Enantiomerically enriched aryloazol-2-yl cyanoethylamino compounds, method of making and method of using thereof

1. An aryloazol-2-yl-cyanoethylamine compound of formula (I) that is enriched in an enantiomer that is significantly more active in vitro and in vivo compared with the other enantiomer, wherein the weight:weight ratio is at least 1.5 or higher in favor of the enantiomer that is significantly more active in vitro and in vivo, or a salt thereof:

P is N;

Q is C—R 2 or N;

V is N;

W is C—R 9 ;

X is C—R 10 ;

Y is C—R 11 ;

R 2 is hydrogen;

R 9 , R 10 and R 11 are independently of one another hydrogen, halogen, C 1 -C 6 -alkyl or halo-C 1 -C 6 -alkyl;

R 3 and R 4 are hydrogen;

R 5 is C 1 -C 6 -alkyl;

R 6 is hydrogen or C 1 -C 6 -alkyl;

R 7 is unsubstituted or substituted phenyl, wherein the substituents may each be independent of one another alkylthio, haloalkylthio, alkoxy, or haloalkoxy;

Z is C(O); and

a is 1.

2. The compound of claim 1 , wherein:

R 5 is methyl.

3. The compound of claim 1 , wherein:

R 5 is methyl; and

R 6 is hydrogen.

4. The aryloazol-2-yl-cyanoethylamine of claim 1 , wherein

Q is C—R 2 ;

R 5 is methyl;

R 6 is hydrogen;

R 7 is substituted phenyl, wherein the substituents may each be independently halo-C 1 -C 6 -alkylthio or halo-C 1 -C 6 -alkoxy.

5. The aryloazol-2-yl-cyanoethylamine of claim 1 , wherein

R 5 is methyl;

R 7 is phenyl substituted by one or more of OCF 3 or SC F 3 ; and

R 9 , R 10 and R 11 are, independently of one another, hydrogen, CI, Br, I or methyl.

6. The aryloazol-2-yl-cyanoethylamine of claim 1 , wherein

Q is N;

R 6 is hydrogen;

R 5 is methyl;

R 7 is phenyl substituted by one or more of OCF 3 or SCF 3 ; and

R 9 , R 10 and R 11 are, independently of one another, hydrogen, CI, Br, I or methyl.

7. The aryloazol-2-yl-cyanoethylamine of claim 5 , wherein:

Q is C—R 2 ;

R 6 is hydrogen;

R 5 is methyl;

R 7 is phenyl substituted by one or more of OCF 3 or SCF 3 ; and

R 9 , R 10 and R 11 are, independently of one another, hydrogen, CI, Br, I or methyl.

8. The arylozaol-2-yl-cyanoethylamine of claim 1 , wherein the arylozaol-2-yl -cyanoethylamine is:

(+)-N-[2-(6-Bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide, or (−)-N-[2-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide.

9. An aryloazol-2-yl-cyanoethylamino pentafluorothiobenzamide derivatives of formula (IH):

Wherein:

P is C—R 1 or N;

Q is C—R 2 or N;

V is N;

W is C—R 9 ;

X is C—R 10 ;

Y is C—R 11 ;

R 1 , R 2 R 9 , R 10 and R 11 are independently of one another hydrogen, amino, amido, cyano, nitro, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkylthio, haloalkylthio, arylthio, alkoxy, phenoxy, alkoxyalkoxy, cycloalkyloxy,

haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkylsulfinyl, haloalkylsulfinyl, SF 5 , alkylsulfonyl, haloalkylsulfonyl, alkylamino, di(alkyl)amino, alkylcarbonylamino, alkylaminoalkoxy, dialkylaminoalkoxy, alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl, formyl, —C(O)OH, unsubstituted or substituted aryl, unsubstituted or substituted arylthio, unsubstituted or substituted aryloxy, or unsubstituted or substituted heteroaryl, wherein the substituents, independent of one another, may be one or more of cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, haloalkylthio, arylthio, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, SF 5 or methylthioamino;

R 3 , R 4 and R 5 are independently of one another hydrogen, halogen, alkyl, hydroxyalkyl, alkylthioalkyl, haloalkyl, alkyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylsulfonyloxyalkyl; unsubstituted or substituted cycloalkyl, wherein the substituents may each be independently halogen and alkyl; unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, wherein the substituents may each be independent of one another cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, haloalkylthio, arylthio, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, SF 5 , alkylamino, or di(alkyl)amino; or

R 4 and R 5 together with the carbon to which they are attached form a cycloalkyl ring;

R 6 is hydrogen, alkyl, alkoxyalkyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl or unsubstituted or substituted

benzyl, wherein the substituents may each be independent of one another cyano, nitro, halogen, alkyl, haloalkyl, alkylthio, haloalkylthio, arylthio, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, SF 5 , alkylamino, or di(alkyl)amino;

R 13a , R 13b , R 14a and R 14b are each independently of one another cyano, nitro, halogen, alkyl, cycloalkyl, haloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted phenoxy, alkylthio, haloalkylthio, arylthio, alkoxy, cycloalkyloxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, SF 5 , alkylamino, di(alkyl)amino, or methylthioamino; and

a is 1, 2 or 3.

10. The compound of claim 9 , wherein P is N and Q is N or C—R 2 .

11. The compound of claim 9 , wherein P is N, Q is N or C—R 2 , and R 3 and R 4 are hydrogen.

12. The compound of claim 9 , wherein P is N, Q is N or C—R 2 , R 3 and R 4 are hydrogen;

R 5 is alkyl or haloalkyl; and

R 6 is H or alkyl.

13. The compound of claim 9 , wherein P is N, Q is N or C—R 2 ;

R 3 , R 4 and R 6 are hydrogen; and

R 5 is C 1 -C 3 -alkyl.

14. The compound of claim 9 , wherein:

P is N;

Q is N or C—R 2 ;

R 3 and R 4 are hydrogen;

R 5 is hydrogen, C 1 -C 3 -alkyl, or halo- C 1 -C 3 -alkyl;

R 6 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl, halo-C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl or halo-C 1 -C 6 -alkoxycarbonyl; and

a is 1.

15. The compound of claim 9 , wherein:

P is N;

Q is N or C—R 2 ;

R 3 , R 4 , R 6 are hydrogen;

R 5 is methyl; and

a is 1 .

16. The compound of claim 9 , wherein the compound is enriched in an enantiomer.

17. A parasiticidal composition comprising an effective amount of a compound of claim 1 or claim 9 and a pharmaceutically acceptable carrier.

18. The composition of claim 17 which further comprises one or more additional active agents.

19. The composition of claim 17 , wherein the additional active agent is an avermectin or milbemycin.

20. The composition of claim 19 , wherein the avermectin or milbemycin is abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, moxidectin, nemadectin, a 5-oxo avermectin or milbemycin derivative, a 5-oxime avermectin or milbemycin derivative, or a combination thereof.

21. A method for treating a parasitic infection or infestation in an animal comprising administering an effective amount of the compound of claim 1 or claim 9 to the animal in need thereof.

22. The method of claim 21 , wherein the parasite is Anaplocephala, Ancylostoma, Anecator, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus, Enterobius, Fasciola, Filaroides, Habronema, Haemonchus, Metastrongylus, Moniezia, Necator, Nematodirus, Nippostrongylus, Oesophagostumum, Onchocerca, Ostertagia, Oxyuris, Paracaris, Schistosoma, Strongylus, Taenia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, Trichostrongylus, Triodontophorous, Uncinaria or Wuchereria , or combinations thereof.

23. The method of claim 21 , wherein the parasite is Haemonchus contortus, Ostertagia circumcincta, Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia curticet or Nematodirus battus , or combinations thereof.

24. The method of claim 21 , wherein the parasites are fleas, ticks, mites, mosquitoes, flies, fly larvae or lice, or combinations thereof.

25. The method of claim 21 , wherein the parasites are fleas or ticks.

26. The method of claim 21 , wherein the compound is administered in combination with an effective amount of an avermectin or milbemycin compound.

27. The method of claim 26 , wherein the avermectin or milbemycin compound is abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, moxidectin, nemadectin, a 5-oxo avermectin or milbemycin derivative, a 5-oxime avermectins or milbemycin derivative, or a combination thereof.

28. The compound of formula (I) of claim 1 wherein the compound is (+)-N-[2-(6-Bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide.

29. The composition of claim 17 , wherein the composition is a pour-on, spot-on, oral drench or injectable composition.

30. The composition of claim 29 , wherein the composition is a pour-on or oral drench composition.