Microbiocidal quinoline (thio)carboxamide derivatives
11178869 · 2021-11-23
Assignee
Inventors
Cpc classification
C07D409/12
CHEMISTRY; METALLURGY
International classification
Abstract
Compounds of the formula (I) wherein the subsitiuents are as defined in claim 1. Furthermore, the present invention relates to agrochemical compositions which comprise compounds of formula (I), to preparation of these compositions, and to the use of the compounds or compositions in agriculture or horticulture for combating, preventing or controlling infestation of plants, harvested food crops, seeds or non-living materials by phytopathogenic microorganisms, in particular fungi. ##STR00001##
Claims
1. A compound of formula ( ) ##STR00098## wherein X is O or S; R.sub.1 is hydrogen, halogen, methyl, or cyano; R.sub.2 is hydrogen, methyl or halogen; R.sub.3 and R.sub.4 are each independently selected from hydrogen, halogen or methyl; R.sub.5 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.3-C.sub.4 cycloalkyl(C.sub.1-C.sub.3)alkyl, wherein the alkyl, alkenyl and cycloalkyl groups may be optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkylthio; R.sub.6 is hydrogen, cyano or C.sub.1-C.sub.4 alkyl, wherein the alkyl may be optionally substituted with 1 to 3 substituents independently selected from halogen and C.sub.1-C.sub.3 alkoxy; R.sub.7 is hydrogen, C.sub.1-C.sub.5 alkyl, C.sub.3-C.sub.7 cycloalkyl, (C.sub.1-C.sub.3 alkyl).sub.3 silyl, phenyl or thiophenyl, wherein the alkyl and cycloalkyl may be optionally substituted with one to three substituents independently selected from halogen, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkylthio, and wherein the phenyl and thiophenyl may be optionally substituted with one to three substituents independently selected from halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl and C.sub.1-C.sub.3 alkoxy; A is a direct bond or C(R.sub.8)(R.sub.9); R.sub.8 and R.sub.9 are independently selected from hydrogen, fluoro and methyl; or a salt, enantiomer or N-oxide thereof, provided the compound is not ##STR00099##
2. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein R.sub.1 is hydrogen, fluoro, chloro, methyl or cyano.
3. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein R.sub.2 is hydrogen, methyl, chloro or fluoro.
4. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein R.sub.3 and R.sub.4 are each independently selected from hydrogen and methyl.
5. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein R.sub.5 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, cyclopropyl or C.sub.3-C.sub.4 cycloalkyl-CH.sub.2—, wherein the alkyl, alkenyl and cycloalkyl groups may be optionally substituted with 1 to 3 substituents independently selected from fluoro, chloro and methyl.
6. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein R.sub.6 is hydrogen or C.sub.1-C.sub.2 alkyl, wherein the alkyl may be optionally substituted with 1 to 3 substituents independently selected from fluoro and methoxy.
7. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein A is a direct bond or CH.sub.2.
8. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein R.sub.7 is C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, phenyl or thiophenyl, wherein the alkyl and cycloalkyl may be optionally substituted with one to three substituents independently selected from fluoro, chloro, methyl and methoxy, and wherein the phenyl and thiophenyl may be optionally substituted with one to three substituents independently selected from fluoro, chloro, trifluoromethyl, methyl and methoxy and A is a direct bond; or, alternatively, R.sub.7 is C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, trimethylsilyl, phenyl or thiophenyl, wherein the alkyl and cycloalkyl may be optionally substituted with one to three substituents independently selected from fluoro, chloro, methyl and methoxy, and wherein the phenyl and thiophenyl may be optionally substituted with one to three substituents independently selected from fluoro, chloro, trifluoromethyl, methyl and methoxy and A is CH.sub.2.
9. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein R.sub.1 is hydrogen, fluoro, chloro or methyl; R.sub.2 is hydrogen, chloro or fluoro; R.sub.3 is methyl and R.sub.4 is hydrogen; or R.sub.3 is hydrogen and R.sub.4 is methyl; or R.sub.3 is hydrogen and R.sub.4 is hydrogen; R.sub.5 is C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.4 alkenyl, cyclopropyl or C.sub.3-C.sub.4 cycloalkyl-CH.sub.2—, wherein the alkyl, alkenyl and cycloalkyl groups may be optionally substituted with 1 to 3 fluoro or one methyl; and R.sub.6 is hydrogen, methyl or ethyl.
10. The compound according to claim 1 wherein X is O or S; R.sub.1 is hydrogen, fluoro, chloro or methyl; R.sub.2 is hydrogen, chloro or fluoro; R.sub.3 is methyl and R.sub.4 is hydrogen; or R.sub.3 is hydrogen and R.sub.4 is methyl; or R.sub.3 is hydrogen and R.sub.4 is hydrogen; R.sub.5 is C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.4 alkenyl, cyclopropyl or C.sub.3-C.sub.4 cycloalkyl-CH.sub.2—, wherein the alkyl, alkenyl and cycloalkyl groups may be optionally substituted with 1 to 3 fluoro or one methyl; R.sub.6 is hydrogen methyl or ethyl; A is a direct bond and R.sub.7 is phenyl or thiophenyl, wherein the phenyl and thiophenyl may be optionally substituted with one to three substituents independently selected from fluoro, chloro and methyl; or, alternatively, A is CH.sub.2 and R.sub.7 is C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, phenyl or thiophenyl, wherein the alkyl cyclopropyl and cyclobutyl may be optionally substituted with one to three fluoro substituents or one methyl; or a salt, enantiomer or N-oxide thereof.
11. The compound according to claim 1 wherein X is O or S; R.sub.1 is fluoro, chloro or methyl; R.sub.2 is hydrogen or fluoro; R.sub.3 and R.sub.4 are both hydrogen; R.sub.6 is hydrogen or methyl; A is a direct bond and R.sub.5 is ethyl, isopropyl, tert-butyl, isopropenyl or cyclopropyl, wherein the ethyl, isopropyl and cyclopropyl groups may be optionally substituted with 1 to 3 fluoro or one methyl and R.sub.7 is phenyl or thiophenyl; or, alternatively, A is CH.sub.2 and R.sub.5 is ethyl, propyl, isobutyl, neo-pentyl, C.sub.3-C.sub.4 alkenyl or cyclopropyl-CH.sub.2—, wherein the ethyl, propyl, isobutyl, neo-pentyl, C.sub.3-C.sub.4 alkenyl and cyclopropyl groups may be optionally substituted with 1 to 3 fluoros or one methyl and R.sub.7 is methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl, wherein the methyl, ethyl, isopropyl, cyclopropyl and cyclobutyl may be optionally substituted with one to three fluoro substituents or one methyl; or a salt, enantiomer or N-oxide thereof.
12. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein X is O.
13. A composition comprising a fungicidally effective amount of a compound of formula (I) as defined in claim 1.
14. The composition according to claim 13, wherein the composition further comprises at least one additional active ingredient and/or a diluent.
15. A method of combating, preventing or controlling phytopathogenic fungi which comprises applying to phytopathogenic fungi, to the locus of phytopathogenic fungi, or to a plant susceptible to attack by phytopathogenic fungi, or to propagation material thereof, a fungicidally effective amount of a compound of formula (I) as defined in claim 1 or a composition comprising a fungicidally effective amount of a compound of formula (I) as defined in claim 1.
16. A compound selected from the group consisting of: N-[4-cyclopropyl- 1-methyl-1-(2,2,2-trifluoroethyl)but-3-ynyl]-8-fluoro-quinoline-3-carboxamide; 8-fluoro-N-(1-isobutyl-1-methyl-but-3-ynyl)quinoline-3-carboxamide; N-(1-isopropyl-3-phenyl-prop-2-ynyl)-8-methyl-quinoline-3-carboxamide; 8-chloro-N-(1-isopropyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide; 8-fluoro-N-(1-isopropyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide; 8-fluoro-N-[4,4,4-trifluoro- 1-(2-phenylethynyl)butyl]quinoline-3-carboxamide; N-(1-tert-butyl-3-phenyl-prop-2-ynyl)-8-fluoro-quinoline-3-carboxamide; N-(1,1-diethyl-3-phenyl-prop-2-ynyl)-8-fluoro-quinoline-3-carboxamide; N-[1,3-dimethyl- 1-(2-phenylethynyl)butyl]-8-fluoro-quinoline-3-carboxamide; N-(1-ethyl-1-methyl-3 -phenyl-prop-2-ynyl)-8-methyl-quinoline-3-carboxamide; 8-cyano-N-(1-ethyl-1-methyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide; 8-chloro-N-(1-ethyl-1-methyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide; 8-fluoro-N-[3-(2-fluorophenyl)-1-i sopropyl- 1-methyl-prop-2-ynyl]quinoline-3-carboxamide; 8-fluoro-N-[1-isopropyl-1-methyl-3-(o-tolyl)prop-2-ynyl]quinoline -3-carboxamide; N-[1-ethyl-1-methyl-3-(o-tolyl)prop-2-ynyl]-8-fluoro-2-methyl-quinoline-3-carboxamide; N-[1-ethyl-1-methyl-3-(o-tolyl)prop-2-ynyl]-8-fluoro-quinoline-3 -carboxamide; N-(1-ethyl-1-methyl-3-phenyl-prop-2-ynyl)-8-fluoro-2-methyl -quinoline-3-carboxamide; N-(1-ethyl-1-methyl-3-phenyl-prop-2-ynyl)-8-fluoro-quinoline-3-carboxamide; 8-fluoro-N-[3-(2-fluorophenyl)-1,1-dimethyl-prop-2-ynyl]quinoline -3-carboxamide; N-[3-(5-cyano-2-methyl-phenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[3-(3,4-difluorophenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3 -carboxamide; N-[1,1-dimethyl-3-(p-tolyl)prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[3-(2,5-dimethylphenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[3-(5-chloro-2-methoxy-phenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; 8-fluoro-N-[3-(5-fluoro-2-methyl-phenyl)-1,1-dimethyl-prop-2-ynyl]quinoline-3-carboxamide; N-[3-(2,4-difluorophenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[3-(2,3-dimethylphenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; 8-fluoro-N-[3-(4-fluorophenyl)-1,1-dimethyl-prop-2-ynyl]quinoline -3-carboxamide; 8-fluoro-N-[3-(4-methoxyphenyl)-1,1-dimethyl-prop-2-ynyl]quinoline -3-carboxamide; 8-fluoro-N-[3-(3-methoxyphenyl)-1,1-dimethyl-prop-2-ynyl]quinoline -3-carboxamide; N-[3-(3,5-dimethylphenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[3-(2-cyano-5-methyl-phenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[3-(3,4-dimethylphenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[3-(2,4-dimethylphenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[3-(4-cyano-2-methyl-phenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[1,1-dimethyl-3-(5-methyl-2-thienyl)prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[3-(3-cyanophenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro-quinoline -3-carboxamide; 8-fluoro-N-[3-(2-methoxyphenyl)-1,1-dimethyl-prop-2-ynyl]quinoline -3-carboxamide N-[3-(4-chloro-3-methoxy-phenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[1,1-dimethyl-3-(m-tolyl)prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[3-(3,5-difluorophenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[3-(2-cyanophenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro-quinoline -3-carboxamide; N-[1,1-dimethyl-3-[4-(trifluoromethyl)phenyl]prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; 8-fluoro-N-[3-2-methoxy-5-(trifluoromethyl)phenyl]-1,1-dimethyl -prop-2-ynyl]quinoline-3-carboxamide; 8-fluoro-N-[3-(3-fluoro-4-methoxy-phenyl)-1,1-dimethyl-prop-2-ynyl]quinoline-3-carboxamide; 8-fluoro-N-[3-(2-fluoro-5-methyl-phenyl)-1,1-dimethyl-prop-2-ynyl]quinoline-3-carboxamide; 8-fluoro-N-(1-isopropyl-1-methyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide; N-[1,1-dimethyl-3-(o-tolyl)prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[1,1-dimethyl-3-[3-(trifluoromethyl)phenyl]prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-(1,1-dimethyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide; N-(1,1-dimethyl-3-phenyl-prop-2-ynyl)-8-fluoro-2-methyl-quinoline-3-carboxamide; N-(1,1-dimethyl-3-phenyl-prop-2-ynyl)-8-fluoro-4-methyl-quinoline-3-carboxamide; 8-fluoro-N-(4-methoxy-1,1-dimethyl-but-2-ynyl)quinoline-3-carboxamide; N-(1,1-dimethylbut-2-ynyl)-8-fluoro-quinoline-3-carboxamide; N-(1,1-dimethylprop-2-ynyl)-8-fluoro-quinoline-3-carboxamide; N-(1,1-dimethyl-3-phenyl-prop-2-ynyl)-8-fluoro-quinoline-3-carboxamide; N-[(1R)-4-cyclopropyl-1-methyl-1-(2,2,2-trifluoroethyl)but-3-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[(1S)-4-cyclopropyl-1-methyl-1-(2,2,2-trifluoroethyl)but-3-ynyl]-8-fluoro-quinoline-3-carboxamide; 8-fluoro-N-[(1R)-3-methyl-1-(2-phenylethynyl)butyl]quinoline-3-carboxamide; 8-fluoro-N-[(1S)-3-methyl-1-(2-phenylethynyl)butyl]quinoline-3-carboxamide; N-[(1S)-1,3-dimethyl-1-(2-phenylethynyl)butyl]-8-fluoro-quinoline -3-carboxamide; N-[(1R)-1,3-dimethyl-1-(2-phenylethynyl)butyl]-8-fluoro-quinoline -3-carboxamide; 8-fluoro-N-[(1S)-1-isopropyl-1-methyl-3-phenyl-prop-2-ynyl]quinoline-3-carboxamide; and 8-fluoro-N-[(1R)-1-isopropyl-1-methyl-3-phenyl-prop-2-ynyl]quinoline-3-carboxamide.
17. The compound of claim 16, wherein the compound is selected from the group consisting of: N-[4-cyclopropyl-1-methyl-1-(2,2,2-trifluoroethyl)but-3-ynyl]-8-fluoro-quinoline-3-carboxamide; and 8-fluoro-N-(1-isobutyl-1-methyl-but-3-ynyl)quinoline-3-carboxamide.
18. The compound of claim 16, wherein the compound is selected from the group consisting of: N-(1-isopropyl-3-phenyl-prop-2-ynyl)-8-methyl-quinoline-3-carboxamide; 8-chloro-N-(1-isopropyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide; 8-fluoro-N-(1-isopropyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide; 8-fluoro-N-[4,4,4-trifluoro- 1-(2-phenylethynyl)butyl]quinoline-3-carboxamide; N-(1-tert-butyl-3-phenyl-prop-2-ynyl)-8-fluoro-quinoline-3-carboxamide; N-(1,1-diethyl-3-phenyl-prop-2-ynyl)-8-fluoro-quinoline-3-carboxamide N-[1,3-dimethyl-1-(2-phenylethynyl)butyl]-8-fluoro-quinoline-3-carboxamide; N-(1-ethyl-1-methyl-3-phenyl-prop-2-ynyl)-8-methyl-quinoline-3-carboxamide; 8-cyano-N-(1-ethyl-1-methyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide; 8-chloro-N-(1-ethyl-1-methyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide; 8-fluoro-N-[3-(2-fluorophenyl)-1-isopropyl-1-methyl-prop-2-ynyl]quinoline-3-carboxamide; 8-fluoro-N-[1-isopropyl-1-methyl-3-(o-tolyl)prop-2-ynyl]quinoline -3-carboxamide; N-[1-ethyl-1-methyl-3-(o-tolyl)prop-2-ynyl]-8-fluoro-2-methyl-quinoline-3-carboxamide; N-[1-ethyl-1-methyl-3-(o-tolyl)prop-2-ynyl]-8-fluoro-quinoline-3 -carboxamide; N-(1-ethyl-1-methyl-3-phenyl-prop-2-ynyl)-8-fluoro-2-methyl -quinoline-3-carboxamide; N-(1-ethyl-1-methyl-3-phenyl-prop-2-ynyl)-8-fluoro-quinoline-3 -carboxamide; 8-fluoro-N-[3 -(2-fluorophenyl)- 1,1-dimethyl-prop-2-ynyl]quinoline-3-carboxamide; N-[3-(5-cyano-2-methyl-phenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro-quinoline-3 -carboxamide; N-[3 -(3 ,4-difluorophenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[1,1-dimethyl-3-(p-tolyl)prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[3-(2,5-dimethylphenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[3-(5-chloro-2-methoxy-phenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; 8-fluoro-N-[3-(5-fluoro-2-methyl-phenyl)-1,1-dimethyl-prop-2-ynyl]quinoline-3 -carboxamide; N-[3-(2,4-difluorophenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[3-(2,3 -dimethylphenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; 8-fluoro-N-[3-(4-fluorophenyl)- 1,1-dimethyl-prop-2-ynyl]quinoline-3-carboxamide; 8-fluoro-N-[3-(4-methoxyphenyl)-1,1-dimethyl-prop-2-ynyl]quinoline-3-carboxamide; 8-fluoro-N-[3-(3-methoxyphenyl)-1,1-dimethyl-prop-2-ynyl]quinoline-3-carboxamide; N-[3-(3,5-dimethylphenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[3-(2-cyano-5-methyl-phenyl)- 1,1-dimethyl-prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[3-(3,4-dimethylphenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[3-(2,4-dimethylphenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[3-(4-cyano-2-methyl-phenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[1,1-dimethyl-3-(5-methyl-2-thienyl)prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[3 -(3 -cyanophenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; 8-fluoro-N-[3-(2-methoxyphenyl)-1,1-dimethyl-prop-2-ynyl]quinoline -3-carboxamide; N-[3-(4-chloro-3-methoxy-phenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[1,1-dimethyl-3-(m-tolyl)prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[3-(3,5-difluorophenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro -quinoline-3-carboxamide; N-[3-(2-cyanophenyl)-1,1-dimethyl-prop-2-ynyl]-8-fluoro-quinoline -3-carboxamide; N-[1,1-dimethyl-3-[4-(trifluoromethyl)phenyl]prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; 8-fluoro-N-[3-[2-methoxy-5-(trifluoromethyl)phenyl]-1,1-dimethyl -prop-2-ynyl]quinoline-3-carboxamide; 8-fluoro-N-[3 -(3 -fluoro-4-methoxy-phenyl)-1,1-dimethyl-prop-2-ynyl]quinoline-3 -carboxamide; 8-fluoro-N-[3-(2-fluoro-5-methyl-phenyl)-1,1-dimethyl-prop-2-ynyl]quinoline-3-carboxamide; 8-fluoro-N-(1-isopropyl-1-methyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide; N-[1,1-dimethyl-3-(o-tolyl)prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[1,1-dimethyl-3-[3-(trifluoromethyl)phenyl]prop-2-ynyl]-8-fluoro-quinoline-3-carboxamide; N-(1,1-dimethyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide; N-(1,1-dimethyl-3-phenyl-prop-2-ynyl)-8-fluoro-2-methyl-quinoline-3-carboxamide; N-(1,1-dimethyl-3-phenyl-prop-2-ynyl)-8-fluoro-4-methyl-quinoline-3-carboxamide; 8-fluoro-N-(4-methoxy-1,1-dimethyl-but-2-ynyl)quinoline-3-carboxamide; N-(1,1-dimethylbut-2-ynyl)-8-fluoro-quinoline-3-carboxamide; N-(1,1-dimethylprop-2-ynyl)-8-fluoro-quinoline-3-carboxamide; and N-(1,1-dimethyl-3-phenyl-prop-2-ynyl)-8-fluoro-quinoline-3-carboxamide.
19. The compound of claim 16, wherein the compound is selected from the group consisting of: N-[(1R)-4-cyclopropyl-1-methyl-1-(2,2,2-trifluoroethyl)but-3-ynyl]-8-fluoro-quinoline-3-carboxamide; N-[(1S)-4-cyclopropyl-1-methyl-1-(2,2,2-trifluoroethyl)but-3-ynyl]-8-fluoro-quinoline-3-carboxamide; 8-fluoro-N-[(1R)-3-methyl-1-(2-phenylethynyl)butyl]quinoline-3 -carboxamide; 8-fluoro-N-[(1S)-3-methyl-1-(2-phenylethynyl)butyl]quinoline-3 -carboxamide; N-[(1S)-1,3-dimethyl-1-(2-phenylethynyl)butyl]-8-fluoro-quinoline -3-carboxamide; N-[(1R)- 1,3-dimethyl-1-(2-phenylethynyl)butyl]-8-fluoro-quinoline -3-carboxamide; 8-fluoro-N-[(1S)-1-isopropyl-1-methyl-3-phenyl-prop-2-ynyl]quinoline-3 -carboxamide; and 8-fluoro-N-[(1R)-1 sopropyl- 1-methyl-3 -phenyl-prop-2-ynyl]quinoline-3-carboxamide.
Description
EXAMPLES
(1) 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.
(2) 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:
(3) Method G:
(4) Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions), Capillary: 3.00 kV, Cone range: 30 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 50 l/h, Desolvation Gas Flow: 650 l/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° 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
(5) Method H:
(6) Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions), Capillary: 3.00 kV, Cone range: 30V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 50 l/h, Desolvation Gas Flow: 650 l/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° 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
(7) Method W:
(8) Spectra were recorded on a Mass Spectrometer (ACQUITY UPLC) from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.0 kV, Cone: 30V, Extractor: 3.00 V, Source Temperature: 150° C., Desolvation Temperature: 400° C., Cone Gas Flow: 60 L/Hr, Desolvation Gas Flow: 700 L/Hr, Mass range: 140 to 800 Da), DAD Wavelength range (nm): 210 to 400, and an Acquity UPLC from Waters: Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=Water/Methanol 9:1, 0.1% formic acid, B=Acetonitrile+0.1% formic acid, gradient: 0-100% B in 2.5 min; Flow (ml/min) 0.75
(9) Method I:
(10) 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 (kV) 3.5, Cone (V) 30.00, Extractor (V) 3.00, Source Temperature (° C.) 150, Desolvation Temperature (° C.) 400, Cone Gas Flow (L/Hr) 60, Desolvation Gas Flow (L/Hr) 700, Mass range: 140 to 800 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. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters ACQUITY UPLC HSS T3; Column length: 30 mm; Internal diameter of column: 2.1 mm; Particle Size: 1.8 micron; Temperature: 60° C., DAD Wavelength range (nm): 210 to 400. Solvent Gradient A: Water/Methanol 9:1, 0.1% formic acid and Solvent B: Acetonitrile, 0.1% formic acid
(11) TABLE-US-00003 Time A B Flow rate (minutes) (%) (%) (ml/min) 0 100 0 0.75 2.5 0 100 0.75 2.8 0 100 0.75 3.0 100 0 0.75
Formulation Examples
(12) TABLE-US-00004 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% —
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.
(13) TABLE-US-00005 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%
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.
(14) TABLE-US-00006 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%
Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.
(15) TABLE-US-00007 Dusts a) b) c) Active ingredient [compound of formula (I)] 5% 6% 4% talcum 95% — — Kaolin — 94% — mineral filler — — 96%
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.
(16) TABLE-US-00008 Extruder granules Active ingredient [compound of formula (I)] 15% sodium lignosulfonate 2% carboxymethylcellulose 1% Kaolin 82%
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.
(17) TABLE-US-00009 Coated granules Active ingredient [compound of formula (I)] 8% polyethylene glycol (mol. wt. 200) 3% Kaolin 89%
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.
(18) TABLE-US-00010 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%
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.
(19) TABLE-US-00011 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% in water) monoazo-pigment calcium salt 5% Silicone oil (in the form of a 75% emulsion in water) 0.2% Water 45.3%
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
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.
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.
The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.
PREPARATION EXAMPLES
Example 1: This Example Illustrates the Preparation of N-[4-cyclopropyl-1-methyl-1-(2,2,2-trifluoroethyl)but-3-ynyl]-8-fluoro-quinoline-3-carboxamide
Step 1: Preparation ethyl 5-cyclopropyl-2-(2,2,2-trifluoroethyl)pent-4-ynoate
(20) ##STR00024##
(21) To a solution of ethyl-4,4,4-trifluorobutyrate (1.3 g, 7.49 mmol) in tetrahydrofuran (0.33M, 22 mL) was added at −50° C., Lithium diisopropylamine (2M) (1.2 eq, 4.5 mL, 8.99 mmol). The solution was stirred at −50° C. for 1 h. 3-bromoprop-1-ynylcyclopropane (1.2 eq, 1.59 g, 8.99 mmol) was added at −50° C. and the brown solution was stirred from this temperature to rt for 3h. The reaction mixture was quenched with NaHCO.sub.3 saturated aqueous, and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over Na.sub.2SO.sub.4 anhydrous, filtered and concentrated. Purification by flash chromatography to give ethyl 5-cyclopropyl-2-(2,2,2-trifluoroethyl)pent-4-ynoate (0.63 g, 34% yield) as a yellow liquid: LC-MS (Method G), Rt=1.09 min, MS: (M+1)=249;
(22) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.57-0.78 (m, 4H) 1.15-1.22 (m, 1H) 1.30 (t, 3H) 2.40-2.83 (m, 5H) 4.21 (q, 2H).
Step 2: Preparation of ethyl 5-cyclopropyl-2-methyl-2-(2,2,2-trifluoroethyl)pent-4-ynoate
(23) ##STR00025##
(24) To a solution of ethyl 5-cyclopropyl-2-(2,2,2-trifluoroethyl)pent-4-ynoate (0.63 g, 2.6 mmol) in tetrahydrofuran (0.33M, 8 mL) was added at −50° C., Lithium diisopropylamine (2M) (1.3 eq, 1.7 mL, 3.3 mmol). The solution was stirred at −50° C. for 1 h. Iodomethane (1.2 eq, 0.20 mL, 3.1 mmol) was added at −50° C. and the brown solution was stirred from this temperature to rt for 3 h. The reaction mixture was quenched with NaHCO.sub.3 saturated aqueous, and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over Na.sub.2SO.sub.4 anhydrous, filtered and concentrated. Purification by flash chromatography to give ethyl 5-cyclopropyl-2-methyl-2-(2,2,2-trifluoroethyl)pent-4-ynoate (0.42 g, 62% yield) as a brown liquid: LC-MS (Method G), Rt=1.12 min, MS: (M+1)=263;
(25) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.58-0.79 (m, 4H) 1.15-1.40 (m, 6H) 2.40-2.72 (m, 4H) 4.21 (q, 2H).
(26) .sup.19F (400 MHz, CHLOROFORM-d) δ ppm −61.
Step 3: Preparation of 5-cyclopropyl-2-methyl-2-(2,2,2-trifluoroethyl)pent-4-ynoic acid
(27) ##STR00026##
(28) Ethyl 5-cyclopropyl-2-methyl-2-(2,2,2-trifluoroethyl)pent-4-ynoate (0.42 g, 1.07 mmol) was stirred in dioxane (5 mL, 0.3M) and ethanol (5 mL, 0.3M). Sodium hydroxide (0.45 g, 7 eq, 11.3 mmol) was added and the yellow solution was stirred at 90° C. for 2h. The reaction mixture was acidified with HCl (1M) and extracted twice with dichloromethane. The organic phase was washed with brine, dried over Na.sub.2SO.sub.4 anhydrous, filtered and concentrated to give 5-cyclopropyl-2-methyl-2-(2,2,2-trifluoroethyl)pent-4-ynoic acid (0.29 g, 76% yield) as a brown liquid: LC-MS (Method G), Rt=0.95 min, MS: (M+1)=235;
(29) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.58-0.79 (m, 4H) 1.15-1.25 (m, 1H) 1.40 (s, 3H) 2.45-2.75 (m, 4H).
(30) .sup.19F (400 MHz, CHLOROFORM-d) δ ppm −61.
Step 4: Preparation of (4-methoxyphenyl)methyl N-[4-cyclopropyl-1-methyl-1-(2,2,2-trifluoroethyl)but-3-ynyl]carbamate
(31) ##STR00027##
(32) To a solution of 5-cyclopropyl-2-methyl-2-(2,2,2-trifluoroethyl)pent-4-ynoic acid (0.18 g, 0.79 mmol) in toluene (4 mL, 0.2M) was added triethylamine (3 eq, 0.33 mL, 2.38 mmmol) and diphenylphosphoryl azide (1.6 eq, 0.36 g, 1.27 mmol). The brown solution was stirred at rt for 1 h (azide formed). 4-methoxybenzyl alcohol (3 eq, 0.30 mL, 2.38 mmol) was then added. The solution was stirred 1h at 80° C. then 16h at 110° C. The reaction mixture was slowly quenched into NaHCO.sub.3 saturated aqueous and extracted twice with ethyl acetate. The organic phase was washed once with a thiosulfate solution and once with brine, dried over Na.sub.2SO.sub.4 anhydrous, filtered and concentrated. Purification by flash chromatography to give (4-methoxyphenyl)methyl N-[4-cyclopropyl-1-methyl-1-(2,2,2-trifluoroethyl)but-3-ynyl]carbamate (0.21 g, 71% yield) as a colourless liquid LC-MS (Method G), Rt=1.15 min, MS: (M+1)=370;
(33) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.60-0.65 (m, 2H) 0.75-0.80 (m, 2H) 1.17-1.25 (m, 1H) 1.48 (s, 3H) 2.50-2.65 (m, 3H) 2.95 (m, 1H) 3.82 (s, 3H) 4.89 (br, 1H, NH) 5.03 (s, 2H) 6.90 (d, 2H) 7.30 (d, 2H).
(34) .sup.19F (400 MHz, CHLOROFORM-d) δ ppm −60.
(35) Step 5: Preparation of 6-cyclopropyl-1,1,1-trifluoro-3-methyl-hex-5-yn-3-amine; hydrochloride
(36) ##STR00028##
(37) To a solution of 4-methoxyphenyl)methyl N-[4-cyclopropyl-1-methyl-1-(2,2,2-trifluoroethyl)but-3-ynyl]carbamate (0.11 g, 0.30 mmol) in dichloromethane (1.5 mL, 0.2M) was added Hydrogen chloride (4M in dioxane) (0.6 mL, 8 eq, 2.38 mmol). The solution was stirred at rt for 1h. Crude was concentrated to give 6-cyclopropyl-1,1,1-trifluoro-3-methyl-hex-5-yn-3-amine; hydrochloride (0.055 g, 76% yield) as a yellow gum, LC-MS (Method G), Rt=0.56 min, MS: (M+1)=206;
(38) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.78 (d, 2H) 1.32 (m, 1H) 1.66 (s, 3H) 2.75-2.87 (m, 4H) 8.80 (b, 2H, NH2).
(39) .sup.19F (400 MHz, CHLOROFORM-d) δ ppm −60.
Step 6: Preparation of N-[4-cyclopropyl-1-methyl-1-(2,2,2-trifluoroethyl)but-3-ynyl]-8-fluoro-quinoline-3-carboxamide
(40) ##STR00029##
(41) To a solution of 6-cyclopropyl-1,1,1-trifluoro-3-methyl-hex-5-yn-3-amine; hydrochloride (0.050 g, 0.21 mmol) in dichloromethane (2.1 mL, 0.1M) and triethylamine (0.12 mL, 4 eq, 0.83 mmol) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.065 g, 1.6 eq, 0.33 mmol) followed by O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.13 g, 1.6 eq, 0.33 mmol) and 8-fluoroquinoline-3-carboxylic acid (0.079 g. 2 eq, 0.41 mmol). The solution was stirred at rt for 16h. The reaction mixture was quenched with NaHCO.sub.3 saturated aqueous and extracted twice with dichloromethane. The organic phase was washed with brine, dried over Na.sub.2SO.sub.4 anhydrous, filtered and concentrated. Purification by flash chromatography to give N-[4-cyclopropyl-1-methyl-1-(2,2,2-trifluoroethyl)but-3-ynyl]-8-fluoro-quinoline-3-carboxamide (0.073 g, 93% yield) as a white solid, mp=110-112° C., LC-MS (Method G), Rt=1.06 min, MS: (M+1)=379;
(42) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.58-0.63 (m, 2H) 0.72-0.78 (m, 2H) 1.22 (m, 1H) 1.68 (s, 3H) 2.70-2.82 (m, 2H) 2.92 (d, 1H) 6.47 (s, 1H, NH) 7.51 (m, 1H) 7.58 (m, 1H) 7.70 (d, 1H) 8.55 (s, 1H) 9.22 (s, 1H).
(43) .sup.19F (400 MHz, CHLOROFORM-d) δ ppm −60, −124.5.
Example 2: Preparation of 8-fluoro-N-(1-isopropyl-1-methyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide
Step 1: Preparation of 3,4-dimethyl-1-phenyl-pent-1-yn-3-amine
(44) ##STR00030##
(45) To a solution of iodobenzene (12.0 mmol, 2.50 g) in a mixture of tetrahydrofuran (61 mL, 0.2 M) and diisopropylamine (30 mL) was added 3,4-dimethylpent-1-yn-3-amine hydrochloride (1.20 equiv., 15.0 mmol, 2.10 g), copper (I) iodide (0.10 equiv., 1.2 mmol, 0.23 g) and Bis(triphenylphosphine)palladium(II) dichloride (0.10 equiv., 1.2 mmol, 0.85 g) and the reaction mixture was stirred at room temperature for 20 h. The mixture was filtered over a pad of silica gel and the pad was washed with ethyl acetate. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Flash Chromatography to give 3,4-dimethyl-1-phenyl-pent-1-yn-3-amine (2.05 g, 10.9 mmol, 90% yield) as a dark yellow oil. Rt=0.86 min (Method H), MS: (M+1)=189;
(46) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.12 (br d, J=2.57 Hz, 6H) 1.40-1.55 (m, 3H) 1.77-2.03 (m, 1H) 7.27-7.37 (m, 3H) 7.43 (dd, J=7.52, 2.02 Hz, 2H).
Step 2: Preparation of 8-fluoro-N-(1-isopropyl-1-methyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide
(47) ##STR00031##
(48) To a suspension of 8-fluoroquinoline-3-carboxylic acid (1.0 mmol, 0.20 g) in dichloromethane (5.2 mL, 0.2 M) was added triethylamine (1.5 equiv., 1.6 mmol, 0.22 mL) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.5 equiv., 1.6 mmol, 0.31 g), 1-hydroxy-7-azabenzotriazole (1.5 equiv., 1.6 mmol, 0.22 g) and 3,4-dimethyl-1-phenyl-pent-1-yn-3-amine (1.0 equiv., 1.0 mmol, 0.20 g) and the mixture was stirred at room temperature for 2 h 30 min. The reaction mixture was diluted with ethyl acetate. The mixture was washed with an aqueous solution of citric acid (1 M), saturated aqueous bicarbonate solution, brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 8-fluoro-N-(1-isopropyl-1-methyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide (0.26 g, 0.72 mmol, 69% yield) as a brown solid. Rt=1.83 min (Method H), MS: (M+1)=361.6;
(49) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (dd, J=8.99, 6.79 Hz, 6H) 1.96 (s, 3H) 2.77-2.95 (m, 1H) 6.47-6.58 (m, 1H) 7.32-7.41 (m, 3H) 7.49-7.56 (m, 3H) 7.56-7.63 (m, 1H) 7.70-7.82 (m, 1H) 8.55-8.68 (m, 1H) 9.25-9.41 (m, 1H); .sup.19F NMR (377 MHz, CHLOROFORM-d) δ ppm −129.84-−118.63 (m, 1F).
Example 3: Preparation of the Single Isomers of 8-fluoro-N-(1-isopropyl-1-methyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide
(50) The racemic 8-fluoro-N-(1-isopropyl-1-methyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide mixture was submitted to chiral resolution by preparative HPLC chromatography using the conditions outlined hereafter to deliver (S)-8-fluoro-N-(1-isopropyl-1-methyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide and (R)-8-fluoro-N-(1-isopropyl-1-methyl-3-phenyl-prop-2-ynyl)quinoline-3-carboxamide.
(51) Analytical HPLC Method:
(52) SFC:
(53) Waters Acquity UPC.sup.2/QDa
(54) PDA Detector Waters Acquity UPC.sup.2
(55) Column: Daicel SFC CHIRALPAK® IF, 3 □m, 0.3 cm×10 cm, 40° C.
(56) Mobile phase: A: CO.sub.2 B: MeOH gradient: 20-40% B in 1.8 min
(57) ABPR: 1800 psi
(58) Flow rate: 2.0 ml/min
(59) Detection: 240 nm
(60) Sample concentration: 1 mg/mL in Hept/iPr 50/50
(61) Injection: 1 μL
(62) Preparative HPLC Method:
(63) Autopurification System from Waters: 2767 sample Manager, 2489 UVNisible Detector,
(64) 2545 Quaternary Gradient Module.
(65) Column: Daicel CHIRALPAK® IF, 5 μm, 1.0 cm×25 cm
(66) Mobile phase: Hept/EtOH 95/05
(67) Flow rate: 10 ml/min
(68) Detection: UV 240 nm
(69) Sample concentration: 60 mg/mL in/EtOAc
(70) Injection: 80-160 μl
(71) TABLE-US-00012 First eluting enantiomer Second eluting enantiomer Retention time (min) ~1.23 Retention time (min) ~1.52 Chemical purity (area % Chemical purity (area % at 240 nm) 99 at 240 nm) 99 Enantiomeric excess (%) >99 Enantiomeric excess (%) >99
Example 4: Preparation of N-(8-fluoro-2-methyl-3-quinolyl)-2,2-dimethyl-4-(o-tolyl)but-3-ynamide
Step 1: Preparation of N-(8-fluoro-2-methyl-3-quinolyl)-2,2-dimethyl-but-3-ynamide
(72) ##STR00032##
(73) To a solution of 2,2-dimethylbut-3-ynoic acid (8.9 mmol, 1.0 g) in dichloroethane (45 mL, 0.2 M) was added triethylamine (1.5 equiv., 13 mmol, 1.9 mL) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.5 equiv., 13 mmol, 2.6 g), 1-hydroxy-7-azabenzotriazole (1.5 equiv., 13 mmol, 1.9 g) and 8-fluoro-2-methyl-quinolin-3-amine (1.0 equiv., 8.9 mmol, 1.6 g) and the mixture was stirred at 60° C. for 20 h. The reaction mixture was cooled down to room temperature and diluted with ethyl acetate. The mixture was then washed with an aqueous solution of citric acid (1 M), saturated aqueous bicarbonate solution, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography to afford N-(8-fluoro-2-methyl-3-quinolyl)-2,2-dimethyl-but-3-ynamide (1.7 g, 6.3 mmol, 71% yield) as a brown solid. Mp 132-135° C., Rt=1.33 min (Method H), MS: (M+1)=271.4;
(74) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.66 (s, 6H) 2.74-2.80 (m, 1H) 2.80-2.85 (m, 3H) 7.30-7.36 (m, 1H) 7.44 (td, J=7.98, 4.95 Hz, 2H) 7.59 (d, J=8.07 Hz, 1H) 8.94 (br s, 1H) 9.04 (d, J=1.47 Hz, 1H); .sup.19F NMR (377 MHz, CHLOROFORM-d) δ ppm −126.81 (s, 1F)
Step 2: Preparation of N-(8-fluoro-2-methyl-3-quinolyl)-2,2-dimethyl-4-(o-tolyl)but-3-ynamide
(75) ##STR00033##
(76) To a solution of 1-iodo-2-methylbenzene (0.92 mmol, 0.21 g) in a mixture of tetrahydrofuran (4.6 mL, 0.2 M) and diisopropylamine (2.3 mL) was added N-(8-fluoro-2-methyl-3-quinolyl)-2,2-dimethyl-but-3-ynamide (1.0 equiv., 0.92 mmol, 0.25 g), copper (I) iodide (0.10 equiv., 0.092 mmol, 0.018 g) and Bis(triphenylphosphine)palladium(II) dichloride (0.10 equiv., 1.2 mmol, 0.017 g) and the reaction mixture was stirred at room temperature for 20 h. The mixture was filtered over a pad of silica gel and the pad was washed with ethyl acetate. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Flash Chromatography to give N-(8-fluoro-2-methyl-3-quinolyl)-2,2-dimethyl-4-(o-tolyl)but-3-ynamide (0.22 g, 0.61 mmol, 66% yield) as a dark brown resin. Rt=1.98 min (Method H), MS: (M+1)=361.5;
(77) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54-1.97 (m, 1H) 1.70-1.82 (m, 1H) 1.76 (s, 4H) 2.52 (s, 3H) 2.77 (s, 3H) 7.20-7.27 (m, 1H) 7.27-7.37 (m, 3H) 7.40-7.48 (m, 1H) 7.48-7.52 (m, 1H) 7.57-7.63 (m, 1H) 9.01 (s, 1H) 9.05-9.13 (m, 1H);
(78) .sup.19F NMR (377 MHz, CHLOROFORM-d) δ ppm −126.60 (br s, 1F)
(79) TABLE-US-00013 TABLE E Physical data of compounds of formula I wherein A is C(R.sub.8)(R.sub.9); [M + H] RT (meas- MP Entry IUPAC name STRUCTURE (min) ured) Method ° C. E-1 N-[4-cyclopropyl-1- methyl-1-(2,2,2- trifluoroethyl)but-3- ynyl]-8-fluoro- quinoline-3- carboxamide
(80) TABLE-US-00014 TABLE F Physical data of compounds of formula I wherein A is a direct bond: [M + H] RT (meas- MP Entry IUPAC name STRUCTURE (min) ured) Method ° C. F-1 N-(1-isopropyl-3- phenyl-prop-2-ynyl)- 8-methyl-quinoline-3- carboxamide
(81) TABLE-US-00015 TABLE G Physical data of compounds of formula I as individual enantiomers: [M + H] RT (meas- MP Entry IUPAC name STRUCTURE (min) ured) Method (chiral) ° C. G- 1 N-[(1R)-4- cyclopropyl-1- methyl-1-(2,2,2- trifluoroethyl)but- 3-ynyl]-8-fluoro- quinoline-3- carboxamide
Biological Examples
(82) Botryotinia fuckeliana (Botrytis cinerea)/Liquid Culture (Gray Mould)
(83) 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° C. and the inhibition of growth is determined photometrically 3-4 days after application.
(84) The following compounds of Table E gave at least 80% disease control at 200 ppm when compared to untreated control leaf disks under the same conditions, which show extensive disease development:
(85) E-1, E-2, F-1, F-3, F-4, F-5, F-6, F-7, F-9, F-10, F-11, F-12, F-13, F-14, F-15, F-16, F-17, F-18, F-19, F-20, F-21, F-22, F-23, F-24, F-25, F-26, F-27, F-28, F-29, F-30, F-32, F-33, F-34, F-35, F-36, F-37, F-38, F-39, F-40, F-41, F-42, F-43, F-45, F-46, F-47, F-48, F-49, F-50, F-51, F-55, G-1, G-2, G-3, G-4, G-5, G-6, G-7, G-8
Fusarium culmorum/Liquid Culture (Head Blight)
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° C. and the inhibition of growth is determined photometrically 3-4 days after application.
(86) The following compounds of Table E gave at least 80% disease control at 200 ppm when compared to untreated control leaf disks under the same conditions, which show extensive disease development:
(87) E-1, E-2, F-1, F-2, F-3, F-4, F-5, F-6, F-7, F-9, F-10, F-11, F-12, F-13, F-14, F-15, F-16, F-17, F-18, F-19, F-20, F-21, F-22, F-23, F-24, F-25, F-26, F-27, F-28, F-29, F-30, F-32, F-33, F-34, F-35, F-36, F-37, F-38, F-39, F-40, F-41, F-42, F-43, F-45, F-46, F-47, F-48, F-49, F-50, F-51, F-53, F-54, F-55, G-1, G-2, G-3, G-4, G-5, G-6, G-7, G-8
Glomerella lagenarium (Colletotrichum lagenarium)/Liquid Culture (Anthracnose)
(88) 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° C. and the inhibition of growth is measured photometrically 3-4 days after application.
(89) The following compounds of Table E gave at least 80% disease control at 200 ppm when compared to untreated control leaf disks under the same conditions, which show extensive disease development:
(90) E-1, E-2, F-3, F-5, F-6, F-7, F-9, F-10, F-11, F-12, F-13, F-14, F-15, F-16, F-17, F-18, F-19, F-20, F-21, F-22, F-23, F-24, F-25, F-26, F-27, F-28, F-29, F-30, F-32, F-33, F-37, F-38, F-39, F-40, F-41, F-42, F-43, F-45, F-46, F-47, F-48, F-49, F-50, F-51, F-53, F-55, G-3, G-4, G-5, G-7, G-8
Monographella nivalis (Microdochium nivale)/Liquid Culture (Foot Rot Cereals)
(91) 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° C. and the inhibition of growth is determined photometrically 4-5 days after application.
(92) The following compounds of Table E gave at least 80% disease control at 200 ppm when compared to untreated control leaf disks under the same conditions, which show extensive disease development:
(93) E-1, F-1, F-2, F-3, F-4, F-5, F-6, F-7, F-9, F-10, F-11, F-12, F-13, F-15, F-16, F-17, F-18, F-19, F-20, F-21, F-23, F-24, F-25, F-26, F-27, F-28, F-29, F-30, F-32, F-33, F-34, F-35, F-36, F-37, F-38, F-39, F-40, F-41, F-42, F-45, F-46, F-47, F-48, F-49, F-51, F-54, F-55, G-1, G-3, G-5, G-6, G-7, G-8
Mycosphaerella graminicola (Septoria tritici)/Liquid Culture (Septoria Blotch)
(94) 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° C. and the inhibition of growth is determined photometrically 4-5 days after application.
(95) The following compounds of Table E gave at least 80% disease control at 200 ppm when compared to untreated control leaf disks under the same conditions, which show extensive disease development:
(96) E-1, F-3, F-4, F-5, F-7, G-3
(97) Magnaporthe grisea (Pyricularia oryzae)/Liquid Culture (Rice Blast)
(98) 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° C. and the inhibition of growth is determined photometrically 3-4 days after application.
(99) The following compounds gave at least 80% control of Magnaporthe grisea at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(100) F-1, F-3, F-4, F-5, F-7, F-9, F-10, F-11, F-12, F-13, F-14, F-15, F-16, F-17, F-46, F-47, F-48, F-49, F-50, F-51, G-3, G-4, G-5, G-6, G-7, G-8
(101) Fusarium culmorum/Wheat/Spikelet Preventative (Head Blight)
(102) Wheat spikelets cv. Monsun are placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. The spikelets are inoculated with a spore suspension of the fungus 1 day after application. The inoculated spikelets are incubated at 20° C. and 60% rh under a light regime of 72 h semi darkness followed by 12 h light/12 h darkness in a climate chamber and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check spikelets (6-8 days after application).
(103) The following compounds gave at least 80% control of Fusarium culmorum at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(104) F-3, F-7, F-9, F-10, F-11, F-12, F-14, F-16, F-17, F-24, F-25, F-28, F-29, F-39, F-40, F-45, F- 46, F-47, F-49, G-4, G-7
(105) Pyrenophora teres/Barley/Leaf Disc Preventative (Net Blotch)
(106) Barley leaf segments cv. Hasso are placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water. The leaf segmens are inoculated with a spore suspension of the fungus 2 days after application. The inoculated leaf segments are incubated at 20° C. and 65% rh under a light regime of 12 h light/12 h darkness in a climate cabinet and the activity of a compound is assessed as disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (5-7 days after application).
(107) The following compounds gave at least 80% control of Pyrenophora teres at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(108) F-1, F-2, F-11, F-17, F-21, F-29, F-35, F-55, G-4
(109) Sclerotinia sclerotiorum/Liquid Culture (Cottony Rot)
(110) 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° C. and the inhibition of growth is determined photometrically 3-4 days after application.
(111) 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:
(112) F-5, F-7, F-9, F-10, F-11, F-12, F-15, F-50, F-51, G-5, G-7
(113) Gaeumannomyces graminis/Liquid Culture (Take-All of Cereals)
(114) 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° C. and the inhibition of growth is determined photometrically 4-5 days after application. 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:
(115) F-4, F-5, F-6, F-7, F-10, F-12, F-13, F-23, F-24, F-25, F-46, F-47, F-48, F-49, F-51, F-55, G-3, G-4, G-5, G-6, G-8