MICROBIOCIDAL HETEROBICYCLIC DERIVATIVES

Abstract

Intermediates for compounds of the formula (I):

##STR00001##

Claims

1. A compound of formula (XA): ##STR00145## wherein R.sub.5a is fluoro or hydrogen; and R.sub.5b fluoro or hydrogen; or a compound of formula (XB): ##STR00146## wherein R.sub.5a is fluoro or hydrogen; and R.sub.5b is fluoro or hydrogen; or a compound of formula (XC): ##STR00147## wherein R.sub.5a is fluoro or hydrogen; and R.sub.5b is fluoro or hydrogen; or a compound of formula (XD): ##STR00148## wherein R.sub.5a is fluoro or hydrogen; and R.sub.5b is fluoro or hydrogen.

2. The compound of claim 1, wherein the compound is the compound of formula (XA).

3. The compound of claim 2, wherein R.sub.5a is fluoro; and R.sub.5b is fluoro.

4. The compound of claim 2, wherein R.sub.5a is hydrogen; and R.sub.5b is hydrogen.

5. The compound of claim 2, wherein R.sub.5a is fluoro; and R.sub.5b is hydrogen.

6. The compound of claim 2, wherein R.sub.5a is hydrogen; and R.sub.5b is fluoro.

7. The compound of claim 1, wherein the compound is the compound of formula (XB).

8. The compound of claim 7, wherein R.sub.5a is fluoro; and R.sub.5b is fluoro.

9. The compound of claim 7, wherein R.sub.5a is hydrogen; and R.sub.5b is hydrogen.

10. The compound of claim 7, wherein R.sub.5a is fluoro; and R.sub.5b is hydrogen.

11. The compound of claim 7, wherein R.sub.5a is hydrogen; and R.sub.5b is fluoro.

12. The compound of claim 1, wherein the compound is the compound of formula (XC).

13. The compound of claim 12, wherein R.sub.5a is fluoro; and R.sub.5b is fluoro.

14. The compound of claim 12, wherein R.sub.5a is hydrogen; and R.sub.5b is hydrogen.

15. The compound of claim 12, wherein R.sub.5a is fluoro; and R.sub.5b is hydrogen.

16. The compound of claim 12, wherein R.sub.5a is hydrogen; and R.sub.5b is fluoro.

17. The compound of claim 1, wherein the compound is the compound of formula (XD).

18. The compound of claim 17, wherein R.sub.5a is fluoro; and R.sub.5b is fluoro.

19. The compound of claim 17, wherein R.sub.5a is hydrogen; and R.sub.5b is hydrogen.

20. The compound of claim 17, wherein R.sub.5a is fluoro; and R.sub.5b is hydrogen.

21. The compound of claim 17, wherein R.sub.5a is hydrogen; and R.sub.5b is fluoro.

Description

EXAMPLES

[0243] The Examples which follow serve to illustrate the invention. Certain compounds of the invention can be distinguished from known compounds by virtue of greater efficacy at low application rates, which can be verified by the person skilled in the art using the experimental procedures outlined in the Examples, using lower application rates if necessary, for example 50 ppm, 12.5 ppm, 6 ppm, 3 ppm, 1.5 ppm, 0.8 ppm or 0.2 ppm.

[0244] Throughout this description, temperatures are given in degrees Celsius and “m.p.” means melting point. LC/MS means Liquid Chromatography Mass Spectroscopy and the description of the apparatus and the methods are:

[0245] Method G:

[0246] Spectra were recorded on a Mass Spectrometer (ACQUITY UPLC) from Waters (SQD, SQDII or ZQ Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 0 L/Hr, Desolvation Gas Flow: 650 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 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

[0247] Method H:

[0248] Spectra were recorded on a Mass Spectrometer (ACQUITY UPLC) from Waters (SQD, SQDII or ZQ Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 0 L/Hr, Desolvation Gas Flow: 650 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 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

FORMULATION EXAMPLES

[0249]

TABLE-US-00003 Wettable powders a) b) c) active ingredient [compound of formula (I)] 25%  50% 75% sodium lignosulfonate 5%  5% — sodium lauryl sulfate 3% —  5% sodium diisobutylnaphthalenesulfonate —  6% 10% phenol polyethylene glycol ether —  2% — (7-8 mol of ethylene oxide) highly dispersed silicic acid 5% 10% 10% Kaolin 62%  27% —

[0250] The active ingredient is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.

TABLE-US-00004 Powders for dry seed treatment a) b) c) active ingredient [compound of formula (I)] 25% 50% 75% light mineral oil  5%  5%  5% highly dispersed silicic acid  5%  5% — Kaolin 65% 40% — Talcum — 20

[0251] The active ingredient is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording powders that can be used directly for seed treatment.

TABLE-US-00005 Emulsifiable concentrate active ingredient [compound of formula (I)] 10% octylphenol polyethylene glycol ether  3% (4-5 mol of ethylene oxide) calcium dodecylbenzenesulfonate  3% castor oil polyglycol ether (35 mol of ethylene oxide)  4% Cyclohexanone 30% xylene mixture 50%

[0252] Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.

TABLE-US-00006 Dusts a) b) c) Active ingredient [compound of formula (I)]  5%  6%  4% talcum 95% — — Kaolin — 94% — mineral filler — — 96%

[0253] Ready-for-use dusts are obtained by mixing the active ingredient with the carrier and grinding the mixture in a suitable mill. Such powders can also be used for dry dressings for seed.

TABLE-US-00007 Extruder granules Active ingredient [compound of formula (I)] 15% sodium lignosulfonate  2% carboxymethylcellulose  1% Kaolin 82%

[0254] The active ingredient is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.

TABLE-US-00008 Coated granules Active ingredient [compound of formula (I)] 8% polyethylene glycol (mol. wt. 200) 3% Kaolin 89% 

[0255] The finely ground active ingredient is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.

TABLE-US-00009 Suspension concentrate active ingredient [compound of formula (I)] 40% propylene glycol 10% nonylphenol polyethylene glycol ether (15 mol of ethylene oxide)  6% Sodium lignosulfonate 10% carboxymethylcellulose  1% silicone oil (in the form of a 75% emulsion in water)  1% Water 32%

[0256] The finely ground active ingredient is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.

TABLE-US-00010 Flowable concentrate for seed treatment active ingredient [compound of formula (I)] 40%  propylene glycol 5% copolymer butanol PO/EO 2% tristyrenephenole with 10-20 moles EO 2% 1,2-benzisothiazolin-3-one (in the form of a 20% solution 0.5%.sup.  in water) monoazo-pigment calcium salt 5% Silicone oil (in the form of a 75% emulsion in water) 0.2%.sup.  Water 45.3%  

[0257] The finely ground active ingredient is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.

Slow Release Capsule Suspension

[0258] 28 parts of a combination of the compound of formula (I) are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed.

[0259] The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns.

[0260] The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.

PREPARATION EXAMPLES

[0261] Using the techniques described both above and below compounds of formula (I) may be prepared.

Example 1: This Example Illustrates the Preparation of 5-fluoro-1-[8-fluoroimidazo(1,2-a)pyrimidin-3-yl]-3,3,4,4-tetramethyl-isoquinoline

Step 1: N′-(3-fluoro-2-pyridyl)-N,N-dimethyl-formamidine

[0262] 1.50 g (13.4 mmol) 2-amino-3-fluoro-pyridine and 1.99 g (16.2 mmol) N,N-dimethylformamide dimethylacetal in 15 ml methanol were heated under reflux during 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (heptane/ethylacetate=1:1) to give N′-(3-fluoro-2-pyridyl)-N,N-dimethyl-formamidine as a colourless oil.

Step 2: 8-fluoroimidazo(1,2-a)pyrimidin-3-carbonitrile

[0263] To 2.11 g (12.6 mmol) N′-(3-fluoro-2-pyridyl)-N,N-dimethyl-formamidine in 30 ml isopropanol was added 1.54 g (18.3 mmol) sodium bicarbonate and 1.1 ml (14.9 mmol) bromoacetonitrile and the mixture was stirred at 80° C. overnight. The reaction mixture was concentrated, extracted with water/ethylacetate, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (heptane/ethylacetate=1:1) to give 8-fluoroimidazo(1,2-a)pyrimidin-3-carbonitrile as an oil, which crystallised from tert-butylmethylether/heptane (1:2) as a beige powder, m.p. 157-158° C.

Step 3: 5-fluoro-1-(8-fluoroimidazo(1,2-a)pyrimidin-3-yl)-3,3,4,4-tetramethyl-isoquinoline

[0264] To a cooled suspension (0° C.) of 0.13 g (0.80 mmol) 8-fluoroimidazo(1,2-a)pyrimidin-3-carbonitrile in 1.8 ml conc. sulfuric acid, 0.17 g (0.89 mmol) 3-(2-fluorophenyl)-2,3-dimethyl-butan-2-ol was added within 20 min. and the mixture was stirred for 1 h at this temperature. The reaction mixture was poured into ice-water and the pH was adjusted to 8 using sodium hydroxide. The aqueous phase was extracted with ethylacetate, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (heptane/ethylacetate=4:1) to give 5-fluoro-1-(8-fluoroimidazo(1,2-a)pyrimidin-3-yl)-3,3,4,4-tetramethyl-isoquinoline as a beige powder, m.p. 156-157° C.

Preparation of 3-(2-fluorophenyl)-2,3-dimethyl-butan-2-ol

Step 1: ethyl-2-(2-fluorophenyl)-2-methyl-propanoate

[0265] To the suspension of 27.4 g (0.69 mol) sodium hydride in 220 ml tetrahydrofuran was added dropwise a mixture of 50.0 g (0.27 mol) ethyl-2-(2-fluorophenyl)acetate and 117.9 g (0.82 mmol) iodomethane in 60 ml tetrahydrofuran at room temperature. After stirring overnight 70 ml saturated ammoniumchloride solution was slowly added. The reaction mixture was poured into 300 ml ice-water and extracted with ethylacetate, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (heptane/ethylacetate=19:1) to give ethyl-2-(2-fluorophenyl)-2-methyl-propanoate as a yellowish oil.

Step 2: 3-(2-fluorophenyl)-2,3-dimethyl-butan-2-ol

[0266] 52.1 g (0.25 mol) ethyl-2-(2-fluorophenyl)-2-methyl-propanoate and 207 ml (0.12 mol) lanthanum(III) chloride bis(lithium chloride) complex solution (0.6 M in THF) were stirred for 1.5 h at room temperature. Then 248 ml (0.74 mol) methylmagnesium bromide solution (3.0 M in diethyl ether) was added dropwise at 0° C. After stirring overnight at room temperature 60 ml saturated ammoniumchloride solution was slowly added under cooling. 200 ml water was added and stirring continued for 30 min. The reaction mixture was extracted with tert-butyl methylether, filtered over Celite, the phases separated and the waterphase extracted with tert-butyl methylether. The organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 3-(2-fluorophenyl)-2,3-dimethyl-butan-2-ol as a yellowish solid, m.p. 42-43° C.

Example 2: This Example Illustrates the Preparation of 5-fluoro-3,3,4,4-tetramethyl-1-pyrazolo[1,5-a]pyridin-3-yl-isoquinoline

Step 1: pyrazolo[1,5-a]pyridine-3-carbonitrile

[0267] To a solution of 0.2 g (0.8967 mmol) pyridin-1-ium-1-amine hydroiodide and 0.18 g (1.3003 mmol) potassium carbonate in 2 mL N,N-dimethylformamide, 0.085 mL (0.9869 mmol, 0.082 g) (E)-3-methoxyprop-2-enenitrile at room temperature were added dropwise. The reaction mixture was stirred over night at 80° C. The reaction mixture was concentrated under reduced pressure and the residue was extracted with diethylether/water. The combined organic phase was washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (cyclohexane/ethyl acetate=1:1) to give 0.07 g (0.489 mmol) pyrazolo[1,5-a]pyridine-3-carbonitrile as beige solid, m.p. 124-127° C.

Step 2: 5-fluoro-3,3,4,4-tetramethyl-1-pyrazolo[1,5-a]pyridin-3-yl-isoquinoline

[0268] To a solution of 0.07 g (0.489 mmol) pyrazolo[1,5-a]pyridine-3-carbonitrile in 0.8 mL sulfuric acid 0.115 g (0.5868 mmol) 3-(2-fluorophenyl)-2,3-dimethyl-butan-2-ol was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for three hours then it was poured on cold water, basified with 8M NaOH to pH 10 and washed three times with dichloromethane. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (cyclohexane/ethyl acetate=3:1) to give 0.0573 g (0.169 mmol) 5-fluoro-3,3,4,4-tetramethyl-1-pyrazolo[1,5-a]pyridin-3-yl-isoquinoline as beige solid, m.p. 105-108° C.

Example 3: This Example Illustrates the Preparation of 4,4-difluoro-3,3-dimethyl-1-(8-methylimidazol[1,2-a]pyridin-3-yl)isoquinoline

Step 1: 1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3,3-dimethyl-4H-isoquinoline

[0269] To an ice cooled (0° C.) solution of 1.00 g (4.50 mmol) 8-bromoimidazo[1,2-a]pyridine-3-carbonitrile in 9.8 mL conc. sulfuric acid was slowly added 1.01 g (6.76 mmol) 2-methyl-1-phenyl-propan-2-ol over 15 min and the resulting solution was stirred for additional 60 min at 0-5° C. The reaction mixture was poured into ice-water and the pH was adjusted to 9 with 4 N sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, dried over sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by flash chromatography (heptane/ethyl acetate=3:1) to give 1.04 g (2.94 mmol) 1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3,3-dimethyl-4H-isoquinoline as light yellow powder.

Step 2: 1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3,3-dimethyl-isoquinolin-4-one

[0270] To a solution of 0.625 g (1.77 mmol) 1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3,3-dimethyl-4H-isoquinoline in 50 mL carbon tetrachloride was added 0.661 g (3.52 mmol) N-bromosuccinimide and 0.076 g (0.44 mmol) azoisobutyronitrile at RT. The resulting mixture was warmed to 77° C. and stirred for 120 min at this temperature. After cooling to RT, the reaction was diluted with dichloromethane, successively washed with water and brine, dried over sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by flash chromatography (heptane/ethyl acetate=2:1) to give 0.634 g (1.73 mmol) 1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3,3-dimethyl-isoquinolin-4-one as off-white solid, m.p. 204-208° C.

Step 3: 1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-4,4-difluoro-3,3-dimethyl-isoquinoline

[0271] 0.33 g (0.81 mmol) 1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3,3-dimethyl-isoquinolin-4-one was suspended in 0.51 mL 2,2-difluoro-1,3-dimethylimidazoline at RT, warmed to 100° C. and stirred over night at this temperature. The resulting solution was cooled to RT and slowly added into ice-cold, saturated bicarbonate solution. This mixture was extracted with ethyl acetate; the organic layer was washed with brine, dried over sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by flash chromatography (toluene/ethyl acetate=1:0-9:1) to afford 0.136 g (0.35 mmol) 1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-4,4-difluoro-3,3-dimethyl-isoquinoline as white solid, m.p. 173° C.

Step 4: 4,4-difluoro-3,3-dimethyl-1-(8-methylimidazo[1,2-a]pyridin-3-yl)isoquinoline

[0272] To a solution of 0.09 g (0.23 mmol) 1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-4,4-difluoro-3,3-dimethyl-isoquinoline in 3 mL dioxane (degased) was added 0.072 mL (0.25 mmol) trimethylboroxine (3.5 M in THF), 0.307 g (0.92 mmol) cesium carbonate and 0.020 g (0.02 mmol) [Pd(dppf)Cl.sub.2] at RT. The resulting suspension was warmed to 95° C. and maintained for 90 min at this temperature. After cooling to RT, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by flash chromatography (heptane/ethyl acetate=3:2-2:1) to afford 0.073 g (0.22 mmol) 4,4-difluoro-3,3-dimethyl-1-(8-methylimidazo[1,2-a]pyridin-3-yl)isoquinoline as light brown oil.

Example 4: This example illustrates the preparation of 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4-difluoro-3,3-dimethyl-isoquinoline

Step 1: Preparation of 3,3-dimethyl-2H-isoquinoline-1,4-dione

[0273] 1) To a solution of 3,3-dimethyl-2,4-dihydroisoquinolin-1-one (57.1 mmol, 10.0 g) in CCl4 (285 mL) at room temperature was added N-bromosuccinimide (171 mmol, 30.5 g) and AlBN (8.5 mmol, 1.43 g) and the reaction mixture was stirred at 70° C. for 3 hours. The reaction mixture was allowed to cool down to room temperature, concentrated under vacuo and diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated to give 4,4-dibromo-3,3-dimethyl-2H-isoquinolin-1-one (25.2 g) as a light yellow solid which was used directly in the next step without further purification: LC-MS (Method H) UV Detection: 220 nm, Rt=1.34; MS: (M+1)=332-334-336; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.57 (s, 6H) 7.21 (br. s, 1H) 7.70-7.77 (m, 1H) 7.78-7.85 (m, 1H) 8.06-8.14 (m, 1H) 8.23-8.30 (m, 1H).

[0274] 2) To a solution of 4,4-dibromo-3,3-dimethyl-2H-isoquinolin-1-one (20.0 g) in a mixture of water (450 mL) and tetrahydrofuran (225 mL) was added sodium carbonate (135 mmol, 14.3 g) and the mixture was stirred at room temperature for 12 h and at 70° C. for 4 h 30 min. The reaction mixture was allowed to cool down to room temperature, diluted with water, acidified to pH 3-4 with 90 mL of a 2 M solution of hydrochloric acid and extracted with dichloromethane. The combined organic extracts were dried over Na2SO4, filtered and concentrated to give 3,3-dimethyl-2H-isoquinoline-1,4-dione (9.95 g) as a yellow solid: LC-MS (Method H) UV Detection: 220 nm, Rt=0.81; MS: (M+1)=190; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.77 (s, 3H) 1.97 (s, 3H) 7.39 (s, 1H) 7.46-7.58 (m, 1H) 7.60-7.71 (m, 1H) 7.98-8.22 (m, 2H).

Step 2: Preparation of 1-chloro-3,3-dimethyl-isoquinolin-4-one

[0275] To a solution of N,N-dimethylformamide (2.3 mL, 30 mmol) in dichloromethane (52 mL) at room temperature was added oxalyl chloride (20 mmol, 1.8 mL) dropwise over a period of 35 min and the white suspension was vigorously stirred for 15 min until the gas evolution stopped. A solution of 3,3-dimethyl-2H-isoquinoline-1,4-diose (2.5 g, 13 mmol) in dichloromethane (25 mL) was then added dropwise and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into an ice-cooled mixture of saturated aqueous NaHCO.sub.3 solution and pentane, and the organic phase was separated. The aqueous phase was then extracted with pentane, and the combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to give 1-chloro-3,3-dimethyl-isoquinolin-4-one (2.5 g) as a yellow solid: LC-MS (Method H) UV Detection: 220 nm, Rt=1.34; MS: (M+1)=208-210; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 6H) 7.62-7.69 (m, 1H) 7.73-7.81 (m, 1H) 7.90 (dd, J=8.07, 0.73 Hz, 1H) 8.04 (dd, J=7.50, 0.90 Hz, 1H).

Step 3: Preparation of 3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one

[0276] To a solution of 1-chloro-3,3-dimethyl-isoquinolin-4-one (2.10 g, 9.1 mmol) in triethylamine (20 mL) was added at room temperature CuI (0.17 g, 0.9 mmol), bis-triphenylphosphine Palladium(II) dichloride (320 mg, 0.46 mmol) followed by dropwise addition of ethynyltrimethylsilane (1.9 mL, 14 mmol). The black solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl and the extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash chromatography gave 3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one (2.35 g) as a dark yellow oil: LC-MS (Method G), Rt=1.21 UV Detection: 220 nm; MS: (M+1)=270; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.32 (s, 9H) 1.51 (s, 6H) 7.63-7.69 (m, 1H) 7.79-7.83 (m, 1H) 7.98 (dd, 2H) 8.05 (dd, 1H).

Step 4: Preparation of 1-ethynyl-3,3-dimethyl-isoquinolin-4-one

[0277] To a solution of 3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one (1.0 g, 3.7 mmol) in methanol (7.5 mL) was added at room temperature K.sub.2CO.sub.3 (570 mg, 4.1 mmol). The reaction mixture was stirred at room temperature for 1 h, quenched with water (pH 8/9), and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash chromatography gave 1-ethynyl-3,3-dimethyl-isoquinolin-4-one (700 mg) as a brown oil: LC-MS (Method G), Rt=0.84, UV Detection: 220 nm; MS: (M+1)=198; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 6H) 3.28 (s, 1H) 7.65-7.70 (m, 1H) 7.79-7.85 (m, 1H) 7.98-8.04 (m, 1H) 8.06-8.12 (s, 1H).

Step 5: Preparation of 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-3,3-dimethyl-isoquinolin-4-one

[0278] To a white suspension of 2,3-dimethylpyridin-1-ium-1-amine iodide (1.0 g, 4.1 mmol) in dichloromethane (20 mL) was added diazabicycloundecene (623 mg, 4.1 mmol) followed by dropwise addition of 1-ethynyl-3,3-dimethyl-isoquinolin-4-one (700 mg, 3.2 mmol) dissolved in dichloromethane (10 mL), over a period of 30 min. The resulting brown mixture was stirred at room temperature for 1 hour, till disappearance of the 1-ethynyl-3,3-dimethyl-isoquinolin-4-one starting material. The reaction mixture was quenched with water, the organic phase was separated and washed with saturated aqueous NH.sub.4Cl. The water phase was extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash chromatography gave 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-3,3-dimethyl-isoquinolin-4-one (410 mg) as orange solid: mp=152°-153° C., LC-MS (Method G), Rt=0.86, UV Detection: 220 nm; MS: (M+1)=318; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.57 (s, 6H) 2.42 (s, 3H) 2.72 (s, 3H) 7.15 (d, 1H) 7.62-7.85 (m, 3H) 8.15 (d, 1H) 8.35 (s, 1H).

Step 6: Preparation of 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4-difluoro-3,3-dimethyl-isoquinoline

[0279] A solution of 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-3,3-dimethyl-isoquinolin-4-one (370 mg, 1.2 mmol) in 2,2-difluoro-1,3-dimethylimidazolidine (14 mmol, 1.8 ml) was stirred at 105° C. for 24 hours. The reaction mixture was allowed to cool down to room temperature, diluted with dichloromethane then quenched by slow addition to an ice cooled saturated aqueous NaHCO.sub.3 solution. The 2 phases were separated, and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash chromatography to give 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4-difluoro-3,3-dimethyl-isoquinoline (328 mg) as a beige solid: mp=160-161° C., LC-MS (Method G) UV Detection: 220 nm, Rt=1.03, MS: (M+1)=340; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 6H) 2.40 (s, 3H) 2.79 (s, 3H) 7.15 (d, 1H) 7.57-7.68 (m, 2H) 7.72 (d, 1H) 7.85 (d, 1H) 7.94 (d, 1H) 8.21 (s, 1H). .sup.19F NMR (400 MHz, CHLOROFORM-d) δ ppm −112.

Example 5: This Example Illustrate the Preparation of 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4,6-trifluoro-3,3-dimethyl-isoquinoline

Step 1: Preparation of 6-fluoro-3,3-dimethyl-2H-isoquinoline-1,4-dione

[0280] Preparation was performed via an analogous synthetic route to that described for 3,3-dimethyl-2H-isoquinoline-1,4-dione 6-fluoro-3,3-dimethyl-2H-isoquinoline-1,4-dione (example 4, step 1):

[0281] LC-MS (Method H) UV Detection: 220 nm, Rt=0.94; MS: (M+1)=208; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.56 (s, 6H) 7.35 (br. s, 1H) 7.43-7.50 (m, 1H) 7.68-7.74 (m, 1H) 8.25-8.30 (m, 1H). 19F (400 MHz, CHLOROFORM-d) δ ppm −103

Step 2: Preparation of 1-chloro-6-fluoro-3,3-dimethyl-isoquinolin-4-one

[0282] To a solution of N,N-dimethylformamide (1.6 mL, 21 mmol) in dichloromethane (36 mL) at room temperature was added oxalyl chloride (14 mmol, 1.6 mL) dropwise over a period of 30 min and the white suspension was vigorously stirred for 25 min until the gas evolution stopped. A solution of 6-fluoro-3,3-dimethyl-2H-isoquinoline-1,4-dione (2.0 g, 9.7 mmol) in dichloromethane (20 mL) was then added dropwise at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was poured into an ice-cooled mixture of saturated aqueous NaHCO.sub.3 solution and pentane, and the organic phase was separated. The aqueous phase was then extracted with pentane, and the combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to give 1-chloro-6-fluoro-3,3-dimethyl-isoquinolin-4-one (1.95 g) as a dark yellow oil, that was used without purification in the next synthetic step: LC-MS (Method H) UV Detection: 220 nm, Rt=1.42; MS: (M+1)=226-228

Step 3: Preparation of 6-fluoro-3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one

[0283] To a solution of 1-chloro-6-fluoro-3,3-dimethyl-isoquinolin-4-one (1.4 g, 6.0 mmol) in triethylamine (12 mL) was added at room temperature CuI (116 mg, 0.6 mmol), bis-triphenylphosphine Palladium(II) dichloride (214 mg, 0.3 mmol) followed by dropwise addition of ethynyltrimethylsilane (1.3 mL, 9.1 mmol). The black solution was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl and the extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash chromatography gave 6-fluoro-3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one (1.25 g) as a orange solid: LC-MS (Method G), Rt=1.22 UV Detection: 220 nm; MS: (M+1)=288; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.32 (s, 9H) 1.52 (s, 6H) 7.47-7.52 (m, 1H) 7.70-7.76 (m, 1H) 8.0-8.05 (m, 1H). .sup.19F (400 MHz, CHLOROFORM-d) δ ppm −104.

Step 4: Preparation of 1-ethynyl-6-fluoro-3,3-dimethyl-isoquinolin-4-one

[0284] To a solution of 6-fluoro-3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one (1.25, 4.3 mmol) in dichloromethane (17 mL) was added at room temperature potassium fluoride (0.56 g, 9.6 mmol) and 18-crown-6 (1.2 g, 4.3 mmol). The reaction mixture was stirred at room temperature for 30 min, quenched with saturated aqueous NaHCO.sub.3, and extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash chromatography gave 1-ethynyl-6-fluoro-3,3-dimethyl-isoquinolin-4-one. (610 mg) as a brown oil: LC-MS (Method G), Rt=0.90, UV Detection: 220 nm; MS: (M+1)=216; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.53 (s, 6H) 3.31 (s, 1H) 7.46-7.52 (m, 1H) 7.70-7.75 (m, 1H) 8.02-8.07 (m, 1H). .sup.19F (400 MHz, CHLOROFORM-d) δ ppm −103

Step 5: Preparation of 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-6-fluoro-3,3-dimethyl-isoquinolin-4-one

[0285] To a solution of 2,3-dimethylpyridin-1-ium-1-amine 2,4,6-trimethylbenzenesulfonate (750 mg, 2.3 mmol) in dimethylformamide (8 mL) was first added potassium carbonate (490 mg, 3.5 mmol) followed by dropwise addition of 1-ethynyl-6-fluoro-3,3-dimethyl-isoquinolin-4-one (600 mg, 2.8 mmol) dissolved in dimethylformamide (4 mL), over a period of 30 min. The resulting brown mixture was stirred at room temperature for 2 days, till disappearance of the 1-ethynyl-5-fluoro-3,3-dimethyl-isoquinolin-4-one starting material. The reaction mixture was quenched with water, and extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash chromatography gave 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-6-fluoro-3,3-dimethyl-isoquinolin-4-one (295 mg) as a brown solid: mp=168-170° C., LC-MS (Method G), Rt=0.92, UV Detection: 220 nm; MS: (M+1)=336; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.60 (s, 6H) 2.45 (s, 3H) 2.80 (s, 3H) 7.18 (d, 1H) 7.39-7.48 (m, 1H) 7.73-7.95 (m, 3H) 8.23 (br s, 1H). .sup.19F NMR (400 MHz, CHLOROFORM-d) δ ppm −106

Step 6: Preparation of 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4,6-trifluoro-3,3-dimethyl-isoquinoline

[0286] A solution of 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-6-fluoro-3,3-dimethyl-isoquinolin-4-one (280 mg, 0.84 mmol) in 2,2-difluoro-1,3-dimethylimidazolidine (1.3 ml) was stirred at 105° C. for 24 hours. The reaction mixture was allowed to cool down to room temperature, diluted with dichloromethane then quenched by slow addition to an ice cooled saturated aqueous NaHCO.sub.3 solution. The two phases were separated, and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash chromatography to give 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4,6-trifluoro-3,3-dimethyl-isoquinoline (235 mg) as a beige solid: mp=183-185° C., LC-MS (Method G) UV Detection: 220 nm, Rt=1.09, MS: (M+1)=358; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 6H) 2.45 (s, 3H) 2.80 (s, 3H) 7.19 (d, 1H) 7.22-7.27 (m, 1H) 7.55 (dd, 1H) 7.72-7.77 (m, 1H) 7.95 (d, 1H) 8.21 (br s, 1H). .sup.19F NMR (400 MHz, CHLOROFORM-d) δ ppm −106, −113.

Example 6: This Example Illustrates the 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4,5-trifluoro-3,3-dimethyl-isoquinoline

Step 1: Preparation of 5-fluoro-3,3-dimethyl-2H-isoquinoline-1,4-dione

[0287] 1) To a solution of 5-fluoro-3,3-dimethyl-2,4-dihydroisoquinolin-1-one (5.0 g, 25.9 mmol) in CCl4 (100 mL) at room temperature was added N-bromosuccinimide (44 mmol, 7.9 g) and AlBN (2.6 mmol, 0.43 g) and the reaction mixture was stirred at 70° C. for 2 hours, until starting material has disappeared. The reaction mixture was allowed to cool down to room temperature, concentrated under vacuo and diluted with ethyl acetate, washed with water and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to give 4-bromo-5-fluoro-3,3-dimethyl-2,4-dihydroisoquinolin-1-one (6.6 g) as a light yellow solid which was used directly in the next step without further purification: LC-MS (Method G) UV Detection: 220 nm, Rt=0.83; MS: (M+1)=272-274; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (s, 3H) 1.55 (s, 3H) 5.30 (s, 1H) 6.15 (br. s, 1H) 7.24-7.30 (m, 1H) 7.40-7.50 (m, 1H) 7.90 (d, 1H). .sup.19F NMR (400 MHz, CHLOROFORM-d) δ ppm −119

[0288] 2) A solution of 4-bromo-5-fluoro-3,3-dimethyl-2,4-dihydroisoquinolin-1-one (6.6 g) in a mixture of water (120 mL) and tetrahydrofuran (120 mL) was stirred at 90° C. overnight. The reaction mixture was allowed to cool down to room temperature, diluted with saturated aqueous NaHCO.sub.3 to pH 7-8 and extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and concentrated. Purification by flash chromatography gave 5-fluoro-4-hydroxy-3,3-dimethyl-2,4-dihydroisoquinolin-1-one (3.54 g) as a white solid: LC-MS (Method G) UV Detection: 220 nm, Rt=0.60; MS: (M+1)=210; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20 (s, 3H) 1.50 (s, 3H) 2.5 (br. d, 1H) 4.7 (d, 1H) 5.75 (br. s, 1H) 7.27-7.30 (m, 1H) 7.40-7.48 (m, 1H) 7.85 (d, 1H). .sup.19F NMR (400 MHz, CHLOROFORM-d) δ ppm −113

[0289] 3) To a solution of 5-fluoro-4-hydroxy-3,3-dimethyl-2,4-dihydroisoquinolin-1-one (3.54 g, 16.9 mmol) in dichloromethane (200 ml) was added Dess-Martin periodinane (18.6 mmol, 8.15 g) at 0° C. The reaction mixture was stirred for 2 hour at temperature between 0 and 10° C. and quenched with saturated aqueous NaHCO.sub.3. The organic phase was separated and washed with sodium thiosulfate solution and brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash chromatography to give 5-fluoro-3,3-dimethyl-2H-isoquinoline-1,4-dione (3.08 g) as a white solid: LC-MS (Method G) UV Detection: 220 nm, Rt=0.68; MS: (M+1)=208; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.53 (s, 6H) 2.5 (br. d, 1H) 4.7 (d, 1H) 6.52 (br. s, 1H) 7.38-7.43 (m, 1H) 7.72-7.8 (m, 1H) 8.10 (d, 1H).

Step 2: Preparation of 1-chloro-5-fluoro-3,3-dimethyl-isoquinolin-4-one

[0290] To a solution of dimethylformamide (1.0 mL, 13.5 mmol) in dichloromethane (25 mL), at room temperature, was added oxalyl chloride (1.2 mL, 13.5 mmol) dropwise over a period of 30 min the white suspension was vigorously stirred at the same temperature for 1 hour until the gas evolution stopped. A solution of 5-fluoro-3,3-dimethyl-2H-isoquinoline-1,4-dione (2.0 g, 9.65 mmol) in dichloromethane (25 mL) was then added dropwise and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into an ice-cooled saturated aqueous NaHCO.sub.3 solution and pentane, and the organic phase was separated. The aqueous phase was then extracted with pentane, and the combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to give 1-chloro-5-fluoro-3,3-dimethyl-isoquinolin-4-one (2.05 g) as a yellow solid: LC-MS (Method G), Rt=0.91 UV Detection: 220 nm; MS: (M+1)=226-228; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 6H) 7.36-7.44 (m, 1H) 7.77-7.81 (m, 2H).

Step 3: Preparation of 5-fluoro-3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one

[0291] To a solution of 1-chloro-5-fluoro-3,3-dimethyl-isoquinolin-4-one (2.04 g, 9.0 mmol) in triethylamine (18 mL) was added at room temperature CuI (174 mg, 0.90 mmol), bis-triphenylphosphine Palladium(II) dichloride (0.32 g, 0.45 mmol) followed by dropwise addition of ethynyltrimethylsilane (1.9 mL, 13.6 mmol). The black solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl and the extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash chromatography gave 5-fluoro-3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one (2.25 g) as a yellow solid: LC-MS (Method G), Rt=1.16 UV Detection: 220 nm; MS: (M+1)=288; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.30 (s, 9H) 1.51 (s, 6H) 7.29-7.34 (m, 1H) 7.75-7.81 (m, 2H). .sup.19F (400 MHz, CHLOROFORM-d) δ ppm −108.

Step 4: Preparation of 1-ethynyl-5-fluoro-3,3-dimethyl-isoquinolin-4-one

[0292] To a solution of 5-fluoro-3,3-dimethyl-1-(2-trimethylsilylethynyl)isoquinolin-4-one (2.25 g, 7.8 mmol) in dichloromethane (31 mL) was added at room temperature potassium fluoride (2.2eq, 1.0 g, 17.2 mmol) and 18-crown-6 (2.09 g, 7.8 mmol). The reaction mixture was stirred at room temperature for 30 min, quenched with saturated aqueous NaHCO.sub.3, and extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash chromatography gave 1-ethynyl-5-fluoro-3,3-dimethyl-isoquinolin-4-one (1.46 g) as a yellow solid: LC-MS (Method G), Rt=0.83, UV Detection: 220 nm; MS: (M+1)=216; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 6H) 3.28 (s, 1H) 7.32-7.37 (m, 1H) 7.75-7.83 (m, 2H).

Step 5: Preparation of 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-5-fluoro-3,3-dimethyl-isoquinolin-4-one

[0293] To a solution of 2,3-dimethylpyridin-1-ium-1-amine 2,4,6-trimethylbenzenesulfonate (1.0 g, 3.1 mmol) in dimethylformamide (16 mL) was first added potassium carbonate (650 mg, 4.6 mmol) followed by dropwise addition of 1-ethynyl-5-fluoro-3,3-dimethyl-isoquinolin-4-one (1.0 g, 4.65 mmol) dissolved in dimethylformamide (6 mL), over a period of 30 min. The resulting brown mixture was stirred at room temperature for 16 hours, till disappearance of the 1-ethynyl-5-fluoro-3,3-dimethyl-isoquinolin-4-one starting material. The reaction mixture was quenched with water, and extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. Purification by flash chromatography gave 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-5-fluoro-3,3-dimethyl-Isoquinolin-4-one (380 mg) as a brown solid: mp=139-141° C., LC-MS (Method G), Rt=0.95, UV Detection: 220 nm; MS: (M+1)=336; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54 (s, 6H) 2.38 (s, 3H) 2.75 (s, 3H) 7.15 (d, 1H) 7.32 (t, 1H) 7.58 (d, 1H) 7.68-7.71 (m, 1H) 7.78 (d, 1H) 8.16 (s, 1H). .sup.19F NMR (400 MHz, CHLOROFORM-d) δ ppm −112.

Step 6: Preparation of 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4,5-trifluoro-3,3-dimethyl-isoquinoline

[0294] A solution of 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-5-fluoro-3,3-dimethyl-isoquinolin-4-one (360 mg, 1.1 mmol) in 2,2-difluoro-1,3-dimethylimidazolidine (1.7 ml) was stirred at 105° C. for 24 hours. The reaction mixture was allowed to cool down to room temperature, diluted with dichloromethane then quenched by slow addition to an ice cooled saturated aqueous NaHCO.sub.3 solution. The two phases were separated, and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash chromatography to give 1-(6,7-dimethylpyrazolo[1,5-a]pyridin-3-yl)-4,4,5-trifluoro-3,3-dimethyl-isoquinoline (310 mg) as a beige solid: mp=185-187° C., LC-MS (Method G) UV Detection: 220 nm, Rt=1.14, MS: (M+1)=358; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 6H) 2.40 (s, 3H) 2.78 (s, 3H) 7.17 (d, 1H) 7.31 (t, 1H) 7.51-7.60 (m, 2H) 7.90 (d, 1H) 8.15 (s, 1H). .sup.19F NMR (400 MHz, CHLOROFORM-d) δ ppm −110, −113.

[0295] The following table gives analytical data for compounds of formula (I) prepared using synthetic techniques described above.

TABLE-US-00011 TABLE E Physical data of compounds of formula (I) RT [M + H] No. Compound name STRUCTURE (min) (measured) Method MP ° C. E-1 5-fluoro-1-imidazo[1,2- a]pyridin-3-yl-3,3,4,4- tetramethyl-isoquinoline [00052] 0.91 322 G 129- 130 E-2 7-fluoro-1-imidazo[1,2- a]pyridin-3-yl-3,3,4,4- tetramethyl-isoquinoline [00053] 0.89 322 G E-3 5-chloro-1-imidazo[1,2- a]pyridin-3-yl-3,3- dimethyl-4H-isoquinoline [00054] 0.92 310 G E-4 5-fluoro-1-(6- fluoroimidazo[1.2- a]pyridin-3-yl)-3,3,4,4- tetramethyl-isoquinoline [00055] 1.13 340 G 200- 202 E-5 5-chloro-1-(6- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3- dimethyl-4H-isoquinoline [00056] 1.11 328 G 142- 143 E-6 5-fluoro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3,4,4- tetramethyl-isoquinoline [00057] 1.10 340 G 156- 157 E-7 1-[8- (difluoromethoxy)imidazo [1,2-a]pyridin-3-yl]-5- fluoro-3,3,4,4-tetramethyl- isoquinoline [00058] 1.15 388 G 121- 122 E-8 1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-5-fluoro- 3,3,4,4-tetramethyl- isoquinoline [00059] 1.15 402 G E-9 5-fluoro-3,3,4,4- tetramethyl-1-(8- methylimidazo[1,2- a]pyridin-3-yl)isoquinoline [00060] 0.95 336 G 160- 161 E-10 5-fluoro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3- dimethyl-4H-isoquinoline [00061] 0.99 312 G E-11 5-chloro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3- dimethyl-4H-isoquinoline [00062] 1.09 328 G 122- 123 E-12 4-bromo-5-chloro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3- dimethyl-4H-isoquinoline [00063] 1.12 408 G 213- 214 E-13 4-bromo-5-fluoro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3- dimethyl-4H-isoquinoline [00064] 1.06 392 G 211- 212 E-14 5-fluoro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3- dimethyl-4H-isoquinolin- 4-ol [00065] 0.77 328 G 219- 219 E-15 5-chloro-1-[8- (difluoromethoxy)imidazo [1,2-a]pyridin-3-yl]-3,3- dimethyl-4H-isoquinoline [00066] 1.14 376 G 114- 115 E-16 1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-5-fluoro- 3,3-dimethyl-4H- isoquinoline [00067] 374 1.05 G 179- 181 E-17 5-fluoro-3,3-dimethyl-1- (8- methylsulfanylimidazo[1,2- a]pyridin-3-yl)-4H- isoquinoline [00068] 340 0.96 G 119- 120 E-18 5-fluoro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3- dimethyl-isoquinolin-4- one [00069] 0.90 326 G 160- 161 E-19 4,4,5-trifluoro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-3,3- dimethyl-isoquinoline [00070] 1.06 348 G 145- 146 E-20 5-fluoro-1-(8- fluoroimidazo[1,2- a]pyridin-3-yl)-N-methoxy- 3,3-dimethyl-isoquinolin- 4-imine [00071] 1.08 355 G E-21 1-(8-ethylimidazo[1,2- a]pyridin-3-yl)-5-fluoro- 3,3,4,4-tetramethyl- isoquinoline [00072] 1.02 350 G E-22 1-(8- cyclopropylimidazo[1,2- a]pyridin-3-yl)-5-fluoro- 3,3,4,4-tetramethyl- isoquinoline [00073] 1.03 362 G E-23 1-(8-ethynylimidazo[1,2- a]pyridin-3-yl)-5-fluoro- 3,3,4,4-tetramethyl- isoquinoline [00074] 1.06 346 G 169- 170 E-24 5-fluoro-1-(8- methoxyimidazo[1,2- a]pyridin-3-yl)-3,3,4,4- tetramethyl-isoquinoline [00075] 0.92 352 G 130- 130 E-25 5-fluoro-1-(6- methoxyimidazo[1,2- a]pyridin-3-yl)-3,3,4,4- tetramethyl-isoquinoline [00076] 1.05 352 G 214- 215 E-26 3-(5-fluoro-3,3,4,4- tetramethyl-1- isoquinolyl)imidazo[1,2- a]pyridin-6-ol [00077] 0.85 338 G 321- 322 E-27 3-(5-fluoro-3,3,4,4- tetramethyl-1- isoquinolyl)imidazo[1,2- a]pyridin-8-ol [00078] 0.91 338 G 271- 272 E-28 5-fluoro-3,3,4,4- tetramethyl-1-(8-prop-2- ynoxyimidazo[1,2- a]pyridin-3-yl)isoquinoline [00079] 1.01 376 G E-29 5-fluoro-3,3,4,4- tetramethyl-1-[8- (trifluoromethyl)imidazo[1, 2-a]pyridin-3- yl]isoquinoline [00080] 1.22 390 G 141- 142 E-30 5-fluoro-3,3,4,4- tetramethyl-1-(5- methylimidazo[1,2- a]pyridin-3-yl)isoquinoline [00081] 0.87 336 G 139- 140 E-31 5-fluoro-3,3,4,4- tetramethyl-1-(7- methylimidazo[1,2- a]pyridin-3-yl)isoquinoline [00082] 1.02 336 G E-32 1-(8-chloroimidazo[1,2- a]pyridin-3-yl)-5-fluoro- 3,3,4,4-tetramethyl- isoquinoline [00083] 1.14 356 G 167- 168 E-33 3,3,4,4-tetramethyl-1-(8- methylimidazo[1,2- a]pyridin-3-yl)isoquinoline [00084] 0.88 318 G E-34 4-bromo-1-(8- bromoimidazo[1,2- a]pyridin-3-yl)-5-fluoro- 3,3-dimethyl-4H- isoquinoline [00085] 1.11 452 G 217- 218 E-35 1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-5-fluoro- 3,3-dimethyl-4H- isoquinolin-4-ol [00086] 0.83 390 G 204- 205 E-36 1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-5-fluoro- 3,3-dimethyl-isoquinolin- 4-one [00087] 0.95 388 G 146- 147 E-37 1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-4,4,5- trifluoro-3,3-dimethyl- isoquinoline [00088] 1.10 309 G 209- 210 E-38 3-(5-fluoro-3,3,4,4- tetramethyl-1- isoquinolyl)imidazo[1,2- a]pyridine-8-carbonitrile [00089] 1.12 437 G 212- 213 E-39 4,4,5-trifluoro-3,3- dimethyl-1-(8- methylimidazo[1,2- a]pyridin-3-yl)isoquinoline [00090] 0.99 344 G E-40 1-(2,8- dimethylimidazo[1,2- a]pyridin-3-yl)-5-fluoro- 3,3,4,4-tetramethyl- isoquinoline [00091] 0.93 350 G E-41 1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-3,3- dimethyl-4H-isoquinoline [00092] 0.84 356 G 132- 133 E-42 1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-3,3- dimethyl-isoquinolin-4- one [00093] 0.96 370 G 204- 205 E-43 1-(8-bromoimidazo[1,2- a]pyridin-3-yl)-4,4- difluoro-3,3-dimethyl- isoquinoline [00094] 1.11 392 G 173- 173 E-44 5-fluoro-1-(7- iodoimidazo[1,2-a]pyridin- 3-yl)-3,3,4,4-tetramethyl- isoquinoline [00095] 1.21 448 G E-45 4,4-difluoro-3,3-dimethyl- 1-(8-methylimidazo[1,2- a]pyridin-3-yl)isoquinoline [00096] 0.95 326 G E-46 3-(5-fluoro-3,3,4,4- tetramethyl-1- isoquinolyl)imidazo[1,2- a]pyridine-7-carbonitrile [00097] 1.12 347 G 193- 194 E-47 1-(8-chloro-7-methyl- imidazo[1,2-a]pyridin-3- yl)-5-fluoro-3,3,4,4- tetramethyl-isoquinoline [00098] 1.14 370 G 185- 186 E-48 5-fluoro-1-(7- methoxyimidazo[1,2- a]pyridin-3-yl)-3,3,4,4- tetramethyl-isoquinoline [00099] 0.99 352 G 139- 140 E-49 3-(5-fluoro-3,3,4,4- tetramethyl-1- isoquinolyl)imidazo[1,2- a]pyridin-7-ol [00100] 0.88 338 G 246- 247 E-50 1-(7,8- dimethylimidazo[1,2- a]pyridin-3-yl)-5-fluoro- 3,3,4,4-tetramethyl- isoquinoline [00101] 0.91 350 G 185- 186 E-51 4,4-dimethyl-1-(8- methylimidazo[1,2- a]pyridin-3-yl)-3H- isoquinoline [00102] 0.73 290 G E-52 1-(8-methylimidazo[1,2- a]pyridin-3-yl)spiro[4H- isoquinoline-3,1′- cyclobutane] [00103] 0.80 302 G E-53 1-(8-methylimidazo[1,2- a]pyridin-3-yl)spiro[3H- isoquinoline-4,1′- cyclobutane] [00104] 1.14 302 G 127- 129 E-54 1-(7-iodoimidazo[1,2- a]pyridin-3-yl)-3,3- dimethyl-4H-isoquinoline [00105] 1.57 402.1 H 190- 193 E-55 4,4-difluoro-3,3-dimethyl- 1-(7-methylimidazo[1,2- a]pyridin-3-yl)isoquinoline [00106] 1.26 326.3 H E-56 1-(7,8- dichloroimidazo[1,2- a]pyridin-3-yl)-4,4- difluoro-3,3-dimethyl- isoquinoline [00107] 1.19 381 G >210 E-57 1-(7,8- dimethylimidazo[1,2- a]pyridin-3-yl)-4,4- difluoro-3,3-dimethyl- isoquinoline [00108] 0.88 340 G 159- 161 E-58 5-fluoro-3,3,4,4- tetramethyl-1- pyrazolo[1,5-a]pyridin-3- yl-isoquinoline [00109] 0.74 322 G 124- 126 E-59 5-fluoro-3,3,4,4- tetramethyl-1-(7- methylpyrazolo[1,5- a]pyridin-3-yl)isoquinoline [00110] 0.81 336 G 134- 136 E-60 5-bromo-3,3-dimethyl-1- pyrazolo[1,5-a]pyridin-3- yl-4H-isoquinoline [00111] 0.78 354- 356 G E-61 5-fluoro-3,3-dimethyl-1- pyrazolo[1,5-a]pyridin-3- yl-4H-isoquinoline [00112] 0.67 294 G E-62 5-fluoro-3,3,4,4- tetramethyl-1-(2- methylpyrazolo[1,5- a]pyridin-3-yl)isoquinoline [00113] 0.77 335 G E-63 1-(6,7- dimethylpyrazolo[1,5- a]pyridin-3-yl)-5-fluoro- 3,3,4,4-tetramethyl- isoquinoline [00114] 0.88 350 G 175- 176 E-64 1-(6,7- dimethylpyrazolo[1,5- a]pyridin-3-yl)-3,3- dimethyl-isoquinolin-4- one [00115] 0.86 318 G 152- 153 E-65 1-(6,7- dimethylpyrazolo[1,5- a]pyridin-3-yl)-4,4- difluoro-3,3-dimethyl- isoquinoline [00116] 1.03 340 G 160- 161 E-66 4,4-difluoro-3,3-dimethyl- 1-(7-methylpyrazolo[1,5- a]pyridin-3-yl)isoquinoline [00117] 0.97 326 G 105- 107 E-67 3,3-dimethyl-1-(7- methylpyrazolo[1,5- a]pyridin-3-yl)isoquinolin- 4-one [00118] 0.77 304 G 110- 112 E-68 3,3-dimethyl-1-(4- methylpyrazolo[1,5- a]pyridin-3-yl)isoquinolin- 4-one [00119] 0.83 304 G 140- 141 E-69 4,4-difluoro-3,3-dimethyl- 1-(4-methylpyrazolo[1,5- a]pyridin-3-yl)isoquinoline [00120] 0.99 326 G 113- 114 E-70 1-(6,7- dimethylpyrazolo[1,5- a]pyridin-3-yl)-4,4,6- trifluoro-3,3-dimethyl- isoquinoline [00121] 1.09 358 G 183- 185 E-71 1-(6,7- dimethylpyrazolo[1,5- a]pyridin-3-yl)-4,4,5- trifluoro-3,3-dimethyl- isoquinoline [00122] 1.14 358 G 185- 187 E-72 1-(6,7- dimethylpyrazolo[1,5- a]pyridin-3-yl)-5-fluoro- 3,3-dimethyl-isoquinolin- 4-one [00123] 0.95 336 G 139- 141 E-73 5-fluoro-3,3-dimethyl-1- (4-methylpyrazolo[1,5- a]pyridin-3-yl)isoquinolin- 4-one [00124] 0.89 322 G 141- 143 E-74 1-(6,7- dimethylpyrazolo[1,5- a]pyridin-3-yl)-6-fluoro- 3,3-dimethyl-isoquinolin- 4-one [00125] 0.92 336 G 168- 170 E-75 6-fluoro-3,3-dimethyl-1- (4-methylpyrazolo[1,5- a]pyridin-3-yl)isoquinolin- 4-one [00126] 0.89 322 G 180- 183 E-78 1-(6-bromo-7-methyl- pyrazolo[1,5-a]pyridin-3- yl)-3,3-dimethyl- isoquinolin-4-one [00127] 1.13 382- 384 G 166- 168 E-79 1-(6-bromo-7-methyl- pyrazolo[1,5-a]pyridin-3- yl)-4,4-difluoro-3,3- dimethyl-isoquinoline [00128] 1.34 404- 406 G 180- 182 E-80 4,4-difluoro-3,3-dimethyl- 1-pyrazolo[1,5-a]pyridin- 3-yl-isoquinoline [00129] 0.97 312 G 78- 82 E-81 1-(6-bromopyrazolo[1,5- a]pyridin-3-yl)-4,4- difluoro-3,3-dimethyl- isoquinoline [00130] 1.17 390- 392 G 127- 129 E-82 1-(6-bromopyrazolo[1,5- a]pyridin-3-yl)-3,3- dimethyl-isoquinolin-4- one [00131] 0.96 368- 370 G 147- 149 E-83 4,4-difluoro-3,3-dimethyl- 1-(6-methylpyrazolo[1,5- a]pyridin-3-yl)isoquinoline [00132] 0.96 326 G 105- 107 E-84 1-(4-bromopyrazolo[1,5- a]pyridin-3-yl)-3,3- dimethyl-isoquinolin-4- one [00133] 0.85 368- 370 G 148- 151 E-85 3-(4,4-difluoro-3,3- dimethyl-1- isoquinolyl)pyrazolo[1,5- a]pyridine-6-carbonitrile [00134] 1.06 337 G 191- 194 E-86 1-(6-ethylpyrazolo[1,5- a]pyridin-3-yl)-4,4- difluoro-3,3-dimethyl- isoquinoline [00135] 1.04 340 G E-87 1-(6-chloropyrazolo[1,5- a]pyridin-3-yl)-4,4- difluoro-3,3-dimethyl- isoquinoline [00136] 1.16 346- 348 G 113- 118 E-88 4,4-difluoro-1-(6-fluoro-7- methyl-pyrazolo[1,5- a]pyridin-3-yl)-3,3- dimethyl-isoquinoline [00137] 1.13 344 G 115- 118 E-89 4,4-difluoro-1-(4- fluoropyrazolo[1,5- a]pyridin-3-yl)-3,3- dimethyl-isoquinoline [00138] 0.89 330 G E-90 1-(6-ethnylpyrazolo[1,5- a]pyridin-3-yl)-4,4- difluoro-3,3-dimethyl- isoquinoline [00139] 1.10 336 G 145- 147 E-91 1-(6-chloro-7-methyl- pyrazolo[1,5-a]pyridin-3- yl)-4,4-difluoro-3,3- dimethyl-isoquinoline [00140] 1.23 360- 362 G 166- 168 E-92 4,4-difluoro-1-(7- methoxypyrazolo[1,5- a]pyridin-3-yl)-3,3- dimethyl-isoquinoline [00141] 0.87 342 G 120- 124 E-93 1-(7-chloropyrazolo[1,5- a]pyridin-3-yl)-4,4- difluoro-3,3-dimethyl- isoquinoline [00142] 1.11 346- 348 G 129- 132 E-94 [00143] 0.82 328 G 124- 126 E-95 [00144] 0.77 314 G

BIOLOGICAL EXAMPLES

[0296] Botryotinia fuckeliana (Botrytis cinerea)/Liquid Culture (Gray Mould)

[0297] Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (Vogels broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 3-4 days after application. The following compounds gave at least 80% control of Botryotinia fuckeliana at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:

[0298] E-1, E-6, E-7, E-8, E-9, E-10, E-11, E-19, E-21, E-22, E-23, E-24, E-27, E-29, E-30, E-31, E-32, E-33, E-38, E-39, E-40, E-44, E-45, E-46, E-47, E-48, E-49, E-50, E-51, E-52, E-53, E-55, E-56, E-57, E-58, E-59, E-60, E-62, E-63, E-64, E-65, E-66, E-67, E-68, E-69, E-70, E-71, E-72, E-74, E-75, E-76, E-77, E-78, E-79, E-80, E-81, E-82, E-83, E-85, E-86, E-87, E-88, E-89, E-91, E-92, E-93, E-95, E-95.

Glomerella lagenarium (Colletotrichum lagenarium) Liquid Culture (Anthracnose)

[0299] Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is measured photometrically 3-4 days after application.

[0300] The following compounds gave at least 80% control of Glomerella lagenarium at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:

[0301] E-1, E-2, E-3, E-6, E-7, E-8, E-9, E-10, E-11, E-14, E-16, E-17, E-19, E-21, E-22, E-24, E-27, E-29, E-30, E-31, E-32, E-33, E-37, E-38, E-39, E-40, E-44, E-45, E-46, E-47, E-48, E-49, E-50, E-52, E-55, E-57, E-58, E-59, E-62, E-63, E-64, E-65, E-66, E-67, E-69, E-70, E-71, E-72, E-74, E-76, E-77, E-78, E-79, E-80, E-81, E-82, E-83, E-86, E-87, E-88, E-89, E-90, E-91, E-92, E-93, E-94, E-95.

Fusarium culmorum/Liquid Culture (Head Blight)

[0302] Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 3-4 days after application.

[0303] The following compounds gave at least 80% control of Fusarium culmorum at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:

[0304] E-1, E-6, E-8, E-9, E-21, E-31, E-32, E-33, E-39, E-44, E-45, E-47, E-50, E-55, E-57, E-59, E-63, E-64, E-65, E-66, E-67, E-69, E-70, E-71, E-72, E-74, E-76, E-78, E-79, E-80, E-81, E-82, E-83, E-86, E-87, E-88, E-89, E-91, E-92, E-93, E-94.

Gaeumannomyces graminis/Liquid Culture (Take-all of Cereals)

[0305] Mycelial fragments of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 4-5 days after application.

[0306] The following compounds gave at least 80% control of Gaeumannomyces graminis at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:

[0307] E-1, E-6, E-9, E-25, E-37, E-38, E-39, E-41, E-58, E-63, E-64, E-65, E-66, E-69, E-71, E-76, E-79, E-80, E-81, E-82, E-83, E-86, E-87, E-88, E-90, E-91, E-92, E-94.

Monographella nivalis (Microdochium nivale)/Liquid Culture (Foot Rot Cereals)

[0308] Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24 and the inhibition of growth is determined photometrically 4-5 days after application.

[0309] The following compounds gave at least 80% control of Monographella nivalis at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:

[0310] E-6, E-9, E-15, E-21, E-22, E-24, E-29, E-33, E-38, E-39, E-44, E-45, E-52, E-53, E-57, E-59, E-64, E-65, E-66, E-67, E-69, E-70, E-71, E-72, E-76, E-78, E-80, E-81, E-82, E-83, E-88, E-89, E-90, E-91, E-92, E-93, E-94.

Mycosphaerella graminicola (Septoria tritici)/Liquid Culture (Septoria blotch)

[0311] Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 4-5 days after application.

[0312] The following compounds gave at least 80% control of Mycosphaerella graminicola at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:

[0313] E-22, E-39, E-44, E-80, E-81, E-82, E-83, E-86, E-87, E-88, E-93

Magnaporthe grisea (Pyricularia oryzae)/Rice/Leaf Disc Preventative (Rice Blast)

[0314] Rice leaf segments cv. Ballila are placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water. The leaf segments are inoculated with a spore suspension of the fungus 2 days after application. The inoculated leaf segments are incubated at 22° C. and 80% r.h. under a light regime of 24 h darkness followed by 12 h light/12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (5-7 days after application).

[0315] The following compounds gave at least 50% control of Magnaporthe grisea at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:

[0316] E-6, E-8, E-9, E-31, E-33, E-39, E-45, E-57, E-59, E-63, E-66, E-69, E-70, E-71, E-81, E-83, E-86, E-87, E-88, E-91, E-92, E-93, E-94, E-95.

Magnaporthe grisea (Pyricularia oryzae)/Liquid Culture (Rice Blast)

[0317] Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 3-4 days after application. The following compounds gave at least 80% control of Magnaporthe grisea at 60 ppm when compared to untreated control under the same conditions, which showed extensive disease development:

[0318] E-50, E-51, E-52, E-53, E-55, E-56, E-57, E-63, E-64, E-65, E-66, E-67, E-69, E-70, E-71, E-72, E-74, E-76, E-77, E-78, E-79, E-80, E-81, E-82, E-83, E-85, E-86, E-87, E-88, E-89, E-90, E-91, E-92, E-93, E-94, E-95.

Sclerotinia sclerotiorum/Liquid Culture (Cottony Rot)

[0319] Mycelia fragments of a newly grown liquid culture of the fungus are directly mixed into nutrient broth (Vogels broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format) the nutrient broth containing the fungal material is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 3-4 days after application. The following compounds gave at least 80% control of Sclerotinia sclerotiorum at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:

[0320] E-50, E-51, E-52, E-55, E-57, E-64, E-65, E-66, E-67, E-69, E-70, E-71, E-72, E-79, E-80, E-81, E-82, E-83, E-86, E-87, E-88, E-89, E-91, E-93.