HETEROCYCLIC COMPOUNDS FOR THE CONTROL OF INVERTEBRATE PESTS

Abstract

The invention relates to compounds of formula (I) wherein the variables have the meanings as defined in the specification, to compositions comprising them, to active compound combinations comprising them, and to their use for protecting growing plants and animals from attack or infestation by invertebrate pests, furthermore, to seed comprising such compounds.

##STR00001##

Claims

1. Compounds A compound of formula I ##STR00063## wherein R.sup.1 is H, OH, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halocycloalkyl, C.sub.1-C.sub.5-alkoxy, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-halocycloalkyl, which groups are unsubstituted, or partially or fully substituted with R.sup.11; or C(═N—R.sup.11)R.sup.12, C(O)R.sup.11a; R.sup.11 is CN, C(O)NH.sub.2, C(S)NH.sub.2, CO.sub.2H, NO.sub.2, NR.sup.12R.sup.13, OR.sup.14, Si(CH.sub.3).sub.3; C.sub.1-C.sub.6-haloalkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-haloalkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.2-C.sub.6-haloalkynyl; C.sub.3-C.sub.4-cycloalkyl-C.sub.1-C.sub.2-alkyl, which ring is unsubstituted or substituted with 1 or 2 halogen; 3- to 6-membered heterocyclyl, 5- or 6-membered hetaryl, or phenyl, which rings are unsubstituted or substituted with halogen, C.sub.1-C.sub.3-haloalkyl, and/or CN; R.sub.11a is C(O)NR.sup.12R.sup.13, C(S)NR.sup.12R.sup.13, C(O)OR.sup.14, NR.sup.12R.sup.13, OR.sup.14, C.sub.1-C.sub.5-alkyl, C.sub.1-C.sub.5-haloalkyl; C.sub.2-C.sub.5-alkenyl; C.sub.2-C.sub.5-haloalkenyl; C.sub.2-C.sub.5-alkynyl; C.sub.2-C.sub.5-haloalkynyl; C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.2-alkyl; C.sub.3-C.sub.4-cycloalkyl-C.sub.1-C.sub.2-alkyl, which ring is unsubstituted or substituted with 1 or 2 halogen; 3- to 6-membered heterocyclyl which rings are unsubstituted or substituted with halogen, C.sub.1-C.sub.3-haloalkyl, and/or CN; R.sup.12, R.sup.13 are independently from each other H, C.sub.1-C.sub.4-haloalkyl, C.sub.3-C.sub.6-cycloalkyl, C(O)—C.sub.1-C.sub.4-alkyl, C(O)—C.sub.1-C.sub.4-haloalkyl, C(O)—C.sub.3-C.sub.4-cycloalkyl, C(O)—C.sub.3-C.sub.4-halocycloalkyl, S(O).sub.m—C.sub.1-C.sub.4-alkyl, S(O).sub.m—C.sub.1-C.sub.4-haloalkyl, S(O).sub.m—C.sub.3-C.sub.4-cycloalkyl, S(O).sub.m—C.sub.3-C.sub.4-halocycloalkyl; m is 0, 1, or 2; R.sup.14 is H, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halo¬cycloalkyl, C.sub.3-C.sub.4-cycloalkyl-C.sub.1-C.sub.2-alkyl, C.sub.3-C.sub.4-halocycloalkyl-C.sub.1-C.sub.2-alkyl, C(O)—C.sub.1-C.sub.4-alkyl, C(O)—C.sub.1-C.sub.4-haloalkyl, C(O)—C.sub.3-C.sub.4-cycloalkyl, C(O)—C.sub.3-C.sub.4-halo¬cyclo¬alkyl; R.sup.2 is H, CN, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl, C.sub.2-C.sub.3-alkynyl; R.sup.3 is pyridine, pyrimidine, pyrazine, or pyridazine, which rings are unsubstituted or substituted with (R.sup.11).sub.n and/or 1 to 3 halogen; n is 0, 1, 2, or 3; W is N or C—R.sup.4; with the proviso that W is not C—R.sup.4, if R.sup.3 is pyridine; R.sup.4 are independently from each other H, halogen, OH, CN, C.sub.1-C.sub.4-haloalkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-haloalkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, S(O).sub.m—C.sub.1-C.sub.4-alkyl, S(O).sub.m—C.sub.1-C.sub.4-haloalkyl, S(O).sub.m—C.sub.3-C.sub.4-cycloalkyl, S(O).sub.m—C.sub.3-C.sub.4-halocycloalkyl; Q is a 5- to 10-membered heteroaryl comprising as ring members 1 to 4 heteroatoms selected from N, O and S which may be oxidized, wherein at least one ring member heteroatom is N, which heteroaryl is unsubstituted, or partially or fully substituted with groups independently selected from R.sup.5; R.sup.5 halogen, OH, CN, SF.sub.5, COOH, CONH.sub.2, NO.sub.2, or C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.3-haloalkoxy, S(O).sub.m—C.sub.1-C.sub.6-alkyl, S(O).sub.m—C.sub.3-C.sub.6-cycloalkyl, S(O).sub.m—C.sub.1-C.sub.3-haloalkyl, S(O).sub.m—phenyl, NR.sup.12R.sup.13, NR.sup.12CO—C.sub.1-C.sub.4-alkyl, NHCO-phenyl, CO.sub.2—C.sub.1-C.sub.4-alkyl, CONR.sup.12R.sup.13, CONR.sup.12(C.sub.3-C.sub.6-cycloalkyl), C(═NO—C.sub.1-C.sub.4-alkyl)R.sup.12; phenyl and 5- to 6-membered heteroaryl, wherein aromatic rings are unsubstituted, or substituted with 1 to 2 halogen and/or CN; R.sup.5 groups being unsubstituted, or partially or fully substituted with R.sup.11; two R.sup.5 present on the same carbon atom may together form a group ═O, ═S, ═NH, ═N(C.sub.1-C.sub.6-alkyl), ═NO(C.sub.1-C.sub.6-alkyl), ═NN(H)(C.sub.1-C.sub.6-alkyl), or ═NN(C.sub.1-C.sub.6-alkyl).sub.2; and the N-oxides, stereoisomers, and agriculturally or veterinarily acceptable salts thereof.

2. The compound of formula I according to claim 1, wherein R.sup.1 is H, OH, C.sub.1-C.sub.2-alkyl, c-C.sub.3H.sub.5CH.sub.2, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.2-alkyl, C(═O)R.sup.11a with R.sup.11a being c-C.sub.3H.sub.5CH.sub.2 or C.sub.1-C.sub.4-alkoxy.

3. The compound of formula I according to claim 1, which corresponds to formula I.N. ##STR00064##

4. The compound of formula I according to claim 1, which corresponds to formula I.1 ##STR00065##

5. The compound of formula I according to claim 1, which corresponds to formula I.2 ##STR00066## wherein T is CH, CR.sup.5, N, O, or S which may be oxidized; V is C or N; Z is C or N; Q′ is CH, CR.sup.5, or N; and Q″ is CH, CR.sup.5, or N; with the proviso that 2 or 3 of T, V, Z, Q′, and Q″ are a heteroatom.

6. The compound of formula I according to claim 1, to wherein Q is a 5-membered hetaryl containing at least one N as ring member, which ring is partially or fully substituted with R.sup.5.

7. The compound of formula I according to claim 1, to wherein Q is a 6-membered hetaryl containing at least one N as ring member, which ring is partially or fully substituted with R.sup.5.

8. The compound of formula I according to claim 1, to wherein Q is selected from the group consisting of Q1 to Q18 ##STR00067## ##STR00068## ##STR00069## wherein R.sup.51, R.sup.52, R.sup.53 are independently from each other H or R.sup.5; and # is the bond to the remainder of the molecule.

9. The compound of formula I according to claim 1, which consist consists mainly of the isomer I.A. ##STR00070##

10. An agricultural or veterinary composition comprising at least one compound according to claim 1 and/or at least one agriculturally or veterinarily acceptable salt thereof, and at least one inert liquid and/or solid agriculturally or veterinarily acceptable carrier.

11. An agricultural composition for combating animal pests comprising at least one compound as defined in claim 1 and at least one inert liquid and/or solid acceptable carrier and, optionally, at least one surfactant.

12. A method for combating or controlling invertebrate pests, comprising contacting said pest or its food supply, habitat or breeding grounds with a pesticidally effective amount of at least one compound as defined in claim 1.

13. A method for protecting growing plants from attack or infestation by invertebrate pests, comprising contacting a plant, or soil or water in which the plant is growing, with a pesticidally effective amount of at least one compound as defined in claim 1.

14. A seed comprising a compound as defined in 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.

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

Description

A. PREPARATION EXAMPLES

[0261] With appropriate modification of the starting materials, the procedures given in the synthesis description were used to obtain further compounds I. The compounds obtained in this manner are listed in the table that follows, together with physical data.

[0262] The products shown below were characterized by melting point determination, by NMR spectroscopy or by the masses ([m/z]) or retention time (RT; [min.]) determined by HPLC MS or HPLC spectrometry.

[0263] HPLC MS=high performance liquid chromatography-coupled mass spectrometry;

[0264] HPLC method A: Shimadzu Nexera UHPLC+Shimadzu LCMS 20-20, ESI; Column: Phenomenex Kinetex 1.7 μm XB-C18 100A, 50×2.1 mm; Mobile Phase: A: water+0.1% TFA; B: ACN; Temperature: 60° C.; Gradient: 5% B to 100% B in 1.50 min; 100% B 0.25 min; Flow: 0.8 mL/min to 1.0 mL/min in 1.51 min; MS method: ESI positive; Mass range (m/z): 100-700.

Example 1: Preparation of N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-amine [I-1]

[0265] Step 1: A solution of 2-chloro-3,5-bis(trifluoromethyl)aniline (10 g, 0.038 mol) in MeCN (60 mL) was added slowly over 5 min into a solution of H.sub.2O.sub.4 (60 mL) and H.sub.2O (60 mL) at 0° C., and stirred at that temperature for additional 10 min. NaNO.sub.2 (4.6 g, 0.133 mol) in H.sub.2O (40 mL) was added dropwise to the above mixture over 5 min, upon which the internal temperature reached 10° C., and stirred at that temperature for 10 min. A solution of KI (22 g, 66.5 mmol) in H.sub.2O (60 mL) was added dropwise at 0° C. and stirred for 2 h. Then TLC analysis (PE, Rf=0.6) showed complete reaction. The organic phase was separated, and the aqueous phase was extracted with MTBE (2×50 mL). The combined organic phases were washed with NaHCO.sub.3 solution (2×100 mL, sat. aq.), Na.sub.2S.sub.2O.sub.3 solution (2×100 mL sat. aq.), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Purification by column chromatography (PE) afforded 2-chloro-1-iodo-3,5-bis(trifluoromethyl)benzene (13 g, 93%) as a light brown oil. .sup.1H-NMR (CDCl.sub.3, 400 MHz, RT): δ ppm 8.32 (s, 1H) 7.95 (s, 1H).

[0266] Step 2: To a solution of 2-chloro-1-iodo-3,5-bis(trifluoromethyl)benzene (12 g, 32 mmol) in NMP (50 mL) at 25° C. under a N.sub.2 atmosphere was added CuCN (4.2 g, 48 mmol), and the resulting mixture was heated at 120° C. for 16 h. Then TLC analysis (PE/EtOAc=10:1, Rf=0.2) showed complete reaction. The reaction mixture was quenched with H.sub.2O (200 mL), extracted with EtOAc (3×200 mL), and the combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Purification by column chromatography (PE/EtOAc=50:1, Rf=0.3) afforded 2-chloro-3,5-bis(trifluoromethyl)benzonitrile (7.0 g, 80%) as yellow solid. .sup.1H-NMR (CDCl.sub.3, 400 MHz, RT): δ ppm 8.16 (br d, J=9.3Hz, 2H).

[0267] Step 3: To a solution of 2-chloro-3,5-bis(trifluoromethyl)benzonitrile (3.50 g, 12.8 mmol) in THF (100 mL) at 25° C. under a N.sub.2 atmosphere was added t-BuOK (1.70 g, 15.3 mmol), and the resulting mixture was stirred at that temperature for 30 min. Propan-2-one oxime (CAS-No. 127-06-0; 1.12 g, 15.3 mmol) in THF (20 mL) was added to the above mixture and stirred at 25° C. for 2 h. Then TLC analysis (PE/EtOAc=10:1, Rf=0.5) showed complete reaction. The reaction mixture was quenched with NH.sub.4Cl solution (100 mL, sat. aq.), extracted with EtOAc (2×100 mL), and the combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude 2-(isopropylideneamino)oxy-3,5-bis¬(trifluoromethyl)benzonitrile (3.0 g) as a brown oil, which was directly used in the next step without any further purification.

[0268] Step 4: To a solution of crude 2-(isopropylideneamino)oxy-3,5-bis(trifluoromethyl)benzonitrile (3.0 g, 9.7 mmol) in MeOH (10 mL) at 25° C. under a N.sub.2 atmosphere was added HCl/MeOH (150 mL) and SOCl.sub.2 (11.2 g, 9.49 mol), and the reaction mixture was stirred at that temperature for 72 h. Then TLC analysis (PE/EtOAc=5:1, Rf=0.4) showed complete reaction. The reaction mixture was concentrated, and the residue quenched with NaHCO.sub.3 solution (200 mL, sat. aq.) to adjust the pH to 7. The aqueous phase was extracted with EtOAc (2×100 mL), and the combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Purification by column chromatography (PE/EtOAc=10:1, Rf=0.5) afforded 5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-amine (2.0 g, 77%) as a red solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, RT): δ ppm 8.70 (s, 1H), 8.23 (s, 1H), 6.95 (s, 2H).

[0269] Step 5: To a solution of 5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-amine (800 mg, 2.96 mmol) in toluene (10 mL) at 25° C. under a N.sub.2 atmosphere was added Ti(OiPr).sub.4 (2.50 g, 8.88 mmol) and 1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanone (672 mg, 3.55 mmol, Example 8), before the mixture was heated at 100° C. for 16 h. Then LCMS showed complete reaction. Then, and the solution was used directly in the next step without further purification.

[0270] Step 6: To the solution obtained in Step 5 (ca. 10 mL in toluene) was added EtOH (20 mL) and the solution was cooled to 0° C. NaBH(OAc).sub.3 (1.25 g, 3.92 mmol) and Na(CN)BH.sub.3 (372 mg, 3.92 mmol) were added slowly, and the reaction mixture was heated at 50° C. for 16 h. Then LCMS showed that the reaction was complete. The reaction was quenched with H.sub.2O (100 mL), filtered and the filter cake was washed with EtOAC (2×50 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic phases were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by preparative HPLC afforded N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-amine (220 mg, 34%) as a white solid.

[0271] LCMS (Method A): 1.14, 443.7

[0272] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz, RT): δ ppm 9.01 (d, J=4.8Hz, 2H) 8.79 (s, 1 H) 8.21-8.28 (m, 2 H) 8.16 (s, 1H) 7.66 (t, J=4.8Hz, 1H) 5.79 (quin, J=7.1Hz, 1H) 1.73 (d, J=6.7Hz, 3H).

Example 2: Preparation of N-[(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)methyl]-5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-amine [I-2]

[0273] Step 1: To a solution of 5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-amine (1.00 g, 3.70 mmol; cf. Example 1) and ethyl 2-oxoacetate (567 mg, 5.55 mmol) in MeOH (10 mL) at 0° C. was added HSiEt.sub.3 (1.29 g, 11.1 mmol) and F.sub.3CCO.sub.2H (1.27 g, 11.1 mmol), the cooling bath was removed, and the reaction was stirred at ambient temperature for 2 h. Then TLC-analysis (PE/EtOAc=5:1, Rf=0.7) showed the reaction was complete. The mixture was poured into NaHCO.sub.3 solution (20 mL, sat. aq.), the aqueous phase was extracted with CH.sub.2Cl.sub.2 (3×5 mL), and the combined organic extracts were washed with NaCl solution (5 mL, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by silica gel column afforded ethyl 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]amino]acetate (1.30 g, 98%) as a white solid.

[0274] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 8.08 (s, 1H), 8.00 (s, 1H), 5.16 (br s, 1H), 4.33 (q, J=7.1Hz, 2H), 4.23 (d, J=5.3Hz, 2H), 1.38-1.34 (m, 3H).

[0275] Step 2: To a solution of ethyl 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]amino]acetate (1.30 g, 3.65 mmol) in a sealed pot was added NH.sub.3, 7 M in MeOH (20 mL) at ambient temperature before the reaction mixture was heated to 70° C. and stirred at that temperature for 48 h. Then TLC analysis (EtOAc, Rf=0.7) showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, the crude product was triturated with CH.sub.2Cl.sub.2 (8 mL), and filtered to afford 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]amino]acetamide (600 mg, 50%) as a yellow solid.

[0276] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, RT): δ ppm 8.93-8.76 (m, 1H), 8.27 (s, 1H), 7.82 (t, J=5.8Hz, 1H), 7.56 (br s, 1H), 7.17 (br s, 1H), 3.88 (d, J=6.0Hz, 2H).

[0277] Step 3: To a solution of 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]amino]acetamide (300 mg, 0.916 mmol) in CH.sub.2Cl.sub.2 (3.0 mL) at ambient temperature was added N,N-dimethylformamide dimethyl acetal (218 mg, 1.83 mmol) before the reaction mixture was heated to 50° C. and stirred at that temperature for 3 h. Then TLC analysis (EtOAc, Rf=0.6) showed the reaction was complete. The mixture was concentrated under reduced pressure to afford 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]amino]-N-(dimethylaminomethylene)acetamide (350 mg, crude) as yellow oil which was used directly in the next step without any further purification.

[0278] Step 4: To a solution of 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]amino]-N-(dimethylaminomethylene)acetamide (350 mg, 0.92 mmol) in 1,4-dioxane (3.0 mL) at ambient temperature was added pyrimidin-2-ylhydrazine (101 mg, 0.92 mmol), after 5 min added AcOH (3.0 mL), and after additional 5 min the reaction mixture was heated to 80° C. and stirred at that temperature for 1.5 h. Then TLC (EtOAc=100%, Rf=0.5) and LCMS analysis showed the reaction was complete. The mixture was concentrated under reduced pressure, adjusted to pH=7 with NaHCO.sub.3 solution (sat. aq.), the aqueous phase was extracted with EtOAc (3×20 mL), and the combined organic extracts were washed with NaCl solution (10 mL, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated. Purification by column chromatography on silica gel (EtOAc/PE 4:1) followed by trituration with CH.sub.2Cl.sub.2 (3 mL) afforded N-[(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)methyl]-5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-amine [I-2] (194 mg, 49%) as a yellow solid.

[0279] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 8.94 (d, J=4.8Hz, 2H), 8.18 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.43 (t, J=4.8Hz, 1H), 6.14 (br t, J=5.0Hz, 1H), 5.31 (d, J=5.1Hz, 2H).

Example 3: Preparation of N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine [I-3]

[0280] Step 1: To a solution of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (2.26 g, 10 mmol) in THF (20 ml) was added Boc.sub.2O (4.4 g, 20 mmol), NH.sub.4HCO.sub.3 (1.6 g, 20 mmol), pyridine (1.6 g, 20 mmol) and the mixture was stirred at 20° C. for 24 h. Then the resulting reaction mixture was concentrated, diluted with EtOAc (40 mL) and the organic phase was washed with H.sub.2O (50 mL), NaCl solution (50 mL, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 2-chloro-5-(trifluoromethyl)pyridine-3-carboxamide (2 g, crude) as a yellow solid, which was used directly in the next step without further purification.

[0281] Step 2: To a solution of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxamide (1.95 g, 8.7 mmol) in CH.sub.2Cl.sub.2 (40 mL) at 0° C. was added Et.sub.3N (3.6 g, 34.8 mmol) and trifluoroacetic anhydride (3.6 g, 17.4 mmol, CAS-No. 407-25-0) dropwise, before the mixture was allowed to warm to 20° C. and stirred at that temperature for 4 h. The resulting mixture was poured into ice water (100 mL) and the aqueous phase was extracted with CH.sub.2Cl.sub.2 (2×50 mL). The combined organic extracts were washed with NaCl solution (2×50 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by column chromatography (PE/EtOAc=10:1) afforded 2-chloro-5-(trifluoromethyl)pyridine-3-carbonitrile (1.1 g, 53% over 2 steps) as yellow solid.

[0282] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT) δ ppm 8.88 (d, J=1.6Hz, 1 H), 8.25 (d, J=2.4Hz, 1H).

[0283] Step 3: 2-Chloro-5-(trifluoromethyl)pyridine-3-carbonitrile (1 g, 5 mmol), ethanehydroxamic acid (0.45 g, 6 mmol), and K.sub.2CO.sub.3 (1.4 g, 10 mmol) were dissolved in H.sub.2O (30 mL) at 20° C., and the mixture was heated at 60° C. for 6 h. Then the resulting solution was filtered and the filter cake collected to give 5-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine (0.8 g, 80%) as a white solid.

[0284] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz, RT): δ ppm 8.95 (d, J=1.6Hz, 1H), 8.80 (d, J=1.9 Hz, 1H), 6.90 (s, 2H).

[0285] Step 4: To a solution of 5-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine (0.8 g, 4.0 mmol) and 1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanone (0.91 g, 4.8 mmol, prepared according to Example 1) in toluene (10 ml) at 20° C. was added Ti(OiPr)4 (2.25 g, 8 mol), and the mixture was heated at 100° C. for 16 h. Then the reaction temperature was reduced to 50° C., MeOH (3 mL) and NaBH.sub.3(CN) (0.51 g, 8.0 mmol) were added, and stirring was continued at that temperature for 16 h. The reaction mixture was quenched by mixing with ice water (30 mL) and EtOAc (30 mL), followed by stirring for an additional 1 h at 20° C. The quenched reaction mixture was filtered through a pad of celite eluting with EtOAc (30 mL), and the aqueous phase was extracted with EtOAc (30 mL). The combined organic extracts were washed with NaCl solution (30 mL, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by prep-HPLC afforded N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5-(trifluoromethyl)isoxazolo[5,4-b]pyridin-3-amine [I-3] (0.13 g, 9%) as a yellow solid.

[0286] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 8.94 (d, J=4.8Hz, 2H), 8.80 (d, J=1.5Hz, 1H), 8.27 (d, J=1.6Hz, 1H), 8.07 (s, 1H), 7.43 (t, J=4.8Hz, 1H), 6.32-6.20 (m, 1H), 6.03 (br d, J=8.9Hz, 1H), 1.79 (d, J=6.6Hz, 3H).

Example 4: Preparation of 1-methyl-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5-(trifluoromethyl)indazol-3-amine [I-4]

[0287] Step 1: In an autoclave, NaOAc (3.5 g, 42.3 mmol) was added to a solution of methylhydrazine (6 g, 42.3 mmol) in n-BuOH (5 mL) at 25° C., and the resulting mixture was stirred at that temperature for 30 min. Then, 2-fluoro-5-(trifluoromethyl)benzonitrile (4 g, 21.1 mmol) was added, and the mixture was heated at 130° C. for 72 h. Then TLC (PE/EtOAc=3:1, Rf=0.2) showed that the reaction was complete. The reaction mixture was quenched with H.sub.2O (50 mL), the aqueous phase was extracted with EtOAc (3×50 mL), and the combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Trituration with MTBE (100 mL), followed by filtration and collection of the filter cake afforded 1-methyl-5-(trifluoromethyl)indazol-3-amine (3 g, 67%) as a white oil.

[0288] .sup.1H-NMR (CDCl.sub.3, 400 MHz, RT): δ ppm 7.85 (s, 1H), 7.55 (dd, J=8.8, 0.9Hz, 1H), 7.28 (d, J=7.9 Hz, 1H), 4.00-4.28 (m, 2H), 3.89 (s, 3H).

[0289] Step 2: To a solution of 1-methyl-5-(trifluoromethyl)indazol-3-amine (400 mg, 1.86 mmol) in toluene (10 mL) at ambient temperature (RT, 20-25° C.) under a N.sub.2 atmosphere was added Ti(O-iPr).sub.4 (1.5 g, 3.58 mmol), followed by 1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanone (422 mg, 2.83 mmol, prepared according to Example 1), and the mixture was heated to 100° C. for 16 h. Then LCMS showed completion of the reaction, and the mixture was used in the next step as toluene solution without any further purification.

[0290] Step 3: The above toluene solution (ca. 10 mL) was diluted with EtOH (10 mL), cooled to 0° C., NaBH(OAc).sub.3 (788 mg, 3.7 mmol) and Na(CN)BH.sub.3 (233 mg, 3.7 mmol) were slowly added, and the reaction mixture then heated at 50° C. for 16 h. Then LCMS indicated completion of the reaction. The reaction mixture was quenched into H.sub.2O (100 mL), filtered and the filter cake washed with EtOAc (2×50 mL). The aqueous phase was extracted with EtOAc (2×50 mL), and the combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Purification by preparative HPLC afforded 1-methyl-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl] (trifluoromethyl)indazol-3-amine (200 mg, 37%) as a white solid.

[0291] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz, RT): δ ppm 9.03 (d, J=4.9Hz, 2H), 8.25 (s, 1H), 8.07 (s, 1H), 7.67 (t, J=4.9 Hz, 1H), 7.46-7.52 (m, 1H), 7.38-7.44 (m, 1H), 7.08 (d, J=8.9Hz, 1H), 5.74-5.83 (m, 1H), 3.47 (s, 3H), 1.69 (d, J=6.9Hz, 3H).

Example 5: Preparation of 5,7-dichloro-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-1,2-benzothiazol-3-amine [I-5]

[0292] Step 1: To a solution of 2-amino-3,5-dichloro-benzonitrile (200 mg, 1.07 mmol) in MeCN (7 mL) at 0° C. was added a solution of tert-butylnitrite (220 mg, 2.14 mmol) and CuCl.sub.2 (172 mg, 2.14 mmol) in MeCN (2 mL). The resulting reaction mixture was allowed to warm to 25° C. and stirred at that temperature for 16 h. Then TLC (PE/EtOAc=5:1, Rf=0.5) showed the reaction was completed. The reaction mixture was quenched with H.sub.2O (20 mL), the aqueous phase was extracted with EtOAc (2×20 mL), and the combined organic extracts were washed with NaCl solution (20 mL, sat. aq.), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Purification by preparative TLC afforded 2,3,5-trichlorobenzonitrile (176 mg, 88%) as a white solid.

[0293] .sup.1H-NMR (CDCl.sub.3, 400 MHz, RT): δ ppm 7.72 (d, J=2.4Hz, 1H), 7.60 (d, J=2.4Hz, 1H).

[0294] Step 2: To a solution of 2,3,5-trichlorobenzonitrile (600 mg, 2.9 mmol) in DMF (12 mL) at 25° C. was added Na.sub.2S (336 mg, 4.36 mmol), and the resulting mixture was stirred at that temperature for 8 h. Then TLC (PE/EtOAc=5:1, Rf=0.5) showed that the reaction was complete. The reaction mixture was quenched into H.sub.2O (20 mL), the pH adjusted to 3-4 with 2M HCl (10 mL), the aqueous phase extracted with EtOAc (2×20 mL), and the combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Purification by column chromatography (PE/EtOAc=5:1, Rf=0.3) afforded 3,5-dichloro-2-sulfanyl-benzonitrile (700 mg) as a yellow oil.

[0295] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz, RT): δ ppm 7.29 (d, J=2.4Hz, 1H), 7.71 (d, J=2.4Hz, 1H).

[0296] Step 3: To a solution of 3,5-dichloro-2-sulfanyl-benzonitrile (2 g, 9.8 mmol) in NH.sub.3.Math.H.sub.2O (60 mL) at 0° C. was added NaOH solution (ca. 3% in H.sub.2O, 20 mL) and NaOCl solution (ca. 7% in H.sub.2O, 6 mL). The resulting reaction mixture was allowed to warm to 20° C. and stirred at that temperature for 16 h. Then TLC (PE/EtOAc=5:1, Rf=0.2) showed that the reaction was complete. The reaction mixture was quenched into water (100 mL), extracted with EtOAc (2×50 mL), and the combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Purification by column chromatography (PE/EtOAc=5:1, Rf=0.3) afforded 5,7-dichloro-1,2-benzothiazol-3-amine (1.5 g, 75%) as a yellow solid.

[0297] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz, RT): δ ppm 8.27 (d, J=2.0Hz, 1H), 7.88 (d, J=2.0Hz, 1H), 7.20 (d, J=2.0Hz, 2H).

[0298] Step 4: To a solution of 5,7-dichloro-1,2-benzothiazol-3-amine (500 mg, 2.3 mmol) in toluene (10 mL) at 25° C. under a N.sub.2 atmosphere was added Ti(O-iPr).sub.4 (1.3 g, 4.6 mmol), followed by 1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanone (520 mg, 2.7 mmol, prepared according to Example 1), and the mixture was heated at 100° C. for 16 h. Then LCMS showed the reaction was complete. The reaction mixture was used the next step as toluene solution without any purification.

[0299] Step 5: The above toluene solution (ca. 10 mL) was diluted with EtOH (20 mL), cooled to 0° C., NaBH(OAc).sub.3 (970 mg, 4.6 mmol) and Na(CN)BH.sub.3 (285 mg, 4.6 mmol) were added slowly, and the reaction mixture was heated at 50° C. for 16 h. Then LCMS showed that the reaction was completed. The reaction was quenched into H.sub.2O (100 mL), filtered and the filter cake was washed with EtOAc (2×50 mL). The aqueous phase was extracted with EtOAc (2×50 mL), and the combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Purification by prep-HPLC afforded 5,7-dichloro-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-1,2-benzothiazol-3-amine [I-5] (220 mg, 44%) as white solid.

[0300] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz, RT): δ ppm 8.98 (d, J=4.8Hz, 2H), 8.41 (d, J=1.7Hz, 1H), 8.26 (d, J=8.0Hz, 1H), 8.11 (s, 1H), 7.82 (d, J=1.7Hz, 1H), 7.63 (t, J=4.9Hz, 1H), 5.99 (quin, J=7.1Hz, 1H), 1.70 (d, J=6.9Hz, 3H).

Example 6: Preparation of 8-chloro-N-(cyclopropylmethyl)-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine [I-6]

[0301] Step 1: To a solution of 2,3-dichloro-5-(trifluoromethyl)pyridine (5.00 g, 23.2 mmol) in EtOH (50 mL) was added N.sub.2H.sub.4.Math.H.sub.2O (2.36 g, 46.3 mmol) and the reaction mixture was stirred for 6 h at 90° C. Then TLC analysis (PE/EtOAc=1:1) showed the reaction was complete. The reaction mixture was concentrated, the residue extracted with EtOAc (3×50 mL), and the combined organic extracts were washed with NaCl solution (30 mL, sat. aq.), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give [3-chloro-5-(trifluoromethyl)-2-pyridyl]hydrazine (4.6 g, 94%) as white solid.

[0302] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz, RT): δ ppm 4.47 (s, 2H), 7.91 (d, J=2.0Hz, 1H), 8.36 (d, J=0.86Hz, 1H), 8.52 (s, 1H).

[0303] Step 2: To a solution of [3-chloro-5-(trifluoromethyl)-2-pyridyl]hydrazine (3.85 g, 18.3 mmol) in EtOH/H.sub.2O (77 mL/15.4 mL) was added BrCN (2.9 g, 27.4 mmol) in EtOH/H.sub.2O (5.8 mL/1.2 mL) dropwise, and the mixture was stirred at 20° C. for 6 h. Then TLC (PE/EtOAc=1:1) showed that the reaction was complete. The reaction mixture was concentrated, the residue quenched with H.sub.2O (20 mL), the aqueous phase extracted with EtOAc (2×30 mL), and the combined organic phases were washed with NaCl solution (30 mL, sat. aq.), dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE/EtOAc=100:0 to 45:55, gradient) afforded 8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (2.2 g, 51%) as yellow solid. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz, RT): δ ppm 6.84-6.90 (m, 2H), 7.50-7.54 (m, 1H), 8.77-8.80 (m, 1H).

[0304] Step 3: To a solution of 8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1 g, 4.2 mmol) and 1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanone (800 mg, 4.2 mmol, prepared according to Example 1) in toluene (20 mL) was added Ti(OiPr).sub.4 (0.91 g, 3.2 mmol) and the mixture was heated at 110° C. for 4 h. Then TLC analysis (PE/EtOAc=1:1) showed that the reaction was complete. The mixture was cooled to 20-25° C., EtOH (10 mL) and NaBH.sub.3CN (2.7 g, 42 mmol) were added, and the resulting mixture was stirred at 40° C. for 16 h, then TLC analysis (DCM/MeOH=10:1) showed the reaction was complete. The reaction mixture was quenched with H.sub.2O (15 mL), filtered, the filtrate was extracted with EtOAc (3×10 mL), and the combined organic phases were washed with NaCl solution (20 mL, sat. aq.), dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. Purification by silica gel column chromatography (DCM/MeOH=100:0 to 12:88, gradient) to give 8-chloro-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1.3 g, 75%).

[0305] .sup.1H-NMR (CDCl.sub.3, 400 MHz, RT): δ ppm 1.81 (d, J=6.8Hz, 3H), 6.32 (d, J=9.4Hz, 1H), 6.44 (dd, J=9.38, 6.8Hz, 1H), 7.20 (d, J=1.0Hz, 1H), 7.40 (t, J=4.9Hz, 1H), 8.01 (s, 1H), 8.18 (s, 1H) 8.90 (d, J=4.8Hz, 2H).

[0306] Step 4: To a solution of 8-chloro-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine (1.3 g, 3.2 mmol) in DMF (13 mL) at 0° C. was added NaH (4.8 g, 4.8 mmol) portion wise, and the mixture was stirred at that temperature for 0.5 h. (bromomethyl)cyclopropane (0.8 mL, 6.4 mmol) was added, and the resulting mixture was allowed to slowly warm to ambient temperature over 4 h. Then TLC analysis (DCM/MeOH=10:1) showed that the reaction was complete. The reaction mixture was quenched with NH.sub.4Cl solution (8 mL, sat. aq.), extracted with EtOAc (3×10 mL), and the combined organic extracts were washed with NaCl solution (15 mL, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by preparative HPLC afforded the title 8-chloro-N-(cyclopropylmethyl)-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine [I-6] (210 mg, 14%) as a yellow solid.

[0307] .sup.1H-NMR (CDCl.sub.3, 400 MHz, RT): δ ppm 8.52 (br s,1H), 8.36 (br d, J=4.4Hz, 2H), 7.94 (s, 1H), 7.43 (s, 1H), 6.81 (t, J=4.8Hz, 1H), 6.34-6.50 (m, 1H), 3.82 (br d, J=7.0Hz, 2H), 1.89 (br d, J=7.1Hz, 3H), 1.11 (br dd, J=5.9, 2.2Hz, 1H), 0.47-0.69 (m, 2H), 0.25 (br d, J=3.6 Hz, 2H).

Example 7: Preparation of 2-methyl-5-(1,1,2,2,2-pentafluoroethyl)-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-4-(trifluoromethyl)pyrazol-3-amine [I-7]

[0308] Step 1: To a solution of 5-fluoro-1-methyl-3-(1,1,2,2,2-pentafluoroethyl)-4-(trifluoromethyl)pyrazole (75.2 mg, 0.263 mmol, CAS-No. 104315-28-8) and 1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine (50.0 mg, 0.263 mmol, prepared according to WO2017/192385) in MeCN (3.0 mL) at ambient temperature was added Cs.sub.2CO.sub.3 (171 mg, 0.525 mmol), and the resulting reaction mixture was heated at 65° C. for 10 h. Then the reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography (CyH/EtOAc 100:0 to 0:100, gradient) to give the title 2-methyl-5-(1,1,2,2,2-pentafluoroethyl)-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-4-(trifluoromethyl)pyrazol-3-amine [I-7] (28.0 mg, 22%) as a slightly yellowish oil.

[0309] .sup.1H-NMR (CDCl.sub.3, 400 MHz, RT): δ ppm 8.30 (s, 1H), 8.29 (s, 2H), 6.58 (t, J=4.8Hz, 1H), 5.90 (d, J=8.2Hz, 1H), 5.49 (dq, J=8.3, 6.9Hz, 1H), 3.78 (s, 3H), 1.70 (d, J=6.9 Hz, 3H).

Example 8: Preparation of 1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethenone

[0310] Step 1: To a solution of 2-hydroxypropanamide (7 g, 79 mmol) in CH.sub.2Cl.sub.2 (100 mL) at 25° C. under a N.sub.2 atmosphere was added dimethylformamide dimethylacetal (24 g, 200 mmol, CAS-No. 4637-24-5), and the reaction mixture was heated at 50° C. for 2 h. Then TLC analysis (EtOAc, Rf=0.1) showed that the reaction was complete, and the resulting solution was concentrated to give crude N-(dimethylaminomethylene)-2-hydroxy-propanamide (12 g) as a yellow oil, which was used in the next step without further purification.

[0311] Step 2: To a solution of N-(dimethylaminomethylene)-2-hydroxy-propanamide (7 g, 63 mmol) in a mixture of 1,4-dioxane (90 mL) and AcOH (90 mL) at 90° C. was added a solution of pyrimidin-2-ylhydrazine (12 g, 85 mmol) in 1,4-dioxane (90 mL) dropwise, and stirring was continued at 90° C. for 2 h. Then TLC (PE/EtOAc=3:1, Rf=0.4) showed the reaction was complete. The resulting reaction mixture was concentrated under reduced pressure, and the residue quenched with Na-HCO.sub.3 solution (200 mL, sat. aq.). The aqueous phase was extracted with CH.sub.2Cl.sub.2/i-PrOH (3:1, 3×100 mL), and the combined organic extracts dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by column chromatography (EtOH/EtOAc=1:3, Rf=0.3) afforded 1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanol (5.2 g, 35%) as yellow solid.

[0312] .sup.1H-NMR (CDCl.sub.3, 400 MHz, RT): δ ppm 8.92 (d, J=4.9Hz, 2H), 8.05 (s, 1H), 7.44 (t, J=4.9Hz, 1H), 5.24-5.37 (m, 1H), 5.18 (d, J=5.1Hz, 1H), 1.76 (d, J=6.7Hz, 3H).

[0313] Step 3: To a solution of 1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanol (5.2 g, 27.2 mmol) in CH.sub.2Cl.sub.2 (200 mL) at 0° C. was added Dess-Martin-Periodinane (CAS-No. 87413-09-0; 17 g, 42.8 mmol) slowly under N.sub.2, before the reaction mixture was allowed to warm to 25° C. and stirred at that temperature for 16 h. Then TLC analysis (EtOAc, Rf=0.4) showed that the reaction was complete. The resulting solution was quenched into H.sub.2O (100 mL), extracted with DCM (3×100 mL), and the combined organic extracts were washed with NaHCO.sub.3 solution (2×200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Purification by column chromatography (PE/EtOAc=1:1, Rf=0.23) afforded 1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethenone (3.5 g, 69% yield) as a yellow solid.

[0314] .sup.1H-NMR (CDCl.sub.3, 400 MHz, RT): δ ppm 8.85 (d, J=4.9Hz, 2H), 8.13 (s, 1H), 7.45 (t, J=4.9Hz, 1H), 2.76 (s, 3H).

Example 9: Preparation of 5,7-dichloro-1-oxo-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-1,2-benzothiazol-3-amine [I-8] and 5,7-dichloro-1,1-dioxo-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-1,2-benzothiazol-3-amine [I-9]

[0315] Step 1: To a solution of 5,7-dichloro-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-1,2-benzothiazol-3-amine [I-5] (900 mg, 2.6 mmol) in CH.sub.2Cl.sub.2 (10 mL) at ambient temperature was added meta-chloroperoxybenzoic acid (660 mg, 3.9 mmol) and stirring was continued at that temperature for 20 h. After that time, the reaction mixture was quenched with H.sub.2O (100 mL), the aqueous phase extracted with DCM/i-PrOH 3:1 (3×100 mL), and the combined organic extracts were dried over Na.sub.2SO.sub.4, filtered, and concentrated.

[0316] Purification by preparative HPLC afforded 5,7-dichloro-1,1-dioxo-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-1,2-benzothiazol-3-amine [I-9] (116 mg, 11%) as a yellow solid and 5,7-dichloro-1-oxo-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-1,2-benzothiazol-3-amine [I-8] (65 mg, 6.1%) as yellow solid.

[0317] [I-9]: .sup.1H-NMR (400 MHz, DMSO-d.sub.6, RT): δ ppm 8.92 (d, J=4.8Hz, 2H), 8.23 (s, 1H), 8.18 (br s, 1H), 8.06 (d, J=1.2Hz, 1H), 7.59 (t, J=4.8Hz, 1H), 6.04 (q, J=6.9Hz, 1H), 1.69 (d, J=6.8Hz, 3H).

[0318] [I-8]: .sup.1H-NMR (400 MHz, DMSO-d.sub.6, RT): δ ppm 9.58-9.45 (m, 1H), 9.02-8.93 (m, 2H), 8.42-8.34 (m, 1H), 8.25-8.18 (m, 1H), 7.98 (d, J=1.3Hz, 1H), 7.67-7.58 (m, 1H), 6.26-6.10 (m, 1H), 1.78-1.67 (m, 3H).

Example 10: tert-butyl 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-methoxycarbonyl-amino]propanoate

[0319] Step 1: To a solution of tert-butyl 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-methoxycarbonyl-amino]-acetate (550 mg, 1.24 mmol, cf. Example 15) in CH.sub.2Cl.sub.2 (16 mL) at −60° C. under a N.sub.2 atmosphere was added potassium bis(trimethylsilyl)amide (1.86 mL, 1.86 mmol), followed after 0.5 h by the dropwise addition of MeOTf (408 mg, 2.49 mmol). The resulting reaction mixture was stirred between −60° C. to 0° C. for 12 h, then TLC analysis (PE/EtOAc=5:1) showed the reaction was complete. The reaction mixture was poured into an ice cooled NH.sub.4Cl solution (100 mL, sat. aq.), the aqueous phase was extracted with CH.sub.2Cl.sub.2 (3×50 mL), and the combined organic extracts were washed with NaCl solution (sat. aq.), dried over Na.sub.2SO.sub.4, filtrated and concentrated under reduced pressure. Purification by column chromatography on silica gel (EtOAc/PE 0:100 to 7:93, gradient) afforded tert-butyl 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-methoxycarbonyl-amino]propanoate contaminated with starting material (450 mg).

[0320] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 8.33 (s, 1H), 8.05 (s, 1H), 4.99 (q, J=7.15Hz, 1H), 3.87 (s, 3H), 1.63 (d, J=7.28Hz, 3H), 1.42 (s, 9H).

[0321] The above tert-butyl 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-methoxycarbonylamino]propanoate could, after acidic Boc-cleavage, then be further elaborated into e.g. compound 1-36 analogously as described in Example 11.

Example 11: Preparation of N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)propyl]-5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-amine [I-28]

[0322] Step 1: To a solution of 5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-amine (270 mg, 1.00 mmol; cf. Example 1) and ethyl 2-oxobutanoate (195 mg, 1.50 mmol) in 1,2-dichloroethane (3.0 mL) at ambient temperature was added Et.sub.3SiH (349 mg, 3.00 mmol) and F.sub.3CCO.sub.2H (342 mg, 11.1 mmol) before the reaction mixture was heated to 80° C. and stirred at that temperature for 36 h. Then TLC analysis (PE/EtOAc=5:1, Rf=0.6) showed the reaction was complete. The mixture was poured into H.sub.2O (10 mL), the aqueous phase extracted with CH.sub.2Cl.sub.2 (3×5 mL), and the combined organic extracts were washed with NaCl solution (5 mL, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by silica gel column (EtOAc in PE=7%) afforded ethyl 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]amino]butanoate (300 mg, 86%) as a white solid.

[0323] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 8.06 (s, 1H), 7.96 (s, 1H), 5.40 (br d, J=7.6 Hz, 1H), 4.60-4.42 (m, 1H), 4.39-4.21 (m, 2H), 2.21-2.08 (m, 1H), 1.93 (qd, J=7.2, 14.0Hz, 1H), 1.36 (t, J=7.1Hz, 3H), 1.03 (t, J=7.4Hz, 3H).

[0324] Step 2: To a solution of ethyl 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]amino]butanoate (1.5 g, 3.91 mmol) in THF (20 mL) at 0° C. was added LiOHH.sub.2O (328 mg, 7.80 mmol) in H.sub.2O (10 mL), before the reaction mixture was allowed to warm to ambient temperature and stirred at that temperature for 3 h. Then TLC analysis (PE/EtOAc=1:1, Rf=0.5) showed the reaction was complete. The mixture was poured into H.sub.2O (20 mL), the aqueous phase extracted with EtOAc (3×30 mL), and the combined organic extracts were washed with NaCl solution (10 mL, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (PE/EtOH=3:1) afforded 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]amino]butanoic acid (1.2 g, 86%) as a yellow solid.

[0325] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, RT): δ ppm 8.96 (s, 1H), 8.32-8.19 (m, 1H), 7.95 (s, 1H), 7.71 (br d, J=8.0Hz, 1H), 4.09-3.94 (m, 1H), 2.01-1.70 (m, 2H), 0.99 (t, J=7.4Hz, 3H)

[0326] Step 3: To a solution of 2[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]amino]butanoic acid (1.20 g, 3.40 mmol) in THF (10 mL) at ambient temperature was added Boc2O (1.46 g, 6.80 mmol), pyridine (529 mg, 6.80 mmol) and NH.sub.4HCO.sub.3 (529.3 mg, 6.8 mmol), and the reaction mixture was stirred at that temperature for 16 h. Then TLC analysis (PE/EtOAc=1:1, Rf=0.4) showed the reaction was complete. The mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (EtOAc in PE=70%) to give 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]amino]butanamide (1.0 g, 83%) as a yellow solid.

[0327] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, RT): δ ppm 8.93 (s, 1H), 8.30-8.18 (m, 1H), 7.65-7.55 (m, 2H), 7.11 (s, 1H), 4.37 (t, J=5.1Hz, 1H), 1.92-1.67 (m, 2H), 1.17 (t, J=7.1Hz, 3H).

[0328] Step 4: To a solution of 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]amino]butanamide (1.0 g, 2.8 mmol) in CH.sub.2Cl.sub.2 (10 mL) at ambient temperature was added N,N-dimethylformamide dimethyl acetal (672 mg, 5.64 mmol) before the resulting reaction mixture was heated to 50° C. and stirred at that temperature for 2 h. Then TLC analysis (EtOAc, Rf=0.6) showed the reaction was complete. The mixture was concentrated under reduced pressure to give 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]amino]-N-(dimethylaminomethylene)butanamide (1.2 g, crude) as a yellow oil, which was used directly in the next step without any further purification.

[0329] Step 5: To a solution of 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]amino]-N-(dimethylaminomethylene)butanamide (1.2 g, 2.9 mmol) in 1,4-dioxane (4.0 mL) at ambient temperature was added pyrimidin-2-ylhydrazine (321 mg, 2.92 mmol) and, after stirring for additional 5 min, AcOH (4 mL), before the reaction mixture was heated to 80° C. and stirred at that temperature for 1.5 h. Then the mixture was concentrated under reduced pressure, adjusted the pH =7 with Na—HCO.sub.3 (sat. aq.), extracted the aqueous phase with EtOAc (3×30 mL), and the combined organic extracts were washed with NaCl solution (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. Purification by preparative HPLC (TFA) afforded N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)propyl]-5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-amine [I-28] (441 mg, 33%) as a white solid.

[0330] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 8.97 (d, J=4.9Hz, 2H), 8.14 (s, 2H), 7.93 (s, 1H), 7.49 (t, J=4.8Hz, 1H), 6.68 (br d, J=9.7Hz, 1H), 6.23 (dt, J=4.9, 8.8Hz, 1H), 2.32-2.21 (m, 1H), 2.11 (quint, J=7.4, 14.6Hz, 1H), 1.17 (t, J=7.4Hz, 3H).

Example 12: Preparation of 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]amino]ethyl benzoate [I-39]

[0331] Preparation of 2-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethylamino]ethyl benzoate:

[0332] Step 1: To a mixture of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (100 g, 0.76 mol) and Et.sub.3N (76 g, 0.76 mol) in CH.sub.2Cl.sub.2 (1.0 L) at 0° C. under a N.sub.2 atmosphere was added PhC(O)Cl (106 g, 0.76 mol) dropwise, the cooling bath was removed, and the reaction mixture was stirred at ambient temperature for 6 h. Then the organic phase was washed with H.sub.2O (1 L) and NaCl solution (1L, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was re-dissolved in MeOH (1 L), Amberlyst-15 (100 g) was added at ambient temperature, and the resulting mixture was stirred at that temperature for 16 h. TLC analysis (PE/EtOAc=1:1, Rf=0.4) showed the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated to afford 2,3-dihydroxypropyl benzoate (110 g, crude) as a colorless oil, which could be used in the next step without further purification.

[0333] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 8.11-8.00 (m, 2H), 7.62-7.52 (m, 1H), 7.50-7.40 (m, 2H), 4.51-4.33 (m, 2H), 4.12-4.05 (m, 1H), 3.86-3.64 (m, 2H).

[0334] Step 2: To a mixture of 2,3-dihydroxypropyl benzoate (65 g, 0.33 mol) and NalO.sub.4 (141 g, 0.66 mol) in CH.sub.2Cl.sub.2 (600 mL) at ambient temperature was added NaHCO.sub.3 (30 mL, sat. aq.), and the resulting reaction mixture was stirred at that temperature for 6 h. Then TLC analysis (PE/EtOAc=1:1, Rf=0.4) showed the reaction was complete. The mixture was dried over Na.sub.2SO.sub.4 and concentrated to give 2-oxoethyl benzoate (55 g, crude) as colorless oil, which could be used directly in the next step without further purification.

[0335] Step 3: To a solution of 1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine (45 g, 0.20mo1, prepared as described in WO2017/192385) in MeOH (500 mL) at ambient temperature was added Et.sub.3N (20 g, 0.20 mol), 2-oxoethyl benzoate (49 g, 0.30 mol), and 4A MS (100 g). After 10 min, NaCNBH.sub.3 (37 g, 0.6 mol) was added in small potions and stirring was continued at that temperature for 16 h. Then TLC analysis (EtOAc/EtOH=3:1, Rf=0.5) showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (EtOH/EtOAc=30%) and preparative HPLC (NH.sub.4HCO.sub.3) afforded 2-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethylamino]ethyl benzoate (21 g, 31%) as a colorless oil.

[0336] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, RT): δ ppm 8.95 (d, J=4.9Hz, 2H), 8.15 (s, 1H), 7.91-7.84 (m, 2H), 7.66-7.55 (m, 2H), 7.53-7.42 (m, 2H), 4.74 (q, J=6.6Hz, 1H), 4.25-4.11 (m, 2H), 2.84-2.65 (m, 2H), 2.59 (br s, 1H), 1.43 (d, J=6.8Hz, 3H).

Preparation of 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]amino]ethyl benzoate [I-39]

[0337] Step 1: A mixture of 2-chloro-1-iodo-3,5-bis(trifluoromethyl)benzene (50 g, 0.13mol), Et.sub.3N (27 g, 0.27 mol), Pd(OAc).sub.2 (1.0 g, cat.), and 1,1′-bis(diphenylphosphino)ferrocene (1.0 g, cat.) in MeOH (300 mL)/MeCN (1.2 L), under a CO atmosphere (gas, 50 psi) was heated to 50° C. and stirred at that temperature for 12 h. Then TLC analysis (PE, Rf=0.4) showed the reaction was complete. The mixture was concentrated under reduced pressure and purified by column chromatography (PE) to give methyl 2-chloro-3,5-bis(trifluoromethyl)benzoate (37 g, 89%) as a yellow oil. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, RT): δ ppm 8.47 (s, 1H), 8.35 (s, 1H), 3.93 (s, 3H).

[0338] Step 2: To a solution of methyl 2-chloro-3,5-bis(trifluoromethyl)benzoate (110 g, 0.36 mmol) in THF (1.0 L) at ambient temperature and under a N.sub.2 atmosphere was added NaOMe (29 g, 0.54 mol) in one potion, and the resulting reaction mixture was stirred at that temperature for 16 h. Then TLC analysis (PE/EtOAc=10:1, Rf=0.6) showed the reaction was complete. The mixture was concentrated, the residue was diluted with NH.sub.4Cl solution (1 L, sat. aq.), the aqueous phase was extracted with EtOAc (2×500 mL), and the combined organic extracts were washed with NaCl solution (1 L, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by column chromatography (EtOAc/PE 5:95) afforded methyl 2-methoxy-3,5-bis(trifluoromethyl)benzoate (100 g, 92%) as colorless oil.

[0339] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 8.30 (d, J=2.1Hz, 1H), 8.01 (d, J=2.3Hz, 1H), 4.00 (s, 3H), 3.99 (s, 3H).

[0340] Step 3: To a solution of methyl 2-methoxy-3,5-bis(trifluoromethyl)benzoate (100 g, 0.33 mmol) in CH.sub.2Cl.sub.2 (1.0 L), at ambient temperature and under a N.sub.2 atmosphere, was added BBr.sub.3 (124 g, 0.50 mol) dropwise and the resulting reaction mixture was stirred at that temperature for 2 h. Then TLC analysis (EtOAc/PE 10:90, Rf=0.4) showed the reaction was complete. The mixture was poured into ice water (1.5 L), the aqueous phase was extracted with CH.sub.2Cl.sub.2 (2×500 mL), and the combined organic extracts were washed with NaCl solution (1 L, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by column chromatography (EtOAc/PE 10:90) afforded methyl 2-hydroxy-3,5-bis(trifluoromethyl)benzoate (67 g, 70%) as a white solid.

[0341] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 11.9 (s, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 4.08-4.03 (m, 3H).

[0342] Step 4: To a solution of methyl 2-hydroxy-3,5-bis(trifluoromethyl)benzoate (26 g, 90 mmol) in THF (300 mL) at ambient temperature was added NaBH.sub.4 (10 g, 270 mmol) in portions before the reaction mixture was heated to 60° C. and stirred at that temperature for 16 h. Then TLC analysis (PE/EtOAc 10:1, Rf=0.2) showed the reaction was complete. The mixture was poured into NH.sub.4Cl solution (500 mL, sat. aq.), the aqueous phase was extracted with EtOAc (500 mL), and the organic extracts were washed with NaCl solution (500 mL, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by column chromatography (EtOAc/PE 30:70) afforded 2-(hydroxymethyl)-4,6-bis(trifluoromethyl)phenol (15.5 g, 66%) as white solid.

[0343] Step 5: To a mixture of 2-(hydroxymethyl)-4,6-bis(trifluoromethyl)phenol (31 g, 0.12mol) in CH.sub.2Cl.sub.2 (300 mL) at 0° C. was added DMP (101 g, 0.24mo1; CAS-No. 87413-09-0) in portions before the cooling bath was removed and the reaction mixture stirred at ambient temperature for 4 h. Then TLC analysis (PE/EtOAc=10:1, Rf=0.5) showed the reaction was complete. The mixture was poured into Na.sub.2SO.sub.3 (1.5 L, sat. aq.), the aqueous phase extracted with CH.sub.2Cl.sub.2 (2×500 mL), and the combined organic extracts were washed with NaCl solution (500 mL, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by column chromatography (EtOAc/PE 20:80) afforded 2-hydroxy-3,5-bis(trifluoromethyl)benzaldehyde (14 g, 46%) as yellow oil.

[0344] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 12.1 (s, 1H), 10.0 (s, 1H), 8.07 (s, 2H).

[0345] Step 6: To a mixture of 2-hydroxy-3,5-bis(trifluoromethyl)benzaldehyde (14 g, 54 mmol) and HONH.sub.2.Math.HCl (4.5 g, 65 mmol) in EtOH (14 mL) at ambient temperature was added NaOAc (6.6 g, 81 mmol) and the resulting reaction mixture was stirred at that temperature for 2 h. Then TLC analysis (PE/EtOAc=10:1, Rf=0.4) showed that the reaction was complete. The mixture was concentrated under reduced pressure, the residue was diluted with H.sub.2O (200 mL), the aqueous phase was extracted with EtOAc (2×100 mL), and the combined organic extracts were washed with NaCl solution (1 L, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated. Purification by column chromatography (EtOAc/PE 25:75) afforded 2-hydroxy-3,5-bis(trifluoromethyl)benzaldehyde oxime (7.0 g, 47%) as a yellow solid.

[0346] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, RT): δ ppm 12.2 (brs, 1H), 12.0 (brs, 1H), 8.60 (s, 1H), 8.16 (d, J=1.3Hz, 1H), 7.88 (s, 1H).

[0347] Step 7: To a solution of 2-hydroxy-3,5-bis(trifluoromethyl)benzaldehyde oxime (273 mg, 1.0 mmol) in DMF (3.0 mL) at 15° C. under a N.sub.2 atmosphere was added N-chlorosuccinimide (266 mg, 2.0 mmol) and the resulting reaction mixture was stirred at that temperature for 2 h, before it was heated at 35° C. for an additional 0.5 h. Then TLC analysis (PE/EtOAc=10:1) showed that the reaction was complete. The mixture was poured into H.sub.2O (10 mL), the aqueous phase was extracted with CH.sub.2Cl.sub.2 (10 mL), and the organic extracts were washed with HCl solution (10 mL, 0.5N in H.sub.2O) and NaCl solution (10 mL, sat. aq.), dried over Na.sub.2SO.sub.4, and filtered. Concentration under reduced pressure afforded 2-dihydroxy-3,5-bis(trifluoromethyl)benzimidoyl chloride (308 mg, crude) as yellow oil which was directly used in the next step omitting any intermediate storage.

[0348] Step 8: To a solution of 2-dihydroxy-3,5-bis(trifluoromethyl)benzimidoyl chloride (308 mg, 1.0 mmol) in CH.sub.2Cl.sub.2 (10 mL) at 0° C. and under a N.sub.2 atmosphere was added a solution of 2-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethylamino]ethyl benzoate (338 mg, 1.0 mmol) and iPr.sub.2NEt (142 mg, 1.1 mmol), and the resulting reaction mixture was stirred between 0-15° C. for 12 h. Then the mixture was poured into H.sub.2O (20 mL), the aqueous phase was extracted with CH.sub.2Cl.sub.2 (2×20 mL), and the combined organic extracts were washed with HCl solution (20 mL, 0.5N in H.sub.2O) and NaCl solution (20 mL, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford 2-[[N-hydroxy-C-[2-hydroxy-3,5-bis(trifluoromethyl)phenyl]carbon-imidoyl-]-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]amino]ethyl benzoate (400 mg, crude) as yellow oil.

[0349] Step 9: To a solution of 2-[[N-hydroxy-C-[2-hydroxy-3,5-bis(trifluoromethyl)phenyl]carbon-imidoyl-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]amino]ethyl benzoate (400 mg, 0.657 mmol) in THF (10 mL) at 15° C. under a N.sub.2 atmosphere was added 1,1′-carbonyldiimidazole (213 mg, 1.31 mmol), and the resulting reaction mixture was stirred at that temperature for 12 h. The mixture was poured into H.sub.2O (20 mL), the aqueous phase was extracted with EtOAc (2×20 mL), and the combined organic extracts were washed with NaCl solution (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. Purification by column chromatograph on silica gel (THF/PE =0:100 to 50:50, gradient) afforded 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]amino]ethyl benzoate [I-39] (80 mg, 20%) as a yellow solid.

[0350] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 8.71 (br d, J=4.63Hz, 2H), 8.06 (s, 1H), 7.89-7.93 (m, 2H), 7.66 (s, 1H), 7.49-7.55 (m, 2H), 7.34-7.39 (m, 2H), 7.30 (t, J=4.82Hz, 1H), 6.75 (q, J=7.09Hz, 1H), 4.53 (t, J=5.88Hz, 2H), 4.06-4.16 (m, 2H), 1.91 (d, J=7.13Hz, 3H).

Example 13: Preparation of 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]amino]ethanol [I-40]

[0351] Step 1: To a solution of 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]amino]ethyl benzoate [I-39] (110 mg, 0.186 mmol; cf. Example 12) in MeOH (5 mL) at 15° C. was added K.sub.2CO.sub.3 (51 mg, 0.372 mmol) and the resulting reaction mixture was stirred at that temperature for 3 h. Then the mixture was poured into NH.sub.4Cl solution (10 mL, sat. aq.), the aqueous phase was extracted with EtOAc (2×15 mL), and the combined organic extracts were washed with NaCl solution (20 mL, sat. aq.), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral, MeCN-H.sub.2O) to give 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]amino]ethanol [I-40] (80 mg, 44%) as a yellow solid.

[0352] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 8.91 (d, J=4.88Hz, 1H), 8.88-8.93 (m, 1H), 8.20 (br s, 1H), 8.06 (s, 1H), 7.75 (d, J=1.38Hz, 1H), 7.42 (t, J=4.88Hz, 1H), 7.36 (s, 1H), 6.70 (q, J=7.13Hz, 1H), 4.60 (t, J=7.94Hz, 2H), 3.84-4.18 (m, 2H), 1.72 (d, J=7.13Hz, 3H).

Example 14: Preparation of N-(2-methoxyethyl)-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-amine [I-41]

[0353] Step 1: To a solution of 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]amino]ethanol [I-40] (100 mg, 0.205 mmol, cf. Example 13) in MeCN (1.5 mL) at 15° C. was added Ag.sub.2O (118 mg, 0.512 mmol) and Mel (58 mg, 0.41 mmol), and the resulting reaction mixture was stirred at that temperature for 12 h. Then the mixture was filtered, and the filtrate was concentrated and purified by preparative TLC (EtOAc=100%) to give N-(2-methoxyethyl)-N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-amine [I-41] (60 mg, 58%) as a yellow solid.

[0354] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 8.85 (d, J=4.88Hz, 2H), 8.05 (s, 1H), 7.32-7.39 (m, 3H), 6.48 (q, J=7.09Hz, 1H), 4.42 (t, J=7.69Hz, 2H), 4.07 (q, J=8.17Hz, 1H), 3.80 (q, J=7.42Hz, 1H), 3.59 (s, 3H), 1.79 (d, J=7.13Hz, 3H).

Example 15: tert-butyl 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-methoxycarbonyl-amino]acetate

[0355] Step 1: To a solution of 5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-amine (1.50 g, 5.55 mmol) in THF (15 mL) at 0° C. under a N.sub.2 atmosphere was added potassium bis(trimethylsilyl)amide (1.0M in THF, 11.1 mL, 11.1 mmol), followed after 0.5 h by the dropwise addition of methyl chloroformate (1.57 g, 16.7 mmol), and the resulting reaction mixture was stirred between 0-25° C. for 12 h. Then TLC analysis (PE/EtOAc=5:1) showed the reaction was complete. The reaction mixture was poured into H.sub.2O (50 mL), the aqueous phase was extracted with EtOAc (2×50 mL), and the combined organic extracts were washed with NaCl solution (sat. aq.), dried over Na.sub.2SO.sub.4, filtrated, and concentrated under reduced pressure. Purification by column chromatography on silica gel (EtOAc/PE=0:100 to 15:85, gradient) afforded methyl N-[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-N-methoxycarbonyl-carbamate (1.4 g, 65%) as a yellow solid.

[0356] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 8.91 (s, 1H), 8.12 (s, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 7.70 (br s, 1H), 3.94 (s, 3H), 3.87 (s, 6H).

[0357] Step 2: To a solution of methyl N-[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-N-methoxycarbonyl-carbamate (1.0 g, 2.6 mmol) in MeCN (30 mL) at ambient temperature under a N.sub.2 atmosphere was added tert-butyl 2-bromoacetate (1.52 g, 7.77 mmol) and K.sub.2CO.sub.3 (1.07 g, 7.77 mmol), before the mixture was heated to 80° C. and stirred at that temperature for 16 h. Then TLC (PE/EtOAc=5:1) showed the reaction was completed. The reaction mixture was poured into H.sub.2O (50 mL), the aqueous phase was extracted with EtOAc (2×30 mL), and the combined organic extracts were washed with NaCl solution (sat. aq.), dried over Na.sub.2SO.sub.4, filtrated, and concentrated under reduced pressure. Purification by column chromatograph on silica gel (EtOAc/PE 0:100 to 10:90, gradient) afforded tert-butyl 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-methoxycarbonyl-amino]acetate (1.2 g) as white solid.

[0358] .sup.1H-NMR (400 MHz, CDCl.sub.3, RT): δ ppm 8.52 (br s, 1H), 8.04 (s, 1H), 4.61 (s, 2H), 3.94 (s, 3H), 1.48 (s, 9H).

[0359] The above tert-butyl 2-[[5,7-bis(trifluoromethyl)-1,2-benzoxazol-3-yl]-methoxycarbonyl-amino]-acetate could, after acidic Boc-cleavage, then be further elaborated into e.g. compound 1-35 analogously as described in Example 11 above.

##STR00022##

TABLE-US-00002 TABLE 1 (the dotted line in R.sup.3 denotes the bond to the core structure of formula I*) phys. data [HPLC Rt [min], M + H HPLC No. R.sup.1 R.sup.2 R.sup.3 Q R.sup.51 R.sup.52 R.sup.53 [m/z]] method I-1 H CH.sub.3 [00023] Q1 CF.sub.3 CF.sub.3 — 1.14, 443.7 A I-2 H H [00024] Q1 CF.sub.3 CF.sub.3 — 1.14, 429.9 A I-3 H CH.sub.3 [00025] Q2 CF.sub.3 — — 0.93, 377.0 A I-4 H CH.sub.3 [00026] Q3 H CF.sub.3 CH.sub.3 1.01, 388.7 A I-5 H CH.sub.3 [00027] Q4 Cl Cl — 1.16, 391.7 A I-6 CH.sub.2—c-C.sub.3H.sub.5 CH.sub.3 [00028] Q5 Cl CF.sub.3 — 1.05, 463.8 A I-7 H CH.sub.3 [00029] Q10 CH.sub.3 CF.sub.3 C.sub.2F.sub.5 1.06, 456.8 A I-8 H CH.sub.3 [00030] Q19 Cl Cl — 0.82, 407.7 A I-9 H CH.sub.3 [00031] Q7 Cl Cl — 0.89, 423.7 A I-10 H CH.sub.3 [00032] Q1 CF.sub.3 H — 0.99, 376.0 A I-11 CH.sub.2—c-C.sub.3H.sub.5 CH.sub.3 [00033] Q5 CF.sub.3 Cl — 1.05, 463.9 A I-12 H CH.sub.3 [00034] Q5 Cl CF.sub.3 — 0.88, 409.9 A I-13 H CH.sub.3 [00035] Q5 CF.sub.3 Cl — 0.86, 409.8 A I-14 H CH.sub.3 [00036] Q20 CF.sub.3 H — 0.88, 325.7 A I-15 H CH.sub.3 [00037] Q1 H CF.sub.3 — 0.99, 376.0 A I-16 H CH.sub.3 [00038] Q3 Cl Cl CH.sub.3 1.09, 389.0 A I-17 H CH.sub.3 [00039] Q1 CF.sub.3 CF.sub.3 — 1.28, 523.9 A I-18 H CH.sub.3 [00040] Q1 CF.sub.3 CF.sub.3 — 1.21, 375.0 A I-19 H CH.sub.3 [00041] Q6 Br — — 0.84, 388.8 A I-20 CH.sub.2CH.sub.2—OCH.sub.3 CH.sub.3 [00042] Q1 CF.sub.3 CF.sub.3 — 1.21, 501.9 A I-21 H CH.sub.3 [00043] Q1 CF.sub.3 CF.sub.3 — 1.31, 511.9 A I-22 H CH.sub.3 [00044] Q1 CF.sub.3 CF.sub.3 — 1.42, 510.9 A I-23 H CH.sub.3 [00045] Q1 CF.sub.3 CF.sub.3 — 1.25, 443.9 A I-24 H CH.sub.3 [00046] Q1 CF.sub.3 CF.sub.3 — 1.37, 523.8 A I-25 H CH.sub.3 [00047] Q1 CF.sub.3 CF.sub.3 — 1.30, 511.9 A I-26 H CH.sub.3 [00048] Q8 Br CF.sub.3 — 0.95, 454.8 A I-27 H CH.sub.3 [00049] Q1 CF.sub.3 CF.sub.3 — 1.30, 477.9 A I-28 H C.sub.2H.sub.5 [00050] Q1 CF.sub.3 CF.sub.3 — 1.23, 457.9 A I-29 H CH.sub.3 [00051] Q1 CF.sub.3 CF.sub.3 — 1.19, 443.9 A I-30 H CH.sub.3 [00052] Q1 CF.sub.3 CF.sub.3 — 1.26, 478.8 A I-31 H CH.sub.3 [00053] Q1 CF.sub.3 CF.sub.3 — 1.30, 516.0 A I-32 H CH.sub.3 [00054] Q1 CF.sub.3 CF.sub.3 — 1.06, 487.0 A I-33 H CH.sub.3 [00055] Q1 CF.sub.3 CF.sub.3 — 1.25, 509.9 A I-34 H CH.sub.3 [00056] Q1 CF.sub.3 CF.sub.3 — 1.20, 468.9 A I-35 C(O)OCH.sub.3 H [00057] Q1 CF.sub.3 CF.sub.3 — 1.21, 487.9 A I-36 C(O)OCH.sub.3 CH.sub.3 [00058] Q1 CF.sub.3 CF.sub.3 — 1.22, 501.9 A I-37 C(O)OCH.sub.2—c-C.sub.3H.sub.5 CH.sub.3 [00059] Q1 CF.sub.3 CF.sub.3 — 1.32, 542.0 A I-38 C(O)OCH.sub.2—c-C.sub.3H.sub.5 H [00060] Q1 CF.sub.3 CF.sub.3 — 1.32, 528.0 A I-39 CH.sub.2CH.sub.2—OC(O)Ph CH.sub.3 [00061] Q1 CF.sub.3 CF.sub.3 — 1.38, 592.0 A I-40 CH.sub.2CH.sub.2OH CH.sub.3 [00062] Q1 CF.sub.3 CF.sub.3 — 1.23, 488.0 A

[0360] Biological Examples

[0361] If not otherwise specified, the test solutions were prepared as follows:

[0362] The active compound was dissolved at the desired concentration in a mixture of 1:1 (vol:vol) distilled water:acteone. The test solution was prepared at the day of use.

[0363] B.1. Action on Yellow Fever Mosquito (Aedes aegypti)

[0364] For evaluating control of yellow fever mosquito (Aedes aegypti) the test unit consisted of 96-well-microtiter plates containing 200 μl of tap water per well and 5-15 freshly hatched A. aegypti larvae.

[0365] The active compounds 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 μl, using a custom-built micro atomizer, at two replications.

[0366] After application, microtiter plates were incubated at 28±1° C., 80±5% RH for 2 days. Larval mortality was then visually assessed.

[0367] In this test, compounds, I-1, I-2, I-4, I-5, I-10, I-12, I-13, I-15, I-16, I-17, I-18, I-22, I-23, I-24, I-25, I-26, I-27, I-30, I-32, I-33, I-35, I-36, I-37, and I-38, resp. at 2500 ppm showed at least 50% mortality in comparison with untreated controls.

[0368] B.2. Boll Weevil (Anthonomus grandis)

[0369] 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. 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 μl, using a custom-built micro atomizer, at two replications.

[0370] After application, microtiter plates were incubated at about 25±1° C. and about 75±5% relative humidity for 5 days. Egg and larval mortality was then visually assessed. In this test, compound I-1, I-2, I-3, I-4, I-5, I-8, I-9, I-10, I-12, I-13, I-15, I-16, I-17, I-18, I-19, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-36, I-37, and I-38, resp., at 2500 ppm showed at least 50% mortality in comparison with untreated controls.

[0371] B.3. Tobacco Budworm (Heliothis virescens)

[0372] 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. 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 μl, using a custom-built micro atomizer, at two replications.

[0373] After application, microtiter plates were incubated at about 28±1° C. and about 80±5% relative humidity for 5 days. Egg and larval mortality was then visually assessed.

[0374] In this test, compounds I-1, I-4, I-5, I-7, I-10, I-15, I-17, I-18, I-21, I-22, I-23, I-25, I-26, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-36, I-37, and I-38, resp., at 2500ppm showed at least 50% mortality in comparison with untreated controls.

[0375] B.4. Green Peach Aphid (Myzus persicae)

[0376] For evaluating control of green peach aphid (Myzus persicae) through systemic means the test unit consisted of 96-well-microtiter plates containing liquid artificial diet under an artificial membrane.

[0377] The compounds were formulated using a solution containing 75% v/v water and 25% v/v DMSO. Different concentrations of formulated compounds were pipetted into the aphid diet, using a custom-built pipette, at two replications.

[0378] After application, 5-8 adult aphids were placed on the artificial membrane inside the microtiter plate wells. The aphids were then allowed to suck on the treated aphid diet and incubated at about 23 ±1° C. and about 50 ±5% relative humidity for 3 days. Aphid mortality and fecundity was then visually assessed.

[0379] In this test, compounds I-1, I-3, I-5, I-6, I-8, I-9, I-10, I-12, I-13, I-15, I-18, I-19, I-25, I-28, I-36, I-37, and I-38, resp., at 2500 ppm showed at least 50% mortality in comparison with untreated controls.

[0380] B.5. Cowpea Aphid (Aphis craccivora)

[0381] The active compound was dissolved at the desired concentration in a mixture of 1:1 (vol:vol) dis-tilled water: acetone. Surfactant (Kinetic) was added at a rate of 0.01% (vol/vol). The test solution was prepared at the day of use.

[0382] Potted cowpea plants were colonized with approximately 30-50 aphids of various stages by manually transferring aphid-infested leaf clippings 24 hours before application. Plants were sprayed with the test solutions using a DeVilbiss® hand atomizer at 20-30 psi (≈1.38 to 2.07 bar) after the pest population had been checked. Treated plants were maintained on light carts at about 25-26° C. Estimate percent mortality was assessed after 72 hours.

[0383] In this test, compounds I-12, I-13 I-15, I-18, I-27, I-36, I-37, I-38, resp., at 300 ppm showed at least 50% mortality in comparison with untreated controls.

[0384] B.6. Diamond Back Moth (Plutella xylostella)

[0385] The active compound was dissolved at the desired concentration in a mixture of 1:1 (vol:vol) distilled water:acetone. Surfactant (Kinetic) was added at a rate of 0.01% (vol/vol). The test solution was prepared at the day of use. Cabbage leaf discs (60 mm in diameter) were dipped in test solution and air-dried. Treated leaves were placed in petri dishes lined with moistened 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%.

[0386] In this test, compounds I-2, I-7, I-10, I-15, I-17, I-18, I-22, I-23, I-25, I-28, I-29, I-30, I-31, I-33, I-34, I-35, I-36, I-37, and I-38, resp., at 300 ppm showed at least 50% mortality in comparison with untreated controls.

[0387] B.7. Orchid Thrips (Dichromothrips corbetti)

[0388] Dichromothrips corbetti adults used for bioassay were obtained from a colony maintained continuously under laboratory conditions. For testing purposes, the test compound was diluted in a 1:1 mixture of acetone:water (vol:vol), plus Kinetic at a rate of 0.01% v/v.

[0389] Thrips potency of each compound was evaluated by using a floral-immersion technique. Each orchid petal was dipped into treatment solution and allowed to dry in Petri dishes. Treated petals were placed into individual re-sealable plastic along with about 20 adult thrips. All test arenas were held under dark condition and a temperature of about 28° C. for duration of the assay. The percent mortality was recorded 72 hours after treatment.

[0390] In this test, compounds I-2, I-7, I-8, I-12, I-13,1-17, I-18, I-28, I-36,1-37, and I-38, resp., at 300 ppm showed at least 50% mortality in comparison with untreated controls.

[0391] B.8. Green Soldier Stink Bug (Nezara viridula)

[0392] The active compound was dissolved at the desired concentration in a mixture of 1:1 (vol:vol) distilled water:aceteone. Surfactant (Kinetic) was added at a rate of 0.01% (vol/vol). The test solution was prepared at the day of use. Soybean pods were placed in 90×50 mm glass Petri dishes lined with moistened filter paper and inoculated with ten late 3rd instar N. viridula. Using a hand atomizer, an approximately 2 ml solution was sprayed into each Petri dish. Treated set-up was kept at about 25-26° C. and relative humidity of about 65-70%. Percent mortality was recorded after 5 days.

[0393] In this test, compounds I-12, I-15, I-17, I-18, I-37, and I-38, resp., at 300ppm showed at least 50% mortality in comparison with untreated controls.

[0394] B.9. Rice Green Leafhopper (Nephotettix virescens)

[0395] Four to five-week old rice seedlings with cut upper leaf portion were cleaned and washed 24 hours before spraying. The active compounds were formulated in 1:1 acetone:water (vol:vol), and 0.01% vol/vol surfactant (Kinetic) was added. Potted rice seedlings were sprayed with 5-6 ml test solution, air dried, covered with Mylar cages and inoculated with 10 adults. Treated rice plants were kept at about 28-29° C. and relative humidity of about 50-60%. Percent mortality was recorded after 72 hours.

[0396] In this test, compounds I-8, I-13, I-18, I-37, resp., at 300ppm showed at least 50% mortality in comparison with untreated controls.

[0397] B.10. Southern Armyworm (Spodoptera eridania), 2nd instar larvae

[0398] 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 20m1 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. 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. Ten 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 (14:10 light:dark photo-period) to prevent trapping of heat inside the bags. Mortality and reduced feeding were assessed 4 days after treatment, compared to untreated control plants.

[0399] In this test, compounds I-5, I-12, I-13, I-16, I-17, I-18, I-22, I-23, I-24, I-25, I-26, I-30, I-33, I-34, I-36, and I-37, resp., at 300 ppm showed at least 50% mortality in comparison with untreated controls.