NOVEL HETEROARYL-TRIAZOLE COMPOUNDS AS PESTICIDES

Abstract

The present invention relates to novel heteroaryl-triazole compounds of the general formula (I), in which the structural elements X, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the meaning given in the description, to formulations and compositions comprising such compounds and for their use in the control of animal pests including arthropods and insects in plant protection and to their use for control of ectoparasites on animals.

##STR00001##

Claims

1. A compound of the formula (I) ##STR00079## in which X is O or S; Y is a direct bond or CH.sub.2; R.sup.1 is hydrogen; C.sub.1-C.sub.6alkyl optionally substituted with one substituent selected from —CN, —CONH.sub.2, —COOH, —NO.sub.2 and —Si(CH.sub.3).sub.3; C.sub.1-C.sub.6haloalkyl; C.sub.2-C.sub.6alkenyl; C.sub.2-C.sub.6haloalkenyl; C.sub.2-C.sub.6alkynyl; C.sub.2-C.sub.6haloalkynyl; C.sub.3-C.sub.4cycloalkyl-C.sub.1-C.sub.2alkyl- wherein the C.sub.3-C.sub.4cycloalkyl is optionally substituted with one or two halogen atoms; oxetan-3-yl-CH.sub.2— or benzyl optionally substituted with halogen atoms or C.sub.1-C.sub.3haloalkyl; R.sup.2 is phenyl, pyridine, pyrimidine, pyrazine or pyridazine, wherein the phenyl, pyridine, pyrimidine, pyrazine or pyridazine is optionally substituted with one to three substituents, provided the substituent(s) are not on either carbon adjacent to the carbon bonded to the C═X-group, each independently selected from the group consisting of C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkylthio, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, halogen, —NO.sub.2, —SF.sub.5, —CN, —CONH.sub.2, —COOH and —C(S)NH.sub.2; R.sup.3 is C.sub.1-C.sub.3alkyl or C.sub.1-C.sub.3haloalkyl; R.sup.4 is pyridine, pyrimidine, pyrazine or pyridazine, wherein the pyridine, pyrimidine, pyrazine or pyridazine is optionally substituted with one substituent selected from the group consisting of C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.3-C.sub.4cycloalkyl, halogen or hydroxy; R.sup.5 is halogen.

2. The compound according to claim 1, in which X is O or S; Y is a direct bond or CH.sub.2; R.sup.1 is hydrogen; C.sub.1-C.sub.3alkyl optionally substituted with one substituent selected from —CN, —CONH.sub.2, —COOH, —NO.sub.2 and —Si(CH.sub.3).sub.3; C.sub.1-C.sub.3haloalkyl; C.sub.2-C.sub.4alkenyl; C.sub.2-C.sub.4haloalkenyl; C.sub.2-C.sub.4alkynyl; C.sub.2-C.sub.4haloalkynyl; C.sub.3-C.sub.4cycloalkyl-C.sub.1-C.sub.2alkyl- wherein the C.sub.3-C.sub.4cycloalkyl is optionally substituted with one or two halogen atoms; oxetan-3-yl-CH.sub.2—; or benzyl optionally substituted with halogen atoms or C.sub.1-C.sub.3haloalkyl; R.sup.2 is phenyl, pyridine, pyrimidine, pyrazine or pyridazine, wherein the phenyl, pyridine, pyrimidine, pyrazine or pyridazine is optionally substituted with one to three substituents, provided the substituent(s) are not on either carbon adjacent to the carbon bonded to the C═X-group, each independently selected from the group consisting of C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkylthio, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, halogen, —NO.sub.2, —SF.sub.5, —CN, —CONH.sub.2, —COOH and —C(S)NH.sub.2; R.sup.3 is C.sub.1-C.sub.3alkyl or C.sub.1-C.sub.3haloalkyl; R.sup.4 is pyridine, pyrimidine, pyrazine or pyridazine, wherein the pyridine, pyrimidine, pyrazine or pyridazine is optionally substituted with one substituent selected from the group consisting of C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.3-C.sub.4cycloalkyl, halogen or hydroxy; R.sup.5 is halogen.

3. The compound according to claim 1, in which X is O; Y is a direct bond; R.sup.1 is hydrogen; R.sup.2 is phenyl or pyridine, wherein the phenyl or pyridine is optionally substituted with one to three substituents, provided the substituent(s) are not on either carbon adjacent to the carbon bonded to the C═X group, each independently selected from the group consisting of fluorine, chlorine, bromine, —CN, —NO.sub.2, —SF.sub.5, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, difluoromethylthio, and trifluoromethylthio; R.sup.3 is C.sub.1-C.sub.3alkyl; R.sup.4 is pyridine or pyrimidine, wherein the pyridine or pyrimidine is optionally substituted with one substituent selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy; R.sup.5 is fluorine, chlorine, bromine, or iodine.

4. The compound according claim 1, in which X is O; Y is a direct bond; R.sup.1 is hydrogen; R.sup.2 3-chloro-5-(trifluoromethyl)phenyl, 3-bromo-5-(trifluoromethyl)phenyl, 3-chloro-5-(trifluoromethoxy)phenyl, 3-bromo-5-(trifluoromethoxy)phenyl, 3-bromo-5-chlorophenyl, 3,5-dichlorophenyl, 3,5-dibromophenyl, 3,5-bis(trifluoromethyl)phenyl, 2,6-dichloro-pyridin-4-yl, 5-(trifluoromethyl)-pyridin-3-yl, or 2-chloro-6-(trifluoromethyl)-pyridin-4-yl; R.sup.3 is methyl; R.sup.4 is pyrimidin-2-yl, or 5-chloro-pyridin-2-yl; R.sup.5 is chlorine, bromine or iodine.

5. A compound of formula (a) wherein R.sup.1 is hydrogen, R.sup.3 is methyl and Y is a direct bond and wherein. R.sup.4 is pyridine, pyrimidine, pyrazine or pyridazine, wherein the pyridine, pyrimidine, pyrazine or pyridazine is optionally substituted with one substituent selected from the group consisting of C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.3-C.sub.4cycloalkyl, halogen or hydroxy; R.sup.5 is halogen ##STR00080##

6. A compound comprising 1-(5-chloro-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine,1-(5-bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine, 1-(5-iodo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine, (1 S)-1-(5-chloro-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine-hydrochloride, (1 S)-1-(5-bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine-hydrochloride, or (1S)-1-(5-iodo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine-hydrochloride.

7. A formulation, optionally agrochemical formulation, comprising at least one compound of formula (I) according to any of claim 1.

8. The formulation according to claim 6, further comprising at least one extender and/or at least one surface-active substance.

9. The formulation according to claim 6, wherein the compound of formula (I) is in a mixture with at least one further active compound.

10. A method for controlling one or more pests, optionally animal pests, comprising allowing a compound of formula (I) according to claim 1 or a formulation thereof to act on the pests and/or a habitat thereof.

11. The method according to claim 9, wherein the pest is an animal pest and comprises an insect, an arachnid or a nematode, or wherein the pest is an insect, an arachnid or a nematode.

12. A product comprising a compound of formula (I) according to claim 1 or of a formulation thereof for controlling one or more animal pests.

13. A method according to claim 11, wherein the animal pest comprises an insect, an arachnid or a nematode, or that wherein the animal pest is an insect, an arachnid or a nematode.

14. The method according to claim 11 in crop protection.

15. The method according to claim 11 in the field of animal health.

16. A method for protecting seed or a germinating plant from pests, optionally animal pests, comprising contacting the seed with a compound of formula (I) according to any of claim 1 or with a formulation thereof.

17. Seed obtained by a method according to claim 15.

Description

PREPARATION EXAMPLES

Synthesis of 3-chloro-N-[1-(5-chloro-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5-(trifluoromethoxy)benzamide (Example I-001)

[0486] ##STR00014##

[0487] Step 1

tert-Butyl N—[N-[2-(1,3-dioxoisoindolin-2-yl)propanoyl]-C-methylsulfanyl-carbonimidoyl]carbamate

[0488] ##STR00015##

[0489] To 1.09 g (5.0 mmol) (αS)-1,3-dihydro-α-methyl-1,3-dioxo-2H-isoindole-2-acetic acid (Pht-Ala-OH purchased from ABCR) und 0.95 g (5.0 mmol) 1-N-Boc-2-methyl-isothiourea (purchased from ABCR) in THF (30 ml), triethylamine (2.1 ml) and HATU was added, and the reaction mixture was stirred at 80° C. temperature and stirred further 2 h at the same temperature. Then water was added and the mixture was extracted with sodium hydrogencarbonate solution and dichloromethane. After drying the solvent was evaporated. The remaining solid residue was chromatographed with a cyclohexane/acetone gradient on silica gel to afford 1.40 g (purity: 97.0%; yield: 70%) of the racemic title compound.

[0490] Formula: C.sub.18H.sub.21N.sub.3O.sub.5S Molecular weight: 391.44 g/mol

[0491] UPLC-MS (acid) [m/z]: 392.2 [M+H].sup.+

[0492] .sup.1H-NMR peaklist (400 MHz, DMSO-d.sub.6, ppm): δ=11.8958 (0.5); 11.4353 (0.9); 7.9299 (0.5); 7.9221 (1.0); 7.9152 (1.2); 7.9102 (1.0); 7.9063 (1.2); 7.9000 (2.1); 7.8930 (1.1); 7.8847 (2.6); 7.8785 (1.3); 7.8744 (1.2); 7.8627 (0.8); 4.9976 (0.8); 4.9794 (0.8); 3.3230 (9.5); 2.5251 (0.4); 2.5204 (0.6); 2.5117 (8.2); 2.5072 (16.6); 2.5027 (21.9); 2.4981 (15.8); 2.4936 (7.6); 2.2949 (2.4); 1.9720 (6.0); 1.6029 (2.9); 1.5848 (3.0); 1.5719 (1.3); 1.5540 (1.1); 1.4430 (16.0); 1.3971 (11.0); 1.2665 (6.6); −0.0002 (0.5).

[0493] Step 2

tert-Butyl N-[5-[1-(1,3-dioxoisoindolin-2-yl)ethyl]-1-pyrimidin-2-yl-1,2,4-triazol-3-yl]carbamate

[0494] ##STR00016##

[0495] To a solution of 1.0 g (2.55 mmol) tert-Butyl N—[N-[2-(1,3-dioxoisoindolin-2-yl)propanoyl]-C-methylsulfanyl-carbonimidoyl]carbamate in pyridine (50 ml), 337.5 mg (3.06 mmol) 2-hydrazinopyrimidine was added and the reaction mixture was stirred at room temperature for 2 h at 80° C. temperature. Afterwards the solvent was evaporated under vacuo the crude product was chromatographed with a cyclohexane/acetone gradient on silica gel to afford 780 mg (purity: 95.9%; yield: 67%) of the racemic title compound.

[0496] Formula: C.sub.21H.sub.21N.sub.7O.sub.4 Molecular weight: 435.43 g/mol

[0497] UPLC-MS (acid) [m/z]: 436.3 [M+H].sup.+

[0498] .sup.1H-NMR peaklist (600 MHz, DMSO-d.sub.6, ppm): δ=9.9739 (1.2); 8.7635 (2.7); 8.7554 (2.7); 7.8169 (0.6); 7.8126 (0.8); 7.8097 (2.9); 7.8052 (3.0); 7.8020 (0.9); 7.7979 (0.6); 7.4395 (0.7); 7.4315 (1.4); 7.4234 (0.7); 6.0850 (0.8); 6.0732 (0.8); 5.7533 (0.3); 3.3088 (9.2); 2.5080 (3.8); 2.5050 (8.0); 2.5020 (11.1); 2.4989 (8.1); 2.4960 (3.8); 1.9448 (0.4); 1.9123 (0.4); 1.8008 (2.4); 1.7890 (2.4); 1.4365 (16.0); 1.3974 (6.1); −0.0001 (1.9).

[0499] Step 3

2-[1-(5-Amino-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]isoindoline-1,3-dione hydrochloride

[0500] ##STR00017##

[0501] 8.8 g (17.1 mmol) tert-Butyl N-[5-[1-(1,3-dioxoisoindolin-2-yl)ethyl]-1-pyrimidin-2-yl-1,2,4-triazol-3-yl]carbamate was treated with 4N HCl in dioxane solution (150 ml) and the reaction mixture was stirred 18 h at room temperature. Then the reaction mixture was concentrated and the racemic solid residue was used for the halogen introduction (step 4) without purification.

[0502] Formula: C.sub.16H.sub.14ClN.sub.7O.sub.2 Molecular weight: 371.78 g/mol

[0503] HPLC-MS (ESI positive) [m/z]: 336.2 [M−HCl].sup.+

[0504] Step 4

2-[1-(5-Chloro-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]isoindoline-1,3-dione

[0505] ##STR00018##

[0506] To 300.0 mg (0.89 mmol) 2-[1-(5-amino-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]isoindoline-1,3-dione-hydrochloride in acetonitrile (20 ml), 204.5 mg (1.52 mmol) Cu(II)-chloride was added, and then the reaction mixture was treated drop by drop at room temperature with 129.1 mg (1.25 mmol) tert-butyl nitrite. Then the reaction mixture was stirred 1 h at 70° C. temperature. The reaction mixture was treated with acetic acid ethyl ester and then extracted with a saturated NaHCO.sub.3 solution and water. The organic phase was separated, dried and the solvent was evaporated to afford 178 mg (purity: 77%; yield: 56%) of the racemic title compound, which was used for the coupling reaction (step 5) without purification.

[0507] Formula: C.sub.16H.sub.11ClN.sub.6O.sub.2 Molecular weight: 354.75 g/mol

[0508] UPLC-MS (acid) [m/z]: 355.3 [M+H].sup.+

[0509] Step 5

1-(5-Chloro-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine (INT-01)

[0510] ##STR00019##

[0511] To 499.0 mg (2.5 mmol) 2-[1-(5-chloro-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]isoindoline-1,3-dione in ethanol (20 mL), 320.0 mg (3.51 mmol) hydrazine-hydrate were added, and the reaction mixture was heated under reflux. After 30 minutes a colorless precipitate was formed. The reaction mixture was stirred and heated under reflux two additional hours, acetone (2 mL) was added and the heating was continued for further 30 minutes. The reaction mixture was concentrated and the solid residue was treated with ethanol. After filtration, the filtrate was evaporated under reduced pressure to afford 310.0 mg (purity: 70-80%, yield: 98%) of the racemic intermediate INT-01, which was used in step 6 without purification.

[0512] Formula: C.sub.8H.sub.9ClN.sub.6 Molecular weight: 224.65 g/mol

[0513] UPLC-MS (neutral) [m/z]: 225.1 [M+H].sup.+

[0514] Step 6

3-Chloro-N-[1-(5-chloro-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5-(trifluoromethoxy)benzamide

[0515] To 150.0 mg (0.66 mmol) 1-(5-chloro-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine, 164.0 mg (0.66 mmol) 3-chloro-5-(trifluoromethoxy)-benzoic acid, 120 mg (0.92 mmol) DIPEA in DMF (3 mL), 310.0 mg (0.81 mmol) HATU were added, and the reaction mixture was stirred at room temperature over night. The reaction mixture was concentrated under reduced pressure and the solid residue was treated with dichloromethane and then extracted with a saturated aqueous NaHCO.sub.3 solution and water. The organic phase was separated, dried over Na.sub.2SO.sub.4 and the solvent was evaporated under reduced pressure. The remaining solid residue was purified by HPLC with a water/acetonitrile neutral gradient to obtain 122.0 mg (purity: 98.8%; yield: 41%) of the racemic title compound.

[0516] Formula: C.sub.18H.sub.11BrN.sub.6O.sub.2 Molecular weight: 447.20 g/mol

[0517] HPLC-MS neutral (ESI positive) [m/z]: 447.1 [M+H].sup.+

[0518] The compounds of the formulae (I-002)-(I-008) listed in Table 1 below can be prepared analogously.

Synthesis of 3-bromo-N-[1-(5-bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5-(trifluoromethyl)benzamide (Example I-009)

[0519] ##STR00020##

[0520] Step 1

2-[1-(5-Bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]isoindoline-1,3-dione

[0521] ##STR00021##

[0522] To 300.0 mg (0.89 mmol) 2-[1-(5-amino-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]isoindoline-1,3-dione-hydrochloride in acetonitrile (20 ml) (synthesisized according to steps 1-3, example I-001), 350.0 mg (1.56 mmol) Cu(II)-bromide was added, and then the reaction mixture was treated drop by drop at room temperature with 150 mg (1.45 mmol) tert-butyl nitrite. Then the reaction mixture was stirred 1 h at 70° C. temperature. The reaction mixture was treated with acetic acid ethyl ester and then extracted with a saturated NaHCO.sub.3 solution and water. The organic phase was separated, dried over Na.sub.2SO.sub.4 and the solvent was evaporated under reduced pressure. The remaining solid residue was purified by HPLC with a water/MeCN neutral gradient to obtain 234.0 mg (purity: 96.8%; yield: 66%) of the racemic title compound.

[0523] Formula: C.sub.16H.sub.11BrN.sub.6O.sub.2 Molecular weight: 398.01 g/mol

[0524] HPLC-MS (ESI positive) [m/z]: 399.2 [M+H].sup.+

[0525] Step 2

1-(5-Bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine (INT-02)

[0526] ##STR00022##

[0527] To 1.16 g (2.9 mmol) 2-[1-(5-bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]isoindoline-1,3-dione2in ethanol (30 mL), 678.8 mg (7.45 mmol) hydrazine-hydrate were added, and the reaction mixture was heated under reflux. After 30 minutes a colorless precipitate was formed. The reaction mixture was stirred and heated under reflux two additional hours, acetone (20 mL) was added and the heating was continued for further 30 minutes. The reaction mixture was concentrated and the solid residue was treated with ethanol. After filtration, the filtrate was evaporated under reduced pressure to afford 900 mg (purity: 50-60%) of racemic intermediate INT-02, which was used in step 6 without purification.

[0528] Formula: C.sub.8H.sub.9BrN.sub.6 Molecular weight: 269.11 g/mol

[0529] UPLC-MS (neutral): 271.1 [M+H].sup.+

[0530] Step 3

3-Bromo-N-[1-(5-bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5-(trifluoromethyl)benzamide

[0531] To 122.6 mg (0.45 mmol) 1-(5-bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine, 125.0 mg (0.45 mmol) 3-bromo-5-(trifluoromethyl)-benzoic acid (purity: 97%), 81.7 mg (0.63 mmol) DIPEA in 3.76 g (51.5 mmol) DMF, 205.6 mg (0.54 mmol) HATU were added, and the reaction mixture was stirred at room temperature over night. The reaction mixture was concentrated under reduced pressure and the solid residue was treated with dichloromethane and then extracted with a saturated aqueous NaHCO.sub.3 solution and water. The organic phase was separated, dried over Na.sub.2SO.sub.4 and the solvent was evaporated under reduced pressure. The remaining solid residue was purified by HPLC with a water/MeCN neutral gradient to obtain 29.0 mg (purity: 100%; yield: 12%) of the racemic title compound.

[0532] Formula: C.sub.16H.sub.11Br.sub.2F.sub.3N.sub.6O Molecular weight: 520.11 g/mol

[0533] HPLC-MS acid (ESI positive) [m/z]: 521.0 [M+H].sup.+

[0534] The compounds of the formulae (I-010)-(I-016) listed in Table 1 below can be prepared analogously.

Synthesis of 3-chloro-N-[1-[5-chloro-2-(5-chloro-2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-5-(trifluoromethyl)benzamide (Example I-017)

[0535] ##STR00023##

[0536] Step 1

tert-Butyl N-[1-(5-chloro-2-pyridyl)-5-[1-(1,3-dioxoisoindolin-2-yl)ethyl]-1,2,4-triazol-3-yl]carbamate

[0537] ##STR00024##

[0538] To a solution of 16.4 g (41.9 mmol) tert-butyl N—[N-[2-(1,3-dioxoisoindolin-2-yl)propanoyl]-C-methylsulfanyl-carbonimidoyl]carbamate (synthesisized according to Step 1, example I-001), in pyridine (200 ml), 7.2 g (50.3 mmol) 5-chloro-2-hydrazinyl-pyridine was added and the reaction mixture was stirred for 2.5 h at 80° C. temperature. Afterwards the solvent was evaporated under vacuo and the crude product was chromatographed with a cyclohexane/acetone gradient on silica gel to afford 17.9 g (purity: 99.1%; yield: 90.6%) of the racemic title compound.

[0539] Formula: C.sub.22H.sub.21ClN.sub.6O.sub.4 Molecular weight: 468.90 g/mol

[0540] HPLC-MS (ESI positive) [m/z]: 269.1 (M+H].sup.+

[0541] Step 2

tert-Butyl N-[5-(1-aminoethyl)-1-(5-chloro-2-pyridyl)-1,2,4-triazol-3-yl]carbamate

[0542] ##STR00025##

[0543] To 15.0 g (31.9 mmol) tert-butyl N-[1-(5-chloro-2-pyridyl)-5-[1-(1,3-dioxoisoindolin-2-yl)ethyl]-1,2,4-triazol-3-yl]carbamate in ethanol (300 mL), 7.2 g (79.9 mmol) hydrazine-hydrate were added, and the reaction mixture was heated under reflux. After 30 minutes a colorless precipitate was formed. The reaction mixture was stirred and heated under reflux for two additional hours, acetone was added and the heating was continued for further 30 minutes. The reaction mixture was concentrated and the solid residue was treated with ethanol. After filtration, the filtrate was evaporated under reduced pressure to afford 10.8 g (yield: 100%) of the racemic racemic title compounds, which was used in step 3 without purification.

[0544] Formula: C.sub.14H.sub.19ClN.sub.6O.sub.2 Molecular weight: 338.80 g/mol

[0545] HPLC-MS acid (ESI positive) [m/z]: 339.1 [M+H].sup.+

[0546] Step 3

tert-Butyl N-[1-(5-chloro-2-pyridyl)-5-[1-[[3-chloro-5-(trifluoromethyl)benzoyl]amino]ethyl]-1,2,4-triazol-3-yl]carbamate

[0547] ##STR00026##

[0548] To 9.4 g (27.8 mmol) tert-butyl N-[5-(1-aminoethyl)-1-(5-chloro-2-pyridyl)-1,2,4-triazol-3-yl]carbamate, 6.4 g (27.8 mmol) 3-chloro-5-(trifluoromethyl)-benzoic acid (purity: 97%), 4.6 g (36.2 mmol) DIPEA in DMF (300 mL), 12.7 g (33.4 mmol) HATU were added, and the reaction mixture was stirred at room temperature over night. The reaction mixture was concentrated under reduced pressure and the solid residue was treated with dichloromethane and then extracted with a saturated aqueous NaHCO.sub.3 solution and water. The organic phase was separated, dried over Na.sub.2SO.sub.4 and the solvent was evaporated under reduced pressure. The remaining solid residue was purified at first by MPLC with a cyclohexane/acetone gradient (purity: 50.1%) and afterwards by HPLC with a water/MeCN neutral gradient to obtain 4.3 g (purity: 100%; yield: 29%) of the racemic title compound.

[0549] Formula: C.sub.22H.sub.21Cl.sub.2F3N.sub.6O.sub.3 Molecular weight: 545.35 g/mol

[0550] HPLC-MS acid (ESI positive) [m/z]: 545.3 [M+H].sup.+

[0551] Step 4

N-[1-[5-Amino-2-(5-chloro-2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-3-chloro-5-(trifluoromethyl)benzamide

[0552] ##STR00027##

[0553] 4.2 g (7.8 mmol) tert-butyl N-[1-(5-chloro-2-pyridyl)-5-[1-[[3-chloro-5-(trifluoromethyl)benzoyl]amino]ethyl]-1,2,4-triazol-3-yl]carbamate was treated with 4N HCl in dioxane solution (403 ml) and the reaction mixture was stirred 18 h at room temperature. Then the reaction mixture was concentrated and the racemic solid residue was used for the halogen introduction (step 5) without purification.

[0554] Formula: C.sub.17H.sub.13C.sub.12F.sub.3N.sub.6O Molecular weight: 445.23 g/mol

[0555] HPLC-MS acid (ESI positive) [m/z]: 446.1 [M+H].sup.+

[0556] Step 5

3-Chloro-N-[1-[5-chloro-2-(5-chloro-2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-5-(trifluoromethyl)benzamide

[0557] To 300.0 mg (0.67 mmol) N-[1-[5-amino-2-(5-chloro-2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-3-chloro-5-(trifluoromethyl)benzamide in acetonitrile (15 mL), 154.0 mg (1.14 mmol) Cu(II)-chloride was added, and then the reaction mixture was treated drop by drop at room temperature with 97.2 mg (0.94 mmol) tert-butyl nitrite. Then the reaction mixture was stirred for 1 h at 70° C. temperature. The reaction mixture was treated with acetic acid ethyl ester and then extracted with a saturated NaCl solution. Afterwards the solvent was evaporated under vacuo and the crude product was chromatographed with a cyclohexane/acetone gradient on silica gel to afford 78.8 mg g (purity: 100%; yield: 25%) of the racemic title compound.

[0558] Formula: C.sub.17H.sub.11C.sub.13F.sub.3N.sub.5O Molecular weight: 464.66 g/mol

[0559] HPLC-MS acid (ESI positive) [m/z]: 465.1 [M+H].sup.+

[0560] .sup.1H-NMR peaklist (600 MHz, DMSO-d.sub.6, ppm): δ=9.4153 (2.5); 9.4039 (2.5); 8.6405 (4.4); 8.6397 (4.4); 8.6363 (4.6); 8.6354 (4.4); 8.2234 (3.8); 8.2191 (3.7); 8.2089 (4.1); 8.2045 (4.1); 8.1234 (4.3); 8.1208 (2.9); 8.0758 (3.9); 8.0629 (4.2); 7.8635 (5.1); 7.8627 (5.0); 7.8490 (4.7); 7.8482 (4.6); 5.9368 (0.4); 5.9252 (2.1); 5.9137 (3.3); 5.9022 (2.2); 5.8906 (0.4); 3.3194 (43.3); 2.6183 (0.3); 2.6152 (0.5); 2.6122 (0.3); 2.5243 (1.0); 2.5212 (1.2); 2.5180 (1.2); 2.5093 (25.1); 2.5062 (54.5); 2.5031 (77.0); 2.5001 (56.8); 2.4971 (26.3); 2.3902 (0.3); 2.3871 (0.5); 2.3840 (0.3); 1.6404 (11.4); 1.6287 (11.5); 1.3975 (16.0); −0.0001 (4.0).

Synthesis of N-[1-[5-bromo-2-(5-chloro-2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-3-chloro-5-(trifluoromethyl)benzamide (Example I-018)

[0561] ##STR00028##

[0562] To 200.0 mg (0.44 mmol) N-[1-[5-amino-2-(5-chloro-2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-3-chloro-5-(trifluoromethyl)benzamide (synthesisized according to Step 4, example I-017) in MeCN (10 mL), 170.5 mg (0.76 mmol) Cu(II)-bromide was added, and then the reaction mixture was treated drop by drop at room temperature with 64.8 mg (0.62 mmol) tert-butyl nitrite. Then the reaction mixture was stirred for 1 h at 70° C. temperature. The reaction mixture was treated with acetic acid ethyl ester and then extracted with a saturated NaCl solution. Afterwards the solvent was evaporated under vacuo and the crude product was chromatographed with a cyclohexane/acetone gradient on silica gel to afford 93.8 mg (purity: 99.3%; yield: 41%) of the racemic title compound.

[0563] Formula: C.sub.17H.sub.11BrCl.sub.2F.sub.3N.sub.5O Molecular weight: 509.12 g/mol

[0564] HPLC-MS acid (ESI positiv) [m/z]: 510.0 [M+H].sup.+

[0565] .sup.1H-NMR peaklist (600 MHz, DMSO-d.sub.6, ppm): δ=9.4115 (2.6); 9.4001 (2.7); 8.6396 (0.4); 8.6349 (4.7); 8.6311 (4.5); 8.6307 (4.4); 8.2163 (3.4); 8.2120 (3.3); 8.2089 (0.4); 8.2018 (3.6); 8.1975 (3.6); 8.1214 (4.6); 8.0745 (4.3); 8.0615 (4.7); 7.8651 (5.0); 7.8506 (4.6); 5.9417 (0.4); 5.9302 (2.0); 5.9253 (0.4); 5.9186 (3.2); 5.9139 (0.5); 5.9071 (2.1); 5.8955 (0.4); 3.3216 (92.2); 2.6184 (0.4); 2.6154 (0.5); 2.6124 (0.4); 2.5244 (1.1); 2.5214 (1.4); 2.5182 (1.5); 2.5094 (26.3); 2.5064 (55.2); 2.5033 (76.9); 2.5003 (57.3); 2.4973 (27.2); 2.3904 (0.4); 2.3873 (0.5); 2.3843 (0.3); 1.6353 (11.1); 1.6285 (2.0); 1.6237 (11.1); 1.3974 (16.0); −0.0001 (2.7).

Synthesis of 3-chloro-N-[1-[2-(5-chloro-2-pyridyl)-5-iodo-1,2,4-triazol-3-yl]ethyl]-5-(trifluoromethyl)benzamide (Example I-019)

[0566] ##STR00029##

[0567] Method A:

[0568] To 300.0 mg (0.67 mmol) N-[1-[5-amino-2-(5-chloro-2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-3-chloro-5-(trifluoromethyl)benzamide (synthesisized according to step 4, example I-017) in tetrahydrofurane (15 mL), 12.8 mg (0.06 mmol) Cu(I)-iodide and 171.0 (0.67 mmol) iodine was added (argon atmosphere), and then the reaction mixture was treated drop by drop at room temperature with 64.8 mg (0.62 mmol) tert-butyl nitrite. Then the reaction mixture was stirred 1 h at 70° C. temperature. The reaction mixture was treated with acetic acid ethyl ester and then extracted with a saturated NaCl solution. Afterwards the solvent was evaporated under vacuo and the crude product was chromatographed with a cyclohexane/acetone gradient on silica gel to afford 22.0 mg (purity: 99.0%; yield: 6%) of the racemic title compound and 136.0 mg (purity: 97.0%; yield: 46%) racemic 3-chloro-N-[1-[2-(5-chloro-2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-5-(trifluoromethyl)benzamide as side product.

[0569] Method B:

[0570] To 300.0 mg (0.67 mmol) N-[1-[5-amino-2-(5-chloro-2-pyridyl)-1,2,4-triazol-3-yl]ethyl]-3-chloro-5-(trifluoromethyl)benzamide (synthesisized according to step 4, example I-017) in MeCN (10 mL), 9.3 mg (34.7 mmol) diiodomethane was added (argon atmosphere), and then the reaction mixture was treated drop by drop at room temperature with 319.6 mg (3.10 mmol) tert-butyl nitrite. Then the reaction mixture was stirred 3 h at 80° C. temperature. The reaction mixture was treated with acetic acid ethyl ester and then extracted with a saturated NaCl solution. Afterwards the solvent was evaporated under vacuo and the crude product was chromatographed with a cyclohexane/acetone gradient on silica gel to afford 268.1 mg (purity: 100.0%; yield: 72%) of the racemic title compound.

[0571] Formula: C.sub.17H.sub.11BrCl.sub.2FIN.sub.5O Molecular weight: 556.11 g/mol

[0572] HPLC-MS acid (ESI positiv) [m/z]: 556.0 [M+H].sup.+

[0573] .sup.1H-NMR peaklist (600 MHz, DMSO-d.sub.6, ppm): δ=9.3946 (1.4); 9.3829 (1.5); 8.6199 (2.4); 8.6191 (2.4); 8.6157 (2.5); 8.6148 (2.4); 8.1956 (2.0); 8.1913 (1.9); 8.1811 (2.2); 8.1768 (2.2); 8.1195 (2.3); 8.1170 (1.6); 8.0712 (2.1); 8.0689 (1.5); 8.0609 (2.3); 7.8528 (2.7); 7.8520 (2.7); 7.8383 (2.5); 7.8374 (2.5); 5.9340 (1.1); 5.9224 (1.8); 5.9107 (1.1); 3.3185 (30.0); 3.2880 (0.3); 2.6146 (0.4); 2.5236 (0.7); 2.5206 (0.9); 2.5174 (0.9); 2.5087 (17.6); 2.5056 (38.0); 2.5025 (53.6); 2.4995 (39.5); 2.4965 (18.2); 2.3865 (0.3); 1.6176 (5.8); 1.6060 (5.8); 1.3975 (16.0); 1.2507 (1.1); −0.0001 (2.9).

Synthesis of 3-bromo-N-[1-(5-iodo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5-(trifluoromethoxy)benzamide (Example I-020)

[0574] ##STR00030##

[0575] Step 1

2-[1-(5-Iodo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]isoindoline-1,3-dione

[0576] ##STR00031##

[0577] To 11.22 g (30.17 mmol) 2-[1-(5-amino-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]isoindoline-1,3-dione-hydrochloride in acetonitrile (448 ml) (synthesisized according to steps 1-3, example I-001), 180.95 g (675.64 mmol) diiodomethane was added (argon atmosphere), and then the reaction mixture was treated drop by drop at room temperature with 14.31 g (138.82 mmol) tert-butyl nitrite. Then the reaction mixture was stirred 3 h at 80° C. temperature. The reaction mixture was treated with acetic acid ethyl ester and then extracted with a saturated NaCl solution. Afterwards the solvent was evaporated under vacuo and the crude product was chromatographed with a cyclohexane/acetone gradient on silica gel to afford 8.1 g (purity: 99.1%; yield: 60.2%) of the racemic title compound.

[0578] Formula: C.sub.16H.sub.11IN.sub.6O.sub.2 Molecular weight: 446.20 g/mol

[0579] HPLC-MS acid (ESI positiv): 447.0 [M+H].sup.+

[0580] Step 2

1-(5-Iodo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine (INT-03)

[0581] ##STR00032##

[0582] To 3.07 g (6.89 mmol) 2-[1-(5-iodo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]isoindoline-1,3-dione in ethanol (100 mL), 1.56 g (17.2 mmol) hydrazine-hydrate were added, and the reaction mixture was heated under reflux. After 30 minutes a colorless precipitate was formed. The reaction mixture was stirred and heated under reflux for two additional hours, acetone (2 mL) was added and the heating was continued for further 30 minutes. The reaction mixture was concentrated and the solid residue was treated with ethanol. After filtration, the filtrate was evaporated under reduced pressure to afford the racemic intermediate INT-003, which was used in step 3 without purification.

[0583] Formula: C.sub.8H91IN.sub.6 Molecular weight: 316.10 g/mol

[0584] HPLC-MS acid (ESI-positive) [m/z]: 316.9, 317.0 [M+H].sup.+

[0585] Step 3

3-Bromo-N-[1-(5-iodo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-5-(trifluoromethoxy)benzamide

[0586] To 132.9 mg (0.37 mmol) (αS)-Methyl-1-[3-iodo-1-pyrimidinyl-1H-1,2,4-triazol]-5-methane amine, 121.4 mg (0.41 mmol) 3-bromo-5-(trifluoromethoxy)-benzoic acid (purity: 97%), 75.0 mg (0.58 mmol) DIPEA in 3.65 g (50.0 mmol) DMF, 193.7 mg (0.51 mmol) HATU were added, and the reaction mixture was stirred at room temperature over night. The reaction mixture was concentrated under reduced pressure and the solid residue was treated with dichloromethane and then extracted with a saturated aqueous NaHCO.sub.3 solution and water. The organic phase was separated, dried over Na.sub.2SO.sub.4 and the solvent was evaporated under reduced pressure. The remaining solid residue was purified by HPLC with a water/acetonitrile neutral gradient to obtain 91.6 mg (purity: 100%; yield: 38.0%) of the racemic title compound.

[0587] Formula: C.sub.16H.sub.11BrF.sub.3IN.sub.6O.sub.2 Molecular weight: 583.11 g/mol

[0588] HPLC-MS neutral (ESI-positive) [m/z]: 584.9 [M+H].sup.+

[0589] The compounds of the formulae (I-021)-(I-025) listed in Table 1 below can be prepared analogously.

Synthesis of N-[(1S)-1-(5-iodo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide (Example I-027)

[0590] ##STR00033##

[0591] Step 1

tert-Butyl N-[5-[(15)-1-(tert-butoxycarbonylamino)ethyl]-1-pyrimidin-2-yl-1,2,4-triazol-3-yl]carbamate

[0592] ##STR00034##

[0593] To 6.1 g (32.2 mmol) N-Boc-alanin (Boc-Ala-OH purchased from Sigma-Aldrich) und 6.1 g (32.0 mmol) tert-butyl N-methyl-N-(methylsulfanyl-carbonimidoyl)carbamate (ABCR GmbH Product List: AB528361) in dioxane (20 mL), 9.7 g (96.6 mmol) DIPEA and 17.2 g (45.4 mmol) HATU were added, and the reaction mixture was stirred 3 hours at room temperature. Then, to the in-situ formed tert-butyl N—[N-[(2S)-2-(tert-butoxycarbonylamino)propanoyl]-C-methylsulfanyl-carbonimidoyl]-N-methyl-carbamate acetic acid, 5.0 g (45.4 mmol) pyrimidin-2-ylhydrazine were added and the reaction mixture was stirred for 2 h at 50° C. temperature. Afterwards, the reaction mixture was treated with ethyl acetate and then extracted with a saturated aqueous NaCl solution and water. The organic phase was separated, dried over Na.sub.2SO.sub.4 and the solvent was evaporated under reduced pressure. The remaining crude product was chromatographed with a cyclohexane/acetone gradient on silica gel to afford 4.1 g (purity: 90%; yield: 23%) of the title compound. The enantiomeric excess of the chiral title compounds has been determined: ee-value=100%; R.sub.t=9.26 min.

[0594] Formula: C.sub.18H.sub.27N.sub.7O.sub.4 Molecular weight: 405.46 g/mol

[0595] HPLC-MS neutral [m/z]: 406.2 [M+H].sup.+

[0596] .sup.1H-NMR peaklist (400.2 MHz, d.sub.6-DMSO, ppm): δ=9.9069 (0.8); 8.9590 (1.5); 8.9469 (1.5); 8.7705 (0.7); 8.7670 (0.8); 8.7595 (0.8); 8.7560 (0.8); 8.5468 (0.9); 8.5433 (0.9); 8.5258 (1.0); 8.5223 (0.9); 7.6020 (0.9); 7.5899 (1.8); 7.5777 (0.9); 7.5330 (1.0); 7.5220 (1.0); 7.5120 (1.0); 7.5010 (0.9); 3.3288 (11.8); 2.8918 (1.3); 2.7332 (1.0); 2.7319 (1.1); 2.6904 (0.5); 2.5258 (0.4); 2.5210 (0.6); 2.5124 (9.4); 2.5078 (19.4); 2.5032 (25.9); 2.4986 (18.5); 2.4940 (8.7); 1.4523 (16.0); 1.4394 (1.3); 1.4219 (1.2); 1.4180 (1.2); 1.3977 (5.5); 1.3818 (0.3); 1.2936 (4.8); 1.2769 (0.4); 0.0080 (0.9); −0.0002 (28.6); −0.0086 (0.9).

[0597] Step 2

5-[(1S)-1-aminoethyl]-1-pyrimidin-2-yl-1,2,4-triazol-3-amine-hydrochloride

[0598] ##STR00035##

[0599] 7.2 g (17.7 mmol) tert-butyl N-[5-[(1S)-1-(tert-butoxycarbonylamino)ethyl]-1-pyrimidin-2-yl-1,2,4-triazol-3-yl]carbamate were dissolved in 4N HCl-dioxane solution (150 mL) and the mixture was stirred 18 h at room temperature. Then the solvent was evaporated under reduced pressure to afford the title compound, which can be used for the coupling reaction in step 3.

[0600] Formula: C.sub.8H.sub.11N.sub.7 HCl Molecular weight: 241.68 g/mol

[0601] HPLC-MS acid (ESI-positive) [m/z]: 206.2 [M−HCl]+

[0602] Step 3

N-[(1S)-1-(5-amino-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl) benzamide

[0603] ##STR00036##

[0604] To 400 mg (1.55 mmol) bis-3,5-(trifluoromethyl)-benzoic acid, 260 mg (2.0 mmol) DIPEA in acetonitrile (17.3 mL) and 650 mg (1.7 mmol) HATU were added, and the reaction mixture was stirred for 10 minutes. Then 375 mg (1.55 mmol) 5-[(1S)-1-aminoethyl]-1-pyrimidin-2-yl-1,2,4-triazol-3-amine-hydrochloride were added together with triethylamine (1.0 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was treated with water and then extracted with dichloromethane. The separated organic phase was dried over MgSO.sub.4 and was concentrated under reduced pressure. The remaining crude product was chromatographed by preparative HPLC to afford 150 mg (purity: 93.5%; yield: 22%) of the title compound.

[0605] Formula: C.sub.17H.sub.13F.sub.6N.sub.7O Molecular weight: 445.33 g/mol

[0606] HPLC-MS neutral (ESI-positive) [m/z]: 446.1 [M+H].sup.+

[0607] Step 4

N-[(1S)-1-(5-iodo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide

[0608] To 220 mg (0.49 mmol) N-[(1S)-1-(5-amino-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-3,5-bis(trifluoromethyl) benzamide in acetonitrile (20 ml), 270 mg (1.0 mmol) diiodomethane was added (argon atmosphere), and then the reaction mixture was treated drop by drop at room temperature with 75 mg (0.72 mmol) tert-butyl nitrite. Then the reaction mixture was stirred 2 h at 70° C. temperature. The reaction mixture was treated with acetic acid ethyl ester and then extracted with a saturated NaCl solution. Afterwards the solvent was evaporated under vacuo the crude product was chromatographed by HPLC to afford 125 mg (purity: 93.5%; yield: 42.5%) of the title compound. The enantiomeric excess of the chiral title compounds has been determined using chiral HPLC: Chiralcel OD-RH column (4.6 mm×150 mm×5 pm), room temperature, eluting with 0.1% phosphoric acid (A) and acetonitrile (B), gradient A:B 95/5 to 10/90, detecting at 210 nm: ee-value=97% (Rt=10.98 min).

[0609] Formula: C.sub.17H.sub.11F.sub.6IN.sub.6O Molecular weight: 556.21 g/mol

[0610] HPLC-MS acid (ESI positiv): 557.0 [M+H].sup.+

Synthesis of (1S)-1-(5-chloro-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine-hydrochloride

[0611] Step 1

tert-Butyl N-[(1S)-1-[5-(benzyloxycarbonylamino)-2-pyrimidin-2-yl-1,2,4-triazol-3-yl]ethyl] carbamate

[0612] ##STR00037##

[0613] To 200 mg (1.05 mmol) N-Boc-alanin (Boc-Ala-OH purchased from Sigma-Aldrich) and 240 g (1.07 mmol) N-[imino(methylthio)methyl]-carbamic acid phenylmethyl ester (Chemieliva Pharmaceutical Product List; Order number: CA1251032) in N,N-dimethylformamide (5 mL), 320 mg (3.16 mmol) DIPEA and 600 mg (1.57 mmol) HATU were added, and the reaction mixture was stirred 3 hours at room temperature. Then, to the in-situ formed tert-butyl N-[(1S)-2-[[benzyloxycarbonylamino(methylsulfanyl) methylene]amino]-1-methyl-2-oxo-ethyl]carbamate, 140 mg (1.27 mmol) pyrimidin-2-ylhydrazine and acetic acid (0.25 mL) were added and the reaction mixture was stirred for 1 h at 50° C. temperature. Afterwards, the reaction mixture was treated with ethyl acetate and then extracted with a saturated aqueous NaCl solution and water. The organic phase was separated, dried over Na.sub.2SO.sub.4 and the solvent was evaporated under reduced pressure. The remaining crude product was chromatographed with a cyclohexane/acetone gradient on silica gel to afford 239 mg (purity: 96.5%; yield: 47%) of the title compound.

[0614] Formula: C.sub.21H.sub.25N.sub.7O.sub.4 Molecular weight: 439.47 g/mol

[0615] LC-MS neutral [m/z]: 440.2 [M+H].sup.+

[0616] .sup.1H-NMR peaklist (600.1 MHz, d.sub.6-DMSO, ppm): δ=10.3936 (2.8); 8.9644 (3.7); 8.9564 (3.5); 7.6071 (2.6); 7.5990 (4.9); 7.5909 (2.5); 7.4600 (0.9); 7.4473 (1.0); 7.4405 (2.0); 7.4383 (2.6); 7.4265 (4.3); 7.4031 (2.7); 7.4000 (0.8); 7.3910 (4.7); 7.3782 (2.2); 7.3456 (1.5); 7.3370 (0.6); 7.3336 (1.9); 7.3215 (0.6); 5.5211 (0.5); 5.5092 (0.8); 5.4974 (0.6); 5.1592 (8.4); 3.3174 (105.4); 2.6190 (0.4); 2.6161 (0.7); 2.6130 (1.0); 2.6100 (0.7); 2.6071 (0.4); 2.5221 (2.2); 2.5190 (2.7); 2.5159 (2.8); 2.5070 (50.7); 2.5041 (106.9); 2.5010 (147.1); 2.4980 (108.0); 2.4950 (50.4); 2.3879 (0.6); 2.3849 (0.8); 2.3819 (0.6); 1.4435 (3.6); 1.4320 (3.3); 1.2872 (16.0); 1.0400 (0.9); −0.0001 (2.9)

[0617] Step 2

tert-Butyl N-[(1S)-1-(5-amino-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]carbamate

[0618] ##STR00038##

[0619] 560 mg (1.27 mmol) tert-butyl N-[(1S)-1-[5-(benzyloxycarbonylamino)-2-pyrimidin-2-yl-1,2,4-triazol-3-yl]ethyl]carbamate were hydrogenated at room temperature (5 bar, 16 hours) in the presence of 50 g (46.9 mmol) 10% palladium/carbon (Aldrich) catalyst in ethanol (10 mL). The remaining crude product was filtered on silica gel to afford 160 mg (purity: 79%; yield: 32%) of the title compound.

[0620] Formula: C.sub.13H.sub.19N.sub.7O.sub.2 Molecular weight: 305.34 g/mol

[0621] HPLC-MS neutral [m/z]: 306.1 [M+H].sup.+

[0622] Step 3

tert-Butyl N-[(1S)-1-(5-chloro-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl] carbamate

[0623] ##STR00039##

[0624] To 160.0 mg (0.52 mmol) tert-butyl N-[(1S)-1-(5-amino-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]carbamate in acetonitrile (10 mL), 130.0 mg (0.96 mmol) Cu(II)-chloride was added, and then the reaction mixture was treated drop by drop at room temperature with 80.0 mg (0.77 mmol) tert-butyl nitrite. Then the reaction mixture was stirred 2 h at 70° C. temperature. The reaction mixture was treated with acetic acid ethyl ester and then extracted with a saturated NaCl solution. Afterwards the solvent was evaporated under vacuo the crude product was chromatographed by prep. HPLC to afford 47.0 mg (yield: 28%) of the title compound. The enantiomeric excess of the chiral title compounds has been determined via screen OD_RH (acid): ee-value=80%; R.sub.t=9.37 min.

[0625] Formula: C.sub.13H.sub.17ClN.sub.6O.sub.2 Molecular weight: 324.77 g/mol

[0626] .sup.1H-NMR peaklist (600.4 MHz, d.sub.7-DMF): δ=9.0802 (3.6); 9.0725 (3.5); 8.0234 (40.3); 7.7498 (1.4); 7.7418 (2.7); 7.7338 (1.4); 7.4383 (0.8); 7.4266 (0.8); 5.6675 (0.6); 5.6561 (0.8); 5.6450 (0.6); 3.4532 (93.6); 2.9512 (0.8); 2.9207 (13.3); 2.9177 (27.1); 2.9146 (37.5); 2.9115 (27.7); 2.9086 (14.0); 2.7834 (0.8); 2.7503 (13.9); 2.7471 (28.0); 2.7440 (39.2); 2.7408 (28.5); 2.7376 (14.6); 1.5839 (5.6); 1.5725 (5.4); 1.3118 (16.0); 1.1391 (0.6); 0.0053 (2.3); −0.0001 (69.1); −0.0056 (2.8)

[0627] Step 4

(1S)-1-(5-Chloro-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine-hydrochloride

[0628] ##STR00040##

[0629] 337 mg g (1.03 mmol) tert-butyl N-[(1S)-1-(5-chloro-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl] carbamate were dissolved in 4N HCl-dioxane solution (10 mL) and the mixture was stirred 18 h at room temperature. Then the solvent was evaporated under reduced pressure to afford the title compound, which can be used for the coupling reactions. Afterwards the solvent was evaporated to afford 260.0 mg (yield: 96%) of the title compound. The enantiomeric excess of the chiral title compounds has been determined via screen OD_RH (acid): ee-value=100%; Rt=1.39 min.

[0630] Formula: C.sub.8H.sub.9ClN.sub.6 HCl Molecular weight: 261.11 g/mol

[0631] HPLC-MS acid (ESI-positive) [m/z]: 225.0 [M−HCl]+

Synthesis of (1S)-1-(5-bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine-hydrochloride

[0632] Step 1

tert-Butyl N-[(1S)-1-(5-bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl] carbamate

[0633] ##STR00041##

[0634] To 500.0 mg (1.63 mmol) tert-butyl N-[(1S)-1-(5-amino-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]carbamate in acetonitrile (20 mL), 690.0 mg (3.08 mmol) Cu(II)-bromide was added, and then the reaction mixture was treated drop by drop at room temperature with 250.0 mg (2.42 mmol) tert-butyl nitrite. Then the reaction mixture was stirred 2 h at 70° C. temperature. The reaction mixture was treated with acetic acid ethyl ester and then extracted with a saturated NaCl solution. Afterwards the solvent was evaporated under vacuo the crude product was chromatographed with a cyclohexane/acetone gradient on silica gel to afford 333.0 mg (purity: 100%; yield: 55%) of the title compound. The enantiomeric excess of the chiral title compounds has been determined via screen OD_RH (acid): ee-value=100%; Rt=9.63 min.

[0635] Formula: C.sub.13H.sub.7BrN.sub.6O.sub.2 Molecular weight: 369.22 g/mol

[0636] HPLC-MS neutral [m/z]: 369.0 [M+H].sup.+

[0637] Step 2

(1S)-1-(5-Bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine-hydrochloride

[0638] ##STR00042##

[0639] 330 mg (0.89 mmol) tert-butyl N-[(1S)-1-(5-bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl] carbamate were dissolved in 4N HCl-dioxane solution (10 mL) and the mixture was stirred 18 h at room temperature. Then the solvent was evaporated under reduced pressure to afford 250 mg (yield: 91.5%) of the title compound, which can be used for the coupling reactions.

[0640] Formula: C.sub.8H.sub.9BrN.sub.6 HCl Molecular weight: 305.57 g/mol

[0641] HPLC-MS acid (ESI-positive) [m/z]: 270.9 [M−HCl].sup.+

Synthesis of (1S)-1-(5-iodo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine-hydrochloride

[0642] Step 1

tert-Butyl N-[(1S)-1-(5-iodo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl] carbamate

[0643] ##STR00043##

[0644] To 500.0 mg (1.63 mmol) tert-butyl N-[(1S)-1-(5-amino-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]carbamate in acetonitrile (20 mL), 816.7 mg (3.04 mmol) diiodomethane was added, and then the reaction mixture was treated drop by drop at room temperature with 250.0 mg (2.42 mmol) tert-butyl nitrite. Then the reaction mixture was stirred 2 h at 70° C. temperature. The reaction mixture was treated with acetic acid ethyl ester and then extracted with a saturated NaCl solution. Afterwards the solvent was evaporated under vacuo the crude product was chromatographed by prep. HPLC to afford 294.0 mg (purity: 100%; yield: 43%) of the title compound.

[0645] Formula: C.sub.13H.sub.17IN.sub.6O.sub.2 Molecular weight: 416.22 g/mol

[0646] HPLC-MS neutral [m/z]: 417.0 [M+H].sup.+

[0647] Step 2

(1S)-1-(5-Iodo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine-hydrochloride

[0648] ##STR00044##

[0649] 290 mg (0.69 mmol) tert-butyl N-[(1S)-1-(5-iodo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl] carbamate were dissolved in 4N HCl-dioxane solution (10 mL) and the mixture was stirred 18 h at room temperature. Then the solvent was evaporated under reduced pressure to afford the title compound, which can be used for the coupling reactions. The enantiomeric excess of the chiral title compounds has been determined via screen OD_RH (acid): ee-value=100%; R.sub.t=1.41 min.

[0650] Formula: CH.sub.9H.sub.9IN.sub.6 HCl Molecular weight: 352.56 g/mol

[0651] HPLC-MS acid (ESI-positive) [m/z]: 317.0 [M−HCl]+

[0652] Analytical Data of the Compounds

[0653] The determination of [M+H].sup.+ or M.sup.− by LC-MS under acidic chromatographic conditions was done with 1 ml formic acid per liter acetonitrile and 0.9 ml formic acid per liter Millipore water as eluents. The column Zorbax Eclipse Plus C18 50 mm*2.1 mm was used. The temperature of the column oven was 55° C.

[0654] The enantomeric excesses of the intermediate compounds tert-butyl N-[5-[(1S)-1-(tert-butoxycarbonylamino)ethyl]-1-pyrimidin-2-yl-1,2,4-triazol-3-yl]carbamate, tert-butyl N-[(1S)-1-(5-chloro-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl] carbamate, (1S)-1-(5-chloro-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine-hydrochloride [INT-04], tert-butyl N-[(1S)-1-(5-bromo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl] carbamate, (1S)-1-(5-iodo-2-pyrimidin-2-yl-1,2,4-triazol-3-yl) ethanamine-hydrochloride [TNT-06], and example T-027 were determined using chiral HPLC: Chiralcel OD-RH column (4.6 mm×150 mm×5 μm), room temperature, eluting with 0.1% phosphoric acid (A) and acetonitrile (B), gradient A:B 95/5 to 10/90, detecting at 210 nm.

[0655] The determination of the .sup.1H NMR data was effected with a Bruker Avance III 400 MHz equipped with a 1.7 mm TCI cryo probe, a Bruker Avance III 600 MHz equipped with a 5 mm multi-nuclear cryo probe or a Bruker Avance NEO 600 MHz equipped with a 5 mm TCI cryo probe with tetramethylsilane as reference (0.0) and the solvents CD.sub.3CN, CDCl.sub.3 or D.sub.6-DMSO.

[0656] The NMR data of selected examples are listed either in conventional form (6 values, multiplet splitting, number of hydrogen atoms) or as NMR peak lists.

[0657] NMR Peak List Method

[0658] The .sup.1H NMR data of selected examples are stated in the form of .sup.1H NMR peak lists. For each signal peak, first the δ value in ppm and then the signal intensity in round brackets are listed. The pairs of δ value-signal intensity numbers for different signal peaks are listed with separation from one another by semicolons.

[0659] The peak list for one example therefore takes the form of:

[0660] δ.sub.1 (intensity.sub.1); δ.sub.2 (intensity.sub.2); . . . δ.sub.i (intensity.sub.i); . . . ; δ.sub.n (intensity.sub.n)

[0661] The intensity of sharp signals correlates with the height of the signals in a printed example of an NMR spectrum in cm and shows the true ratios of the signal intensities. In the case of broad signals, several peaks or the middle of the signal and the relative intensity thereof may be shown in comparison to the most intense signal in the spectrum.

[0662] For calibration of the chemical shift of .sup.1H NMR spectra, we use tetramethylsilane and/or the chemical shift of the solvent, particularly in the case of spectra which are measured in DMSO. Therefore, the tetramethylsilane peak may but need not occur in NMR peak lists.

[0663] The lists of the .sup.1H NMR peaks are similar to the conventional .sup.1H NMR printouts and thus usually contain all peaks listed in a conventional NMR interpretation.

[0664] In addition, like conventional .sup.1H NMR printouts, they may show solvent signals, signals of stereoisomers of the target compounds which are likewise provided by the invention, and/or peaks of impurities.

[0665] In the reporting of compound signals within the delta range of solvents and/or water, our lists of .sup.1H NMR peaks show the standard solvent peaks, for example peaks of DMSO in DMSO-D.sub.6 and the peak of water, which usually have a high intensity on average.

[0666] The peaks of stereoisomers of the target compounds and/or peaks of impurities usually have a lower intensity on average than the peaks of the target compounds (for example with a purity of >90%).

[0667] Such stereoisomers and/or impurities may be typical of the particular preparation process. Their peaks can thus help in identifying reproduction of our preparation process with reference to “by-product fingerprints”.

[0668] A person skilled in the art calculating the peaks of the target compounds by known methods (MestreC, ACD simulation, but also with empirically evaluated expected values) can, if required, isolate the peaks of the target compounds, optionally using additional intensity filters. This isolation would be similar to the peak picking in question in conventional .sup.1H NMR interpretation.

[0669] Further details of .sup.1H NMR peak lists can be found in the Research Disclosure Database Number 564025.

[0670] The compounds according to the invention described in table 1 below are likewise preferred compounds of the formula (I), wherein R.sup.1 is hydrogen, R.sup.3 is methyl, X is oxygen, Y is a direct bond and R.sup.5 is halogen, according to the invention which are obtained according to or analogously to the preparation examples described above.

##STR00045##

TABLE-US-00001 TABLE 1 ESI mass Example Structure.sup.3) NMR Peaklist.sup.1) [m/z].sup.2) I-001 [00046] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.3731 (2.8); 9.3560 (2.8); 9.0039 (15.6); 8.9917 (16.0); 7.9183 (4.1); 7.9143 (6.4); 7.9104 (4.3); 7.7818 (4.4); 7.7025 (4.2); 7.7001 (4.5); 7.6774 (4.1); 7.6652 (7.8); 7.6531 (4.0); 5.9966 (0.5); 5.9795 (2.3); 5.9622 (3.5); 5.9449 (2.3); 5.9277 (0.5); 5.7577 (9.6); 3.3320 (119.6); 3.1765 (0.4); 3.1634 (0.3); 2.6774 (0.7); 2.6729 (1.0); 2.6684 (0.7); 2.5263 (3.4); 2.5128 (62.7); 2.5085 (123.2); 2.5040 (157.6); 2.4994 (113.4); 2.4950 (55.2); 2.3354 (0.7); 2.3307 (0.9); 2.3263 (0.6); 1.6512 (12.6); 1.6338 (12.6); 1.4302 (0.4); 0.0080 (0.4); −0.0002 (10.7); −0.0085 (0.4) 447.1 [M + H].sup.+ I-002 [00047] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.6096 (3.5); 9.5925 (3.6); 9.0108 (15.6); 8.9987 (16.0); 8.4228 (13.8); 8.3212 (6.1); 7.6795 (4.1); 7.6673 (7.9); 7.6552 (4.0); 6.0565 (0.6); 6.0396 (2.6); 6.0223 (4.0); 6.0050 (2.6); 5.9879 (0.6); 5.7574 (12.4); 3.3342 (185.5); 2.6780 (0.9); 2.6736 (1.2); 2.6691 (1.0); 2.5090 (161.7); 2.5046 (206.5); 2.5003 (155.9); 2.3314 (1.2); 2.3269 (0.9); 1.6837 (14.7); 1.6663 (14.6); 1.2341 (0.4); −0.0001 (9.3) 465.2 [M + H].sup.+ I-003 [00048] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.4530 (3.2); 9.4359 (3.2); 9.0071 (15.7); 8.9949 (16.0); 8.2610 (6.3); 8.1752 (5.9); 8.1010 (6.1); 7.6795 (4.2); 7.6673 (7.9); 7.6551 (4.0); 6.0163 (0.6); 5.9991 (2.5); 5.9818 (3.9); 5.9645 (2.5); 5.9473 (0.5); 5.7574 (12.1); 4.1070 (0.4); 4.0937 (0.4); 3.3733 (1.0); 3.3328 (180.6); 3.1763 (2.0); 3.1632 (2.0); 2.6772 (0.9); 2.6729 (1.2); 2.6683 (0.9); 2.5261 (4.6); 2.5084 (162.5); 2.5039 (205.6); 2.4994 (150.0); 2.3350 (0.9); 2.3308 (1.2); 2.3263 (0.9); 1.6878 (0.4); 1.6587 (14.1); 1.6413 (14.0); 0.0080 (0.5); −0.0002 (12.1); −0.0084 (0.5) 476.1 [M + H].sup.+ I-004 [00049] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.4573 (2.9); 9.4403 (3.0); 9.0074 (15.5); 8.9952 (16.0); 8.1287 (5.6); 8.0732 (11.6); 8.0711 (11.1); 7.6794 (4.1); 7.6672 (7.8); 7.6550 (4.0); 6.0194 (0.5); 6.0022 (2.3); 5.9849 (3.6); 5.9676 (2.3); 5.9502 (0.5); 5.7572 (12.7); 3.3359 (186.8); 3.1768 (0.9); 3.1637 (0.8); 2.6780 (0.7); 2.6733 (0.9); 2.6687 (0.7); 2.5267 (3.5); 2.5132 (63.2); 2.5090 (124.1); 2.5045 (159.1); 2.4999 (115.8); 2.4956 (57.6); 2.3358 (0.7); 2.3312 (0.9); 2.3267 (0.7); 1.6612 (13.0); 1.6438 (12.9); −0.0001 (8.9); −0.0084 (0.3) 433.1 [M + H].sup.+ I-005 [00050] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.3098 (2.2); 9.2926 (2.2); 9.0054 (13.0); 8.9932 (13.3); 7.9551 (0.3); 7.9503 (0.4); 7.8908 (0.4); 7.8150 (2.3); 7.8102 (5.1); 7.8057 (5.1); 7.7921 (16.0); 7.7874 (9.8); 7.6810 (3.4); 7.6688 (6.4); 7.6566 (3.3); 5.9842 (0.4); 5.9672 (1.8); 5.9499 (2.8); 5.9326 (1.8); 5.9152 (0.4); 5.7574 (10.7); 4.1061 (0.7); 4.0930 (0.7); 3.3316 (83.5); 3.1763 (4.1); 3.1632 (4.0); 2.6772 (0.5); 2.6728 (0.7); 2.6683 (0.5); 2.5262 (2.4); 2.5213 (3.9); 2.5127 (45.9); 2.5084 (91.2); 2.5038 (117.5); 2.4992 (84.8); 2.4948 (41.6); 2.3352 (0.5); 2.3306 (0.7); 2.3261 (0.5); 1.6395 (10.1); 1.6221 (10.1); −0.0002 (7.4) 398.1 [M + H].sup.+ I-006 [00051] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.5494 (1.5); 9.5325 (1.5); 9.0085 (7.8); 8.9963 (8.0); 7.8307 (16.0); 7.6870 (2.0); 7.6748 (3.9); 7.6627 (2.0); 5.9915 (1.3); 5.9743 (2.0); 5.9570 (1.3); 5.7567 (8.5); 3.3329 (63.9); 3.1760 (0.6); 3.1631 (0.6); 2.6772 (0.4); 2.6726 (0.5); 2.6682 (0.4); 2.5257 (2.0); 2.5123 (37.6); 2.5082 (71.4); 2.5038 (90.7); 2.4993 (66.0); 2.4950 (33.3); 2.3349 (0.4); 2.3306 (0.5); 2.3261 (0.4); 1.6458 (7.2); 1.6284 (7.1); 1.4371 (0.5); −0.0002 (4.1) 398.1 [M + H].sup.+ I-007 [00052] .sup.1H-NMR (400.2 MHz, d6-DMSO): δ = 9.5391 (2.7); 9.5219 (2.7); 9.1787 (4.8); 9.1745 (4.9); 9.1280 (4.4); 9.1251 (4.4); 9.0139 (15.6); 9.0017 (16.0); 8.5107 (4.6); 7.6832 (4.1); 7.6711 (7.9); 7.6589 (4.0); 6.0517 (0.5); 6.0344 (2.3); 6.0171 (3.7); 5.9998 (2.3); 5.9822 (0.5); 5.7567 (13.4); 3.3372 (295.7); 3.1762 (0.5); 3.1631 (0.5); 2.6775 (0.8); 2.6729 (1.1); 2.6683 (0.8); 2.5263 (3.6); 2.5128 (71.7); 2.5085 (144.0); 2.5039 (186.9); 2.4994 (135.6); 2.4950 (66.7); 2.3353 (0.8); 2.3307 (1.1); 2.3262 (0.8); 1.6750 (13.0); 1.6576 (13.0); −0.0001 (4.9) 398.1 [M + H].sup.+ I-008 [00053] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.6941 (2.5); 9.6771 (2.6); 9.0134 (14.0); 9.0013 (14.3); 8.1969 (6.5); 8.1944 (7.0); 8.1485 (6.7); 7.6888 (3.7); 7.6766 (7.0); 7.6645 (3.6); 6.0521 (0.4); 6.0347 (2.1); 6.0175 (3.3); 6.0002 (2.1); 5.9827 (0.5); 5.7575 (16.0); 3.3314 (91.0); 3.1763 (0.5); 3.1632 (0.5); 2.6775 (0.6); 2.6731 (0.8); 2.6685 (0.6); 2.5264 (3.0); 2.5129 (54.6); 2.5086 (107.6); 2.5041 (138.4); 2.4995 (99.9); 2.4952 (49.1); 2.3354 (0.6); 2.3309 (0.8); 2.3264 (0.6); 1.6694 (11.6); 1.6520 (11.6); −0.0002 (8.9); −0.0085 (0.3) 433.1 [M + H].sup.+ I-009 [00054] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.4495 (2.4); 9.4322 (2.4); 9.0031 (10.0); 8.9909 (10.1); 8.2588 (4.9); 8.1739 (4.7); 8.0991 (4.8); 7.6748 (2.6); 7.6627 (5.0); 7.6505 (2.5); 6.0197 (0.4); 6.0021 (1.7); 5.9847 (2.7); 5.9673 (1.8); 5.9502 (0.4); 5.7572 (16.0); 4.1049 (0.5); 4.0921 (0.5); 3.3301 (102.5); 3.1760 (2.9); 3.1629 (2.8); 2.6769 (0.9); 2.6725 (1.2); 2.6684 (0.9); 2.5078 (158.1); 2.5036 (196.3); 2.4993 (144.5); 2.3345 (0.8); 2.3303 (1.1); 2.3258 (0.8); 1.6529 (9.6); 1.6355 (9.5); −0.0002 (10.3) 521.0 [M + H].sup.+ I-010 [00055] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.6078 (2.3); 9.5904 (2.3); 9.0060 (11.0); 8.9938 (11.2); 8.4199 (9.2); 8.3205 (4.1); 7.6738 (2.8); 7.6659 (1.4); 7.6617 (5.3); 7.6540 (0.8); 7.6495 (2.7); 6.0582 (0.4); 6.0414 (1.7); 6.0240 (2.7); 6.0067 (1.7); 5.9896 (0.4); 5.7552 (16.0); 3.3585 (302.0); 3.1772 (1.0); 3.1641 (1.0); 2.6790 (0.8); 2.6746 (1.1); 2.6700 (0.8); 2.5278 (4.3); 2.5142 (77.6); 2.5100 (149.3); 2.5056 (189.2); 2.5011 (138.2); 2.4969 (69.5); 2.3368 (0.8); 2.3324 (1.0); 2.3278 (0.8); 1.6780 (9.3); 1.6606 (9.2); 1.2343 (0.4); 0.0080 (0.3); −0.0002 (9.6); −0.0085 (0.4) 511.0 [M + H].sup.+ I-011 [00056] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.5460 (1.2); 9.5288 (1.2); 9.0050 (6.7); 8.9928 (6.7); 7.9562 (0.4); 7.8292 (14.8); 7.6829 (1.7); 7.6747 (0.8); 7.6707 (3.2); 7.6626 (0.4); 7.6586 (1.6); 5.9945 (1.0); 5.9772 (1.6); 5.9599 (1.0); 5.7571 (16.0); 3.3306 (25.7); 3.1757 (1.1); 3.1630 (1.0); 2.6770 (0.4); 2.6725 (0.5); 2.6680 (0.4); 2.5259 (1.9); 2.5124 (36.9); 2.5081 (72.5); 2.5035 (92.7); 2.4990 (66.8); 2.4946 (32.7); 2.3347 (0.4); 2.3304 (0.5); 2.3259 (0.4); 1.6403 (5.5); 1.6230 (5.4); −0.0002 (6.7) 444.1 [M + H].sup.+ I-012 [00057] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.3061 (2.5); 9.2888 (2.5); 9.0017 (12.2); 8.9896 (12.4); 7.8139 (2.7); 7.8093 (5.8); 7.8047 (5.3); 7.7902 (16.0); 7.7856 (10.3); 7.6767 (3.2); 7.6645 (6.1); 7.6523 (3.1); 5.9874 (0.4); 5.9700 (1.9); 5.9527 (3.0); 5.9354 (2.0); 5.9180 (0.4); 5.7572 (9.4); 4.1056 (0.8); 4.0926 (0.8); 3.3311 (101.9); 3.1761 (4.4); 3.1630 (4.3); 2.6771 (0.7); 2.6725 (1.0); 2.6681 (0.7); 2.5259 (3.6); 2.5121 (68.0); 2.5081 (129.7); 2.5036 (164.0); 2.4991 (118.8); 2.4949 (59.1); 2.3349 (0.7); 2.3304 (0.9); 2.3259 (0.7); 1.6338 (10.5); 1.6164 (10.5); 0.0080 (0.4); −0.0002 (10.1); −0.0085 (0.4) 443.0 [M + H].sup.+ I−013 [00058] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 10.1990 (1.2); 9.3700 (2.2); 9.3526 (2.2); 8.9997 (9.9); 8.9875 (10.1); 8.7208 (1.0); 8.7167 (1.0); 8.4424 (0.6); 8.4370 (0.6); 8.4209 (0.7); 8.4154 (0.6); 7.9149 (3.5); 7.9115 (4.9); 7.9077 (3.1); 7.8871 (1.0); 7.8656 (0.9); 7.8309 (8.6); 7.7802 (3.7); 7.6975 (3.7); 7.6725 (2.6); 7.6604 (5.0); 7.6482 (2.5); 6.1247 (0.8); 6.1070 (0.8); 5.9990 (0.4); 5.9820 (1.7); 5.9648 (2.6); 5.9474 (1.7); 5.9302 (0.4); 5.7569 (14.6); 3.3326 (148.0); 3.1761 (0.4); 3.1631 (0.4); 2.6771 (0.9); 2.6727 (1.2); 2.6683 (0.9); 2.5259 (4.2); 2.5081 (158.5); 2.5037 (200.2); 2.4993 (145.0); 2.3350 (0.8); 2.3304 (1.1); 492.1 [M + H].sup.+ 2.3260 (0.8); 1.8223 (2.2); 1.8046 (2.3); 1.6453 (9.0); 1.6279 (8.9); 1.4664 (0.4); 1.4626 (0.4); 1.4461 (16.0); 0.0078 (0.4); −0.0002 (12.1) I-014 [00059] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.6899 (1.1); 9.6728 (1.1); 9.0120 (1.7); 9.0086 (5.8); 8.9999 (1.8); 8.9965 (5.9); 8.1926 (3.2); 8.1458 (3.1); 7.6875 (0.4); 7.6834 (1.5); 7.6754 (0.8); 7.6713 (2.9); 7.6633 (0.5); 7.6591 (1.5); 6.0371 (0.9); 6.0197 (1.4); 6.0025 (0.9); 5.7566 (16.0); 3.3294 (97.0); 3.1754 (0.6); 3.1622 (0.6); 2.6763 (0.7); 2.6719 (0.9); 2.6673 (0.7); 2.5252 (3.4); 2.5117 (61.1); 2.5074 (119.5); 2.5029 (152.8); 2.4983 (110.1); 2.4939 (53.9); 2.3341 (0.6); 2.3297 (0.8); 2.3251 (0.6); 1.6629 (4.8); 1.6455 (4.8); 0.0080 (0.4); −0.0002 (10.6); −0.0084 (0.4) 477.0 [M + H].sup.+ I-015 [00060] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.5361 (3.2); 9.5189 (3.2); 9.1764 (6.2); 9.1272 (5.7); 9.0104 (14.9); 8.9982 (15.1); 8.5092 (5.7); 7.6790 (4.0); 7.6669 (7.5); 7.6590 (1.3); 7.6547 (3.8); 6.0550 (0.5); 6.0381 (2.5); 6.0207 (3.9); 6.0033 (2.5); 5.9860 (0.6); 5.7571 (16.0); 3.3363 (242.7); 3.1764 (0.6); 3.1633 (0.6); 2.6776 (0.9); 2.6731 (1.2); 2.6687 (0.9); 2.5262 (4.5); 2.5086 (156.2); 2.5042 (196.7); 2.4997 (142.2); 2.3355 (0.8); 2.3310 (1.1); 2.3264 (0.8); 1.6698 (13.7); 1.6524 (13.5); −0.0002 (2.6) 443.1 [M + H].sup.+ I-016 [00061] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.4539 (3.2); 9.4367 (3.3); 9.0069 (4.8); 9.0034 (15.7); 8.9948 (5.0); 8.9912 (16.0); 8.3168 (0.3); 8.1262 (6.4); 8.0715 (13.2); 8.0697 (12.6); 7.6790 (1.2); 7.6747 (4.2); 7.6668 (2.3); 7.6626 (7.8); 7.6548 (1.3); 7.6504 (4.0); 6.0220 (0.5); 6.0049 (2.4); 5.9876 (3.7); 5.9702 (2.4); 5.9527 (0.5); 5.7572 (12.8); 4.1075 (0.7); 4.0945 (0.7); 3.3341 (249.7); 3.1764 (3.2); 3.1633 (3.2); 2.6774 (1.0); 2.6730 (1.3); 2.6684 (1.0); 2.5262 (5.1); 2.5127 (88.6); 2.5084 (169.8); 2.5040 (216.0); 2.4994 (156.5); 2.4951 (77.0); 2.3352 (0.9); 2.3307 (1.2); 2.3262 (0.9); 1.6553 (12.9); 1.6379 (12.7); −0.0002 (7.2) 476.1 [M + H].sup.+ I−017 [00062] .sup.1H-NMR (600.1 MHz, d.sub.6-DMSO): δ = 9.4153 (2.5); 9.4039 (2.5); 8.6405 (4.4); 8.6397 (4.4); 8.6363 (4.6); 8.6354 (4.4); 8.2234 (3.8); 8.2191 (3.7); 8.2089 (4.1); 8.2045 (4.1); 8.1234 (4.3); 8.1208 (2.9); 8.0758 (3.9); 8.0629 (4.2); 7.8635 (5.1); 7.8627 (5.0); 7.8490 (4.7); 7.8482 (4.6); 5.9368 (0.4); 5.9252 (2.1); 5.9137 (3.3); 5.9022 (2.2); 5.8906 (0.4); 3.3194 (43.3); 2.6183 (0.3); 2.6152 (0.5); 2.6122 (0.3); 2.5243 (1.0); 2.5212 (1.2); 2.5180 (1.2); 2.5093 (25.1); 2.5062 (54.5); 2.5031 (77.0); 2.5001 (56.8); 2.4971 (26.3); 2.3902 (0.3); 2.3871 (0.5); 2.3840 (0.3); 1.6404 (11.4); 1.6287 (11.5); 1.3975 (16.0); −0.0001 (4.0) 465.1 [M + H].sup.+ I-018 [00063] .sup.1H-NMR (600.1 MHz, d.sub.6-DMSO): δ = 9.4115 (2.6); 9.4001 (2.7); 8.6396 (0.4); 8.6349 (4.7); 8.6311 (4.5); 8.6307 (4.4); 8.2163 (3.4); 8.2120 (3.3); 8.2089 (0.4); 8.2018 (3.6); 8.1975 (3.6); 8.1214 (4.6); 8.0745 (4.3); 8.0615 (4.7); 7.8651 (5.0); 7.8506 (4.6); 5.9417 (0.4); 5.9302 (2.0); 5.9253 (0.4); 5.9186 (3.2); 5.9139 (0.5); 5.9071 (2.1); 5.8955 (0.4); 3.3216 (92.2); 2.6184 (0.4); 2.6154 (0.5); 2.6124 (0.4); 2.5244 (1.1); 2.5214 (1.4); 2.5182 (1.5); 2.5094 (26.3); 2.5064 (55.2); 2.5033 (76.9); 2.5003 (57.3); 2.4973 (27.2); 2.3904 (0.4); 2.3873 (0.5); 2.3843 (0.3); 1.6353 (11.1); 1.6285 (2.0); 1.6237 (11.1); 1.3974 (16.0); −0.0001 (2.7). 510.0 I-019 [00064] .sup.1H-NMR (600.1 MHz, d.sub.6-DMSO): δ = 9.3946 (1.4); 9.3829 (1.5); 8.6199 (2.4); 8.6191 (2.4); 8.6157 (2.5); 8.6148 (2.4); 8.1956 (2.0); 8.1913 (1.9); 8.1811 (2.2); 8.1768 (2.2); 8.1195 (2.3); 8.1170 (1.6); 8.0712 (2.1); 8.0689 (1.5); 8.0609 (2.3); 7.8528 (2.7); 7.8520 (2.7); 7.8383 (2.5); 7.8374 (2.5); 5.9340 (1.1); 5.9224 (1.8); 5.9107 (1.1); 3.3185 (30.0); 3.2880 (0.3); 2.6146 (0.4); 2.5236 (0.7); 2.5206 (0.9); 2.5174 (0.9); 2.5087 (17.6); 2.5056 (38.0); 2.5025 (53.6); 2.4995 (39.5); 2.4965 (18.2); 2.3865 (0.3); 1.6176 (5.8); 1.6060 (5.8); 1.3975 (16.0); 1.2507 (1.1); −0.0001 (2.9). 556.0 [M + H].sup.+ I-020 [00065] .sup.1H-NMR (600.1 MHz, d.sub.6-DMSO): δ = 8.9866 (0.3); 8.9785 (0.3); 8.0377 (0.1); 7.6434 (0.2); 3.3274 (16.0); 2.5288 (0.2); 2.5258 (0.3); 2.5227 (0.3); 2.5137 (5.3); 2.5108 (10.9); 2.5078 (15.0); 2.5048 (11.3); 2.5022 (5.5); 1.6265 (0.3); 1.6149 (0.3) 584.9 [M + H].sup.+ I-021 [00066] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.5882 (3.2); 9.5705 (3.3); 9.0105 (0.6); 8.9981 (1.1); 8.9907 (15.6); 8.9785 (16.0); 8.4147 (12.1); 8.3168 (5.7); 7.6520 (4.1); 7.6399 (7.8); 7.6277 (4.0); 6.0534 (0.5); 6.0362 (2.3); 6.0187 (3.7); 6.0012 (2.3); 5.9840 (0.5); 5.7572 (12.3); 3.3331 (190.4); 3.1765 (0.8); 3.1634 (0.8); 2.6774 (1.0); 2.6730 (1.4); 2.6685 (1.0); 2.5262 (4.9); 2.5085 (178.1); 2.5041 (227.2); 2.4996 (165.9); 2.3353 (1.0); 2.3309 (1.3); 2.3264 (1.0); 1.6834 (0.6); 1.6590 (12.8); 1.6416 (12.8); 1.2335 (0.3); 0.0078 (0.4); −0.0002 (11.4); −0.0084 (0.5) 557.0 [M + H].sup.+ I-022 [00067] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.4315 (3.2); 9.4139 (3.3); 9.0068 (0.6); 8.9878 (15.7); 8.9756 (16.0); 8.2532 (6.1); 8.1704 (5.7); 8.0949 (5.9); 7.6530 (4.2); 7.6408 (7.8); 7.6286 (4.0); 6.0130 (0.5); 5.9956 (2.3); 5.9781 (3.6); 5.9606 (2.3); 5.9435 (0.5); 5.7570 (13.2); 3.3367 (288.3); 3.1763 (1.2); 3.1632 (1.2); 2.6774 (1.0); 2.6730 (1.3); 2.6685 (1.0); 2.5262 (5.2); 2.5126 (92.1); 2.5085 (175.4); 2.5041 (222.4); 2.4996 (162.1); 2.3350 (0.9); 2.3309 (1.3); 2.3263 (0.9); 1.6587 (0.6); 1.6345 (12.6); 1.6171 (12.5); −0.0002 (4.0) 566.9 [M + H].sup.+ I-023 [00068] .sup.1H-NMR (600.4 MHz, d.sub.6-DMSO): δ = 9.2600 (2.9); 9.2482 (3.0); 8.9988 (0.6); 8.9907 (0.7); 8.9805 (15.3); 8.9724 (15.6); 8.0218 (3.7); 8.0189 (7.2); 8.0160 (4.0); 7.9454 (0.9); 7.9399 (16.0); 7.9369 (15.0); 7.6476 (4.2); 7.6395 (8.0); 7.6314 (4.1); 5.9610 (0.5); 5.9494 (2.2); 5.9378 (3.6); 5.9261 (2.3); 5.9145 (0.5); 3.3058 (220.0); 3.2821 (0.3); 2.6185 (0.7); 2.6156 (1.4); 2.6126 (2.0); 2.6095 (1.4); 2.6065 (0.7); 2.5216 (4.7); 2.5185 (5.8); 2.5154 (5.7); 2.5066 (108.3); 2.5036 (227.7); 2.5006 (313.6); 2.4975 (229.2); 2.4945 (108.6); 2.3906 (0.6); 2.3876 (1.4); 2.3845 (1.9); 2.3815 (1.4); 2.3785 (0.6); 2.0722 (1.4); 1.6308 (0.5); 1.6192 (0.6); 578.8 [M + H].sup.+ 1.6069 (12.1); 1.5953 (12.1); 0.0053 (0.8); −0.0001 (26.5); −0.0056 (0.8) I-024 [00069] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.6720 (3.4); 9.6546 (3.4); 9.0130 (0.8); 8.9942 (15.4); 8.9821 (15.8); 8.1896 (8.8); 8.1400 (8.8); 7.6762 (0.4); 7.6623 (4.1); 7.6501 (7.7); 7.6380 (3.9); 6.0483 (0.5); 6.0309 (2.5); 6.0134 (3.9); 5.9961 (2.5); 5.9792 (0.6); 5.7569 (16.0); 3.3345 (250.1); 3.1760 (0.6); 3.1630 (0.6); 2.6771 (1.0); 2.6727 (1.4); 2.6684 (1.1); 2.5081 (193.8); 2.5038 (244.5); 2.4994 (180.1); 2.3350 (1.1); 2.3306 (1.4); 2.3263 (1.0); 1.6690 (0.8); 1.6452 (13.9); 1.6278 (13.8); −0.0002 (6.2) 524.0 [M + H].sup.+ I-025 [00070] .sup.1H-NMR (600.4 MHz, d.sub.6-DMSO): δ = 9.2614 (2.9); 9.2495 (3.0); 8.9987 (0.4); 8.9907 (0.6); 8.9804 (15.0); 8.9723 (15.3); 7.9159 (0.8); 7.9108 (14.8); 7.9080 (16.0); 7.8099 (4.4); 7.8071 (7.3); 7.8043 (3.8); 7.6472 (4.1); 7.6391 (7.8); 7.6310 (4.0); 5.9634 (0.5); 5.9520 (2.2); 5.9403 (3.5); 5.9286 (2.3); 5.9170 (0.5); 4.0798 (0.8); 4.0711 (0.8); 3.3269 (0.4); 3.3057 (377.4); 3.2815 (0.6); 3.1733 (3.2); 3.1645 (3.2); 2.6183 (1.0); 2.6154 (2.2); 2.6123 (3.1); 2.6093 (2.2); 2.6062 (1.0); 2.5364 (0.4); 2.5214 (7.2); 2.5183 (8.8); 2.5152 (8.6); 2.5064 (169.1); 2.5034 (354.0); 2.5003 (485.6); 2.4973 (355.9); 2.4943 (169.4); 2.3903 (1.0); 2.3873 (2.1); 2.3843 (3.0); 2.3812 (2.1); 2.3783 (1.0); 1.6326 534.9 [M + H].sup.+ (0.4); 1.6209 (0.5); 1.6087 (12.1); 1.5971 (12.2); 0.0053 (1.1); −0.0001 (34.7); −0.0057 (1.2) I-026 [00071] .sup.1H-NMR (600.1 MHz, d.sub.6-DMSO): δ = 8.9865 (0.2); 8.9784 (0.2); 7.6428 (0.1); 3.3299 (16.0); 2.5289 (0.2); 2.5258 (0.2); 2.5227 (0.2); 2.5137 (3.5); 2.5108 (7.2); 2.5078 (9.8); 2.5048 (7.4); 2.5020 (3.6); 1.6283 (0.2); 1.6167 (0.2) 538.9 [M + H].sup.+ I-027 [00072] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 9.5883 (2.5); 9.5706 (2.5); 8.9925 (15.7); 8.9803 (16.0); 8.4169 (8.4); 8.3132 (3.7); 7.6535 (4.3); 7.6413 (8.0); 7.6291 (4.2); 6.0572 (0.4); 6.0399 (1.9); 6.0224 (3.0); 6.0049 (1.9); 5.9876 (0.4); 5.7573 (0.4); 3.3299 (65.9); 2.6794 (0.3); 2.6748 (0.4); 2.6702 (0.3); 2.5284 (1.6); 2.5236 (2.3); 2.5150 (26.4); 2.5105 (52.7); 2.5058 (69.0); 2.5012 (49.8); 2.4966 (23.7); 2.3327 (0.4); 1.6616 (10.0); 1.6442 (9.9); 0.1460 (0.4); 0.0080 (3.2); −0.0002 (92.8); −0.0086 (3.2); −0.1496 (0.4) 557.0 [M + H].sup.+ .sup.1)‘260 K’ denotes that the measurement was conducted at a temperature of 260 Kelvin. .sup.2)The stated mass corresponds to the peak from the isotope pattern of the [M + H].sup.+ ion with the highest intensity. .sup.3)‘abs’ denotes that the compound was obtained in an enantiomerically enriched or pure form with the major stereoisomer having the absolute configuration depicted in the drawing

TABLE-US-00002 TABLE 2 (Intermediates) ESI mass Example Structure.sup.2) [m/z].sup.1) INT−01 [00073] 225.1 [M + H].sup.+ INT−02 [00074] 271.1 [M + H].sup.+ INT−03 [00075] 316.9, 317.0 [M + H].sup.+ INT−04 [00076] 225.0, [M − HCl].sup.+ INT−05 [00077] 270.9 [M − HCl].sup.+ INT−06 [00078] 317.0 [M − HCl].sup.+ .sup.1)The stated mass corresponds to the peak from the isotope pattern of the [M + H].sup.+ ion with the highest intensity. #denotes that the [M − H].sup.− ion was recorded. .sup.2)‘abs’ denotes that the compound was obtained in an enantiomerically enriched or pure form with the major stereoisomer having the absolute configuration depicted in the drawing.

BIOLOGICAL EXAMPLES

[0671] Rhipicephalus (Boophilus) Microplus—In-Vitro Contact Tests Larval Cattle Tick (Strain Parkhurst, Resistant Against Synthetic Pyrethroids)

[0672] 9 mg compound is solved in 1 mL acetone and diluted with acetone to the desired concentration. 250 μL of the test solution is filled in 25 mL glass test tubes and homogeneously distributed on the inner walls by rotation and tilting on a shaking device (2 h at 30 rpm). With a compound concentration of 900 ppm, an inner surface of 44.7 cm.sup.2 and a homogeneous distribution, a dose of 5 μg/cm.sup.2 is achieved.

[0673] After the solvent has evaporated, each test tube is filled with 20-50 cattle tick larvae (Rhipicephalus microplus), closed with a perforated lid and incubated in a horizontal position at 85% relative humidity and 27° C. in an incubator. After 48 hours efficacy is determined. The larvae are patted on the ground of the tubes and negative geotactic behaviour is recorded. Larvae that climb back to the top of the vial in a manner comparable to untreated control larvae are marked as alive, larvae not climbing back up comparable to untreated control larvae but are moving uncoordinatedly or only twitching their legs are marked as moribund, tick larvae remaining on the bottom and not moving at all are counted as dead.

[0674] A compound shows a good efficacy against Rhipicephalus microplus, if at a compound concentration of 5 μg/cm.sup.2 an efficacy of at least 80% is monitored. An efficacy of 100% means all larvae are dead or moribund; 0% means no larvae are dead or moribund.

[0675] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-002, I-003, I-004, I-006, I-007, I-008, I-009, I-010, I-012, I-015, I-017, I-020, I-021, I-022, I-024.

[0676] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-013, I-019.

[0677] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): 1-016, I-018.

[0678] Rhipicephalus (Boophilus) microplus—Dip Test

[0679] Test animal: cattle ticks (Rhipicephalus microplus) strain Parkhurst, SP-resistant

[0680] Solvent: dimethyl sulfoxide

[0681] To produce a suitable preparation of active compound, 10 mg of active compound are dissolved in 0.5 mL solvent, and the concentrate is diluted with water to the desired concentration.

[0682] This compound solution is pipetted into tubes. 8-10 engorged, adult, female cattle ticks (Rhipicephalus microplus) are placed in perforated tubes. These tubes are immersed in the aqueous compound solution until the ticks are completely moistened. After the liquid has drained off, the ticks are transferred to a filter paper in a plastic tray and stored in a climate chamber.

[0683] After 7 days egg deposition of fertile eggs is monitored. Eggs where fertility is not visible are stored in a climate chamber till hatching after about 42 days. An efficacy of 100% means all eggs are infertile; 0% means all eggs are fertile.

[0684] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 100 ppm: I-002.

[0685] Rhipicephalus (Boophilus) microplus—Injection Test

[0686] Solvent: dimethyl sulfoxide

[0687] To produce a suitable preparation of active compound, 10 mg of active compound are dissolved in 0.5 mL solvent, and the concentrate is diluted with solvent to the desired concentration.

[0688] Five adult engorged female ticks (Rhipicephalus microplus) are injected with 1 μL compound solution into the abdomen. The ticks are transferred into replica plates and incubated in a climate chamber.

[0689] After 7 days egg deposition of fertile eggs is monitored. Eggs where fertility is not visible are stored in a climate chamber till hatching after about 42 days. An efficacy of 100% means all eggs are infertile; 0% means all eggs are fertile.

[0690] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 20 μg/animal: I-002, I-003, I-004, I-005, I-017, I-018, I-019.

[0691] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 4 μg/animal: I-002, I-003, I-004, I-005, I-007, I-008, I-009, I-010, I-013, I-014, I-015, I-016, I-017, I-019.

[0692] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 4 μg/animal: I-006, I-012, I-018.

[0693] Ctenocephalides felis—In-Vitro Contact Tests Adult Cat Flea 9 mg compound is solved in 1 mL acetone and diluted with acetone to the desired concentration. 250 μL of the test solution is filled in 25 mL glass test tubes and homogeneously distributed on the inner walls by rotation and tilting on a shaking device (2 h at 30 rpm). With a compound concentration of 900 ppm, an inner surface of 44.7 cm.sup.2 and a homogeneous distribution, a dose of 5 μg/cm.sup.2 is achieved.

[0694] After the solvent has evaporated, each test tube is filled with 5-10 adult cat fleas (Ctenocephalidesfelis), closed with a perforated lid and incubated in a lying position at room temperature and relative humidity.

[0695] After 48 hours efficacy is determined. The fleas are patted on the ground of the tubes and are incubated on a heating plate at 45-50° C. for at most 5 minutes. Immotile or uncoordinated moving fleas, which are not able to escape the heat by climbing upwards, are marked as dead or moribund.

[0696] A compound shows a good efficacy against Ctenocephalides felis, if at a compound concentration of 5 μg/cm.sup.2 an efficacy of at least 80% is monitored. An efficacy of 100% means all fleas are dead or moribund; 0% means no fleas are dead or moribund.

[0697] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): 1-006, I-020, I-021.

[0698] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-008, I-013, I-024.

[0699] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-009, I-010.

[0700] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 1 μg/cm.sup.2 (=100 g/ha): I-002, I-020, I-021.

[0701] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 1 μg/cm.sup.2 (=100 g/ha): I-008, I-013.

[0702] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 1 μg/cm.sup.2 (=100 g/ha): I-014, I-024.

[0703] Ctenocephalides felis—Oral Test

[0704] Solvent: dimethyl sulfoxide

[0705] To produce a suitable preparation of active compound, 10 mg of active compound are dissolved in 0.5 ml solvent, and the concentrate is diluted with cattle blood to the desired concentration.

[0706] Approximately 20 adult unfed cat fleas (Ctenocephalides felis) are placed in flea chambers. The blood chamber, sealed with parafilm on the bottom, are filled with cattle blood supplied with compound solution and placed on the gauze covered top of the flea chamber, so that the fleas are able to suck the blood. The blood chamber is heated to 37° C. whereas the flea chamber is kept at room temperature.

[0707] After 2 days mortality in % is determined. 100% means all the fleas have been killed; 0% means none of the fleas have been killed.

[0708] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 ppm: I-002, I-003, I-005, I-006, I-007, I-008, I-009, I-010, I-012, I-013, I-014, I-015, I-016, I-020, I-021, I-023.

[0709] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 100 ppm: I-004, I-022.

[0710] Rhipicephalus sanguineus—In-Vitro Contact Tests with Adult Brown Dog Ticks

[0711] 9 mg compound is solved in 1 mL acetone and diluted with acetone to the desired concentration. 250 μL of the test solution is filled in 25 mL glass test tubes and homogeneously distributed on the inner walls by rotation and tilting on a shaking device (2 h at 30 rpm). With a compound concentration of 900 ppm, an inner surface of 44.7 cm.sup.2 and a homogeneous distribution, a dose of 5 μg/cm.sup.2 is achieved.

[0712] After the solvent has evaporated, each test tube is filled with 5-10 adult brown dog ticks (Rhipicephalus sanguineus), closed with a perforated lid and incubated in a lying position at room temperature and relative humidity. After 48 hours efficacy is determined. The ticks are patted on the ground of the tubes and are incubated on a heating plate at 45-50° C. for at most 5 minutes. Immotile or uncoordinated moving ticks, which are not able to escape the heat by climbing upwards, are marked as dead or moribund.

[0713] A compound shows a good efficacy against Rhipicephalus sanguineus, if at a compound concentration of 5 μg/cm.sup.2 an efficacy of at least 80% is monitored. An efficacy of 100% means all ticks are dead or moribund; 0% means no ticks are dead or moribund.

[0714] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-003, I-004, I-005, I-007, I-008, I-009, I-010, I-012, I-014, I-020.

[0715] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): 1-002, I-006, I-013, I-021, I-022, I-024.

[0716] Diabrotica balteata—spray test

[0717] Solvent: 78.0 parts by weight of acetone

[0718] 1.5 parts by weight of dimethylformamide

[0719] Emulsifier: alkylarylpolyglycol ether

[0720] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent, and the concentrate is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[0721] Soaked wheat seeds (Triticum aestivum) are placed in a multiple well plate filled with agar and some water and are incubated for 1 day to germinate (5 seeds per well). The germinated wheat seeds are sprayed with a test solution containing the desired concentration of the active ingredient. Afterwards each unit is infected with 10-20 larvae of the banded cucumber beetle (Diabrotica balteata).

[0722] After 7 days efficacy in % is determined. 100% means all the seedlings have grown up like in the untreated, uninfected control; 0% means none of the seedlings have grown.

[0723] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 g/ha (=32 μg/well): I-001, I-002, I-003, I-004, I-005, I-006, I-009, I-013, I-014, I-016, I-017, I-018, I-019, I-020, I-021, I-022, I-024.

[0724] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 100 g/ha (=32 μg/well): I-008, I-010, I-015.

[0725] Myzus persicae—oral test

[0726] Solvent: 100 parts by weight acetone

[0727] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent, and the concentrate is diluted with water to the desired concentration. 50 μL compound solution is filled in microtiter plates and 150 μL IPL41 insect medium (33%+15% sugar) is added to obtain a total volume of 200 μL per well. Afterwards the plates are sealed with parafilm through which a mixed population of the green peach aphid (Myzus persicae) can suck on the compound preparation.

[0728] After 5 days mortality in % is determined. 100% means all aphids have been killed and 0% means none of the aphids have been killed.

[0729] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 4 ppm: I-001, I-002, I-003, I-004, I-009, I-010, I-013, I-016, I-020, I-021, I-022.

[0730] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 4 ppm: I-006, I-007.

[0731] Myzus persicae—spray test

[0732] Solvent: 78.0 parts by weight acetone [0733] 1.5 parts by weight dimethylformamide

[0734] Emulsifier: alkylarylpolyglycol ether

[0735] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvents and is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[0736] Chinese cabbage (Brassica pekinensis) leaf disks infected with all instars of the green peach aphid (Myzus persicae), are sprayed with a preparation of the active ingredient of the desired concentration.

[0737] After 5 days mortality in % is determined. 100% means all aphids have been killed and 0% means none of the aphids have been killed.

[0738] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 100 g/ha: I-001, I-006, I-007, I-010, I-020, I-021.

[0739] In this test, for example, the following compounds from the preparation examples showed good activity of 70% at an application rate of 100 g/ha: I-009.

[0740] Nezara viridula—Spray Test

[0741] Solvent: 78.0 parts by weight of acetone [0742] 1.5 parts by weight of dimethylformamide

[0743] Emulsifier: alkylarylpolyglycol ether

[0744] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent, and the concentrate is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[0745] Barley plants (Hordeum vulgare) infested with larvae of the southern green stink bug (Nezara viridula) are sprayed with a test solution containing the desired concentration of the active ingredient.

[0746] After 4 days mortality in % is determined. 100% means all the stink bugs have been killed; 0% means none of the stink bugs have been killed.

[0747] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 g/ha: I-008, I-024.

[0748] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 100 g/ha: I-007.

[0749] Spodoptera frukiperda—Spray Test

[0750] Solvent: 78.0 parts by weight acetone [0751] 1.5 parts by weight dimethylformamide

[0752] Emulsifier: alkylarylpolyglycol ether

[0753] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvents and is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[0754] Maize (Zea mays) leaf sections are sprayed with a preparation of the active ingredient of the desired concentration. Once dry, the leaf sections are infested with fall armyworm larvae (Spodoptera frugiperda).

[0755] After 7 days mortality in % is determined. 100% means all caterpillars have been killed and 0% means none of the caterpillars have been killed.

[0756] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 g/ha: I-001, I-002, I-003, I-004, I-005, I-010, I-013, I-016, I-019, I-020, I-021, I-022.

[0757] In this test, for example, the following compounds from the preparation examples showed good activity of 83% at an application rate of 100 g/ha: I-017, I-018.

[0758] In this test, for example, the following compounds from the preparation examples showed good activity of 67% at an application rate of 100 g/ha: I-009.

[0759] Aedes Aegypti Test (AEDSAE Surface Treatment & Contact Assay)

[0760] Solvent: Aceton+2000 ppm rapeseed oil methyl ester (RME)

[0761] In order to produce a sufficient, active ingredient containing solution it is necessary to solve the test compound in the solvent-mix (acetone at 2 mg/ml/RME 2000 ppm). This solution is pipetted onto a glazed tile and after evaporation of the acetone, adult mosquitoes of the species Aedes aegypti strain MONHEIM are placed onto the dried surface. The exposure time is 30 minutes. Mortality in percent (%) is determined 24 hours after contact of the insects to the treated surface. 100% mortality means that all tested insects are dead, whereas 0% means that no insect died.

[0762] The following examples showed in this test efficacy of 80-100% at a surface concentration of 20 mg/m.sup.2: 1-001, I-002, I-003, I-004, I-007, I-010, I-013, I-016, I-018, I-021.

[0763] The following examples showed in this test efficacy of 80-100% at a surface concentration of 4 mg/m.sup.2: I-001, I-002, I-004, I-007, I-008, I-012, I-021.

[0764] Anopheles funestus Test (ANPHFU Surface Treatment & Contact Assay)

[0765] Solvent: Aceton+2000 ppm rapeseed oil methyl ester (RME)

[0766] In order to produce a sufficient, active ingredient containing solution it is necessary to solve the test compound in the solvent-mix (acetone at 2 mg/ml/RME 2000 ppm). This solution is pipetted onto a glazed tile and after evaporation of the acetone, adult mosquitoes of the species Anopheles funestus strain FUMOZ-R (Hunt et al., Med. Vet. Entomol. 2005 September; 19(3): 271-275) are placed onto the dried surface. The exposure time is 30 minutes. Mortality in percent (%) is determined 24 hours after contact of the insects to the treated surface. 100% mortality means that all tested insects are dead, whereas 0% means that no insect died.

[0767] The following examples showed in this test efficacy of 80-100% at a surface concentration of 20 mg/m.sup.2: 1-001, I-007, I-013, I-016, I-018.

[0768] Musca domestica Test (MUSCDO Surface Treatment & Contact Assay)

[0769] Solvent: Aceton+2000 ppm rapeseed oil methyl ester (RME)

[0770] In order to produce a sufficient, active ingredient containing solution it is necessary to solve the test compound in the solvent-mix (acetone at 2 mg/ml/RME 2000 ppm). This solution is pipetted onto a glazed tile and after evaporation of the acetone, adult flies of the species Musca domestica strain WHO-N are placed onto the dried surface. The exposure time is 30 minutes. Mortality in percent (%) is determined 24 hours after contact of the insects to the treated surface. 100% mortality means that all tested insects are dead, whereas 0% means that no insect died.

[0771] The following examples showed in this test efficacy of 80-100% at a surface concentration of 20 mg/m.sup.2: I-001, I-002, I-003, I-010, I-013, I-019, I-021.

[0772] The following examples showed in this test efficacy of 80-100% at a surface concentration of 4 mg/m.sup.2: I-001, I-003, I-021.

[0773] Blattella germanica Test (BLTTGE Surface Treatment & Contact Assay)

[0774] Solvent: Aceton+2000 ppm rapeseed oil methyl ester (RME)

[0775] In order to produce a sufficient, active ingredient containing solution it is necessary to solve the test compound in the solvent-mix (acetone at 2 mg/ml/RME 2000 ppm). This solution is pipetted onto a glazed tile and after evaporation of the acetone, adult animals of the species Blattella germanica strain PAULINIA are placed onto the dried surface. The exposure time is 30 minutes. Mortality in percent (%) is determined 24 hours after contact of the insects to the treated surface. 100% mortality means that all tested insects are dead, whereas 0% means that no insect died.

[0776] The following examples showed in this test efficacy of 80-100% at a surface concentration of 20 mg/m.sup.2: I-002, I-003, I-016, I-021.