AZOLE PESTICIDAL COMPOUNDS

Abstract

The invention relates to the compounds of formula (I), and the N-oxides, stereoisomers, tautomers and agriculturally or veterinarily acceptable salts thereof, wherein the variables are defined according to the description. The compounds of formula (I), the N-oxides, stereoisomers, tautomers, and agriculturally or veterinarily acceptable salts thereof, are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes. The invention also to plant propagation material and to an agricultural and a veterinary composition comprising said compounds.

##STR00001##

Claims

1. A compound of formula I ##STR00643## wherein Q is C(O)N(R.sup.5) or N(R.sup.5)C(O); R.sup.5 is H, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkyl-C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkyl-C.sub.3-C.sub.6-cycloalkyl, phenyl, 5- or 6-membered hetaryl, CH.sub.2 phenyl, CH.sub.2-5- or -6-membered hetaryl, 1,3-dioxolan-2-ylmethyl, or halogen, wherein the alkyl, cycloalkyl, phenyl and hetaryl moieties are unsubstituted or substituted with halogen or CN; A is N or CRA; R.sup.A is H, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, halogen, CN, or NR.sup.6R.sup.7 wherein the alkyl, alkoxy, and cycloalkyl moieties are unsubstituted or substituted with halogen or CN; R.sup.2 is H or C.sub.1-C.sub.6-alkyl, or C.sub.3-C.sub.6-cycloalkyl, wherein the alkyl and cycloalkyl moieties are unsubstituted or substituted with halogen, CN, or C.sub.1-C.sub.6-alkoxy; B.sup.1 is N or CR.sup.B1; B.sup.2 is N or CR.sup.B2; B.sup.3 is N or CR.sup.B3; B.sup.4 is CR.sup.B4; R.sup.B1, R.sup.B2, R.sup.B3, and R.sup.B4 independently of each other are H, halogen, CN, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, or C.sub.1-C.sub.6-alkoxy, wherein the alkyl, alkoxy, and cycloalkyl moieties are unsubstituted or substituted with halogen; D is the moiety DA or DB, ##STR00644## R.sup.3 is H, C.sub.1-C.sub.6-alkyl, or C.sub.3-C.sub.6-cycloalkyl, wherein the alkyl and cycloalkyl moieties are unsubstituted or substituted with halogen or CN; R.sup.4 is H, C.sub.1-C.sub.6-alkyl, or C.sub.3-C.sub.6-cycloalkyl, wherein the alkyl and cycloalkyl moieties are unsubstituted or substituted with halogen, O(CO)C.sub.1-C.sub.6-alkoxy, O(CO)C.sub.1-C.sub.6-alkyl; or CN; or B is a 5- or 6-membered carbocyclic group, wherein 1 or 2 CH.sub.2 moieties of the carbocyclic group may be replaced by a carbonyl group, O, or S, wherein the carbocyclic group is unsubstituted or substituted with R.sup.h; Ar.sup.1 is phenyl or 5- or 6-membered heteroaryl, which are unsubstituted or substituted with R.sup.Ar1, wherein R.sup.Ar1; is halogen, SF.sub.5, NO.sub.2, OH, CN, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocyclyl, C.sub.3-C.sub.6-cycloalkoxy, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, C.sub.3-C.sub.6-heterocyclyl, and cycloalkoxy moieties are unsubstituted or substituted with R.sup.f, C(O)OR.sup.a, NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(O)NR.sup.bR.sup.c, C(O)R.sup.d, NHS(O).sub.mR.sup.e, S(O).sub.mR.sup.e, NS(O)(C.sub.1-C.sub.6-alkyl).sub.2, or SO.sub.2NR.sup.bR.sup.c; R.sup.6 and R.sup.7 are, identical or different, H, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, phenyl, CH.sub.2-phenyl, 5- or 6-membered heteroaryl, CH.sub.2-5- or 6-membered heteroaryl, 1,3-dioxolan-2-ylmethyl, or 2-(methylamino)-2-oxo-ethyl, wherein the alkyl, cycloalkyl, phenyl and heteroaryl moieties are unsubstituted or substituted with halogen, CN, C.sub.1-C.sub.6-alkyl, or C.sub.1-C.sub.6-alkoxy; Ar.sup.2 is phenyl or 5- or 6-membered heteroaryl, which are unsubstituted or substituted with R.sup.Ar2, wherein R.sup.Ar2 is halogen, CN, SCN, SF.sub.5, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkoxy, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, cycloalkyl, and cycloalkoxy moieties are unsubstituted or substituted with halogen or CN, C(O)OR.sup.a, NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(O)NR.sup.bR.sup.c; R.sup.a, R.sup.b, and R.sup.c are, identical or different, H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C(O)C.sub.1-C.sub.6-alkyl, wherein the alkyl, alkenyl, and cycloalkyl moieties are unsubstituted or substituted with halogen; R.sup.d is H or C.sub.1-C.sub.6-alkyl; R.sup.e is C.sub.1-C.sub.6-alkyl or C.sub.3-C.sub.6-cycloalkyl, wherein the alkyl, cycloalkyl moieties are unsubstituted or substituted with halogen; m is 0, 1, or 2; R.sup.f is halogen, OH, CN, SCN, SF.sub.5, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkoxy, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, or C.sub.3-C.sub.6-cycloalkoxyx-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and cycloalkoxy moieties are unsubstituted or substituted with halogen; R.sup.h is halogen, C.sub.1-C.sub.6-alkyl, or C.sub.1-C.sub.6-alkoxy; and N-oxides, stereoisomers, tautomers, and agriculturally or veterinarily acceptable salts thereof.

2. The compound of formula I according to claim 1, wherein D is DB.

3. The compound of formula I according to claim 1, wherein D is a group selected from D5 to D7, which are unsubstituted or substituted with 1 or 2 substituents R.sup.h ##STR00645##

4. The compound of formula I according to claim 1 selected from the compounds of formula I.1 to I.8, wherein the variables are as defined in claim 1. ##STR00646##

5. The compound of formula I according to claim 1, wherein R.sup.5 is H, C.sub.1-C.sub.6-alkyl, or C.sub.1-C.sub.6-alkyl-CN; R.sup.A is H, CN, or C.sub.1-C.sub.6-alkyl; R.sup.2 is H or C.sub.1-C.sub.6-alkyl.

6. The compound of formula\ I according to claim 1, wherein B.sup.1 is CR.sup.B1, B.sup.2 is CR.sup.B2, and B.sup.3 is CR.sup.B3.

7. The compound of formula I according to claim 1, wherein B.sup.1 is N, B.sup.2 is CR.sup.B2, and B.sup.3 is CR.sup.B3.

8. The compound of formula I according to claim 1, wherein R.sup.B1, R.sup.B2, R.sup.B3, and R.sup.B4 independently of each other are H, halogen, CN, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, or C.sub.1-C.sub.6-alkoxy, wherein the alkyl, alkoxy, and cycloalkyl moieties are unsubstituted or substituted with halogen.

9. The compound of formula I according to claim 1, wherein Ar.sup.1 is phenyl which is unsubstituted or substituted with R.sup.Ar1; R.sup.Ar1; is halogen, SF.sub.5, NO.sub.2, OH, CN, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocyclyl, C.sub.3-C.sub.6-cycloalkoxy, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, C.sub.3-C.sub.6-heterocyclyl, and cycloalkoxy moieties are unsubstituted or substituted with R.sup.f, C(O)OR.sup.a, NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(O)NR.sup.bR.sup.c, C(O)R.sup.d, NHS(O).sub.mR.sup.e, NS(O)(C.sub.1-C.sub.6-alkyl).sub.2, SO.sub.2NR.sup.bR.sup.c, or S(O).sub.mR.sup.e; R.sup.a, R.sup.b, and R.sup.c, identical or different, are H, C.sub.1-C.sub.6-alkyl, which are unsubstituted or substituted with halogen; R.sup.d is H or C.sub.1-C.sub.6-alkyl; R.sup.e is C.sub.1-C.sub.6-alkyl or C.sub.1-C.sub.6-haloalkyl; R.sup.f is halogen, OH, CN, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkoxy, which are unsubstituted or substituted with halogen; m is 0, 1, or 2.

10. A composition comprising a compound of formula I according to claim 1, an N-oxide, or an agriculturally acceptable salt thereof, and a further active substance.

11. A method for combating or controlling an invertebrate pest comprising contacting said pest or its food supply, habitat or breeding grounds with a pesticidally effective amount of at least one compound according to claim 1.

12. A method for protecting growing plants from attack or infestation by an invertebrate pest comprising contacting a plant, or soil or water wherein the plant is growing, with a pesticidally effective amount of at least one compound according to claim 1.

13. A seed comprising a compound according to claim 1, or the enantiomers, diastereomers, or salts thereof, in an amount of from 0.1 g to 10 kg per 100 kg of seed.

14. (canceled)

15. A method for treating or protecting an animal from infestation or infection by an invertebrate pest comprising bringing the animal in contact with a pesticidally effective amount of at least one compound of the formula I according to claim 1, a stereoisomer thereof and/or at least one veterinarily acceptable salt thereof.

Description

EXAMPLES

[1361] With appropriate modification of the starting materials, the procedures as described in the preparation examples below were used to obtain further compounds of formula 1. The compounds obtained in this manner are listed in the table C that follows, together with physical data.

[1362] Compounds can be characterized e.g., by coupled High Performance Liquid Chromatography/mass spectrometry (HPLC/MS), by .sup.1H NMR and/or by their melting points.

[1363] Compounds can be characterized e.g., by coupled High Performance Liquid Chromatography/mass spectrometry (HPLC/MS), by .sup.1H NMR and/or by their melting points.

[1364] Analytical HPLCMethod 1: Agilent Eclipse Plus C18, 504.6 mm, ID 5 m; Elution: A=10 mM Amm. Formate (0.1% Formic Acid), B=acetonitrile (0.1% Formic Acid), Flow=1.2 ml/min. at 30 C.; Gradient: 10% B to 100% B3 min, hold for 1 min, 1 min10% B. Run Time=5.01 min.

[1365] Analytical HPLCMethod 2: Kinetex XB C18 1,7 502.1 mm; A=water+0.1% TFA, B=acetonitrile, Flow=0.8 ml/min1.0 ml/min in 1.5 min. at 60 C.; Gradient: 5% B to 100% B1.5 min.

[1366] Analytical HPLCMethod 3: Diamonsil plus 5 m, 303.0 mm; A=Water+0.05% TFA, B=acetonitrile, Flow=2 ml/min at 40 C.; Gradient: 5% B to 95% B0.8 min, hold for 0.75 min, then 95% B to 5% B0.25 min.

[1367] .sup.1H NMR: The signals are characterized by chemical shift (ppm, d [delta]) vs. tetramethyl silane respectively, CDCl.sub.3 for .sup.13C NMR, by their multiplicity and by their integral (relative number of hydrogen atoms given). The following abbreviations are used to characterize the multiplicity of the signals: m=multiplet, q=quartet, t=triplet, d=doublet and s=singlet.

[1368] Abbreviations used are: d for day(s), h for hour(s), min for minute(s), RT/room temperature for 20-25 C., Rt for retention time; DMSO for dimethyl sulfoxide, OAc for acetate, EtOAc for ethyl acetate, IPA for isopropyl alcohol, MeOH for methanol, EtOH for ethanol, THF for tetrahydrofuran, DCM for dichloromethane, DMF for N,N-dimethylformamide and t-BuOH for tert-butanol.

Example C-1

Preparation of N-[5-[4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethyl)benzamide (C-1)

Step 1: Synthesis of 3-(4-bromophenyl)-2-methyl-3-oxo-propanenitrile

[1369] To a stirred solution of ethyl 4-bromobenzoate (30 g) in THF (600 mL) was added potassium tert-butoxide (29.39 g) at ambient temperature. After 10 min propionitrile (7.213 g) was added to a reaction mass at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 h and after completion of the reaction, the mixture was diluted in water. The mixture was extracted with EtOAc and the organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo to obtain the title compound as a yellowish oil (24 g).

[1370] HPLC/MS (method 1): Rt: 1.821 min; m/z=236 (M1).sup.+.

Step 2: Synthesis of 5-(4-bromophenyl)-2,4-dimethyl-pyrazol-3-amine

[1371] To a stirred solution of 3-(4-bromophenyl)-2-methyl-3-oxo-propanenitrile (25 g) in EtOH (250 mL) was added methylhydrazine (26.181 g, 85% solution) at ambient temperature. The reaction mixture was heated at 85 C. for 16 h and after completion of the reaction, EtOH was removed under reduced pressure, crude was dissolved in water. The mixture was extracted with EtOAc and the organic extracts dried over anhydrous sodium sulphate and evaporated in vacuo to obtain the title compound as a solid (23 g).

[1372] HPLC/MS (method 1): Rt: 1.656 min; m/z=266 (M+1).sup.+.

Step 3: Synthesis of N-[5-(4-bromophenyl)-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethyl) benzamide

[1373] To a stirred solution of 5-(4-bromophenyl)-2,4-dimethyl-pyrazol-3-amine (43.5 g) in DCM (430 mL) were added 4-(trifluoromethyl)benzoic acid (31.075 g), N,N,N-diisopropyl ethylamine (118.29 g) and propylphosphonic anhydride (312.03 g, 50% solution in EtOAc) at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was dissolved in water and the mixture was extracted with DCM. The organic extracts were washed with 1 N hydrochloric acid, dried over anhydrous sodium sulphate and evaporated in vacuo to obtain the title compound as a solid (44 g).

[1374] HPLC/MS (method 1): Rt: 2.066 min; m/z=438 (M+1).sup.+.

Step 4: Synthesis of tert-butyl N-[4-[1,4-dimethyl-5-[[4-(trifluoromethyl)benzoyl]amino]pyrazol-3-yl]phenyl]carbamate

[1375] To a stirred solution of N-[5-(4-bromophenyl)-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethyl) benzamide (2.5 g) in 1,4-dioxane (30 mL) were added tert-butyl carbamate (0.802 g), Palladium(II) acetate (0.128 g), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (0.544 g) and cesium carbonate (3.717 g) at ambient temperature under innert atmosphere. The reaction mixture was heated at 100 C. for 16 h and after completion of the reaction, the mixture was dissolved in water. The mixture was extracted with EtOAc, the organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a solid (2.2 g).

[1376] HPLC/MS (method 1): Rt: 1.918 min; m/z=475 (M+1).sup.+.

Step 5: Synthesis of N-[5-(4-aminophenyl)-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethyl) benzamide

[1377] To a stirred solution of tert-butyl N-[4-[1,4-dimethyl-5-[[4-(trifluoromethyl)benzoyl]amino]pyrazol-3-yl]phenyl]carbamate (3.4 g) in DCM (50 mL) was added trifluoro acetic acid (5 mL) at ambient temperature. The reaction mixture was heated at 50 C. for 16 h and after completion of the reaction, the mixture was neutralised with aqueous sodium bicarbonate solution. The mixture was extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a solid (1.2 g).

[1378] HPLC/MS (method 1): Rt: 1.727 min; m/z=375 (M+1).sup.+.

Step 6: Synthesis of (4-nitrophenyl)N-[4-[1,4-dimethyl-5-[[4-(trifluoromethyl)benzoyl]amino]pyrazol-3-yl]phenyl]carbamate

[1379] To a stirred solution N-[5-(4-aminophenyl)-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethyl) benzamide (0.2 g) in THF (4 mL) was added (4-nitrophenyl) carbonochloridate (0.108 g) at 0 C. under innert atmosphere. The reaction mixture was stirred at ambient temperature for 3 h and after completion of the reaction, the solvent from reaction mixture was evaporated in vacuo to obtain the title compound as a solid (0.2 g).

[1380] HPLC/MS (method 1): Rt: 1.885 min; m/z=540 (M+1).sup.+.

Step 7: Synthesis of N-[5-[4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethyl)benzamide (C-1)

[1381] To a stirred solution of (4-nitrophenyl)N-[4-[1,4-dimethyl-5-[[4-(trifluoromethyl)benzoyl]amino]pyrazol-3-yl]phenyl]carbamate (0.2 g) in Acetonitrile (4 mL) were added 2-imino-3-(2-isopropyl-5-methyl-phenyl)thiazolidin-4-one (E1, 0.092 g), N,N,N-diisopropyl ethylamine (0.072 g) and potassium phosphate tribasic (0.118 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 19 h. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to preparative HPLC purification, eluting with a gradient of acetonitrile and water to obtain the title compound as a solid (0.17 g).

[1382] HPLC/MS (method 1): Rt: 1.960 min; m/z=649 (M+1).sup.+.

[1383] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.47 (s, 1H), 9.86 (s, 1H), 8.23 (d, J=8.1 Hz, 2H), 7.97 (d, J=8.2 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H), 7.57 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.0 Hz, 1H), 7.32-7.23 (m, 1H), 7.11-7.04 (m, 1H), 4.39-4.08 (m, 2H), 3.69 (s, 3H), 2.67 (h, J=6.8 Hz, 1H), 2.32 (s, 3H), 2.05 (s, 3H), 1.18 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H).

[1384] Synthesis of 2-imino-3-(2-isopropyl-5-methyl-phenyl)thiazolidin-4-one (E1)

Step 1: Synthesis of 2-chloro-N-(2-isopropyl-5-methyl-phenyl)acetamide

[1385] To a stirred solution of 2-isopropyl-5-methyl-aniline (1.5 g) in THF (100 mL) was added triethyl amine (1.221 g) at ambient temperature and reaction mixture was cooled to 10 C. 2-chloroacetyl chloride was added to reaction mass drop wise over 30 min and reaction mixture was stirred at ambient temperature for 16 h. After completion of the reaction, the mixture was diluted in aqueous sodium bicarbonate solution and reaction mixture was extracted with EtOAc. The organic extracts were washed with brine solution, dried over anhydrous sodium sulphate and evaporated in vacuo to obtain the title compound as a yellowish oil (1.8 g). HPLC/MS (method 1): Rt: 1.813 min; m/z=223.70 (M1).sup.+.

Step 2: Synthesis of 2-imino-3-(2-isopropyl-5-methyl-phenyl)thiazolidin-4-one (E1)

[1386] To a stirred solution of 2-chloro-N-(2-isopropyl-5-methyl-phenyl)acetamide (0.5 g) in acetone (10 mL) was added potassium thiocyanate (0.431 g) at ambient temperature and then reaction mixture was refluxed for 4 h. After completion of the reaction, the mixture was diluted in aqueous sodium bicarbonate solution and extracted with EtOAc. The organic extracts were washed with brine solution, dried over anhydrous sodium sulphate and evaporated in vacuo to obtain the title compound as a solid (0.42 g).

[1387] HPLC/MS (method 1): Rt: 1.675 min; m/z=249 (M+1).sup.+.

Example C-2

Preparation of [(Z)-N-[[4-[1,4-dimethyl-5-[[4-(trifluoromethyl)benzoyl]amino]pyrazol-3-yl]phenyl]carbamoyl]-N-(2-isopropyl-5-methyl-phenyl)carbamimidoyl]sulfanylmethyl acetate (C-2)

[1388] To a stirred solution of (4-nitrophenyl)N-[4-[1,4-dimethyl-5-[[4-(trifluoromethyl)benzoyl]amino]pyrazol-3-yl]phenyl]carbamate (0.45 g) in THF (9 mL) were added [N-(2-isopropyl-5-methyl-phenyl)carbamimidoyl]sulfanylmethyl acetate hydrobromide (E1, 0.234 g) and N,N,N-diisopropyl ethylamine (0.194 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 24 h. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to preparative HPLC purification, eluting with a gradient of acetonitrile and water to obtain the title compound as a solid (0.18 g).

[1389] HPLC/MS (method 1): Rt: 2.205 min; m/z=681 (M+1).sup.+.

[1390] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.27 (s, 1H), 10.46 (s, 1H), 9.72 (s, 1H), 8.23 (dd, J=8.3, 4.3 Hz, 2H), 7.97 (dd, J=8.8, 2.6 Hz, 2H), 7.73 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 7.45 (s, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.26-7.06 (m, 1H), 7.04 (d, J=1.8 Hz, 1H), 5.75 (d, J=9.0 Hz, 1H), 5.60 (s, 1H), 3.70 (d, J=4.6 Hz, 3H), 3.03 (p, J=6.8 Hz, 1H), 2.29 (d, J=6.3 Hz, 3H), 2.06 (d, J=11.8 Hz, 6H), 1.16 (dd, J=10.8, 6.8 Hz, 6H).

Synthesis of [N-(2-isopropyl-5-methyl-phenyl)carbamimidoyl]sulfanylmethyl acetate hydrobromide (E1)

Step 1: N-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]benzamide

[1391] To a stirred solution of 2-isopropyl-5-methyl-aniline (0.4 g) in acetone (5 mL) was added benzoyl isothiocyanate (0.481 g) at 0 C. under innert atmosphere. The reaction mixture was stirred at ambient temperature for 6 h and after completion of the reaction, the solvent from reaction mixture was evaporated in vacuo to obtain the title compound as a solid (0.8 g).

[1392] HPLC/MS (method 1): Rt: 2.153 min; m/z=313 (M+1).sup.+.

Step 2: [(1 E)-1-isobutyl-3-methyl-buta-1,3-dienyl]thiourea

[1393] A stirred solution of N-[(2-isopropyl-5-methyl-phenyl)carbamothioyl]benzamide (0.8 g) in 2 N sodium hydroxide (10 mL) was heated at 90 C. for 2 h. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a solid (0.32 g). HPLC/MS (method 1): Rt: 1.584 min: m/z=209 (M+1).sup.+.

Step 3: Synthesis of [N-(2-isopropyl-5-methyl-phenyl)carbamimidoyl]sulfanylmethyl acetate hydrobromide (E1)

[1394] To a stirred solution of [(1E)-1-isobutyl-3-methyl-buta-1,3-dienyl]thiourea (0.1 g) in Acetone (2 mL) was added bromomethyl acetate (0.081 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 18 h and after completion of the reaction, the solvent from reaction mixture was evaporated in vacuo to obtain the title compound as a oil (0.1 g).

[1395] HPLC/MS (method 1): Rt: 1.936 min; m/z=281 (M+1).sup.+.

Example C-3

Preparation of N-[5-[4-[(2-isopropyl-5-methyl-phenyl)carbamothioylcarbamoylamino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethyl)benzamide (C-3)

[1396] To a stirred solution of [(Z)-N-[[4-[1,4-dimethyl-5-[[4-(trifluoromethyl)benzoyl]amino]pyrazol-3-yl]phenyl]carbamoyl]-N-(2-isopropyl-5-methyl-phenyl)carbamimidoyl]sulfanylmethylacetate (0.325 g) in MeOH (6 mL) was added 7 N Ammonia in MeOH (2 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 18 h. After completion of the reaction, the solvent from reaction mixture was evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a solid (0.085 g).

[1397] HPLC/MS (method 1): Rt: 2.173 min; m/z=609 (M+1).sup.+.

[1398] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.68 (s, 1H), 10.48 (s, 1H), 10.16 (s, 1H), 9.41 (s, 1H), 8.23 (d, J=8.1 Hz, 2H), 7.97 (d, J=8.1 Hz, 2H), 7.71-7.65 (m, 2H), 7.55-7.50 (m, 2H), 7.28-7.21 (m, 2H), 7.15-7.09 (m, 1H), 3.71 (s, 3H), 3.01 (p, J=6.9 Hz, 1H), 2.29 (s, 3H), 2.07 (s, 3H), 1.18 (d, J=6.8 Hz, 6H).

Example C-4

Preparation of N-[5-[4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-N-methyl-4-(trifluoromethyl)benzamide (C-4)

Step 1: N-[5-(4-bromophenyl)-2,4-dimethyl-pyrazol-3-yl]-N-methyl-4-(trifluormethyl)benzamide

[1399] N-[5-(4-bromophenyl)-2,4-dimethyl-pyrazol-3-yl]-4-(trifluormethyl)benzamide (0.5 g) was dissolved in DMF (12.5 mL) and cesium carbonate (0.74 g) and methyl iodide (0.2 g) were added subsequently. The reaction mixture was stirred for 3 h at 50 C. Once the starting material was consumed, the reaction mixture was allowed to cool to room temperature and EtOAc was added. The resulting precipitate was filtered, solvent evaporated and purified by column chromatography to yield N-[5-(4-bromophenyl)-2,4-dimethyl-pyrazol-3-yl]-N-methyl-4-(trifluormethyl)benzamide (0.52 g). .sup.1H NMR (500 MHz, Chloroform-d) 7.54-7.48 (m, 4H), 7.46-7.40 (m, 4H), 3.70 (s, 3H), 3.40 (s, 3H), 1.98 (s, 3H).

Step 2: Tert-butyl-N-[4-[1,4-dimethyl-5-[methyl-[4-(trifluormethyl)benzoyl]amino]pyrazol-3-yl]phenyl]carbamate

[1400] N-[5-(4-bromophenyl)-2,4-dimethyl-pyrazol-3-yl]-N-methyl-4-(trifluormethyl)benzamide (0.52 g) was dissolved in 1,4-dioxane (5 mL) and tert-butyl carbamate (0.20 g), cesium carbonate (0.90 g), Palladium (II) acetate (0.04 g) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (0.14 g) were added subsequently while purging under nitrogen. The resulting mixture was stirred overnight at 100 C. Once the starting material was consumed, the reaction mixture was allowed to cool to room temperature, quenched by addition of water (7 mL) and the organic phases were extracted twice with EtOAc. The combined organic phases were washed with saturated brine solution, dried over magnesium sulfate and evaporated to yield tert-butyl-N-[4-[1,4-dimethyl-5-[methyl-[4-(trifluormethyl)benzoyl]amino]pyrazol-3-yl]phenyl]carbamate (0.52 g).

[1401] .sup.1H NMR (500 MHz, Chloroform-d) 8.05 (m, 2H), 7.82 (m, 2H), 7.57 (m, 2H), 7.46 (m, 2H), 3.75 (s, 3H), 2.12 (s, 3H), 1.68 (s, 3H), 1.59 (s, 9H).

Step 3: N-[5-(4-aminophenyl)-2,4-dimethyl-pyrazol-3-yl]-N-methyl-4-(trifluoromethyl) benzamide

[1402] Tert-butyl-N-[4-[1,4-dimethyl-5-[methyl-[4-(trifluormethyl)benzoyl]amino]pyrazol-3-yl]phenyl]carbamate (0.52 g) was dissolved in DCM (50 mL) and Trifluoroacetic acid (0.25 mL) was added at room temperature. The reaction mixture was stirred for 5 days and additional trifluoroacetic acid (0.36 mL) was added until all the remaining starting material has been consumed. The reaction mixture was neutralized by addition of saturated sodium bicarbonate solution. The organic phases were dried over magnesium sulfate, evaporated and purified with column chromatography to yield N-[5-(4-aminophenyl)-2,4-dimethyl-pyrazol-3-yl]-N-methyl-4-(trifluoromethyl)benzamide (0.2 g). .sup.1H NMR (500 MHz, Chloroform-d) 7.54-7.48 (m, 4H), 7.46-7.40 (m, 4H), 3.72 (s, 3H), 3.42 (s, 3H), 1.99 (s, 3H).

Step 4: N-[5-[4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-N-methyl-4-(trifluormethyl) benzamide (C-4)

[1403] N-[5-(4-aminophenyl)-2,4-dimethyl-pyrazol-3-yl]-N-methyl-4-(trifluoromethyl)benzamide (0.1 g) was dissolved in acetonitrile (7 mL) and cesium carbonate (0.07 g) and 4-nitrophenyl chloroformate (0.05 g) were added subsequently. The reaction mixture was stirred at room temperature for 5 h. Once TLC indicated consumption of starting material, 2-imino-3-(2-isopropyl-5-methyl-phenyl)thiazolidine-4-one (0.07 g) and cesium carbonate (0.08 g) were added. The reaction mixture was stirred overnight at room temperature, solvents were evaporated, and the residue purified by column chromatography to yield N-[5-[4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-N-methyl-4-(trifluormethyl)benzamide (0.04 g). .sup.1H NMR (400 MHz, Chloroform-d) 7.49-7.34 (m, 10H), 6.92-6.87 (m, 1H), 3.95 (d, J=3.1 Hz, 2H), 3.67 (s, 3H), 3.39 (s, 3H), 2.66 (m, 1H), 2.37 (s, 3H), 1.97 (s, 3H), 1.18 (m, 6H)

Example C-5

Preparation of N-[5-[4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]amino]phenyl]-2-methyl-1,2,4-triazol-3-yl]-4-(trifluoromethoxy)benzamide (C-5)

Step 1: Methyl 4-bromobenzenecarboximidate

[1404] To a stirred solution of 4-bromobenzonitrile (10 g) in methanol (100 mL) was added acetyl chloride (43.125 g) at 0 C. The reaction mixture was stirred at ambient temperature for 0.5 h and after completion of the reaction the mixture was evaporated. Solid precipitated was filtered and washed with methyl tert-butyl ether and dried in vacuo to obtain the title compound as off white solid (10 g). HPLC/MS (method 1): Rt: 0.86 min; m/z=214 (M).sup.+.

Step 2: methyl (1Z)-4-bromo-N-cyano-benzenecarboximidate

[1405] To a stirred solution of methyl 4-bromobenzenecarboximidate HCl salt (3 g) in water (50 mL) was added cyanamide (1.374 g) and di-sodium hydrogen phosphate (3.315 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 19 h and after completion of the reaction the mixture was diluted in water. The mixture was extracted with EtOAc and the organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo to obtain the title compound as a yellowish oil (3 g). .sup.1H NMR (300 MHz, Chloroform-d) 8.00 (d, J=8.7 Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 4.08 (s, 3H).

Step 3: 5-(4-bromophenyl)-2-methyl-1,2,4-triazol-3-amine

[1406] To a stirred solution of methyl (1Z)-4-bromo-N-cyano-benzenecarboximidate (5 g) in MeOH (40 mL) and Acetic acid (10 mL) was added methylhydrazine (1.287 g, 85% solution) at ambient temperature. The reaction mixture was heated at 85 C. for 16 h and after completion of the reaction, the reaction mixture was cooled to ambient temperature, solid precipitated was filtered and washed with MeOH and dried in vacuo to obtain the title compound as off white solid (3 g).

[1407] HPLC/MS (method 1): Rt: 1.25 min; m/z=253 (M).sup.+.

Step 4: N-[5-(4-bromophenyl)-2-methyl-1,2,4-triazol-3-yl]-4-(trifluoromethoxy) benzamide

[1408] To a stirred solution of 5-(4-bromophenyl)-2-methyl-1,2,4-triazol-3-amine (1 g) in THF (10 mL) were added Triethylamine (0.8 g) and 4-(trifluoromethoxy)benzoyl chloride (0.97 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was dissolved in water and the mixture was extracted with DCM. The organic extracts were washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulphate and evaporated in vacuo The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a solid (1 g). HPLC/MS (method 1): Rt: 2.13 min; m/z=441 (M).sup.+.

Step 5: Synthesis of tert-butyl N-[4-[1-methyl-5-[[4-(trifluoromethoxy)benzoyl]amino]-1,2,4-triazol-3-yl]phenyl]carbamate

[1409] To a stirred solution of N-[5-(4-bromophenyl)-2-methyl-1,2,4-triazol-3-yl]-4-(trifluoromethoxy) benzamide (6 g) in 1,4-dioxane (60 mL) were added tert-butyl carbamate (2.39 g), tris(dibenzylideneacetone)dipalladium(0) (1.245 g), 5-(di-tert-butylphosphino)-1,3,5-triphenyl-1H-[1,4]bipyrazole (0.689 g) and potassium tert-butoxide (4.578 g) at ambient temperature under inert atmosphere. The reaction mixture was heated at 90 C. for 16 h and after completion of the reaction, the mixture was dissolved in water. The mixture was extracted with EtOAc, the organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a solid (5.8 g). HPLC/MS (method 1): Rt: 2.12 min; m/z=478 (M+1).sup.+.

Step 6: N-[5-(4-aminophenyl)-2-methyl-1,2,4-triazol-3-yl]-4-(trifluoromethoxy)benzamide

[1410] To a stirred solution of tert-butyl N-[4-[1-methyl-5-[[4-(trifluoromethoxy)benzoyl]amino]-1,2,4-triazol-3-yl]phenyl]carbamate (5.8 g) in DCM (80 mL) was added trifluoroacetic acid (5.61 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 6 h and after completion of the reaction, the reaction mixture was quenched with water (100 mL) and neutralized with 10% sodium hydroxide solution. The mixture was extracted with EtOAc. The organic extracts dried over anhydrous sodium sulphate and evaporated in vacuo to obtain the title compound as a solid (4.1 g). HPLC/MS (method 1): Rt: 1.69 min; m/z=378 (M+1).sup.+.

Step 7: Synthesis of N-[5-[4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethyl)benzamide (C-5)

[1411] To a stirred solution of N-[5-(4-aminophenyl)-2-methyl-1,2,4-triazol-3-yl]-4-(trifluoromethoxy) benzamide (0.2 g) in THE (4 mL) were added (4-nitrophenyl) carbonochloridate (0.112 g) and pyridine (0.168 g) at 0 C. The reaction mixture was stirred at ambient temperature for 3 h. After 3 h, 2-imino-3-(2-isopropyl-5-methyl-phenyl)thiazolidin-4-one (E1, 0.132 g) and pyridine (0.168 g) were added. The reaction mixture was stirred at 65 C. for 3 h. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to preparative HPLC purification, eluting with a gradient of acetonitrile and water to obtain the title compound as a solid (0.118 g).

[1412] HPLC/MS (method 1): Rt: 5.84 min; m/z=650 (M1).sup.+.

[1413] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.28 (s, 1H), 9.95 (s, 1H), 8.20-8.15 (m, 2H), 7.86 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.5 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 7.07 (d, J=1.9 Hz, 1H), 4.21 (d, J=17.9 Hz, 1H), 4.10 (d, J=15 Hz, 1H), 3.74 (s, 3H), 2.67 (p, J=6.9 Hz, 1H), 2.32 (s, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H).

Example C-6

Preparation of N-[5-[3-chloro-4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]amino]phenyl]-2-methyl-1,2,4-triazol-3-yl]-4-(trifluoromethoxy)benzamide (C-6)

Step 1: N-[5-(4-amino-3-chloro-phenyl)-2-methyl-1,2,4-triazol-3-yl]-4-(trifluoromethoxy)benz-amide

[1414] To a stirred solution of N-[5-(4-aminophenyl)-2-methyl-1,2,4-triazol-3-yl]-4-(trifluoromethoxy) benzamide (1.5 g) in acetonitrile (15 mL) was added N-chlorosuccinimide (0.531 g) at ambient temperature. The reaction mixture was stirred at 70 C. for 6 h and after completion of the reaction, the mixture was diluted in water. The mixture was extracted with EtOAc and the organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a yellow solid (1.25 g).

[1415] HPLC/MS (method 1): Rt: 2.02 min; m/z=412.2 (M+1).sup.+.

Step 2: N-[5-[3-chloro-4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]amino]phenyl]-2-methyl-1,2,4-triazol-3-yl]-4-(trifluoromethoxy)benzamide (C-6)

[1416] To a stirred solution of N-[5-(4-amino-3-chloro-phenyl)-2-methyl-1,2,4-triazol-3-yl]-4-(trifluoromethoxy)benzamide (1.0 g) in THF (10 mL) was added (4-nitrophenyl) carbochloridate (0.587 g) at 0 C. under inert atmosphere. The reaction mixture was stirred at ambient temperature for 3 h. After this time acetonitrile (10 mL) was added. 2-imino-3-(2-isopropyl-5-methyl-phenyl)thiazolidin-4-one (E1, 0.905 g), N,N,N-diisopropyl ethylamine (0.628 g) and potassium phosphate tribasic (0.635 g) were added at 0 C. The reaction mixture was stirred at 27 C. for 16 h. After completion of the reaction, the mixture was diluted in water. The mixture was extracted with EtOAc and the organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was triturated in MeOH and filtered to obtain the title compound as a white solid (1.2 g). HPLC/MS (method 1): Rt: 2.34 min; m/z=686.4 (M+1).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.32 (s, 1H), 9.08 (s, 1H), 8.20-8.13 (d, 2H), 8.01-7.66 (m, 3H), 7.59 (d, J=8.3 Hz, 2H), 7.44-7.19 (m, 2H), 7.06 (s, 1H), 4.28-4.03 (m, 2H), 3.77 (s, 3H), 2.74-2.60 (m, 1H), 2.31 (s, 3H), 1.29-0.96 (m, 6H).

Example C-7

Preparation of N-[4-cyano-5-[4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]amino]phenyl]-2-methyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide (C-7)

Step 1: Synthesis of 3,5-dibromo-1H-pyrazole-4-carbonitrile

[1417] To a stirred solution of 1H-pyrazole-4-carbonitrile (10 g) in EtOH (25 mL) and water (35 mL) were added sodium acetate (12.336 g) and bromine (6.86 g) at 10 C. The reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was dissolved in water and the mixture was extracted with DCM. The organic extracts dried over anhydrous sodium sulphate and evaporated in vacuo to obtain the title compound (4.9 g). HPLC/MS (method 1): Rt: 1.73 min; m/z=252 (M+2).sup.+.

Step 2: Synthesis of 3,5-dibromo-1-methyl-pyrazole-4-carbonitrile

[1418] To a stirred solution of 3,5-dibromo-1H-pyrazole-4-carbonitrile (4.9 g) in DMF (25 mL) were added cesium carbonate (9.545 g) and methyl iodide (4.158 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 17 h. The reaction mixture was dissolved in water, solid precipitated was filtered and washed with water and dried in vacuo to obtain the title compound as off white solid (50 g). HPLC/MS (method 1): Rt: 1.82 min; m/z=266 (M+1).sup.+.

Step 3: Synthesis of 5-amino-3-bromo-1-methyl-pyrazole-4-carbonitrile

[1419] To a stirred solution of 3,5-dibromo-1-methyl-pyrazole-4-carbonitrile (7 g) in N-methyl-2-pyrrolidone (14 mL) was added 2,4-dimethoxybenzylamine (8.83 mL) at ambient temperature. The reaction mixture was stirred at 140 C. for 2 h. After completion of reaction, 5N hydrochloric acid (50 mL) was added and reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was dissolved in water and the mixture was extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a solid (5.8 g).

[1420] HPLC/MS (method 1): Rt: 1.01 min; m/z=203 (M+2).sup.+.

Step 4: Synthesis of N-(5-bromo-4-cyano-2-methyl-pyrazol-3-yl)-4-(trifluoromethoxy)benzamide

[1421] To a stirred solution of 5-amino-3-bromo-1-methyl-pyrazole-4-carbonitrile (7 g) in DCM (70 mL) were added pyridine (14 mL) and 4-(trifluoromethoxy)benzoyl chloride (6.7 mL) at 0 C. The reaction mixture was stirred at ambient temperature for 24 h. The reaction mixture was dissolved in water and the mixture was extracted with DCM. The organic extracts were washed with 2.5M, hydrochloric acid, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a solid (2.5 g).

[1422] HPLC/MS (method 1): Rt: 2.02 min; m/z=389 (M).sup.+.

Step 5: Synthesis of N-[5-(4-aminophenyl)-4-cyano-2-methyl-pyrazol-3-yl]-4-(trifluoromethoxy) benzamide

[1423] To a stirred solution of N-(5-bromo-4-cyano-2-methyl-pyrazol-3-yl)-4-(trifluoromethoxy)benzamide (3.2 g) in 1,4-dioxane (30 mL) and water (3 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.98 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.602 g) and potassium carbonate (1.70 g) at ambient temperature under inert atmosphere. The reaction mixture was heated at 80 C. for 8 h and after completion of the reaction, the mixture was dissolved in water. The mixture was extracted with EtOAc, the organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a solid (2.05 g). HPLC/MS (method 1): Rt: 1.93 min; m/z=402 (M+1).sup.+.

Step 6: Synthesis of N-[4-cyano-5-[4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]amino]phenyl]-2-methyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide (C-7)

[1424] To a stirred solution of N-[5-(4-aminophenyl)-4-cyano-2-methyl-pyrazol-3-yl]-4-(trifluoro-methoxy) benzamide (0.2 g) in THF (4 mL) were added bis(2,5-dioxopyrrolidin-1-yl) carbonate (0.134 g) and pyridine (0.157 g) at 0 C. The reaction mixture was stirred at ambient temperature for 3 h. After 3h, 2-imino-3-(2-isopropyl-5-methyl-phenyl)thiazolidin-4-one (E1, 0.124 g) and pyridine (0.157 g) were added. The reaction mixture was stirred at 65 C. for 3 h. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic extracts dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a solid (0.175 g). HPLC/MS (method 1): Rt: 2.523 min; m/z=675 (M1).sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.13 (s, 1H), 9.99 (s, 1H), 8.20-8.15 (m, 2H), 7.79 (q, J=8.5 Hz, 4H), 7.62 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.07 (s, 1H), 4.20 (s, 1H), 4.09 (d, J=18.0 Hz, 1H), 3.80 (d, J=2.1 Hz, 3H), 2.67 (p, J=7.3 Hz, 1H), 2.32 (s, 3H), 1.17 (d, J=6.9 Hz, 3H), 1.10 (d, J=6.9 Hz, 3H).

Example C-8

Preparation of N-[5-[3-chloro-4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide (C-8)

Step 1: Synthesis of N-[(1-amino-2-methyl-prop-1-enyl)-methyl-amino]formamide

[1425] To a stirred solution of ethyl 2-cyanopropanoate (4 g) in 1,4-dioxane (40 mL) were added methylhydrazine 80% Solution (1.993 g) at 0 C. The reaction mixture was heated at 110 C. for 17 h and after completion of the reaction, the mixture was evaporated. Solid precipitated was filtered and washed with heptane and dried to obtain the title compound as a solid (2.9 g).

[1426] HPLC/MS (method 1): Rt: 1.90 min; m/z=128.3 (M+1).sup.+.

Step 2: Synthesis of (5-amino-1,4-dimethyl-pyrazol-3-yl) trifluoromethanesulfonate

[1427] To a stirred solution of 3-amino-2,4-dimethyl-1H-pyrazol-5-one (1.6 g) in DMF (20 mL) were added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (5.39 g), N,N,N-diisopropyl ethylamine (4.87 g) at 0 C. The reaction mixture was stirred at ambient temperature for 17 h and after completion of the reaction, the mixture was dissolved in water. The mixture was extracted with EtOAc, the organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a solid (3.15 g).

[1428] HPLC/MS (method 1): Rt: 1.90 min; m/z=260 (M+1).sup.+.

Step 3: Synthesis of [1,4-dimethyl-5-[[4-(trifluoromethoxy)benzoyl]amino]pyrazol-3-yl]trifluoromethanesulfonate

[1429] To a stirred solution of (5-amino-1,4-dimethyl-pyrazol-3-yl) trifluoromethanesulfonate (3 g) in DCM (30 mL) were added pyridine (9.34 mL) and 4-(trifluoromethoxy)benzoyl chloride (2.85 mL) at 0 C. The reaction mixture was stirred at ambient temperature for 24 h. The reaction mixture was dissolved in water and extracted with DCM. The organic extracts were washed with 2.5M hydrochloric acid, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a white solid (3.15 g).

[1430] HPLC/MS (method 1): Rt: 2.16 min; m/z=448 (M+1).sup.+.

Step 4: Synthesis of N-[5-(4-amino-3-chloro-phenyl)-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide

[1431] To a stirred solution of [1,4-dimethyl-5-[[4-(trifluoromethoxy)benzoyl]amino]pyrazol-3-yl]trifluoromethanesulfonate (1 g) in 1,4-dioxane (10 mL) were added 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.595 g), tetrakis(triphenylphosphine)palladium(0) (0.517 g) and potassium carbonate (0.618 g) at ambient temperature under inert atmosphere. The reaction mixture was heated at 120 C. for 18 h and after completion of the reaction, the mixture was dissolved in water. The mixture was extracted with EtOAc, the organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a solid (0.59 g).

[1432] HPLC/MS (method 1): Rt: 2.24 min; m/z=425 (M+1).sup.+.

Step 5: Synthesis of N-[5-[3-chloro-4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide (C-8)

[1433] To a stirred solution of N-[5-(4-amino-3-chloro-phenyl)-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide (0.6 g) in THF (12 mL) were added bis(2,5-dioxopyrrolidin-1-yl) carbonate (0.38 g) and pyridine (0.446 g) at 0 C. The reaction mixture was stirred at ambient temperature for 3 h. After 3 h, 2-imino-3-(2-isopropyl-5-methyl-phenyl)thiazolidin-4-one (E1, 0.351 g) and pyridine (0.446 g) were added. The reaction mixture was stirred at 65 C. for 3 h. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc and heptane to obtain the title compound as a solid (0.45 g).

[1434] HPLC/MS (method 1): Rt: 2.29 min; m/z=699 (M).sup.+.

[1435] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.41 (s, 1H), 9.10 (s, 1H), 8.31-8.11 (m, 2H), 7.87-7.53 (m, 5H), 7.42 (s, 1H), 7.30 (s, 1H), 7.10 (s, 1H), 4.24 (d, J=18.0 Hz, 1H), 4.11 (d, J=18.0 Hz, 1H), 3.72 (s, 3H), 2.70 (s, 1H), 2.34 (s, 3H), 2.09 (s, 3H), 1.22 (s, 3H), 1.12 (d, J=6.9 Hz, 3H).

Example C-112

Preparation of N-[5-[4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]-methyl-amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethoxy) benzamide

Step 1: Synthesis of N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[1436] To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 g) in N,N-Dimethylformamide (10 mL) were added methyl iodide (0.777 g) and potassium carbonate (1.262 g) at ambient temperature under inert atmosphere. The reaction mass was stirred for 18 h at 50 C. and the progress of the reaction was monitored by TLC analysis. After completion of reaction, reaction mass was diluted with water (20 mL) and followed by extracted in EtOAc (25 mL2). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography to afford title compound as a solid (1.0 g).

[1437] HPLC/MS (Method 1): Rt: 2.09 min; m/z=234.3 (M+1)+;

[1438] .sup.1H NMR (500 MHz, DMSO-d6) 7.43-7.37 (m, 2H), 6.52-6.46 (m, 2H), 6.04 (q, J=4.9 Hz, 1H), 2.68 (d, J=5.0 Hz, 3H), 1.25 (s, 12H).

Step 2: Synthesis of N-[2,4-dimethyl-5-[4-(methylamino)phenyl]pyrazol-3-yl]-4-(trifluoro-methoxy)benzamide

[1439] To a stirred solution of [1,4-dimethyl-5-[[4-(trifluoromethoxy)benzoyl]amino]pyrazol-3-yl]trifluoromethanesulfonate (1.2 g) in 1,4-Dioxane (12 mL) were added N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.688 g), Tetrakis (0.620 g) and potassium carbonate (0.742 g) at ambient temperature under inert atmosphere. The reaction mass was stirred for 18 h at 110 C. and the progress of the reaction was monitored by TLC analysis. After completion of reaction, reaction mass was diluted with Water (30 mL) and followed by extracted in EtOAc (40 mL2). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography to afford title compound as a solid (1.01 g).

[1440] HPLC/MS (Method 1): Rt: 1.98 min; m/z=405.3 (M+1)+;

[1441] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.29 (s, 1H), 8.15 (dd, J=8.7, 6.8 Hz, 2H), 7.67-7.54 (m, 4H), 7.41 (d, J=8.3 Hz, 2H), 6.59 (d, J=8.4 Hz, 1H), 3.63 (d, J=6.8 Hz, 3H), 2.71 (d, J=5.0 Hz, 3H), 2.00 (d, J=3.2 Hz, 3H).

Step 3: Synthesis of N-[5-[4-[benzoylcarbamothioyl(methyl)amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide

[1442] To a stirred solution of N-[2,4-dimethyl-5-[4-(methylamino)phenyl]pyrazol-3-yl]-4-(trifluoromethoxy)benzamide (1.01 g) in acetone (15 mL) was added benzoyl isothiocyanate (0.488 g) at ambient temperature under inert atmosphere. The reaction mass was stirred for 19 h at 50 C. and the progress of the reaction was monitored by TLC analysis. After completion of reaction, solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography to afford title compound (1.1 g).

[1443] HPLC/MS (Method 1): Rt: 2.08 min: m/z=568.2 (M+1)+.

Step 4: Synthesis of N-[5-[4-[carbamothioyl(methyl)amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide

[1444] To a stirred solution of N-[5-[4-[benzoylcarbamothioyl(methyl)amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide (1.1 g) in MeOH (11 mL) was added Aq. 2N NaOH (13 mL) at ambient temperature. The reaction mass was stirred for 22 h at 65 C. and the progress of the reaction was monitored by TLC analysis. After completion of reaction, reaction mass pH was adjusted to neutral using 2N HCl (5 mL) and followed by extracted in EtOAc (25 mL2). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography to afford title compound as a solid (0.300 g).

[1445] HPLC/MS (Method 1): Rt: 1.97 min; m/z=464.2 (M+1)+;

[1446] .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.38 (s, 1H), 8.20-8.13 (m, 2H), 7.77-7.70 (m, 2H), 7.67-7.51 (m, 4H), 7.36-7.30 (m, 2H), 3.71 (s, 3H), 3.49 (s, 3H), 2.09 (s, 3H).

Step 5: Synthesis of N-[5-[4-[(4,5-dioxothiazol-2-yl)-methyl-amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide

[1447] To a stirred solution of N-[5-[4-[carbamothioyl(methyl)amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide (0.1 g) in EtOAc (2 mL) were added oxalyl chloride (0.096 g) and Triethylamine (0.052 g) at ambient temperature under inert atmosphere. The reaction mass was stirred for 15 min at ambient temperature and the progress of the reaction was monitored by TLC analysis. After completion of the reaction, reaction mass was diluted with water (10 mL) and followed by extracted in DCM (10 mL2). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford title compound as a solid (0.120 g).

[1448] HPLC/MS (Method 1): Rt: 2.02 min; m/z=517.2 (M).

Step 6: Synthesis of N-[5-[4-[(2-isopropyl-5-methyl-phenyl)carbamothioylcarbamoyl-methyl-amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide

[1449] To a stirred solution of N-[5-[4-[(4,5-dioxothiazol-2-yl)-methyl-amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide (0.140 g) in toluene (2 mL) at ambient temperature and reaction mass was stirred for 25 min at 100 C. The reaction mass was cooled to ambient temperature and was added 2-isopropyl-5-methyl-aniline (0.044 g). The reaction mass was stirred for 2 h at ambient temperature and the progress of the reaction was monitored by TLC analysis. After completion of reaction, the solvent was concentrated under reduced pressure and the crude product was purified by flash chromatography to afford title compound as a solid (0.04 g).

[1450] HPLC/MS (Method 1): Rt: 2.39 min; m/z=639.4 (M+1)+.

Step 7: Synthesis of N-[5-[4-[[(Z)-[3-(2-isopropyl-5-methyl-phenyl)-4-oxo-thiazolidin-2-ylidene]carbamoyl]-methyl-amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide (C-112)

[1451] To a stirred solution of N-[5-[4-[(2-isopropyl-5-methyl-phenyl) carbamothioylcarbamoyl-methyl-amino]phenyl]-2,4-dimethyl-pyrazol-3-yl]-4-(trifluoromethoxy)benzamide (0.040 g) in EtOH (1 mL) were added sodium acetate (0.010 g) and methyl bromo acetate (0.014 g) at ambient temperature. Then reaction mass was stirred at 50 0 for 3 h and monitored by TLC analysis. After completion of reaction, reaction mass was diluted with water (5 mL) and followed by extracted in EtOAc (5 mL2). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography to afford title compound as a solid (0.015 g).

[1452] HPLC/MS (Method 1): Rt: 2.22 min; m/z=679.3 (M+1)+;

[1453] .sup.1H NMR (500 MHz, DMSO-d.sub.6) b 10.36 (s, 1H), 8.18 (d, J=8.3 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.46-7.22 (m, 3H), 7.17-6.72 (m, 4H), 4.22 (d, J=18.0 Hz, 1H), 4.08 (d, J=18.0 Hz, 1H), 3.70 (s, 3H), 3.17 (d, J=71.8 Hz, 4H), 2.16 (s, 3H), 2.06 (s, 3H), 1.11-0.69 (m, 6H).

[1454] All other examples enlisted in table C are synthesized analogously to the methods mentioned in either general procedure or experimental procedure mentioned above.

TABLE-US-00005 TABLE C (I) [00099] No Ar.sup.1Q [00100] [00101] [00102] LC MS/MZ Rt min C-1 [00103] [00104] [00105] [00106] 649 (Method 1) 1.96 C-2 [00107] [00108] [00109] [00110] 681 (Method 1) 2.20 C-3 [00111] [00112] [00113] [00114] 608 (Method 1) 2.61 C-4 [00115] [00116] [00117] [00118] 663.2 (Method 2) 1.33 C-5 [00119] [00120] [00121] [00122] 650 (Method 1) 2.56 C-6 [00123] [00124] [00125] [00126] 686 (Method 1) 2.25 C-7 [00127] [00128] [00129] [00130] 675 (Method 1) 2.55 C-8 [00131] [00132] [00133] [00134] 699 (Method 1) 2.27 C-9 [00135] [00136] [00137] [00138] 675 (Method 1) 2.38 C-10 [00139] [00140] [00141] [00142] 690 (Method 1) 2.27 C-11 [00143] [00144] [00145] [00146] 663 (Method 1) 2.34 C-12 [00147] [00148] [00149] [00150] 689 (Method 2) 1.29 C-13 [00151] [00152] [00153] [00154] 667 (Method 1) 2.41 C-14 [00155] [00156] [00157] [00158] 693 (Method 1) 2.32 C-15 [00159] [00160] [00161] [00162] 678 (Method 1) 2.58 C-16 [00163] [00164] [00165] [00166] 666.8 (Method 1) 2.48 C-17 [00167] [00168] [00169] [00170] 692.9 (Method 1) 2.35 C-18 [00171] [00172] [00173] [00174] 695.7 (Method 1) 1.78 C-19 [00175] [00176] [00177] [00178] 679 (Method 1) 2.34 C-20 [00179] [00180] [00181] [00182] 679 (Method 1) 2.70 C-21 [00183] [00184] [00185] [00186] 709 (Method 1) 2.88 C-22 [00187] [00188] [00189] [00190] 679.6 (Method 2) 1.35 C-23 [00191] [00192] [00193] [00194] 676.6 (Method 2) 1.25 C-24 [00195] [00196] [00197] [00198] 675.7 (Method 1) 2.16 C-25 [00199] [00200] [00201] [00202] 717 (Method 1) 2.42 C-26 [00203] [00204] [00205] [00206] 678 (Method 1) 2.58 C-27 [00207] [00208] [00209] [00210] 720 (Method 1) 2.43 C-28 [00211] [00212] [00213] [00214] 679 (Method 1) 1.35 C-29 [00215] [00216] [00217] [00218] 690.3 (Method 2) 1.29 C-30 [00219] [00220] [00221] [00222] 693 (Method 1) 2.57 C-31 [00223] [00224] [00225] [00226] 663 (Method 1) 2.52 C-32 [00227] [00228] [00229] [00230] 699 (Method 1) 2.77 C-33 [00231] [00232] [00233] [00234] 724 (Method 1) 2.76 C-34 [00235] [00236] [00237] [00238] 624 (Method 1) 2.72 C-35 [00239] [00240] [00241] [00242] 702 (Method 1) 2.59 C-36 [00243] [00244] [00245] [00246] 721 (Method 1) 2.80 C-37 [00247] [00248] [00249] [00250] 653 (Method 1) 1.41 C-38 [00251] [00252] [00253] [00254] 649 (Method 1) 2.77 C-39 [00255] [00256] [00257] [00258] 677 (Method 1) 2.45 C-40 [00259] [00260] [00261] [00262] 681 (Method 1) 2.54 C-41 [00263] [00264] [00265] [00266] 651 (Method 1) 0.83 C-42 [00267] [00268] [00269] [00270] 690 (Method 1) 2.21 C-43 [00271] [00272] [00273] [00274] 716 (Method 1) 2.23 C-44 [00275] [00276] [00277] [00278] 679.53 (Method 1) 2.18 C-45 [00279] [00280] [00281] [00282] 705 (Method 1) 2.61 C-46 [00283] [00284] [00285] [00286] 624 (Method 1) 2.07 C-47 [00287] [00288] [00289] [00290] 606 (Method 1) 2.27 C-48 [00291] [00292] [00293] [00294] 709 (Method 1) 2.53 C-49 [00295] [00296] [00297] [00298] 624 (Method 1) 2.28 C-50 [00299] [00300] [00301] [00302] 620 (Method 1) 2.26 C-51 [00303] [00304] [00305] [00306] 622 (Method 1) 2.32 C-52 [00307] [00308] [00309] [00310] 696.9 (Method 1) 2.59 C-53 [00311] [00312] [00313] [00314] 640 (Method 1) 2.13 C-54 [00315] [00316] [00317] [00318] 679 (Method 1) 2.2 C-55 [00319] [00320] [00321] [00322] 695 (Method 1) 2.22 C-56 [00323] [00324] [00325] [00326] 713 (Method 1) 2.31 C-57 [00327] [00328] [00329] [00330] 713 (Method 1) 2.24 C-58 [00331] [00332] [00333] [00334] 695 (Method 1) 2.18 C-59 [00335] [00336] [00337] [00338] 727.3 (Method 1) 2.36 C-60 [00339] [00340] [00341] [00342] 738.3 (Method 1) 2.28 C-61 [00343] [00344] [00345] [00346] 666.3 (Method 1) 2.17 C-62 [00347] [00348] [00349] [00350] 745.2 (Method 1) 2.29 C-63 [00351] [00352] [00353] [00354] 690.2 (Method 1) 2.17 C-64 [00355] [00356] [00357] [00358] 710 (Method 1) 2.21 C-65 [00359] [00360] [00361] [00362] 710 (Method 1) 2.3 C-66 [00363] [00364] [00365] [00366] 690.3 (Method 1) 2.21 C-67 [00367] [00368] [00369] [00370] 753.4 (Method 1) 2.4 C-68 [00371] [00372] [00373] [00374] 791.4 (Method 1) 2.29 C-69 [00375] [00376] [00377] [00378] 654 (Method 1) 2.26 C-70 [00379] [00380] [00381] [00382] 713 (Method 1) 2.21 C-71 [00383] [00384] [00385] [00386] 645.5 (Method 1) 2.22 C-72 [00387] [00388] [00389] [00390] 690 (Method 1) 2.19 C-73 [00391] [00392] [00393] [00394] 727 (Method 1) 2.22 C-74 [00395] [00396] [00397] [00398] 658 (Method 1) 2.16 C-75 [00399] [00400] [00401] [00402] 713.4 (Method 1) 2.4 C-76 [00403] [00404] [00405] [00406] 725 (Method 1) 2.34 C-77 [00407] [00408] [00409] [00410] 700.4 (Method 1) 2.41 C-78 [00411] [00412] [00413] [00414] 711.4 (Method 1) 2.33 C-79 [00415] [00416] [00417] [00418] 682.2 (Method 1) 2.18 C-80 [00419] [00420] [00421] [00422] 651 (Method 1) 2.2 C-81 [00423] [00424] [00425] [00426] 669 (Method 1) 2.26 C-82 [00427] [00428] [00429] [00430] 756.3 (Method 1) 2.26 C-83 [00431] [00432] [00433] [00434] 712.3 (Method 1) 2.25 C-84 [00435] [00436] [00437] [00438] 715.4 (Method 1) 2.33 C-85 [00439] [00440] [00441] [00442] 702.4 (Method 1) 2.27 C-86 [00443] [00444] [00445] [00446] 724.4 (Method 1) 2.33 C-87 [00447] [00448] [00449] [00450] 714.4 (Method 1) 2.45 C-88 [00451] [00452] [00453] [00454] 669 (Method 1) 2.23 C-89 [00455] [00456] [00457] [00458] 633 (Method 1) 2.18 C-90 [00459] [00460] [00461] [00462] 658 (Method 1) 2.17 C-91 [00463] [00464] [00465] [00466] 649 (Method 1) 2.23 C-92 [00467] [00468] [00469] [00470] 667 (Method 1) 2.26 C-93 [00471] [00472] [00473] [00474] 672 (Method 1) 1.40 C-94 [00475] [00476] [00477] [00478] 732.2 (Method 1) 2.26 C-95 [00479] [00480] [00481] [00482] 658 (Method 1) 2.13 C-96 [00483] [00484] [00485] [00486] 654.2 (Method 2) 1.34 C-97 [00487] [00488] [00489] [00490] 682 (Method 2) 1.35 C-98 [00491] [00492] [00493] [00494] 638.1 (Method 2) 1.32 C-99 [00495] [00496] [00497] [00498] 713.4 (Method 1) 2.39 C-100 [00499] [00500] [00501] [00502] 654.1 (Method 2) 1.36 C-101 [00503] [00504] [00505] [00506] 636.2 (Method 2) 1.34 C-102 [00507] [00508] [00509] [00510] 627.1 (Method 2) 1.24 C-103 [00511] [00512] [00513] [00514] 667 (Method 1) 2.25 C-104 [00515] [00516] [00517] [00518] 645 (Method 2) 1.3 C-105 [00519] [00520] [00521] [00522] 620.1 (Method 2) 1.29 C-106 [00523] [00524] [00525] [00526] 719 (Method 2) 1.38 C-107 [00527] [00528] [00529] [00530] 645.1 (Method 2) 1.24 C-108 [00531] [00532] [00533] [00534] 654 (Method 2) 1.37 C-109 [00535] [00536] [00537] [00538] 685 (Method 1) 2.32 C-110 [00539] [00540] [00541] [00542] 661 (Method 2) 1.32 C-111 [00543] [00544] [00545] [00546] 695 (Method 1) 2.3 C-112 [00547] [00548] [00549] [00550] 679.3 (Method 1) 2.22 C-113 [00551] [00552] [00553] [00554] 707 (Method 2) 1.35 C-114 [00555] [00556] [00557] [00558] 685.8 (Method 2) 1.36 C-115 [00559] [00560] [00561] [00562] 685.1 (Method 2) 1.35 C-116 [00563] [00564] [00565] [00566] 706 (Method 2) 1.38 C-117 [00567] [00568] [00569] [00570] 672 (Method 2) 1.30 C-118 [00571] [00572] [00573] [00574] 733 (Method 1) 2.33 C-119 [00575] [00576] [00577] [00578] 638.1 (Method 2) 1.26 C-120 [00579] [00580] [00581] [00582] 685.2 (Method 1) 2.38 C-121 [00583] [00584] [00585] [00586] 665.3 (Method 1) 2.26 C-122 [00587] [00588] [00589] [00590] 721.4 (Method 1) 2.47 C-123 [00591] [00592] [00593] [00594] 672.3 (Method 1) 2.36 C-124 [00595] [00596] [00597] [00598] 702.9 (Method 3) 1.29 C-125 [00599] [00600] [00601] [00602] 771 (Method 1) 2.36 C-126 [00603] [00604] [00605] [00606] 638 (Method 2) 1.28 C-127 [00607] [00608] [00609] [00610] 665.3 (Method 1) 2.29 C-128 [00611] [00612] [00613] [00614] 666 (Method 1) 2.14 C-129 [00615] [00616] [00617] [00618] 653.3 (Method 1) 2.11 C-130 [00619] [00620] [00621] [00622] 666.3 (Method 1) 2.11 C-131 [00623] [00624] [00625] [00626] 721 (Method 1) 2.32 C-132 [00627] [00628] [00629] [00630] 799.1 (Method 3) 1.28 C-133 [00631] [00632] [00633] [00634] 675 (Method 1) 2.29 C-134 [00635] [00636] [00637] [00638] 641 (Method 1) 2.18

Biological Examples

Example B.1: Action on Yellow Fever Mosquito (Aedes aegypti)

[1455] For evaluating control of yellow fever mosquito (Aedes aegypti) the test unit consisted of 96-well-microtiter plates containing 200 l of tap water per well and 5-15 freshly hatched A. aegypti larvae.

[1456] The active compounds or mixtures were formulated using a solution containing 75% (v/v) water and 25% (v/v) DMSO. Different concentrations of formulated compounds or mixtures were sprayed onto the insect diet at 2.5 l, using a custom-built micro atomizer, at two replications.

[1457] For experimental mixtures in these tests identical volumes of both mixing partners at the desired concentrations respectively, were mixed together.

[1458] After application, microtiter plates were incubated at 28 #1 C., 80 #5% RH for 2 days. Larval mortality was then visually assessed.

[1459] In this test, compounds C-1, C-2, C-3, C-4, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-21, C-22, C-23, C-24, C-25, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36 C-37, C-38, C-40, C-42, C-43, C-44, C-45, C-46, C-47, C-48, C-49, C-50, C-51, C-52, C-53, C-54, C-55, C-56, C-57, C-58, C-59, C-60, C-61, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-71, C-72, C-73, C-74, C-75, C-76, C-77, C-78, C-79, C-80, C-81, C-82, C-83, C-84, C-85, C-86, C-87, C-88, C-89, C-90, C-91, C-92, C-93, C-94, C-95, C-96, C-97, C-98, C-99, C-100, C-101, C-102, C-103, C-104, C-105, C-106, C-107, C-108, C-109, C-111, C-112, C-113, C-114, C-115, C-116, C-118, C-120, C-121, C-122, C-123, C-126, C-127, C-128, and C-130, resp., at 800 ppm showed at least 50% mortality in comparison with untreated controls.

Example B.2: Action on Orchid Thrips (Dichromothrips corbetti)

[1460] Dichromothrips corbetti adults used for bioassay were obtained from a colony maintained continuously under laboratory conditions. For testing purposes, the test compound is diluted in a 1:1 mixture of acetone:water (vol:vol), plus Kinetic HV at a rate of 0.01% v/v.

[1461] Thrips potency of each compound was evaluated by using a floral-immersion technique. All petals of individual, intact orchid flowers were dipped into treatment solution and allowed to dryin Petri dishes. Treated petals were placed into individual re-sealable plastic along with about 20 adult thrips. All test arenas were held under continuous light and a temperature of about 28 C. for duration of the assay. After 3 days, the numbers of live thrips were counted on each petal. The percent mortality was recorded 72 hours after treatment.

[1462] In this test, compounds C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-21, C-22, C-24, C-25, C-26, C-27, C-28, C-30, C-31, C-34, C-35, C-36, C-37, C-38, C-40, C-42, C-43, C-44, C-45, C-48, C-49, C-55, C-56, C-59, C-60, C-61, C-62, C-63, C-65, C-66, C-67, C-68, C-71, C-72, C-75, C-76, C-77, C-78, C-79, C-80, C-81, C-83, C-84, C-85, C-86, C-87, C-88, C-90, C-92, C-93, C-94, C-96, C-97, C-98, C-99, C-100, C-101, C-102, C-103, C-104, C-105, C-106, C-108, C-109, C-110, C-113, C-115, C-116, C-118, C-120, C-121, C-129, and C-130, resp., at 300 ppm showed at least 75% mortality in comparison with untreated controls.

Example B.3: Action on Boll Weevil (Anthonomus grandis)

[1463] For evaluating control of boll weevil (Anthonomus grandis) the test unit consisted of 96-well-microtiter plates containing an insect diet and 5-10 A. grandis eggs.

[1464] The compounds were formulated using a solution containing 75% (v/v) water and 25% (v/v) DMSO. Different concentrations of formulated compounds were sprayed onto the insect diet at 5 pl, using a custom-built micro atomizer, at two replications.

[1465] After application, microtiter plates were incubated at about 251C and about 755% relative humidity for 5 days. Egg and larval mortality were then visually assessed.

[1466] In this test, compounds C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-21, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-42, C-43, C-44, C-45, C-46, C-47, C-48, C-49, C-50, C-51, C-52, C-53, C-54, C-55, C-56, C-57, C-58, C-59, C-60, C-61, C-62, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-71, C-72, C-73, C-74, C-75, C-76, C-77, C-78, C-79, C-80, C-81, C-82, C-83, C-84, C-85, C-86, C-87, C-88, C-89, C-90, C-91, C-92, C-93, C-94, C-95, C-96, C-97, C-98, C-99, C-100, C-101, C-102, C-103, C-104, C-105, C-106, C-107, C-108, C-109, C-110, C-111, C-112, C-113, C-114, C-115, C-116, C-118, C-119, C-120, C-121, C-122, C-126, C-127, C-128, C-129, and C-130, resp., at 800 ppm showed at least 75% mortality in comparison with untreated controls.

Example B.4: Action on Silverleaf Whitefly (Bemisia argentifolii) (Adults)

[1467] The active compounds were formulated by a Tecan liquid handler in 100% cyclohexanone as a 10,000-ppm solution supplied in tubes. The 10,000-ppm solution was serially diluted in 100% cyclohexanone to make interim solutions. These served as stock solutions for which final dilutions were made by the Tecan in 50% acetone:50% water (v/v) into 5 or 10 ml glass vials. A nonionic surfactant (Kinetic) was included in the solution at a volume of 0.01% (v/v). The vials were then inserted into an automated electrostatic sprayer equipped with an atomizing nozzle for application to plants/insects.

[1468] Cotton plants at the cotyledon stage (one plant per pot) were sprayed by an automated electrostatic plant sprayer equipped with an atomizing spray nozzle. The plants were dried in the sprayer fume hood and then removed from the sprayer. Each pot was placed into a plastic cup and about 10 to 12 whitefly adults (approximately 3-5 days old) were introduced. The insects were collected using an aspirator and a nontoxic Tygon tubing connected to a barrier pipette tip. The tip, containing the collected insects, was then gently inserted into the soil containing the treated plant, allowing insects to crawl out of the tip to reach the foliage for feeding. Cups were covered with a reusable screened lid. Test plants were maintained in a growth room at about 25 C. and about 20-40% relative humidity for 3 days, avoiding direct exposure to fluorescent light (24-hour photoperiod) to prevent trapping of heat inside the cup. Mortality was assessed 3 days after treatment, compared to untreated control plants.

[1469] In this test, compound C-6, C-32, C-59, C-60, C-61, C-65, and C-67, resp., at 300 ppm showed at least 75% mortality in comparison with untreated controls.

Example B.5: Action on Tobacco Budworm (Heliothis virescens)

[1470] For evaluating control of tobacco budworm (Heliothis virescens) the test unit consisted of 96-well-microtiter plates containing an insect diet and 15-25 H. virescens eggs.

[1471] The compounds were formulated using a solution containing 75% v/v water and 25% v/v DMSO. Different concentrations of formulated compounds were sprayed onto the insect diet at 10 l, using a custom-built micro atomizer, at two replications.

[1472] After application, microtiter plates were incubated at about 281C and about 805% relative humidity for 5 days. Egg and larval mortality were then visually assessed.

[1473] In this test, compounds C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-21, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-46, C-47, C-48, C-49, C-50, C-51, C-52, C-53, C-54, C-55, C-56, C-57, C-58, C-59, C-60, C-61, C-62, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70 C-71, C-72, C-73, C-74, C-75, C-76, C-77, C-78, C-79, C-80, C-81, C-82, C-83, C-84, C-85, C-86, C-87, C-88, C-89, C-90, C-91, C-92, C-93, C-94, C-95, C-96, C-97, C-98, C-99, C-100, C-101, C-102, C-103, C-104, C-105, C-106, C-107, C-108, C-109, C-110, C-111, C-112, C-113, C-114, C-115, C-116, C-117, C-118, C-120, C-121, C-122, C-123, C-126, C-127, C-128, C-129, and C-130, resp., at 800 ppm showed at least 75% mortality in comparison with untreated controls.

Example B.6: Action on Diamond Back Moth (Plutella xylostella)

[1474] The active compound is dissolved at the desired concentration in a mixture of 1:1 (v/v) distilled water: acetone. Surfactant (Kinetic HV) is added at a rate of 0.01% (v/v). The test solution is prepared at the day of use.

[1475] Leaves of cabbage were dipped in test solution and air-dried. Treated leaves were placed in petri dishes lined with moist filter paper and inoculated with ten 3rd instar larvae. Mortality was recorded 72 hours after treatment. Feeding damages were also recorded using a scale of 0-100%.

[1476] In this test, compounds C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-21, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-30, C-31, C-34, C-35, C-36, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-46, C-47, C-48, C-49, C-50, C-51, C-52, C-53, C-54, C-55, C-56, and C-57, resp., at 300 ppm showed at least 75% mortality in comparison with untreated controls.

Example B.7: Action on Southern Armyworm (Spodoptera eridania), 2nd Instar Larvae

[1477] The active compounds were formulated by a Tecan liquid handler in 100% cyclohexanone as a 10,000-ppm solution supplied in tubes. The 10,000-ppm solution was serially diluted in 100% cyclohexanone to make interim solutions. These served as stock solutions for which final dilutions were made by the Tecan in 50% acetone:50% water (v/v) into 10 or 20 ml glass vials. A nonionic surfactant (Kinetic) was included in the solution at a volume of 0.01% (v/v). The vials were then inserted into an automated electrostatic sprayer equipped with an atomizing nozzle for application to plants/insects.

[1478] Lima bean plants (variety Sieva) were grown 2 plants to a pot and selected for treatment at the 1st true leaf stage. Test solutions were sprayed onto the foliage by an automated electrostatic plant sprayer equipped with an atomizing spray nozzle. The plants were dried in the sprayer fume hood and then removed from the sprayer. Each pot was placed into perforated plastic bags with a zip closure. About 10 to 11 armyworm larvae were placed into the bag and the bags zipped closed. Test plants were maintained in a growth room at about 25 C. and about 20-40% relative humidity for 4 days, avoiding direct exposure to fluorescent light (24-hour photoperiod) to prevent trapping of heat inside the bags. Mortality and reduced feeding were assessed 4 days after treatment, compared to untreated control plants.

[1479] In this test, compounds C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-21, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-40, C-41, C-42, C-43, C-44, C-45, C-46, C-47, C-48, C-49, C-50, C-51, C-52, C-53, C-54, C-55, C-56, C-57, C-58, C-59, C-60, C-61, C-62, C-63, C-65, C-66, C-67, C-68, C-69, C-70, C-71, C-72, C-73, C-74, C-75, C-76, C-77, C-78, C-80, C-81, C-82, C-83, C-84, C-85, C-86, C-87, C-88, C-89, C-90, C-91, C-92, C-93, C-94, C-95, C-96, C-97, C-98, C-99, C-100, C-101, C-102, C-103, C-104, C-105, C-106, C-107, C-108, C-109, C-110, C-111, C-113, C-115, C-116, C-117, C-118, C-119, C-120, C-121, C-122, C-123, C-125, C-126, C-127, C-128, C-129, and C-130, resp., at 300 ppm showed at least 75% mortality in comparison with untreated controls.

Example B.8: Action on Diamond Back Moth (Plutella Xylostella)

[1480] For evaluating control of diamond back moth (Plutella xylostella) the test unit consisted of 96-well-microtiter plates containing an insect diet and 15-25 P. xylostella eggs. The compounds or mixtures were formulated using a solution containing 75% water and 25% DMSO. Different concentrations of formulated compounds or mixtures were sprayed onto the insect diet at 5 l, using a custom-built micro atomizer, at two replications. For experimental mixtures in these tests identical volumes of both mixing partners at the desired concentrations respectively, were mixed together. After application, microtiter plates were incubated at 281 C., 805% RH for 5 days. Egg and larval mortality was then visually assessed.

[1481] In this test, compounds C-58, C-59, C-60, C-61, C-62, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-71, C-72, C-73, C-74, C-75, C-76, C-77, C-78, C-70, C-80, C-81, C-82, C-83, C-84, C-85, C-86, C-87, C-88, C-90, C-91, C-92, C-93, C-94, C-95, C-96, C-97, C-98, C-99, C-100, C-101, C-102, C-103, C-104, C-105, C-106, C-107, C-108, C-109, C-110, C-111, C-112, C-113, C-114, C-115, C-116, C-117, C-118, C-119, C-122, C-123, C-126, C-127, C-128, C-129, and C-130, resp., at 800 ppm showed at least 75% mortality in comparison with untreated controls.

[1482] The beneficial activity of the compounds according to the invention over structurally close compounds known from prior art was demonstrated by the following comparative experiments:

TABLE-US-00006 Structure/Example Example Test B.8 @ 25 ppm [00639] C-119 75 [00640] EP3974414 I-001 0 Test B.8 @ Test B.8 @ Structure/Example Example 25 ppm 100 ppm [00641] C-126 75 100 [00642] EP3974414 I-006 38 0