroimidazo[1,2- a]pyridin-3-yl)-5-fluoro-
3,3,4,4-tetramethyl- isoquinoline ##STR00083## 1.14 356 G 167- 168
E-33 3,3,4,4-tetramethyl-1-(8- methylimidazo[1,2-
a]pyridin-3-yl)isoquinoline ##STR00084## 0.88 318 G E-34
4-bromo-1-(8- bromoimidazo[1,2- a]pyridin-3-yl)-5-fluoro-
3,3-dimethyl-4H- isoquinoline ##STR00085## 1.11 452 G 217- 218 E-35
1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-5-fluoro- 3,3-dimethyl-4H-
isoquinolin-4-ol ##STR00086## 0.83 390 G 204- 205 E-36
1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-5-fluoro-
3,3-dimethyl-isoquinolin- 4-one ##STR00087## 0.95 388 G 146- 147
E-37 1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-4,4,5-
trifluoro-3,3-dimethyl- isoquinoline ##STR00088## 1.10 309 G 209-
210 E-38 3-(5-fluoro-3,3,4,4- tetramethyl-1-
isoquinolyl)imidazo[1,2- a]pyridine-8-carbonitrile ##STR00089##
1.12 437 G 212- 213 E-39 4,4,5-trifluoro-3,3- dimethyl-1-(8-
methylimidazo[1,2- a]pyridin-3-yl)isoquinoline ##STR00090## 0.99
344 G E-40 1-(2,8- dimethylimidazo[1,2- a]pyridin-3-yl)-5-fluoro-
3,3,4,4-tetramethyl- isoquinoline ##STR00091## 0.93 350 G E-41
1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-3,3-
dimethyl-4H-isoquinoline ##STR00092## 0.84 356 G 132- 133 E-42
1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-3,3- dimethyl-isoquinolin-4-
one ##STR00093## 0.96 370 G 204- 205 E-43 1-(8-bromoimidazo[1,2-
a]pyridin-3-yl)-4,4- difluoro-3,3-dimethyl- isoquinoline
##STR00094## 1.11 392 G 173- 173 E-44 5-fluoro-1-(7-
iodoimidazo[1,2-a]pyridin- 3-yl)-3,3,4,4-tetramethyl- isoquinoline
##STR00095## 1.21 448 G E-45 4,4-difluoro-3,3-dimethyl-
1-(8-methylimidazo[1,2- a]pyridin-3-yl)isoquinoline ##STR00096##
0.95 326 G E-46 3-(5-fluoro-3,3,4,4- tetramethyl-1-
isoquinolyl)imidazo[1,2- a]pyridine-7-carbonitrile ##STR00097##
1.12 347 G 193- 194 E-47 1-(8-chloro-7-methyl-
imidazo[1,2-a]pyridin-3- yl)-5-fluoro-3,3,4,4-
tetramethyl-isoquinoline ##STR00098## 1.14 370 G 185- 186 E-48
5-fluoro-1-(7- methoxyimidazo[1,2- a]pyridin-3-yl)-3,3,4,4-
tetramethyl-isoquinoline ##STR00099## 0.99 352 G 139- 140 E-49
3-(5-fluoro-3,3,4,4- tetramethyl-1- isoquinolyl)imidazo[1,2-
a]pyridin-7-ol ##STR00100## 0.88 338 G 246- 247 E-50 1-(7,8-
dimethylimidazo[1,2- a]pyridin-3-yl)-5-fluoro- 3,3,4,4-tetramethyl-
isoquinoline ##STR00101## 0.91 350 G 185- 186 E-51
4,4-dimethyl-1-(8- methylimidazo[1,2- a]pyridin-3-yl)-3H-
isoquinoline ##STR00102## 0.73 290 G E-52 1-(8-methylimidazo[1,2-
a]pyridin-3-yl)spiro[4H- isoquinoline-3,1'- cyclobutane]
##STR00103## 0.80 302 G E-53 1-(8-methylimidazo[1,2-
a]pyridin-3-yl)spiro[3H- isoquinoline-4,1'- cyclobutane]
##STR00104## 1.14 302 G 127- 129 E-54 1-(7-iodoimidazo[1,2-
a]pyridin-3-yl)-3,3- dimethyl-4H-isoquinoline ##STR00105## 1.57
402.1 H 190- 193 E-55 4,4-difluoro-3,3-dimethyl-
1-(7-methylimidazo[1,2- a]pyridin-3-yl)isoquinoline ##STR00106##
1.26 326.3 H E-56 1-(7,8- dichloroimidazo[1,2- a]pyridin-3-yl)-4,4-
difluoro-3,3-dimethyl- isoquinoline ##STR00107## 1.19 381 G >210
E-57 1-(7,8- dimethylimidazo[1,2- a]pyridin-3-yl)-4,4-
difluoro-3,3-dimethyl- isoquinoline ##STR00108## 0.88 340 G 159-
161 E-58 5-fluoro-3,3,4,4- tetramethyl-1- pyrazolo[1,5-a]pyridin-3-
yl-isoquinoline ##STR00109## 0.74 322 G 124- 126 E-59
5-fluoro-3,3,4,4- tetramethyl-1-(7- methylpyrazolo[1,5-
a]pyridin-3-yl)isoquinoline ##STR00110## 0.81 336 G 134- 136 E-60
5-bromo-3,3-dimethyl-1- pyrazolo[1,5-a]pyridin-3-
yl-4H-isoquinoline ##STR00111## 0.78 354- 356 G E-61
5-fluoro-3,3-dimethyl-1- pyrazolo[1,5-a]pyridin-3-
yl-4H-isoquinoline ##STR00112## 0.67 294 G E-62 5-fluoro-3,3,4,4-
tetramethyl-1-(2- methylpyrazolo[1,5- a]pyridin-3-yl)isoquinoline
##STR00113## 0.77 335 G E-63 1-(6,7- dimethylpyrazolo[1,5-
a]pyridin-3-yl)-5-fluoro- 3,3,4,4-tetramethyl- isoquinoline
##STR00114## 0.88 350 G 175- 176 E-64 1-(6,7- dimethylpyrazolo[1,5-
a]pyridin-3-yl)-3,3- dimethyl-isoquinolin-4- one ##STR00115## 0.86
318 G 152- 153 E-65 1-(6,7- dimethylpyrazolo[1,5-
a]pyridin-3-yl)-4,4- difluoro-3,3-dimethyl- isoquinoline
##STR00116## 1.03 340 G 160- 161 E-66 4,4-difluoro-3,3-dimethyl-
1-(7-methylpyrazolo[1,5- a]pyridin-3-yl)isoquinoline ##STR00117##
0.97 326 G 105- 107 E-67 3,3-dimethyl-1-(7- methylpyrazolo[1,5-
a]pyridin-3-yl)isoquinolin- 4-one ##STR00118## 0.77 304 G 110- 112
E-68 3,3-dimethyl-1-(4- methylpyrazolo[1,5-
a]pyridin-3-yl)isoquinolin- 4-one ##STR00119## 0.83 304 G 140- 141
E-69 4,4-difluoro-3,3-dimethyl- 1-(4-methylpyrazolo[1,5-
a]pyridin-3-yl)isoquinoline ##STR00120## 0.99 326 G 113- 114 E-70
1-(6,7- dimethylpyrazolo[1,5- a]pyridin-3-yl)-4,4,6-
trifluoro-3,3-dimethyl- isoquinoline ##STR00121## 1.09 358 G 183-
185 E-71 1-(6,7- dimethylpyrazolo[1,5- a]pyridin-3-yl)-4,4,5-
trifluoro-3,3-dimethyl- isoquinoline ##STR00122## 1.14 358 G 185-
187 E-72 1-(6,7- dimethylpyrazolo[1,5- a]pyridin-3-yl)-5-fluoro-
3,3-dimethyl-isoquinolin- 4-one ##STR00123## 0.95 336 G 139- 141
E-73 5-fluoro-3,3-dimethyl-1- (4-methylpyrazolo[1,5-
a]pyridin-3-yl)isoquinolin- 4-one ##STR00124## 0.89 322 G 141- 143
E-74 1-(6,7- dimethylpyrazolo[1,5- a]pyridin-3-yl)-6-fluoro-
3,3-dimethyl-isoquinolin- 4-one ##STR00125## 0.92 336 G 168- 170
E-75 6-fluoro-3,3-dimethyl-1- (4-methylpyrazolo[1,5-
a]pyridin-3-yl)isoquinolin- 4-one ##STR00126## 0.89 322 G 180- 183
E-78 1-(6-bromo-7-methyl- pyrazolo[1,5-a]pyridin-3-
yl)-3,3-dimethyl- isoquinolin-4-one ##STR00127## 1.13 382- 384 G
166- 168 E-79 1-(6-bromo-7-methyl- pyrazolo[1,5-a]pyridin-3-
yl)-4,4-difluoro-3,3- dimethyl-isoquinoline ##STR00128## 1.34 404-
406 G 180- 182 E-80 4,4-difluoro-3,3-dimethyl-
1-pyrazolo[1,5-a]pyridin- 3-yl-isoquinoline ##STR00129## 0.97 312 G
78- 82 E-81 1-(6-bromopyrazolo[1,5- a]pyridin-3-yl)-4,4-
difluoro-3,3-dimethyl- isoquinoline ##STR00130## 1.17 390- 392 G
127- 129 E-82 1-(6-bromopyrazolo[1,5- a]pyridin-3-yl)-3,3-
dimethyl-isoquinolin-4- one ##STR00131## 0.96 368- 370 G 147- 149
E-83 4,4-difluoro-3,3-dimethyl- 1-(6-methylpyrazolo[1,5-
a]pyridin-3-yl)isoquinoline ##STR00132## 0.96 326 G 105- 107
E-84 1-(4-bromopyrazolo[1,5- a]pyridin-3-yl)-3,3-
dimethyl-isoquinolin-4- one ##STR00133## 0.85 368- 370 G 148- 151
E-85 3-(4,4-difluoro-3,3- dimethyl-1- isoquinolyl)pyrazolo[1,5-
a]pyridine-6-carbonitrile ##STR00134## 1.06 337 G 191- 194 E-86
1-(6-ethylpyrazolo[1,5- a]pyridin-3-yl)-4,4- difluoro-3,3-dimethyl-
isoquinoline ##STR00135## 1.04 340 G E-87 1-(6-chloropyrazolo[1,5-
a]pyridin-3-yl)-4,4- difluoro-3,3-dimethyl- isoquinoline
##STR00136## 1.16 346- 348 G 113- 118 E-88
4,4-difluoro-1-(6-fluoro-7- methyl-pyrazolo[1,5-
a]pyridin-3-yl)-3,3- dimethyl-isoquinoline ##STR00137## 1.13 344 G
115- 118 E-89 4,4-difluoro-1-(4- fluoropyrazolo[1,5-
a]pyridin-3-yl)-3,3- dimethyl-isoquinoline ##STR00138## 0.89 330 G
E-90 1-(6-ethnylpyrazolo[1,5- a]pyridin-3-yl)-4,4-
difluoro-3,3-dimethyl- isoquinoline ##STR00139## 1.10 336 G 145-
147 E-91 1-(6-chloro-7-methyl- pyrazolo[1,5-a]pyridin-3-
yl)-4,4-difluoro-3,3- dimethyl-isoquinoline ##STR00140## 1.23 360-
362 G 166- 168 E-92 4,4-difluoro-1-(7- methoxypyrazolo[1,5-
a]pyridin-3-yl)-3,3- dimethyl-isoquinoline ##STR00141## 0.87 342 G
120- 124 E-93 1-(7-chloropyrazolo[1,5- a]pyridin-3-yl)-4,4-
difluoro-3,3-dimethyl- isoquinoline ##STR00142## 1.11 346- 348 G
129- 132 E-94 ##STR00143## 0.82 328 G 124- 126 E-95 ##STR00144##
0.77 314 G
BIOLOGICAL EXAMPLES
[0296] Botryotinia fuckeliana (Botrytis cinerea)/Liquid Culture
(Gray Mould)
[0297] Conidia of the fungus from cryogenic storage are directly
mixed into nutrient broth (Vogels broth). After placing a (DMSO)
solution of test compound into a microtiter plate (96-well format),
the nutrient broth containing the fungal spores is added. The test
plates are incubated at 24.degree. C. and the inhibition of growth
is determined photometrically 3-4 days after application. The
following compounds gave at least 80% control of Botryotinia
fuckeliana at 20 ppm when compared to untreated control under the
same conditions, which showed extensive disease development:
[0298] E-1, E-6, E-7, E-8, E-9, E-10, E-11, E-19, E-21, E-22, E-23,
E-24, E-27, E-29, E-30, E-31, E-32, E-33, E-38, E-39, E-40, E-44,
E-45, E-46, E-47, E-48, E-49, E-50, E-51, E-52, E-53, E-55, E-56,
E-57, E-58, E-59, E-60, E-62, E-63, E-64, E-65, E-66, E-67, E-68,
E-69, E-70, E-71, E-72, E-74, E-75, E-76, E-77, E-78, E-79, E-80,
E-81, E-82, E-83, E-85, E-86, E-87, E-88, E-89, E-91, E-92, E-93,
E-95, E-95.
Glomerella lagenarium (Colletotrichum lagenarium) Liquid Culture
(Anthracnose)
[0299] Conidia of the fungus from cryogenic storage are directly
mixed into nutrient broth (PDB potato dextrose broth). After
placing a (DMSO) solution of test compound into a microtiter plate
(96-well format), the nutrient broth containing the fungal spores
is added. The test plates are incubated at 24.degree. C. and the
inhibition of growth is measured photometrically 3-4 days after
application.
[0300] The following compounds gave at least 80% control of
Glomerella lagenarium at 20 ppm when compared to untreated control
under the same conditions, which showed extensive disease
development:
[0301] E-1, E-2, E-3, E-6, E-7, E-8, E-9, E-10, E-11, E-14, E-16,
E-17, E-19, E-21, E-22, E-24, E-27, E-29, E-30, E-31, E-32, E-33,
E-37, E-38, E-39, E-40, E-44, E-45, E-46, E-47, E-48, E-49, E-50,
E-52, E-55, E-57, E-58, E-59, E-62, E-63, E-64, E-65, E-66, E-67,
E-69, E-70, E-71, E-72, E-74, E-76, E-77, E-78, E-79, E-80, E-81,
E-82, E-83, E-86, E-87, E-88, E-89, E-90, E-91, E-92, E-93, E-94,
E-95.
Fusarium culmorum/Liquid Culture (Head Blight)
[0302] Conidia of the fungus from cryogenic storage are directly
mixed into nutrient broth (PDB potato dextrose broth). After
placing a (DMSO) solution of test compound into a microtiter plate
(96-well format), the nutrient broth containing the fungal spores
is added. The test plates are incubated at 24.degree. C. and the
inhibition of growth is determined photometrically 3-4 days after
application.
[0303] The following compounds gave at least 80% control of
Fusarium culmorum at 20 ppm when compared to untreated control
under the same conditions, which showed extensive disease
development:
[0304] E-1, E-6, E-8, E-9, E-21, E-31, E-32, E-33, E-39, E-44,
E-45, E-47, E-50, E-55, E-57, E-59, E-63, E-64, E-65, E-66, E-67,
E-69, E-70, E-71, E-72, E-74, E-76, E-78, E-79, E-80, E-81, E-82,
E-83, E-86, E-87, E-88, E-89, E-91, E-92, E-93, E-94.
Gaeumannomyces graminis/Liquid Culture (Take-all of Cereals)
[0305] Mycelial fragments of the fungus from cryogenic storage were
directly mixed into nutrient broth (PDB potato dextrose broth).
After placing a (DMSO) solution of test compound into a microtiter
plate (96-well format), the nutrient broth containing the fungal
spores is added. The test plates are incubated at 24.degree. C. and
the inhibition of growth is determined photometrically 4-5 days
after application.
[0306] The following compounds gave at least 80% control of
Gaeumannomyces graminis at 20 ppm when compared to untreated
control under the same conditions, which showed extensive disease
development:
[0307] E-1, E-6, E-9, E-25, E-37, E-38, E-39, E-41, E-58, E-63,
E-64, E-65, E-66, E-69, E-71, E-76, E-79, E-80, E-81, E-82, E-83,
E-86, E-87, E-88, E-90, E-91, E-92, E-94.
Monographella nivalis (Microdochium nivale)/Liquid Culture (Foot
Rot Cereals)
[0308] Conidia of the fungus from cryogenic storage are directly
mixed into nutrient broth (PDB potato dextrose broth). After
placing a (DMSO) solution of test compound into a microtiter plate
(96-well format), the nutrient broth containing the fungal spores
is added. The test plates are incubated at 24 and the inhibition of
growth is determined photometrically 4-5 days after
application.
[0309] The following compounds gave at least 80% control of
Monographella nivalis at 20 ppm when compared to untreated control
under the same conditions, which showed extensive disease
development:
[0310] E-6, E-9, E-15, E-21, E-22, E-24, E-29, E-33, E-38, E-39,
E-44, E-45, E-52, E-53, E-57, E-59, E-64, E-65, E-66, E-67, E-69,
E-70, E-71, E-72, E-76, E-78, E-80, E-81, E-82, E-83, E-88, E-89,
E-90, E-91, E-92, E-93, E-94.
Mycosphaerella graminicola (Septoria tritici)/Liquid Culture
(Septoria blotch)
[0311] Conidia of the fungus from cryogenic storage are directly
mixed into nutrient broth (PDB potato dextrose broth). After
placing a (DMSO) solution of test compound into a microtiter plate
(96-well format), the nutrient broth containing the fungal spores
is added. The test plates are incubated at 24.degree. C. and the
inhibition of growth is determined photometrically 4-5 days after
application.
[0312] The following compounds gave at least 80% control of
Mycosphaerella graminicola at 20 ppm when compared to untreated
control under the same conditions, which showed extensive disease
development:
[0313] E-22, E-39, E-44, E-80, E-81, E-82, E-83, E-86, E-87, E-88,
E-93
Magnaporthe grisea (Pyricularia oryzae)/Rice/Leaf Disc Preventative
(Rice Blast)
[0314] Rice leaf segments cv. Ballila are placed on agar in a
multiwell plate (24-well format) and sprayed with the formulated
test compound diluted in water. The leaf segments are inoculated
with a spore suspension of the fungus 2 days after application. The
inoculated leaf segments are incubated at 22.degree. C. and 80%
r.h. under a light regime of 24 h darkness followed by 12 h
light/12 h darkness in a climate cabinet and the activity of a
compound is assessed as percent disease control compared to
untreated when an appropriate level of disease damage appears in
untreated check leaf segments (5-7 days after application).
[0315] The following compounds gave at least 50% control of
Magnaporthe grisea at 200 ppm when compared to untreated control
under the same conditions, which showed extensive disease
development:
[0316] E-6, E-8, E-9, E-31, E-33, E-39, E-45, E-57, E-59, E-63,
E-66, E-69, E-70, E-71, E-81, E-83, E-86, E-87, E-88, E-91, E-92,
E-93, E-94, E-95.
Magnaporthe grisea (Pyricularia oryzae)/Liquid Culture (Rice
Blast)
[0317] Conidia of the fungus from cryogenic storage are directly
mixed into nutrient broth (PDB potato dextrose broth). After
placing a (DMSO) solution of test compound into a microtiter plate
(96-well format), the nutrient broth containing the fungal spores
is added. The test plates are incubated at 24.degree. C. and the
inhibition of growth is determined photometrically 3-4 days after
application. The following compounds gave at least 80% control of
Magnaporthe grisea at 60 ppm when compared to untreated control
under the same conditions, which showed extensive disease
development:
[0318] E-50, E-51, E-52, E-53, E-55, E-56, E-57, E-63, E-64, E-65,
E-66, E-67, E-69, E-70, E-71, E-72, E-74, E-76, E-77, E-78, E-79,
E-80, E-81, E-82, E-83, E-85, E-86, E-87, E-88, E-89, E-90, E-91,
E-92, E-93, E-94, E-95.
Sclerotinia sclerotiorum/Liquid Culture (Cottony Rot)
[0319] Mycelia fragments of a newly grown liquid culture of the
fungus are directly mixed into nutrient broth (Vogels broth). After
placing a (DMSO) solution of test compound into a microtiter plate
(96-well format) the nutrient broth containing the fungal material
is added. The test plates are incubated at 24.degree. C. and the
inhibition of growth is determined photometrically 3-4 days after
application. The following compounds gave at least 80% control of
Sclerotinia sclerotiorum at 20 ppm when compared to untreated
control under the same conditions, which showed extensive disease
development:
[0320] E-50, E-51, E-52, E-55, E-57, E-64, E-65, E-66, E-67, E-69,
E-70, E-71, E-72, E-79, E-80, E-81, E-82, E-83, E-86, E-87, E-88,
E-89, E-91, E-93.
* * * * *