MICROBIOCIDAL QUINOLINE DIHYDRO-(THIAZINE)OXAZINE DERIVATIVES
20230142565 · 2023-05-11
Assignee
Inventors
Cpc classification
A01N43/86
HUMAN NECESSITIES
A01N2300/00
HUMAN NECESSITIES
A01N43/86
HUMAN NECESSITIES
A01N2300/00
HUMAN NECESSITIES
International classification
Abstract
Compounds of the formula (I): Formula (I) wherein the substituents are as defined in claim 1, useful as pesticides, especially as fungicides.
##STR00001##
Claims
1. A compound of formula (I): ##STR00085## wherein: X is O or S or S(═O); R.sup.1 is halogen, methyl or cyano; R.sup.2 is hydrogen or halogen; R.sup.3 and R.sup.4 are each independently hydrogen or methyl; R.sup.5 and R.sup.6 are each independently selected from hydrogen, C.sub.1-C.sub.5alkyl, C.sub.1-C.sub.5haloalkyl, cyanoC.sub.1-C.sub.5alkyl, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.5alkyl, C.sub.2-C.sub.5alkenyl, C.sub.2-C.sub.5haloalkenyl, cyanoC.sub.2-C.sub.5alkenyl, C.sub.1-C.sub.3alkoxyC.sub.2-C.sub.5alkenyl, C.sub.2-C.sub.5alkynyl, C.sub.2-C.sub.5haloalkynyl, cyanoC.sub.2-C.sub.5alkynyl, C.sub.1-C.sub.3alkoxyC.sub.2-C.sub.5alkynyl and C.sub.3-C.sub.6cycloalkyl, wherein cycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, cyano, C.sub.1-C.sub.3alkyl and C.sub.1-C.sub.3alkoxy; or R.sup.5 and R.sup.6 together with the carbon atom to which they are attached represent C.sub.3-C.sub.6cycloalkyl, wherein the cycloalkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, cyano and C.sub.1-C.sub.3alkyl; R.sup.7 is hydrogen, C.sub.1-C.sub.4alkyl or C.sub.3-C.sub.4cycloalkyl; A is: (i) heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, (ii) heterobiaryl, wherein the heterobiaryl moiety is a 9- or 10-membered fused aromatic ring system which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, (iii) heterocyclyl, wherein the heterocyclyl moiety is a 4- to 6-membered non-aromatic ring which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, or (iv) heterobicyclyl, wherein the heterobicyclyl moiety is a 7- to 10-membered fused or spirocyclic non-aromatic ring system which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, wherein heteroaryl, heterobiaryl, heterocyclyl and heterobicyclyl are each optionally substituted with 1, 2 or 3 substituents independently selected from R.sup.8, and/or for a heterocyclyl or heterobicyclyl moiety the ring may comprise an S(O).sub.2 or a C═S group; and R.sup.8 is halogen, nitro, cyano, C.sub.1-C.sub.5alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.5alkoxy, C.sub.3-C.sub.5alkenyloxy, C.sub.3-C.sub.5alkynyloxy or C.sub.1-C.sub.5alkylthio; or an agronomically acceptable salt, an N-oxide and/or S-oxide or a stereoisomer thereof.
2. The compound according to claim 1, wherein R.sup.1 is fluoro.
3. The compound according to claim 1, wherein R.sup.2 is hydrogen or fluoro.
4. The compound according to claim 1, wherein R.sup.3 is methyl and R.sup.4 is hydrogen, R.sup.3 is hydrogen and R.sup.4 is methyl, or R.sup.3 and R.sup.4 are hydrogen.
5. The compound according to claim 1, wherein R.sup.5 and R.sup.6 are each independently selected from hydrogen or C.sub.1-C.sub.5alkyl.
6. The compound according to claim 1, wherein R.sup.5 and R.sup.6 together form a —(CH.sub.2).sub.n— group bound to the carbon atom to which they are attached, wherein n is 2, 3, 4 or 5.
7. The compound according to claim 1, wherein R.sup.7 is hydrogen or methyl.
8. The compound according to claim 1, wherein A is selected from: (i) heteroaryl, wherein the heteroaryl moiety is a 5- or 6-membered aromatic ring which comprises 1 or 2 heteroatoms individually selected from N and S; (ii) heterobiaryl, wherein the heterobiaryl moiety is a 9-membered fused aromatic ring system which comprises 1 or 2 heteroatoms individually selected from N and S; (iii) heterocyclyl, wherein the heterocyclyl moiety is a 4- to 6-membered non-aromatic ring which comprises 1 or 2 heteroatoms individually selected from N, O and S; or (iv) heterobicyclyl, wherein the heterobicyclyl moiety is a 7- or 8-membered spirocyclic non-aromatic ring system which comprises 1 or 2 heteroatoms individually selected from N, O and S; wherein heteroaryl, heterobiaryl, heterocyclyl and heterobicyclyl are each optionally substituted with 1 or 2 substituents independently selected from R.sup.8, and/or for a heterocyclyl or heterobicyclyl moiety the ring may comprise an S(O).sub.2 or C═S group; wherein R.sup.8 is fluoro, chloro, nitro, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl and methoxy.
9. The compound according to claim 1, wherein A is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, pyrazolyl, indazolyl, benzimidazolyl, 1,3-benzothiazolyl, isothiazolidinyl, thietanyl, tetrahydrothienyl, tetrahydrothiopyranyl or morpholinyl, wherein each group is optionally substituted with 1 or 2 substituents independently selected from R.sup.8, and/or for isothiazolidinyl, thietanyl, tetrahydrothienyl, tetrahydrothiopyranyl the ring is optionally substituted by two oxo (═O) groups at the sulfur atom; and wherein R.sup.8 is fluoro, chloro, nitro, cyano, methyl, ethyl, trifluoromethyl, cyclopropyl and methoxy.
10. The compound according to claim 1, wherein A is selected from one of: ##STR00086##
11. The compound according to claim 1, wherein X is O.
12. An agrochemical composition comprising a fungicidally effective amount of a compound according to claim 1.
13. The composition according to claim 12, further comprising at least one additional active ingredient and/or an agrochemically-acceptable diluent or carrier.
14. A method of controlling or preventing infestation of useful plants by phytopathogenic microorganisms, wherein a fungicidally effective amount of a compound according to claim 1, or a composition comprising this compound as active ingredient, is applied to the plants, to parts thereof or the locus thereof.
15. Use of a compound according to claim 1 as a fungicide.
Description
EXAMPLES
[0214] The Examples which follow serve to illustrate the invention.
[0215] 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.
[0216] Compounds of Formula (I) 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 (including improved crop tolerance), improved physico-chemical properties, or increased biodegradability).
[0217] 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 described below.
FORMULATION EXAMPLES
Wettable Powders
[0218]
TABLE-US-00002 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% —
[0219] 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.
Powders for Dry Seed Treatment
[0220]
TABLE-US-00003 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
[0221] 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.
Emulsifiable Concentrate
[0222]
TABLE-US-00004 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%
[0223] Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.
Dusts
[0224]
TABLE-US-00005 a) b) c) Active ingredient [compound of formula (I)] 5% 6% 4% talcum 95% — — Kaolin — 94% — mineral filler — — 96%
[0225] 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.
Extruder Granules
[0226]
TABLE-US-00006 Active ingredient [compound of formula (I)] 15% sodium lignosulfonate 2% carboxymethylcellulose 1% Kaolin 82%
[0227] 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.
Coated Granules
[0228]
TABLE-US-00007 Active ingredient [compound of formula (I)] 8% polyethylene glycol (mol. wt. 200) 3% Kaolin 89%
[0229] 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.
Suspension Concentrate
[0230]
TABLE-US-00008 active ingredient [compound of formula (I)] 40% propylene glycol 10% nonylphenol polyethylene glycol ether (15 mol of 6% ethylene oxide) Sodium lignosulfonate 10% carboxymethylcellulose 1% silicone oil (in the form of a 75% emulsion in water) 1% Water 32%
[0231] 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.
Flowable Concentrate for Seed Treatment
[0232]
TABLE-US-00009 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% 0.5%.sup. solution in water) monoazo-pigment calcium salt 5% Silicone oil (in the form of a 75% emulsion in water) 0.2%.sup. Water 45.3%
[0233] 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
[0234] 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.
[0235] 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
List of Abbreviations
[0236] aq=aqueous [0237] Ar=argon [0238] br s=broad singlet [0239] DCM=dichloromethane [0240] dd=doublet of doublet [0241] DMF=N,N-dimethylformamide [0242] d=doublet [0243] EtOAc=ethyl acetate [0244] equ.=equivalent [0245] h=hour(s) [0246] M=molar [0247] m=multiplet [0248] min=minutes [0249] MHz=mega hertz [0250] mp=melting point [0251] ppm=parts per million [0252] RT=room temperature [0253] R.sub.t=retention time [0254] s=singlet [0255] t=triplet [0256] THF=tetrahydrofuran [0257] LC/MS=Liquid Chromatography Mass Spectrometry (description of the apparatus and the methods used for LC/MS analysis are given below).
PREPARATION EXAMPLES
Example A1: 2-(7,8-difluoro-3-quinolyl)-6,6-dimethyl-4-(2-pyridylmethyl)-4,5-dihydro-1,3-thiazine (Compound E.01)
Step 1:
[0258] To a solution of 3-methyl-2-butenal (2.3 mL, 24 mmol) in THE (36 mL) at RT was added titanium ethoxide (7.6 mL, 31 mmol, 1.3 equ.) and 2-methylpropane-2-sulfinamide (3.6 g, 29 mmol, 1.2 equ.). The solution was stirred at 60° C. for 2 h. The reaction mixture was quenched by addition of NaHCO.sub.3 solution, the suspension was filtered over a pad of celite and the filter cake was washed with EtOAc. The filtrate was extracted with EtOAc, the organic phase was washed with brine, dried over MgSO.sub.4, filtered and concentrated to give 2-methyl-N-(3-methylbut-2-enylidene)propane-2-sulfinamide as a colorless liquid.
[0259] LC-MS (Method G), R.sub.t=0.92 min, (M+H)=189.
[0260] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 8.54 (d, 1H), 6.24-6.29 (dt, 1H), 2.07 (d, 3H), 1.99 (d, 3H), 1.22 (s, 9H)
Step 2:
[0261] To a colourless solution of 2-methylpyridine (0.210 mL, 2.08 mmol, 1.3 equ.) in THE (4 mL), cooled at −70° C. under Ar, was added dropwise n-butyllithium (2.5 M in hexanes) (0.90 mL, 2.24 mmol, 1.4 equ.). The solution was stirred at −78° C. for 30 min and then transferred dropwise via cannula to a solution of 2-methyl-N-(3-methylbut-2-enylidene)propane-2-sulfinamide (0.300 g, 1.6 mmol) in THE (4 mL) at −70° C. The solution was then gradually warmed from −70° C. to −20° C. over the course of 3 h. The reaction mixture was quenched with NH.sub.4Cl solution and partitioned between EtOAc and water. The organic phase was washed with brine, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by flash chromatography (cyclohexane: EtOAc) to give 2-methyl-N-[3-methyl-1-(2-pyridylmethyl)but-2-enyl]propane-2-sulfinamide (approx. 1:1 mixture of diastereoisomers) as colorless liquid.
[0262] LC-MS (Method G), R.sub.t=0.64 min, (M+H)=281, R.sub.t=0.69 min, (M+H)=281.
Step 3:
[0263] To a solution of 2-methyl-N-[3-methyl-1-(2-pyridylmethyl)but-2-enyl]propane-2-sulfinamide (0.340 g, 1.21 mmol) in MeOH (2.5 mL), cooled to 5° C., was added dropwise HCl (4 M in dioxane) (0.76 mL, 3.03 mmol, 2.5 equ.). The solution was stirred at 5° C. for 2 h and then concentrated in vacuo. The resulting gum was triturated with pentane to furnish 4-methyl-1-(2-pyridyl)pent-3-en-2-amine; dihydrochloride as a yellow solid.
[0264] LC-MS (Method G), R.sub.t=0.26 min, (M+H)=177.
[0265] .sup.1H NMR (DMSO) δ ppm: 8.74-8.88 (m, 1H), 8.51-8.65 (m, 2H), 8.33-8.46 (m, 1H), 7.77-7.96 (m, 2H), 5.21 (br d, 1H), 4.48-4.58 (m, 1H), 3.50-3.66 (m, 1H), 3.22-3.35 (m, 1H), 1.62 (s, 3H), 1.36 (s, 3H).
Step 4:
[0266] To a solution of 7,8-difluoroquinoline-3-carboxylic acid (0.210 g, 1 mmol) and 4-methyl-1-(2-pyridyl)pent-3-en-2-amine; dihydrochloride (0.336 g, 1.1 mmol, 1.1 equ.) in acetonitrile (5 mL) was added triethylamine (0.492 mL, 3.51 mmol, 3.5 equ.) and propanephosphonic acid anhydride (50% in EtOAc, 1.02 mL, 1.71 mmol, 1.7 equ.) at RT. The resulting solution was stirred at RT for 2 h. The reaction mixture was then diluted with EtOAc and quenched with water. It was then extracted with EtOAc and the organic phase was washed with brine, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by flash chromatography (cyclohexane: EtOAc) to give 7,8-difluoro-N-[3-methyl-1-(2-pyridylmethyl)but-2-enyl]quinoline-3-carboxamide as white solid.
[0267] LC-MS (Method G), R.sub.t=0.76 min, (M+H)=368.
[0268] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 9.40 (d, 1H), 8.86 (br d, 1H), 8.75 (t, 1H), 8.60-8.65 (m, 1H), 7.68-7.76 (m, 2H), 7.48-7.56 (td, 1H), 7.21-7.27 (m, 2H), 5.24-5.32 (m, 1H), 5.03-5.08 (dt, 1H), 3.24-3.31 (dd, 1H), 3.01-3.10 (dd, 1H), 1.89 (d, 3H), 1.70 (d, 3H).
Step 5:
[0269] A solution of 7,8-difluoro-N-[3-methyl-1-(2-pyridylmethyl)but-2-enyl]quinoline-3-carboxamide (0.13 g, 0.35 mmol) and Lawesson's reagent (0.21 g, 0.50 mmol) in 1,4-dioxane (4 mL) was warmed to 100° C. and aged at this temperature for 3 h. The resulting solution was cooled to RT, diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO.sub.4, filtrated and concentrated in vacuo to afford crude 7,8-difluoro-N-[3-methyl-1-(2-pyridylmethyl)but-2-enyl]quinoline-3-carbothioamide. This material was used as such for the next step.
[0270] LC-MS (Method G), R.sub.t=0.92 min, (M+H)=384.
Step 6:
[0271] A solution of unpurified 7,8-difluoro-N-[3-methyl-1-(2-pyridylmethyl)but-2-enyl]quinoline-3-carbothioamide in acetonitrile (3 mL) was treated with trifluoroacetic acid (1.5 mL), the resulting solution was warmed to 80° C. and stirred at this temperature for 16 h. The reaction mixture was then cooled to RT, diluted with ethyl acetate and carefully neutralized with enough aq. NaHCO.sub.3 to reach pH 8-9. The mixture was extracted with EtOAc, the organic phase was washed with brine, dried over Na.sub.2SO.sub.4, filtrated and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, cyclohexane: EtOAc) to afford 2-(7,8-difluoro-3-quinolyl)-6,6-dimethyl-4-(2-pyridylmethyl)-4,5-dihydro-1,3-thiazine as light brown gum.
[0272] LC-MS (Method G), R.sub.t=0.89 min, (M+H)=384.
[0273] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.39 (d, 1H) 8.63 (d, 1H) 8.45-8.51 (m, 1H) 7.76 (brt, 1H) 7.66 (ddd, 1H) 7.42-7.52 (m, 2H) 7.22-7.28 (m, 1H) 4.24-4.39 (m, 1H) 3.19-3.39 (m, 2H) 2.00 (br dd, 1H) 1.51-1.57 (m, 1H) 1.50 (s, 6H).
[0274] .sup.19F NMR (377 MHz, CDCl.sub.3) δ ppm −133.90 (d, 1F) −151.00 (d, 1F).
Example A2: 2-(8-fluoro-3-quinolyl)-6,6-dimethyl-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazine (Compound E.20)
Step 1:
[0275] To an ice cooled solution of 3-(3-pyridyl)propanoic acid (1.0 g, 6.61 mmol) in methanol (5 mL) was slowly added thionyl chloride (1.04 g, 8.60 mmol). The resulting milky solution was stirred at 0-5° C. until LC-MS (method G) indicated full conversion of the acid. The reaction mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and aq. NaHCO.sub.3 solution. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtrated and concentrated in vacuo to afford methyl 3-(3-pyridyl)propanoate as colorless liquid. This material was used as such for the next step without further purification.
[0276] LC-MS (Method G), R.sub.t=0.14 min, (M+H)=166.
[0277] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.46-8.49 (m, 2H), 7.47-7.61 (m, 1H), 7.18-7.25 (m, 1H), 3.67 (s, 3H), 2.96 (t, 2H), 2.65 (t, 2H).
Step 2:
[0278] n-BuLi (2.5M in hexanes, 3.1 mL, 7.75 mmol) was added to diisopropylamine (0.80 g, 7.75 mmol) in dry THE (5 mL) under an argon atmosphere at −70° C. The resulting colorless solution was aged for 30 min at −70° C. and then a solution of methyl 3-(3-pyridyl)propanoate (1.0 g, 6.06 mmol) in THE (5 mL) was added drop wise. The solution was aged for an additional 30 min at −70° C. and then 3-bromo-2-methylpropene (1.12 g, 7.75 mmol) was added dropwise. The resulting orange solution was gradually warmed to 0° C. over 60 min and then quenched with aqueous NH.sub.4Cl solution. The mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtrated and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, cyclohexane:ethyl acetate) to afford methyl 4-methyl-2-(3-pyridylmethyl)pent-4-enoate as colorless oil.
[0279] LC-MS (Method G), R.sub.t=0.62 min, (M+H)=220
[0280] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.36-8.54 (m, 2H) 7.40-7.58 (m, 1H) 7.15-7.25 (m, 1H) 4.81 (s, 1H) 4.75 (s, 1H) 3.58 (s, 3H) 2.74-2.97 (m, 3H) 2.39-2.50 (m, 1H) 2.16-2.27 (m, 1H) 1.75 (s, 3 ppm).
Step 3:
[0281] A solution of methyl 4-methyl-2-(3-pyridylmethyl)pent-4-enoate (0.77 g, 3.75 mmol) in 1,4-dioxane (7 mL)/ethanol (7 mL) was treated with NaOH (0.56 g, 15.0 mmol), warmed to 90° C. and stirred at this temperature for 60 min. The mixture was cooled to 20° C. and concentrated in vacuo. The residue was dissolved in water and aq. HCl (1M) was added to obtain pH 5-6. The resulting mixture was extracted several times with ethyl acetate, the combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtrated and concentrated in vacuo. The resulting crude 4-methyl-2-(3-pyridylmethyl)pent-4-enoic acid was used as such for the next step.
[0282] LC-MS (Method G), R.sub.t=0.38 min, (M+H)=206
[0283] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 11.40 (bs, 1H) 8.47 (d, 1H) 8.42 (dd, 1H) 7.65 (dt, 1H) 7.31 (dd, 1H) 4.85 (d, 2H) 2.78-3.02 (m, 3H) 2.52 (dd, 1H) 2.26 (dd, 1H) 1.80 (s, 3H).
Step 4:
[0284] To a solution of 4-methyl-2-(3-pyridylmethyl)pent-4-enoic acid (0.70 g, 3.4 mmol) in toluene (17 mL) was added triethylamine (1.04 g, 10.2 mmol) and diphenyl phosphoryl azide (1.55 g, 5.4 mmol). The resulting clear solution was stirred for 60 min at 20° C., 4-methoxybenzyl alcohol (1.44 g, 10.2 mmol) was then added, the reaction was warmed to 110° C. and aged for 60 min at this temperature. The mixture was cooled to 20° C., diluted with ethyl acetate and washed with aqueous NaHCO.sub.3. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtrated and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, cyclohexane:ethyl acetate) to afford (4-methoxyphenyl)methyl N-[3-methyl-1-(3-pyridylmethyl)but-3-enyl]carbamate as light yellow gum.
[0285] LC-MS (Method G), R.sub.t=0.74 min, (M+H)=241
[0286] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.38-8.49 (m, 2H) 7.48-7.60 (m, 1H) 7.16-7.27 (m, 3H) 6.84-6.94 (m, 2H) 4.94-5.07 (m, 2H) 4.70-4.86 (m, 2H) 4.53 (br s, 1H) 4.03 (br s, 1H) 3.82 (s, 3H) 2.76-2.93 (m, 2H) 2.07-2.29 (m, 2H) 1.66-1.77 (br s, 3H).
Step 5:
[0287] A solution of (4-methoxyphenyl)methyl N-[3-methyl-1-(3-pyridylmethyl)but-3-enyl]carbamate (0.54 g, 1.6 mmol) in 1,4-dioxane (8 mL) was treated with HCl (4M in 1,4-dioxane, 1.7 g, 6.4 mmol) at 20° C. The resulting solution was warmed to 50° C. and stirred for 2 h at this temperature. The resulting white suspension was cooled to 20° C. and all volatiles removed in vacuo. The residue was triturated with methyl tert-butyl ether to afford 4-methyl-1-(3-pyridyl)pent-4-en-2-amine bis-hydrochloride salt. This material was used as such for the next step.
[0288] LC-MS (Method G), R.sub.t=0.15 min, (M+H)=177.
Step 6:
[0289] To a suspension of 8-fluoroquinoline-3-carboxylic acid (0.17 g, 0.9 mmol) and 4-methyl-1-(3-pyridyl)pent-4-en-2-amine bis-hydrochloride salt (0.20 g, 0.9 mmol) in acetonitrile (2 mL) at 20° C. was sequentially added triethylamine (0.27 g, 2.7 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 0.68 g, 1.1 mmol). The solids gradually dissolved and the resulting solution was stirred for 17 h at 20° C. Water was then added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO.sub.4, filtrated and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, cyclohexane:ethyl acetate:ethanol) to afford 8-fluoro-N-[3-methyl-1-(3-pyridylmethyl)but-3-enyl]quinoline-3-carboxamide.
[0290] LC-MS (Method G), R.sub.t=0.70 min, (M+H)=350.
Step 7:
[0291] A suspension of 8-fluoro-N-[3-methyl-1-(3-pyridylmethyl)but-3-enyl]quinoline-3-carboxamide (0.095 g, 0.27 mmol) and Lawesson's reagent (0.14 g, 0.33 mmol) in 1,4-dioxane (2 mL) was warmed to 100° C. and stirred at this temperature for 1 h. The resulting orange solution was cooled to 20° C., diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO.sub.4, filtrated and concentrated in vacuo. The residue was filtrated through short plug of silica (eluent: ethyl acetate) and the filtrate concentrated in vacuo. The resulting oil containing 8-fluoro-N-[3-methyl-1-(3-pyridylmethyl)but-3-enyl]quinoline-3-carbothioamide was used as such for the cyclization.
[0292] The oil obtained above was dissolved in acetonitrile (1 mL)/trifluoroacetic acid (0.2 mL), warmed to 85° C. and stirred at this temperature for 18 h. The resulting dark solution was cooled to 20° C., diluted with ethyl acetate and neutralized with aq. NaOH (1 M) solution to pH 8-9. This mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over MgSO.sub.4, filtrated and concentrated in vacuo. The residue was purified by flash chromatography (silica, cyclohexane:ethyl acetate) to afford 2-(8-fluoro-3-quinolyl)-6,6-dimethyl-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazine.
[0293] LC-MS (Method G), R.sub.t=0.86 min, (M+H)=366.
[0294] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 9.44 (d, 1H), 8.63 (d, 1H), 8.49-8.57 (m, 2H), 7.75-7.81 (m, 1H), 7.70 (d, 1H), 7.51-7.57 (m, 1H), 7.43-7.50 (m, 1H), 7.29-7.34 (m, 1H), 3.97-4.05 (m, 1H), 3.09-3.23 (m, 2H), 1.82-1.90 (m, 2H), 1.50 (s, 3H),), 1.46 (s, 3H).
[0295] .sup.19F NMR (377 MHz, CDCl.sub.3) δ ppm −125.22 (s, 1F).
Example A3: 2-(7,8-difluoro-3-quinolyl)-4-[(6-fluoro-3-pyridyl)methyl]-6,6-dimethyl-4,5-dihydro-1,3-thiazine (Compound E.24)
Step 1:
[0296] A suspension of methoxymethyl(triphenyl)phosphonium chloride (4.5 g, 13 mmol) in dry THE (15 mL)/dimethylsulfoxide (2 mL) was cooled to 5° C. and potassium tert-butoxide (1.3 g, 12 mmol) was added. The resulting red mixture was aged for 20 min at 0° C. and then 2-fluoropyridine-5-carbaldehyde (1.0 g, 7.8 mmol) in THE (8 mL) was added slowly. The reaction mixture was gradually warmed to room temperature over 60 min and then quenched by addition of water. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO.sub.4, filtrated and concentrated under reduced pressure. The residue was purified by flash chromatography (silica, cyclohexane:EtOAc) to afford 2-fluoro-5-(2-methoxyvinyl)pyridine as an approximately 1:1 mixture of E/Z-isomers.
[0297] LC-MS (Method G), R.sub.t=0.78 and 0.82 min, (M+H)=154
Step 2:
[0298] 2-fluoro-5-(2-methoxyvinyl)pyridine (0.30 g, 1.96 mmol) was dissolved in formic acid (2 mL), warmed to 60° C. and aged for 60 min at this temperature. The reaction mixture was then cooled to room temperature, diluted with water and extracted with DCM. The combined organic layers were dried over MgSO.sub.4 and filtrated. 2-methylpropane-2-sulfinamide (0.24 g, 1.96 mmol) was added to the filtrate and the solution concentrated under reduced pressure to a volume of approximately 3 mL. MgSO.sub.4 was added to this solution and stirred for additional 30 min at room temperature. The mixture was then filtrated and the filtrate partitioned between water and EtOAc. The organic layer was washed with pH 7-phosphate buffer, dried over MgSO.sub.4, filtrated and concentrated in vacuo. The residue was purified by flash chromatography (silica, cyclohexane:EtOAc) to afford N-[2-(6-fluoro-3-pyridyl)ethylidene]-2-methyl-propane-2-sulfinamide as light yellow oil.
[0299] LC-MS (Method G), R.sub.t=0.81 min, (M+H)=243.
[0300] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 8.17 (t, 1H), 8.12 (d, 1H), 7.58-7.78 (m, 1H), 6.86-7.04 (dd, 1H), 3.87 (d, 2H), 1.19 (s, 9H).
Step 3:
[0301] To a solution of N-[2-(6-fluoro-3-pyridyl)ethylidene]-2-methyl-propane-2-sulfinamide (0.12 g, 0.49 mmol) in THE (2 mL) was sequentially added indium powder (0.05 g, 0.49 mmol), 3-bromo-2-methylpropene (0.10 g, 0.74 mmol) and BF.sub.3-etherate (˜10 μL) at room temperature. The resulting mixture was warmed to 60° C. and stirred for 30 min at this temperature. The reaction mixture was then cooled to room temperature, diluted with EtOAc and filtrated through Celite. The filtrate was washed with water, dried over MgSO.sub.4, filtrated and concentrated in vacuo. The residue was purified by flash chromatography (silica, cyclohexane:EtOAc) to afford N-[1-[(6-fluoro-3-pyridyl)methyl]-3-methyl-but-3-enyl]-2-methyl-propane-2-sulfinamide as light yellow oil.
[0302] LC-MS (Method G), R.sup.t=0.93 min, (M+H)=299.
[0303] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 8.03 (d, 1H) 7.65 (td, 1H) 6.88 (dd, 1H) 4.92 (s, 1H) 4.82 (s, 1H) 3.53-3.69 (m, 1H) 2.71-2.94 (m, 2H) 2.16-2.35 (m, 2H) 1.73 (s, 3H) 1.15 (s, 9H).
Step 4:
[0304] An ice-cooled solution of N-[1-[(6-fluoro-3-pyridyl)methyl]-3-methyl-but-3-enyl]-2-methyl-propane-2-sulfinamide (0.23 g, 0.68 mmol) in 1,4-dioxane (1 mL) was treated with HCl (4 M in 1,4-dioxane, 0.7 mL, 2.7 mmol). The resulting suspension was stirred for 40 min at 5° C. and then all volatiles were removed under reduced pressure. The solid residue was triturated with tertbutyl methyl ether to afford crude 1-(6-fluoro-3-pyridyl)-4-methyl-pent-4-en-2-amine hydrochloride as white solid.
[0305] This solid was suspended in acetonitrile (5 mL) and 7,8-difluoroquinoline-3-carboxylic acid (0.18 g, 0.8 mmol), triethylamine (0.38 g, 3.7 mmol) and propyl phosphonic anhydride (50% in EtOAc, 0.94 g, 1.47 mmol) was added sequentially at room temperature. The resulting solution was stirred at room temperature for 40 min. Water was then added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO.sub.4, filtrated and concentrated in vacuo. The residue was purified by flash chromatography (silica, cyclohexane:EtOAc) to afford 7,8-difluoro-N-[1-[(6-fluoro-3-pyridyl)methyl]-3-methyl-but-3-enyl]quinoline-3-carboxamide as beige solid.
[0306] LC-MS (Method G), R.sub.t=0.96 min, (M+H)=386.
[0307] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 9.21 (d, 1H), 8.54 (m, 1H), 8.09 (d, 1H), 7.69-7.78 (m, 2H), 7.50-7.58 (m, 1H), 6.90-6.95 (m, 1H), 5.99-6.09 (m, 1H), 4.84-4.95 (m, 2H), 4.50-4.60 (m, 1H), 3.00-3.10 (m, 1H), 2.96-3.11 (m, 1H), 2.40-2.46 (m, 1H), 2.27-2.36 (m, 1H), 1.79 (s, 3H).
[0308] .sup.19F NMR (377 MHz, CDCl.sub.3) δ ppm −70.44 (s, 1F), −135.78 (d, 1F), −150.10 (d, 1F).
Step 5:
[0309] A suspension of 7,8-difluoro-N-[1-[(6-fluoro-3-pyridyl)methyl]-3-methyl-but-3-enyl]quinoline-3-carboxamide (0.27 g, 0.56 mmol) and Lawesson's reagent (0.28 g, 0.67 mmol) in 1,4-dioxane (6 mL) was warmed to 100° C. and stirred at this temperature for 90 min. The resulting orange solution was cooled to room temperature, diluted with EtOAc and washed with water. The organic layer was washed with brine, dried over MgSO.sub.4, filtrated and concentrated in vacuo. The residual oil was diluted with acetonitrile (5 mL) and treated with trifluoroacetic acid (2.6 mL) at room temperature. The resulting mixture was warmed to 85° C. and aged at this temperature for 16 h. The reaction mixture was then cooled to room temperature, neutralized with aqueous NaOH (2 M) to pH 8-9 and partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO.sub.4, filtrated and concentrated under reduced pressure. The residue was purified flash chromatography (silica, cyclohexane:EtOAc) to afford 2-(7,8-difluoro-3-quinolyl)-4-[(6-fluoro-3-pyridyl)methyl]-6,6-dimethyl-4,5-dihydro-1,3-thiazine as light yellow gum.
[0310] LC-MS (Method G), R.sub.t=1.16 min, (M+H)=402.
[0311] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm: 9.43 (d, 1H), 8.48 (t, 1H), 8.16-8.22 (m, 1H), 7.79-7.90 (td, 1H), 7.59-7.74 (ddd, 1H), 7.43-7.52 (td, 1H), 6.88-6.96 (dd, 1H), 3.91-4.01 (m, 1H), 3.07-3.17 (m, 2H), 1.82-1.89 (dd, 1H), 1.45-1.50 (m, 7H).
[0312] .sup.19F NMR (377 MHz, CDCl.sub.3) δ ppm: −71.32 (s, 1F), −133.67 (d, 1F), −150.83 (d, 1F).
Example A4: 4-[(4-chloropyrazol-1-yl)methyl]-2-(7,8-difluoro-3-quinolyl)-6,6-dimethyl-4,5-dihydro-1,3-thiazine (Compound E.10)
Step 1:
[0313] To a solution of 2-((tert-butoxycarbonyl)amino)-4-methylpent-4-enoic acid (0.15 g, 0.63 mmol) and N-methylmorpholine (0.06 g, 0.63 mmol) in tetrahydrofurane (2 mL) at −10° C. was added iso-butyl chloroformate (0.08 g, 0.63 mmol) dropwise over 20 minutes. The reaction was stirred for 30 min at −5-−10° C., then stirring was stopped and the precipitate was allowed to settle. The supernatant was transferred to a separate flask and a solution of sodium borohydride (0.05 g, 1.26 mmol) in ice cold water (0.5 mL) was added slowly at 0-5° C. The reaction was allowed to warm to 20° C. and was stirred for 1 hr. The reaction mixture was then partioned between ethyl acetate and aqueous NaHCO.sub.3, the organic layer was dried over Na.sub.2SO.sub.4, filtrated and concentrated in vacuo.
[0314] The residual oil was dissolved in dichloromethane (5 mL). The solution was cooled to 5° C. and 4-dimethylaminopyridine (1 small crystal), triethylamine (0.10 g, 0.98 mmol) and p-toluene sulfonyl chloride (0.12 g, 0.6 mmol) was added sequentially. The reaction mixture was gradually warmed to 20° C. over 90 min. Water was then added and the mixture was extracted with dichloromethane. The organic layer was washed with aqueous HCl (1 M), dried over Na.sub.2SO.sub.4, filtrated and concentrated by in vacuo. The residue was purified by flash chromatography (silica, cyclohexane:ethyl acetate) to afford [2-(tert-butoxycarbonylamino)-4-methyl-pent-4-enyl] 4-methylbenzenesulfonate as white solid.
[0315] LC-MS (Method G), R.sup.t=1.11 min.
[0316] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.79 (d, 2H) 7.36 (d, 2H) 4.79 (s, 1H) 4.68 (s, 1H) 3.69-4.23 (m, 3H) 2.46 (s, 3H) 2.18-2.23 (m, 2H) 1.69 (s, 3H) 1.41 (s, 9H).
Step 2:
[0317] To a solution of [2-(tert-butoxycarbonylamino)-4-methyl-pent-4-enyl] 4-methylbenzenesulfonate (0.21 g, 0.45 mmol) in N,N-dimethylformamide (4 mL) was added 4-chloro-1H-pyrazole (0.1 g, 0.9 mmol) and Cs.sub.2CO.sub.3 (0.45 g, 1.4 mmol). The resulting suspension was warmed to 80° C. and stirred for 90 min at this temperature. All volatiles were removed in vacuo and the residue was purified by flash chromatography (silica, cyclohexane:ethyl acetate) to afford tert-butyl N-[1-[(4-chloropyrazol-1-yl)methyl]-3-methyl-but-3-enyl]carbamate.
[0318] LC-MS (Method G), R.sub.t=1.05 min, (M+Na)=322.
[0319] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.45 (s, 1H) 7.38 (s, 1H) 4.87 (s, 1H) 4.74 (s, 1H) 3.97-4.38 (m, 3H) 2.15 (d, 2H) 1.75 (s, 3H) 1.44 (s, 9H).
Step 3:
[0320] tert-butyl N-[1-[(4-chloropyrazol-1-yl)methyl]-3-methyl-but-3-enyl]carbamate (0.06 g, 0.2 mmol) was dissolved in 1,4-dioxane (0.4 mL) and HCl (4 M in 1,4-dioxane, 0.5 mL, 2 mmol) was added at 20° C. The resulting mixture was stirred for 6 h at 20° C., toluene was then added and all volatiles were removed in vacuo. The residual solid was suspended in acetonitrile (2 mL) and 7,8-difluoroquinoline-3-carboxylic acid (0.06 g, 0.3 mmol), triethylamine (0.2 g, 2 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 0.22 g, 0.34 mmol) was added sequentially. The resulting solution was stirred at 20° C. for 18 h, aqueous NaHCO.sub.3 was then added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by flash chromatography (silica, cyclohexane:ethyl acetate) to afford N-[1-[(4-chloropyrazol-1-yl)methyl]-3-methyl-but-3-enyl]-7,8-difluoro-quinoline-3-carboxamide as white solid.
[0321] LC-MS (Method G), R.sub.t=0.96 min, (M+H)=391.
[0322] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.38 (d, 1H) 8.67 (d, 1H) 7.70-7.88 (m, 2H) 7.49-7.61 (m, 2H) 7.45 (s, 1H) 4.92 (s, 1H) 4.77 (s, 1H) 4.72-4.75 (m, 1H) 4.24-4.51 (m, 2H) 2.38 (dd, 1H) 2.13 (dd, 1H) 1.86 (s, 3H).
[0323] .sup.19F NMR (377 MHz, CDCl.sub.3) δ ppm −131.80 (d, 1F) −150.17 (d, 1F).
Step 4:
[0324] A solution of N-[1-[(4-chloropyrazol-1-yl)methyl]-3-methyl-but-3-enyl]-7,8-difluoro-quinoline-3-carboxamide (0.075 g, 0.19 mmol) and Lawesson's reagent (0.10 g, 0.25 mmol) in 1,4-dioxane (4 mL) was warmed to 100° C. and stirred at this temperature for 20 h. The resulting solution was cooled to room temperature and all volatiles were removed in vacuo. The residue was diluted with toluene (3 mL), trifluoroacetic acid (0.6 mL) was added at room temperature and the resulting solution was warmed to 80° C. After 11 h at 80° C., the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with aqueous NaHCO.sub.3. The organic layer was washed with water and brine, and concentrated in vacuo. The residue was purified by reverse phase HPLC (C.sub.18-modified silica, acetonitrile:water) to afford 4-[(4-chloropyrazol-1-yl)methyl]-2-(7,8-difluoro-3-quinolyl)-6,6-dimethyl-4,5-dihydro-1,3-thiazine as light yellow oil.
[0325] LC-MS (Method G), R.sub.t=1.16 min, (M+H)=407
[0326] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 9.43 (d, 1H) 8.49 (s, 1H) 7.67 (ddd, 1H) 7.60 (s, 1H) 7.38-7.55 (m, 2H) 4.40-4.60 (m, 2H) 4.13-4.19 (m, 1H) 1.86 (dd, 1H) 1.49 (d, 6H) 1.30-1.42 (m, 1H).
[0327] .sup.19F NMR (377 MHz, CDCl.sub.3) δ ppm −133.44 (d, 1F) −150.70 (d, 1F).
Example A5: (4S or 4R)-2-(7,8-difluoro-3-quinolyl)-6,6-dimethyl-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazine enantiomer 1 of 2 & enantiomer 2 of 2. (Compounds E.31 and E.32)
[0328] The enantiomers of 2-(7,8-difluoro-3-quinolyl)-6,6-dimethyl-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazine were separated by preparative SFC (Sepiatec Prep SFC 100) over a chiral stationary phase (Daicel CHIRALPAK® OZ, 5 m, 2.0 cm×25 cm). Mobile phase: A: CO.sub.2 B: EtOH, isocratic: 15% B in 25 min, backpressure: 150 bar, flow rate: 60 ml/min, GLS pump: 5 ml/min ethanol, detection: UV 245 nm, sample concentration: 50 mg/mL in MeOH, Injection: 500 μl. Compound E.31 (enantiomer 1 of 2) was obtained as first eluting isomer, compound E.32 (enantiomer 2 of 2) was obtained as second eluting isomer.
Analytical Methods
Method G:
[0329] 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.
Method H1:
[0330] Spectra were recorded on a SFC Waters Acquity UPC.sup.2/QDa with detection on a PDA Detector Waters Acquity UPC.sup.2. Column: Daicel SFC CHIRALPAK® OZ, 3 m, 0.3 cm×10 cm, 40° C., Mobile phase: A: CO.sub.2 B: 2-propanol, isocratic: 15% B in 4.8 min, ABPR: 1800 psi, Flow rate: 2.0 ml/min, Detection: 240 nm, Sample concentration: 1 mg/mL in acetonitrile, Injection: 1 μL
Method H2:
[0331] Spectra were recorded on a SFC Waters Acquity UPC.sup.2/QDa with detection on a PDA Detector Waters Acquity UPC.sup.2. Column: Daicel SFC CHIRALPAK® OZ, 3 m, 0.3 cm×10 cm, 40° C., Mobile phase: A: CO.sub.2 B: ethanol, isocratic: 15% B in 6.8 min, ABPR: 1800 psi, Flow rate: 2.0 ml/min, Detection: 342 nm, Sample concentration: 1 mg/mL in methanol/2-propanol mixture, Injection: 1 μL.
TABLE-US-00010 TABLE E Melting point (mp) and/or LC/MS data (retention time (R.sub.t)) for compounds of Formula (I): R.sub.t [M + H] mp Entry IUPAC name STRUCTURE (min) (measured) Method (° C.) E.01 2-(7,8-difluoro-3-quinolyl)- 6,6-dimethyl-4-(2- pyridylmethyl)-4,5-dihydro- 1,3-thiazine
BIOLOGICAL EXAMPLES/TEST METHODS
[0332] Botryotinia fuckeliana (Botrytis cinerea)/Liquid Culture (Gray Mould)
[0333] 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.
[0334] 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:
E.01, E.02, E.03, E.04, E.05, E.06, E.07, E.09, E.10, E.11, E.12, E.13, E.14, E.15, E.16, E.17, E.19, E.22, E.23, E.24, E.26, E.29, E.30.
[0335] Glomerella lagenarium (Colletotrichum lagenarium)/Liquid Culture (Anthracnose)
[0336] 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.
[0337] 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:
E.01, E.05, E.11.
[0338] Fusarium culmorum/Liquid Culture (Head Blight)
[0339] 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.
[0340] 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:
E.01, E.02, E.04. E.06, E.07, E.23, E.24, E.25, E.29, E.30.
[0341] Monographella nivalis (Microdochium nivale)/Liquid Culture (Foot Rot Cereals)
[0342] 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.
[0343] 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:
E.01, E.02, E.03, E.04, E.05, E.06, E.07, E.09, E.10, E.11, E.12, E.13, E.14, E.15, E.16, E.17, E.18, E.19, E.22, E.23, E.24, E.25, E.26, E.29, E.30.
[0344] Mycosphaerella graminicola (Septoria tritici)/Liquid Culture (Septoria Blotch)
[0345] 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.
[0346] The following compounds gave at least 80% control of Mycosphaerella graminicola at 6 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
E.02, E.09, E.10, E.11, E.12, E.13, E.14, E.15, E.16, E.20, E.29, E.30.