FLAVIVIRUS INHIBITORS

Abstract

The invention relates to compounds that are inhibitors of Flavivirus NS2B-NS3 proteases and inhibit replication of flavivirus in cells. Compounds of this invention are useful alone or in combination with other agents for use in the treatment of infections caused by Flaviviruses, in particular by Dengue, West Nile, Zika, Japan Encephalitis viruses.

Claims

1. A compound of general formula (I): ##STR00237## wherein: m and n are each independently selected from 0, 1 and 2; R.sub.1a and R.sub.1b are independently selected from H and C.sub.1-6alkyl optionally substituted with one or more substituents selected from: hydroxy, OC.sub.1-3alkyl, halogen, NH.sub.2, NHCOC.sub.1-6alkyl, NHCOOC.sub.1-6alkyl, NHC(O)NHC.sub.1-6alkyl, NHSO.sub.2C.sub.1-6alkyl, NHC.sub.1-3alkyl, N(C.sub.1-3alkyl).sub.2, or a cyclic amine selected from aziridine, azetidine, pyrrolidine, pyperidine, morpholine, piperazine, N-methylpyperazine; or R.sub.1a and R.sub.1b are linked together to form a C.sub.3-6-cycloalkyl ring or a C.sub.4-6-heterocycloalkyl ring; or R.sub.1a is linked to R.sub.3 to form a partially unsaturated aromatic or heteroaromatic bicycle; or R.sub.1b doesn't exist and CR.sub.1a is CCH.sub.2; R.sub.2a and R.sub.2b are independently selected from H and C.sub.1-6alkyl optionally substituted with one or more substituents selected from: hydroxy, OC.sub.1-3alkyl, halogen, NH.sub.2, NHCOC.sub.1-6alkyl, NHCOOC.sub.1-6alkyl, NHC.sub.1-3alkyl, N(C.sub.1-3alkyl).sub.2, or a cyclic amine selected from aziridine, azetidine, pyrrolidine, pyperidine, morpholine, piperazine, N-methylpyperazine; or R.sub.2a and R.sub.2b are linked together to form a C.sub.3-6-cycloalkyl ring or a C.sub.4-6-heterocycloalkyl ring; or any two of R.sub.1a and R.sub.2a or of R.sub.1b and R.sub.2b are linked together to form a C.sub.3-6cycloalkyl or a C.sub.3-6 heterocycloalkyl; R.sub.3 is heterocycloalkyl, aromatic or heteroaromatic ring, each of said heterocycloalkyl, aromatic or heteroaromatic ring being optionally substituted with one or more substituents independently selected from halogen, hydroxy, NH.sub.2, NHCOC.sub.1-6alkyl, NHCOOC.sub.1-6alkyl, NHC(O)NHC.sub.1-6alkyl, NHSO.sub.2C.sub.1-6alkyl, NHC.sub.1-3alkyl, N(C.sub.1-3alkyl).sub.2, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.1-6alkoxy, cyano, B(OH).sub.2, aryl, heteroaryl wherein said aryl or heteroaryl ring are optionally substituted with one or more substituents each independently selected from halogen, hydroxy, cyano, NH.sub.2, NHCOC.sub.1-6alkyl, NHCOOC.sub.1-6alkyl, NHC.sub.1-3alkyl, N(C.sub.1-3alkyl).sub.2, C.sub.3-6cycloalkyl, aziridine, azetidine, pyrrolidine, pyperidine, morpholine, piperazine, N-methylpyperazine, C.sub.1-6alkyl, C.sub.1-6alkoxy, wherein said C.sub.1-6 alkyl, C.sub.1-6alkoxy are optionally substituted with one or more halogen, hydroxy, NH.sub.2, NHCOCH.sub.3, NHCOOC.sub.1-6alkyl, NHC.sub.1-3alkyl, N(C.sub.1-3alkyl).sub.2, aziridine, azetidine, pyrrolidine, pyperidine, morpholine, piperazine and N-methylpyperazine; R.sub.4 is a ring of formula (II): ##STR00238## wherein R.sub.6 is CF.sub.3, F, Cl, CN or C.sub.1-3alkyl, cyclopropyl, CHF.sub.2; X is CR.sub.7 or N; R.sub.7 is at each occurrence independently selected from H, halogen, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl, hydroxy; or R.sub.4 is 4-trifluoromethylphenyl, thiophene, thiazole, imidazole, pyrazole, oxazole, oxadiazole, naphthalene, quinoline, isoquinoline, quinazoline or napthyridine, wherein each of said ring is optionally substituted with one or more substituents selected from halogen, C.sub.1-6alkyl, hydroxy, haloC.sub.1-6alkyl, C.sub.1-6alkoxy, NH.sub.2, NHC(O)C.sub.1-6alkyl, CN; or R.sub.4 is phenyl and R.sub.3 is a phenyl ring substituted with an heteroaromatic ring optionally substituted with one or more substituents selected from halogen, C.sub.1-6alkyl, C.sub.1-6alkoxy; R.sub.5 is H, C.sub.1-6alkyl, C.sub.1-6haloalkyl or halogen; or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, provided that compounds indicated below are not included: ##STR00239## ##STR00240##

2. The compound according to claim 1 wherein: R.sub.1b and R.sub.2b are H; and/or m and n are each independently selected from 0, 1; and/or R.sub.5 is H.

3. The compound according to claim 1 wherein m is 1 and n is 0; R.sub.1a is H and R.sub.1b is H or C.sub.1-3alkyl optionally substituted with hydroxy or NH.sub.2.

4. The compound according to claim 1 wherein R.sub.3 is phenyl, naphthyl, biphenyl, phenyl substituted with an heteroaromatic ring or an heteroaromatic ring substituted with a second heteroaromatic ring, wherein each of said phenyl, naphthyl or heteroaromatic ring is optionally substituted with one or more substituents each independently selected from halogen, hydroxy, cyano, B(OH).sub.2, NH.sub.2, NHCOC.sub.1-6alkyl, NHCOOC.sub.1-6alkyl, NHC.sub.1-3alkyl, N(C.sub.1-3alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6alkoxy, pyrrolidine, pyperidine, morpholine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein said C.sub.1-6alkyl, C.sub.1-6alkoxy are optionally substituted with one or more halogen, hydroxy, NH.sub.2, N(CH.sub.3).sub.2, morpholine or pyrrolidine.

5. The compound according to claim 1 wherein R.sub.4 is 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolinyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 3-methyl-5-trifluoromethylphenyl, 3-methoxy-5-trifluoromethylphenyl, 3-cyanophenyl, 3-cyclopropylphenyl, 5-(cyclopropyl)pyridine-3-yl, 4-fluoro-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-4-yl, 2-(trifluoromethyl)thiazol-5-yl, 3-methyl-5-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methyl-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-6-yl, 3-difluoromethylphenyl, 4-(trifluoromethyl)pyrimidin-2-yl, 2-(trifluoromethyl)pyridine-4-yl.

6. The compound according to claim 1 wherein: R.sub.3 is selected from: a) phenyl substituted with a 5- or 6 membered heteroaromatic ring preferably selected from: pyrimidine, thiophene, pyridine, pyrazole, isoxazole, pyridazine, pyrazine, imidazole; or b) 5- or 6-membered heteroaromatic ring preferably selected from pyridine, pyrimidine, thiophene, pyrazine and pyridazine, each of said 5- or 6 membered heteroaromatic ring substituted with a phenyl, isoindoline or with a 5- or 6-membered heteroaromatic ring preferably selected from pyrimidine, isoxazole, pyrazole, pyrazine, imidazole, pyridazine, pyridine; wherein in a) or b) each of said phenyl, 5- or 6-membered heteroaromatic ring is optionally substituted with one or more substituents independently selected from: C.sub.1-3alkyl, C.sub.1-3alkoxy, C.sub.3-6cycloalkyl, CF.sub.3, C.sub.5-6heterocycloalkyl, O(CH.sub.2).sub.2NH.sub.2, O(CH.sub.2).sub.2OH, hydroxy, halogen; and R.sub.4 is 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolinyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 3-methyl-5-trifluoromethylphenyl, 3-methoxy-5-trifluoromethylphenyl, 3-cyanophenyl, 3-cyclopropylphenyl, 5-(cyclopropyl)pyridine-3-yl, 4-fluoro-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-4-yl, 2-(trifluoromethyl)thiazol-5-yl, 3-methyl-5-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methyl-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-6-yl, 3-difluoromethylphenyl, 4-(trifluoromethyl)pyrimidin-2-yl, 2-(trifluoromethyl)pyridine-4-yl; and m is 1 and n is 0; R.sub.1a is H and R.sub.1b is H or C.sub.1-3alkyl optionally substituted with hydroxy or NH.sub.2.

7. The compound according to claim 1 having the general formula (III): ##STR00241## or having the general formula (IV): ##STR00242## or having the general formula (V): ##STR00243##

8. The compound according to claim 1 wherein R.sub.3 is selected from the following structures: ##STR00244## ##STR00245## ##STR00246## wherein each of the phenyl or heteroaromatic ring can be optionally further substituted by one or two substituents independently selected from methyl, CF.sub.3, halogen, cyclopropyl, methoxy, cyano.

9. The compound according to claim 1 wherein R.sub.4 is selected from the following structures. ##STR00247##

10. A compound of general formula (I) according to claim 1 selected from the following list: (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)phenyl) carbamoyl)amide; (naphthalen-2-ylcarbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)thiazol-2-yl)carbamoyl)amide; (3-benzyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-phenyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; ((3-chlorophenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide (3-(1-(3,4-dichlorophenyl)propan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (3-(2,3-dihydro-1H-inden-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; ((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)(quinolin-6-ylcarbamoyl)amide; (R)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (S)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)amide; (3-([1,1-biphenyl]-4-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (3-(naphthalen-2-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl) amide; (3-(4-(thiophen-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (3-((2-methyl-[1,1-biphenyl]-4-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (3-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-benzyl-4-chloro-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl) amide; (3-(1-phenylcyclopropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (3-(4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (3-([1,1-biphenyl]-3-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (3-(2-phenylpropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl) amide; (3-(pyridin-3-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (R)-(3-(2-hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (S)-(3-(2-hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (R)-(3-(1-hydroxy-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; ((3-methyl-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide; ((3-methoxy-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-(1-phenylvinyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl) amide; (3-(3-phenylprop-1-en-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (S)-(3-(1-fluoro-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (3-(1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl) amide; (3-(4-(pyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (S)-(3-(1-phenyl-3-(pyrrolidin-1-yl)propan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(2-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(pyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (3-(2,2,2-trifluoro-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (R)-(3-(1-hydroxy-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(3-bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl) amide; (3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl) amide; (3-(4-(isoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (R)-(3-(1-amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (3-(3-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (3-(3-(pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (3-(3-(1-methyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(3-(2-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (S)-(3-(1-amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl) carbamoyl)amide; (3-((4-(morpholinomethyl)-[1,1-biphenyl]-4-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-(4-(2-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-((1R,2S)-2-phenylcyclopentyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (3-(4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (3-(4-(pyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (3-(4-(4-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(2-methoxypyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (3-(4-(2-hydroxypyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (S)-(3-(1-([1,1-biphenyl]-4-yl)-3-aminopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (R)-(3-(1-([1,1-biphenyl]-4-yl)-3-aminopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(pyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (S)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (S)-(3-(1-([1,1-biphenyl]-4-yl)-3-acetamidopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (R)-(3-(1-([1,1-biphenyl]-4-yl)-3-acetamidopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (R)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl) pyridin-3-yl)carbamoyl)amide; (S)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (R)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (S)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl) pyridin-3-yl)carbamoyl)amide; (S)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (S)-(3-(1-(4-(4-methylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; ((3-(trifluoromethyl)phenyl)carbamoyl)(3-(4-(4-(trifluoromethyl)pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (R)-(3-(1-(4-(4-methylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(3-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (3-(3-(4-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(4-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (3-(4-(3-methylpyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (3-(3-methyl-4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (3-(4-(3,5-dimethylisoxazol-4-yl)-3-methylbenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(2-(2-hydroxyethoxy)-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(4-cyclopropylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(2-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (3-(4-(5-methylpyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (3-(3-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(1,5-dimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(1,3-dimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; ((3-(trifluoromethyl)phenyl)carbamoyl)(3-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-(4-(1,4-dimethyl-1H-imidazol-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (R)-(3-(2-amino-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(pyrimidin-5-yl)thiophen-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(3-methyl-4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (R)-(3-(2-amino-1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((6-(pyrimidin-5-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(1,2-dimethyl-1H-imidazol-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(4-cyanopyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(4-fluoro-6-oxo-1,6-dihydropyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((4-(4-methylpyrimidin-5-yl)thiophen-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(4-methoxy-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(4-(2-hydroxyethoxy)-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; ((3-chlorophenyl)carbamoyl)(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; ((3-cyanophenyl)carbamoyl)(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl); (3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)(phenylcarbamoyl)amide amide; (S)-(3-(2-amino-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(1,4-dimethyl-1H-imidazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(isoindolin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(2-(aminomethyl)phenyl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-boronopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(4-(2-(dimethylamino)ethoxy)-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(2-(2-(dimethylamino)ethoxy)-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-((5-(5-methylpyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-((5-(5-methylpyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; ((3-(trifluoromethyl)phenyl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-((5-(2-methoxy-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-((5-(2-methoxy-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(4-methoxy-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(4-methoxy-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; ((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-((2-methyl-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((4-methyl-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(1,4-dimethyl-1H-imidazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-((2-methyl-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; ((3-cyclopropylphenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; ((3-(trifluoromethyl)phenyl)carbamoyl)(3-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-((5-(4-cyanopyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-((5-(pyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; ((5-cyclopropylpyridin-3-yl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; ((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)(3-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-((5-(4-cyanopyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((4-methyl-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)thiazol-5-yl)carbamoyl)amide; (3-((5-(4-cyclopropylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-methyl-5-(trifluoromethyl)phenyl)carbamoyl)amide; ((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((2-methoxy-4-methyl-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(pyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)amide; (3-((5-(4-methylpyridazin-3-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((3-methyl-[3,4-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((3-fluoro-[3,4-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)thiazol-2-yl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; ((3-(difluoromethyl)phenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((3,5-difluoro-[3,4-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)pyrimidin-2-yl)carbamoyl)amide; (3-((2-chloro-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((6-(3,5-dimethylisoxazol-4-yl)pyridazin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((2-(3,5-dimethylisoxazol-4-yl)pyrimidin-5-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; (3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; ((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-((5-(4-chloropyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(4,6-dichloropyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,6-dimethoxypyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; ((3-cyclopropylphenyl)carbamoyl)(3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-((4,6-dimethyl-[5,5-bipyrimidin]-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((6-(4,6-dimethylpyrimidin-5-yl)pyridazin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; (3-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; (3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (R)-(3-(1-(4-(4,6-dimethylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; (R)-(3-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; (S)-(3-(1-(4-(4,6-dimethylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; (S)-(3-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

11. A compound according to claim 1 wherein said compound is an inhibitor of NS2B-NS3 protease of a Flavivirus, preferably an inhibitor of the NS2B-NS3 protease of Zika and/or Dengue and/or West Nile and/or Japan Encephalitis virus.

12. (canceled)

13. A method for the treatment of a Flavivirus infection, selected from the group consisting of Dengue, West Nile, Zika, and Japan Encephalitis virus, comprising administering to a subject in need thereof a compound according to claim 1.

14. A method for the treatment of Flavivirus infection, comprising administering to a subject in needed thereof a compound of general Formula (I): ##STR00248## wherein: m and n are each independently selected from 0, 1 and 2; R.sub.1a and R.sub.1b are independently selected from H and C.sub.1-6alkyl optionally substituted with one or more substituents selected from: hydroxy, OC.sub.1-3alkyl, halogen, NH.sub.2, NHCOC.sub.1-6alkyl, NHCOOC.sub.1-6alkyl, NHC(O)NHC.sub.1-6alkyl, NHSO.sub.2C.sub.1-6alkyl, NHC.sub.1-3alkyl, N(C.sub.1-3alkyl).sub.2, or a cyclic amine selected from aziridine, azetidine, pyrrolidine, pyperidine, morpholine, piperazine, N-methylpyperazine; or R.sub.1a and R.sub.1b are linked together to form a C.sub.3-6-cycloalkyl ring or a C.sub.4-6-heterocycloalkyl ring; or R.sub.1a is linked to R.sub.3 to form a partially unsaturated aromatic or heteroaromatic bicycle; or R.sub.1b doesn't exist and CR.sub.1a is CCH.sub.2; R.sub.2a and R.sub.2b are independently selected from H and C.sub.1-6alkyl optionally substituted with one or more substituents selected from: hydroxy, OC.sub.1-3alkyl, halogen, NH.sub.2, NHCOC.sub.1-6alkyl, NHCOOC.sub.1-6alkyl, NHC.sub.1-3alkyl, N(C.sub.1-3alkyl).sub.2, or a cyclic amine selected from aziridine, azetidine, pyrrolidine, pyperidine, morpholine, piperazine, N-methylpyperazine; or R.sub.2a and R.sub.2b are linked together to form a C.sub.3-6-cycloalkyl ring or a C.sub.4-6-heterocycloalkyl ring; or any two of R.sub.1a and R.sub.2a or of R.sub.1b and R.sub.2b are linked together to form a C.sub.3-6cycloalkyl or a C.sub.3-6heterocycloalkyl; R.sub.3 is heterocycloalkyl, aromatic or heteroaromatic ring, each of said heterocycloalkyl, aromatic or heteroaromatic ring being optionally substituted with one or more substituents independently selected from halogen, hydroxy, NH.sub.2, NHCOC.sub.1-6alkyl, NHCOOC.sub.1-6alkyl, NHC(O)NHC.sub.1-6alkyl, NHSO.sub.2C.sub.1-6alkyl, NHC.sub.1-3alkyl, N(C.sub.1-3alkyl).sub.2, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.1-6alkoxy, cyano, B(OH).sub.2, aryl, heteroaryl wherein said aryl or heteroaryl ring are optionally substituted with one or more substituents each independently selected from halogen, hydroxy, cyano, NH.sub.2, NHCOC.sub.1-6alkyl, NHCOOC.sub.1-6alkyl, NHC.sub.1-3alkyl, N(C.sub.1-3alkyl).sub.2, C.sub.3-6cycloalkyl, aziridine, azetidine, pyrrolidine, pyperidine, morpholine, piperazine, N-methylpyperazine, C.sub.1-6alkyl, C.sub.1-6alkoxy, wherein said C.sub.1-6alkyl, C.sub.1-6alkoxy are optionally substituted with one or more halogen, hydroxy, NH.sub.2, NHCOC.sub.1-6alkyl, NHCOOC.sub.1-6alkyl, NHC.sub.1-3alkyl, N(C.sub.1-3alkyl).sub.2, aziridine, azetidine, pyrrolidine, pyperidine, morpholine, piperazine and N-methylpyperazine; R.sub.4 is an aromatic or heteroaromatic ring optionally substituted with one or more substituents each independently selected from halogen, hydroxy, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.1-6alkoxy, cyano, NHC.sub.1-3 alkyl, N(C.sub.1-3alkyl).sub.2, aziridine, azetidine, pyrrolidine, pyperidine, morpholine, piperazine and N-methylpyperazine; R.sub.5 is H, C.sub.1-6alkyl, C.sub.1-6haloalkyl or halogen; or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.

15. The method according to claim 14 wherein: R.sub.1b and R.sub.2b are H; and/or m and n are each independently selected from 0, 1; and/or R.sub.3 is phenyl, naphthyl, biphenyl, phenyl substituted with an heteroaromatic ring or an heteroaromatic ring substituted with a second heteroaromatic ring, wherein each of said phenyl, naphthyl or heteroaromatic ring is optionally substituted with one or more substituents each independently selected from halogen, hydroxy, cyano, B(OH).sub.2, NH.sub.2, NHCOC.sub.1-6alkyl, NHCOOC.sub.1-6alkyl, NHC.sub.1-3alkyl, N(C.sub.1-3alkyl).sub.2, C.sub.1-6alkyl, C.sub.1-6alkoxy, pyrrolidine, pyperidine, morpholine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein said C.sub.1-6alkyl, C.sub.1-6alkoxy are optionally substituted with one or more halogen, hydroxy, NH.sub.2, N(CH.sub.3).sub.2, morpholine or pyrrolidine; and/or R.sub.4 is selected from 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, naphthyl, 5-(trifluoromethyl)thiazol-2-yl, 3-chlorophenyl, 3-fluoro-5-trifluoromethylphenyl, quinolinyl, 5-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 3-methyl-5-trifluoromethylphenyl, 3-methoxy-5-trifluoromethylphenyl, 3-cyanophenyl, 3-cyclopropylphenyl, 5-(cyclopropyl)pyridine-3-yl, 4-fluoro-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-4-yl, 2-(trifluoromethyl)thiazol-5-yl, 3-methyl-5-trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methyl-3-trifluoromethylphenyl, 2-(trifluoromethyl)pyridin-6-yl, 3-difluoromethylphenyl, 4-(trifluoromethyl)pyrimidin-2-yl, 2-(trifluoromethyl)pyridine-4-yl.

16. The method according to claim 14 wherein: m is 1 and n is 0; and/or R.sub.1a is H and R.sub.1b is H or C.sub.1-3alkyl optionally substituted with hydroxy or NH.sub.2; and/or R.sub.5 is H.

17. The method according to claim 14, wherein the compound is selected from: (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; and (3-phenethyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide.

18. The method according to claim 14, further comprising administering a at least one further therapeutic agent.

19. (canceled)

20. The method of claim 14, wherein the Flavivirus is selected from the group consisting of Dengue, West Nile, Zika and Japan Encephalitis virus.

21. A compound of claim 1, wherein said compound of Formula (I) is selected from: (3-(4-(Pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (R)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide; (3-(4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl) pyridin-3-yl)carbamoyl)amide; (3-(4-(2-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-(4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(pyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide; (S)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (S)-(3-(1-(4-(4-methylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(4-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(3,5-Dimethylisoxazol-4-yl)-3-methylbenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(2-Methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(2-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(5-methylpyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(trifluoromethyl)phenyl)carbamoyl)(3-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (R)-(3-(2-amino-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate; (3-(3-methyl-4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(4-methoxy-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(4-(2-hydroxyethoxy)-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; ((3-(trifluoromethyl)phenyl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-((5-(2-methoxy-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(4-methoxy-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; ((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-((2-methyl-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((4-methyl-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; ((3-(trifluoromethyl)phenyl)carbamoyl)(3-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; ((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)(3-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-((5-(4-cyanopyrirmidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((2-methoxy-4-methyl-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(pyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(4-methylpyridazin-3-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((3-methyl-[3,4-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((3-fluoro-[3,4-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)thiazol-2-yl)carbamoyl)amide; (3-((5-(3,5-dimethylisoxazol-4-yl)pyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((3,5-difluoro-[3,4-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((2-chloro-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((6-(3,5-dimethylisoxazol-4-yl)pyridazin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; ((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide; (3-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide; (3-((5-(3,6-dimethoxypyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-((4,6-dimethyl-[5,5-bipyrimidin]-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide; (3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; (3-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide; (R)-(3-(1-(4-(4,6-dimethylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

22. A compound of claim 1, selected from the group consisting of (3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide and (3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide.

Description

GENERAL EXPERIMENTAL DETAILS

[0320] Solvents and reagents were obtained from commercial suppliers and were used without further purification. Silica gel chromatography purifications were performed on prepacked cartridges on a Biotage system. UPLC-MS analyses were performed on a Waters Acquity UPLC, equipped with a diode array and a ZQ mass spectrometer, using an X-Terra C18 column (5 m, 4.650 mm) or a BEH C18 column (1.7 m, 2.150 mm). Mobile phase comprised a linear gradient of binary mixtures of H.sub.2O containing 0.1% formic acid (A), and MeCN containing 0.1% formic acid (B). The linear gradient used is: (A): 90% (0.1 min), 90%-0% (2.6 min), 0% (0.3 min), 0%-90% (0.1 min) with a 0.5 mL/min flow. .sup.1H, .sup.19F, .sup.13C NMR spectra were at 400, 377 and 101 MHz on a 400 MHz Bruker spectrometer. Chemical shift () are reported in parts per million downfield to tetramethylsilane using CDCl.sub.3 as a solvent unless otherwise noted. Coupling constants (J) are reported in Hertz (Hz). Multiplicities are reported as singlet (s), broad (br), doublet (d), doublet of doublets (dd), doublet of doublets of doublets (ddd), triplet (t), doublet of triplet (dt) or multiplet (m). Unless indicated, spectra were acquired at 300 K. Temperatures are expressed in degrees Celsius ( C.) and are uncorrected. The reported yields are the actual isolated yields of purified material and are not optimized. The purity of Intermediates 1-10, 23 and 24 and Examples 1-30, 34, 38-43, 46-48, 50-53, 55-64, 67-69, 71-98, 100, 101, 103-115 and 117-124 was assessed in a Waters Acquity UPLC, equipped with a diode array and a ZQ mass spectrometer a BEH C18 column (1.7 m, 2.150 mm). Mobile phase comprised a linear gradient of binary mixtures of H.sub.2O containing 0.1% formic acid (A), and MeCN containing 0.1% formic acid (B). The linear gradient of B used is: 10% (0.1 min), 10-100% (1.5 min), 100% (0.3 min), 100-10% (0.1 min) with a 0.5 mL/min flow. Run time: 3 min. The purity of Intermediates 11-22, 25-30 and Examples 30-32, 35-37, 44, 45, 49, 54, 65, 66, 70, 99, 102 and 116 was assessed in a Waters Acquity UPLC, equipped with a diode array and a ZQ mass spectrometer a BEH C18 column (1.7 m, 2.150 mm). Mobile phase comprised a linear gradient of binary mixtures of H.sub.2O containing 0.05% TFA (A), and MeCN containing 0.05% TFA (B). The linear gradient of B used is: 5% (0.1 min), 5-100% (2.8 min), 100% (0.2 min), 100-5% (0.8 min) with a 0.5 mL/min flow. Run time: 3 min. Unless otherwise indicated, commercially available reagents and solvents (HPLC grade) were used without further purification. Where the synthesis of intermediates and starting materials is not described, these compounds are commercially available or can be made from commercially available compounds by standard methods or by extension of the Examples herein. During any of the synthetic sequences described herein it may be necessary and/or desirable to protect sensitive or reactive groups or any of the molecules concerned, this may be achieved by means of conventional protecting groups, such as those described in Protecting Groups in Organic Synthesis (3.sup.rd Edition, Greene, T. W. and Wuts, P. G. M.; Wiley Interscience, 1999) and Protecting Groups (Kocienski, P. J.; Thieme, 1994).

Example 1: (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide

##STR00016##

Step 1: 1-Phenylpropan-2-amine (Intermediate 1)

[0321] Ammonium formate (24.44 g, 387.54 mmol) was dissolved in a mixture of water (9 mL) and methanol (80 mL) and the solution was treated with 1-phenylpropan-2-one (4.95 mL, 37.26 mmol) and Pd/C (10% w/w) (1.19 g, 11.18 mmol). The mixture was stirred at rt for 16 h then filtered through a pad of Celite and washed with methanol. The filtrate was evaporated under reduced pressure to get a white powder which was suspended in EtOAc (150 mL) and stirred at rt for 1 h. The solid formed was isolated by filtration to get the desired product as a salt (4.2 g). 500 mg of isolated product were dissolved in methanol (1.5 mL) and charged on a SCX cartridge (5 g). The resin was washed with methanol followed by a 2 M NH.sub.3 solution in methanol. After removal of the solvents under reduced pressure the title compound was obtained as a white powder (350 mg, 58%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.30-7.26 (m, 2H), 7.20-7.17 (m, 3H), 3.03-2.96 (m, 1H), 2.55-2.48 (m, 2H), 0.95 (d, J=4.0 Hz, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.9H.sub.13N 135.10, found 136 (M+H).sup.+. HPLC t.sub.R 0.59 min.

Step 2: 2-((1-Phenylpropan-2-yl)amino)acetonitrile (Intermediate 2)

[0322] A suspension of 1-phenylpropan-2-amine (Intermediate 1) (1.31 g, 9.71 mmol) and DIPEA (3.44 mL, 19.42 mmol) in MeCN (11.8 mL) was treated with 2-bromoacetonitrile (0.47 mL, 6.8 mmol) and the reaction mixture was stirred at rt for 16 h. Solvent was then removed under reduced pressure and the residue treated with water (10 mL) and extracted with EtOAc (350 mL). The collected organics were washed with brine, dried over Na.sub.2SO.sub.4, and evaporated under reduced pressure to get the title compound as a colourless oil (1.45 g, 86%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.32-7.28 (m, 2H), 7.22-7.18 (m, 3H), 3.73-3.61 (m, 2H), 2.95-2.90 (m, 1H), 2.77 (dd, J.sub.1=4.0 Hz, J.sub.2=12.0 Hz, 1H), 2.46-2.41 (m, 2H), 0.92 (d, J=4.0 Hz, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.11H.sub.14N.sub.2 174.12, found 175 (M+H).sup.+. HPLC t.sub.R 0.81 min.

Step 3: 5-Amino-3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 3)

[0323] A solution of 2-((1-phenylpropan-2-yl)amino)acetonitrile (Intermediate 2) (1.4 g, 8.03 mmol) in THE (3.9 mL) was treated with tert-butyl nitrite (3.84 mL, 32.14 mmol). The solution was stirred at rt for 4 h. Then, 4 N HCl in dioxane (13.1 mL, 52.23 mmol) was added and the reaction mixture was stirred at rt for 18 h. Diethyl ether was added to the mixture and the precipitate formed was collected by filtration and washed with diethyl ether to afford the title compound as a white powder (1.39 g, 82%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.71 (s, 2H), 8.20 (s, 1H), 7.34-7.21 (m, 5H), 5.33-5.27 (m, 1H), 3.32-3.30 (m, 2H), 1.65 (d, J=4.0 Hz, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.11H.sub.14N.sub.3O.sup.+ 204.11, found 204 (M+H).sup.+. HPLC t.sub.R 0.84 min.

Step 4: (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide (Example 1)

[0324] A solution of 3-(trifluoromethyl)benzoic acid (277.6 mg, 1.46 mmol) in toluene (1.7 mL, 0.016 mol) was treated with TEA (0.22 mL, 1.61 mmol) and DPPA (0.35 mL, 1.61 mmol). The mixture was heated at 70 C. for 1 h then Intermediate 3 (175 mg, 0.730 mmol) was added and the mixture stirred at 80 C. for 2 h. Mixture was cooled to rt and quenched with addition of 1 N NaHCO.sub.3 (aq. sol.) and extracted with EtOAc. The combined organic phase was washed with water and brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The residue obtained was triturated with petroleum ether to get the title compound as a light-yellow solid (258 mg, 87%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.65 (s, 1H), 8.32 (s, 1H), 8.27 (br s, 1H), 7.68 (br d, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.31-7.27 (m, 2H), 7.24-7.19 (m, 4H), 5.16-5.11 (m, 1H), 3.32 (m, 2H), 1.65 (d, J=8.0 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.17F.sub.3N.sub.4O.sub.2 390.13; found 391 (M+H).sup.+. HPLC t.sub.R 2.0 min.

[0325] Examples 5, 12, 18 and 33 were synthesized according to the above procedure (Scheme 1) by reacting with the appropriate starting materials.

Example 5: (3-phenethyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide

[0326] The title compound was obtained as a beige solid reacting 2-phenylethan-1-amine in Step 2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.69 (s, 1H), 8.25 (br s, 1H), 8.24 (br s, 1H), 7.72 (br d, J=8.3 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.35-7.22 (m, 6H), 4.82 (t, J=7.1 Hz, 2H), 3.32 (t, J=7.1 Hz, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.15F.sub.3N.sub.4O.sub.2 376.11; found 377 (M+H).sup.+. HPLC t.sub.R 1.90 min.

Example 12: (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)(quinolin-6-ylcarbamoyl) amide

[0327] The title compound was obtained as a beige solid reacting quinoline-6-carboxylic acid in Step 4. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.88 (s, 1H), 8.87 (d, J=3.5 Hz, 1H), 8.53-8.51 (br m, 2H), 8.31 (s, 1H), 7.99 (br s, 2H), 7.68-7.65 (m, 1H), 7.33-7.22 (m, 5H), 5.21-5.16 (m, 1H), 3.34-3.32 (m, 2H), 1.68 (d, J=6.6 Hz, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.19N.sub.5O.sub.2 373.15; found 374 (M+H).sup.+. HPLC t.sub.R 1.24 min.

Example 18: (3-(naphthalen-2-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide

[0328] The title compound was obtained as a white powder reacting 5-amino-3-(naphthalen-2-ylmethyl)-1,2,3-oxadiazol-3-ium chloride in Step 4. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.63 (br s, 1H), 8.17 (s, 1H), 8.10 (d, J=15.5 Hz, 2H), 7.96-7.90 (m, 3H), 7.64 (br d, J=8.3 Hz, 1H), 7.58 (dd, J.sub.1=8.6 Hz, J.sub.2=1.8 Hz, 1H), 7.53-7.50 (m, 2H), 7.37-7.33 (m, 1H), 7.14 (d, J=7.7 Hz, 1H), 5.89 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.15F.sub.3N.sub.4O.sub.2 412.11; found 411 (MH).sup.. HPLC t.sub.R2.06 min.

Example 33: ((3-methyl-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0329] The title compound was obtained as a white powder reacting 3-methyl-5-(trifluoromethyl)benzoic acid in Step 4. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.59 (s, 1H), 8.33 (s, 1H), 8.04 (br s, 1H), 7.56 (br s, 1H), 7.32-7.20 (m, 5H), 7.05 (s, 1H), 5.16-5.11 (m, 1H), 3.35-3.29 (m, 2H), 2.32 (s, 3H), 1.66 (d, J=6.8 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.23 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.19F.sub.3N.sub.4O.sub.2 404.15; found 405 (M+H).sup.+. HPLC t.sub.R 2.09 min.

(R)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 13) & (S)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 14)

##STR00017##

Step 1: (R)-(3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 13) & (S)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 14)

[0330] (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl) amide (Example 1) (45 mg, 0.115 mmol) was subjected to SFC purification (Column: Chiralpak IA (cellulose)Run time 19 minEluent: MeOHMethod: 15% MeOH (2 min), 15-20% MeOH (8 min), 20% MeOH (7 min), 20-15% MeOH (1 min), 15% MeOH (1 min) to get (R)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 13) (1.sup.st eluted compound) as a white powder (10.2 mg, 23%). .sup.13C NMR (101 MHz, DMSO-d.sub.6) 172.6, 159.0, 141.9, 136.0, 129.4, 128.8, 128.5, 127.0, 125.7, 123.0, 121.3, 117.2, 113.6, 102.8, 62.8, 40.5, 19.3. LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.17F.sub.3N.sub.4O.sub.2 390.13; found 391 (M+H).sup.+. HPLC t.sub.R 2.0 min, and (S)-(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 14) (2.sup.nd eluted compound) as a white powder (10.7 mg, 24%). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.17F.sub.3N.sub.4O.sub.2 390.13; found 391 (M+H).sup.+. HPLC t.sub.R 2.0 min.

Example 3: (Naphthalen-2-ylcarbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide

##STR00018##

Step 1: 5-(1H-Imidazole-1-carboxamido)-3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 4)

[0331] A solution of CDI (223 mg, 1.38 mmol) in a mixture of DMF/MeCN (3 mL/0.5 mL) was treated with Intermediate 3 (300 mg, 1.25 mmol). The solution was stirred at rt for 1 h. After concentration under reduced pressure the title compound was obtained as a crude, which was used directly in the next reaction. LCMS (ES.sup.+) m/z calculated for C.sub.15H.sub.16N.sub.5O.sub.2 298.13, found 320 (M+Na).sup.+. HPLC t.sub.R 1.06 min.

Step 2: 5-(3-Methyl-1H-imidazol-3-ium-1-carboxamido)-3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium chloride iodide (Intermediate 5)

[0332] A solution of crude Intermediate 4 (417 mg, 1.25 mmol) in anhydrous MeCN (19 mL) was treated with iodomethane (0.33 mL, 5.37 mmol). The mixture was stirred at rt for 16 h. After concentration under reduced pressure the title compound was obtained as a yellow oil crude, which was used directly in the next reaction.

Step 3: (Naphthalen-2-ylcarbamoyl)(3-(I-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide (Example 3)

[0333] A solution of crude Intermediate 5 (60 mg, 0.13 mmol) in chloroform (1 mL) was treated with naphthalen-2-amine (18.1 mg, 0.13 mmol) in chloroform (1 mL) and DBU (0.04 mL, 0.25 mmol). The mixture was stirred at reflux overnight and the solvent was then evaporated under reduced pressure. The title compound was obtained after purification by automated RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). Fractions containing product were lyophilized to give the title compound as a solid (28.4 mg, 60%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.56 (br s, 1H), 8.35 (s, 1H), 8.34 (br s, 1H), 7.78-7.75 (m, 2H), 7.70 (d, J=8.0 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.34-7.28 (m, 3H), 7.25-7.21 (m, 3H), 5.19-5.14 (m, 1H), 3.33-3.31 (m, 2H), 1.67 (d, J=8.0 Hz, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.20N.sub.4O.sub.2 372.16; found 373 (M+H).sup.+. HPLC t.sub.R 1.93 min.

[0334] Example 4 was synthesized according to the above procedure (Scheme 3) by reacting with the appropriate starting material.

Example 4: (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl) thiazol-2-yl)carbamoyl)amide

[0335] The title compound was obtained as a beige solid reacting Intermediate 5 and 5-(trifluoromethyl)thiazol-2-amine in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.78 (br s, 1H), 8.46 (s, 1H), 7.92 (br d, J=1.3 Hz, 1H), 7.32-7.20 (m, 5H), 5.25-5.19 (m, 1H), 3.36-3.30 (m, 2H), 1.67 (d, J=6.8 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 59.51 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.16H.sub.14F.sub.3N.sub.5O.sub.2S 397.08; found 398 (M+H).sup.+. HPLC t.sub.R 1.91 min.

Example 6: (3-Benzyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl) amide

##STR00019##

Step 1: 2-(Benzylamino)acetonitrile (Intermediate 6)

[0336] The title compound was prepared using the procedure reported for the synthesis of Intermediate 2 starting from benzylamine (1.01 mL, 9.3 mmol). The crude product was purified by chromatography on silica gel (eluting with 100% DCM) to give the title compound as a colorless oil (1.06 g, 78%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.36-7.32 (m, 4H), 7.28-7.23 (m, 1H), 3.76 (d, J=8.0 Hz, 2H), 3.58 (d, J=8.0 Hz, 2H), 3.04-2.98 (m, 1H). LCMS (ES.sup.+) m/z calculated for C.sub.9H.sub.10N.sub.2 146.08, found 147 (M+H).sup.+. HPLC t.sub.R 0.98 min.

Step 2: 5-Amino-3-benzyl-1,2,3-oxadiazol-3-ium chloride (Intermediate 7)

[0337] The title compound was prepared using the procedure reported for the synthesis of Intermediate 3 starting from Intermediate 6 (877 mg, 6.0 mmol). After filtration the title compound was obtained as a solid (786 mg, 62%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.84 (br s, 2H), 8.15 (br s, 1H), 7.57-7.45 (br m, 5H), 5.91 (br s, 2H).

Step 3: (3-Benzyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 6)

[0338] A solution of 5-amino-3-benzyl-1,2,3-oxadiazol-3-ium chloride (Intermediate 7) (30 mg, 0.170 mmol) in anhydrous pyridine (1.02 mL) was cooled at 0 C. and 1-isocyanato-3-(trifluoromethyl)benzene (0.05 mL, 0.34 mmol) was added. The reaction mixture was left warming to rt and stirred for 18 h. After evaporation of the solvent under reduced pressure, the crude product was purified by chromatography on silica gel (eluting with 10-50% EtOAc in petroleum ether) to give the title compound as a solid (27.1 mg, 44%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.71 (s, 1H), 8.19 (br s, 2H), 7.71 (br d, J=8.0 Hz, 1H), 7.58-7.56 (m, 2H), 7.48-7.41 (m, 4H), 7.21 (br d, J=8.0 Hz, 1H), 5.78 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.17H.sub.13F.sub.3N.sub.4O.sub.2 362.10; found 363 (M+H).sup.+. HPLC t.sub.R 1.87 min.

[0339] Examples 2, 7, 8, 9, 10, 11, 19, 25, 27, 28, 29, 38, 46, 47, 59, 68, 69, 113, 114 and 115 were synthesized according to the above procedure (Scheme 4) by reacting with the appropriate starting materials.

Example 2: (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl) phenyl)carbamoyl)amide

[0340] The title compound was obtained as a beige solid reacting Intermediate 3 and 1-isocyanato-4-(trifluoromethyl)benzene in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.29 (s, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.57 (d, J=8.6 Hz, 2H), 7.32-7.21 (m, 5H), 5.20-5.14 (m, 1H), 3.32-3.29 (m, 2H), 1.66 (d, J=6.8 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 59.88 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.17F.sub.3N.sub.4O.sub.2 390.13; found 391 (M+H).sup.+. HPLC t.sub.R 2.01 min.

Example 7: (3-phenyl-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl) amide

[0341] The title compound was obtained as a beige solid reacting 5-amino-3-phenyl-1,2,3-oxadiazol-3-ium chloride in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.82 (s, 1H), 8.68 (s, 1H), 8.29 (s, 1H), 8.10 (br d, J=8.1 Hz, 2H), 7.80-7.71 (m, 4H), 7.47 (t, J=7.9 Hz, 1H), 7.25 (br d, J=7.5 Hz, 1H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.25 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.16H.sub.11F.sub.3N.sub.4O.sub.2 348.08; found 349 (M+H).sup.+. HPLC t.sub.R 1.85 min.

Example 8: ((3-chlorophenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0342] The title compound was obtained as a white solid reacting 1-chloro-3-isocyanatobenzene in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.54 (s, 1H), 8.30 (s, 1H), 7.88 (t, J=2.0 Hz, 1H), 7.45 (dd, J=8.3 Hz, J.sub.2=1.1 Hz, 1H), 7.32-7.21 (m, 6H), 6.94 (dd, J.sub.1=7.9 Hz, J.sub.2=1.1 Hz, 1H), 5.20-5.12 (m, 1H), 3.33-3.28 (m, 2H), 1.66 (d, J=6.6 Hz, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.17ClN.sub.4O.sub.2 356.10; found 357 (M+H).sup.+. HPLC t.sub.R 1.92 min.

Example 9: (3-(1-(3,4-dichlorophenyl)propan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0343] The title compound was obtained as a white solid reacting 5-amino-3-(1-(3,4-dichlorophenyl)propan-2-yl)-1,2,3-oxadiazol-3-ium chloride in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.71 (s, 1H), 8.37 (s, 1H), 8.28 (br s, 1H), 7.70 (br d, J=8.1 Hz, 1H), 7.60-7.57 (m, 2H), 7.45 (t, J=8.0 Hz, 1H), 7.24-7.20 (m, 2H), 5.23-5.15 (m, 1H), 3.39-3.28 (m, 2H), 1.64 (d, J=6.6 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.15C.sub.12F.sub.3N.sub.4O.sub.2 458.05; found 459 (M+H).sup.+. HPLC t.sub.R 2.22 min.

Example 10: (3-(2,3-dihydro-1H-inden-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0344] The title compound was obtained as a beige solid reacting 5-amino-3-(2,3-dihydro-1H-inden-2-yl)-1,2,3-oxadiazol-3-ium chloride in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.69 (s, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.72 (br d, J=8.1 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.35-7.32 (m, 2H), 7.28-7.21 (m, 3H), 5.71-5.65 (m, 1H), 3.67 (dd, J.sub.1=16.9 Hz, J.sub.2=7.7 Hz, 2H), 3.52 (dd, J.sub.1=16.9 Hz, J.sub.2=4.4 Hz, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.26 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.15F.sub.3N.sub.4O.sub.2 388.11; found 389 (M+H).sup.+. HPLC t.sub.R 1.96 min.

Example 11: ((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0345] The title compound was obtained as a beige solid reacting Intermediate 3 and 1-fluoro-3-isocyanato-5-(trifluoromethyl)benzene in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.87 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.71 (br d, J=11.6 Hz, 1H), 7.32-7.20 (m, 5H), 7.12 (br d, J=8.3 Hz, 1H), 5.19-5.14 (m, 1H), 3.33-3.29 (m, 2H), 1.66 (d, J=6.8 Hz, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.16F.sub.4N.sub.4O.sub.2 408.12; found 409 (M+H).sup.+. HPLC t.sub.R 2.11 min.

Example 19: (3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide

[0346] The title compound was obtained as a yellow solid reacting 5-amino-3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium chloride in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.71 (s, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.72 (br d, J=8.3 Hz, 1H), 7.68 (br d, J=7.7 Hz, 2H), 7.54 (br d, J=8.1 Hz, 2H), 7.44 (br t, J=7.9 Hz, 1H), 7.22 (br d, J=7.7 Hz, 1H), 5.78 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.17H.sub.12BrF.sub.3N.sub.4O.sub.2 440.01; found 441 (M+H).sup.+. HPLC t.sub.R 2.03 min.

Example 25: (3-(1-phenylcyclopropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide

[0347] The title compound was obtained as a yellow solid reacting 5-amino-3-(1-phenylcyclopropyl)-1,2,3-oxadiazol-3-ium chloride in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.24 (br s, 2H), 7.69 (br d, J=8.1 Hz, 1H), 7.54-7.52 (m, 2H), 7.48-7.41 (m, 4H), 7.22 (br d, J=7.7 Hz, 1H), 2.02-1.99 (m, 2H), 1.72-1.69 (m, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.27 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.15F.sub.3N.sub.4O.sub.2 388.11; found 389 (M+H).sup.+. HPLC t.sub.R 2.03 min.

Example 27: (3-([1,1-biphenyl]-3-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0348] The title compound was obtained as a white solid reacting 3-([1,1-biphenyl]-3-ylmethyl)-5-amino-1,2,3-oxadiazol-3-ium chloride in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.63 (s, 1H), 8.19 (s, 1H), 8.12 (br s, 1H), 7.86 (s, 1H), 7.69-7.62 (m, 4H), 7.49 (br d, J=4.8 Hz, 2H), 7.43 (t, J=7.6 Hz, 2H), 7.37-7.31 (m, 2H), 7.14 (br d, J=7.7 Hz, 1H), 5.77 (s, 2H). .sup.19F-NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.17F.sub.3N.sub.4O.sub.2 438.13; found 439 (M+H).sup.+. HPLC t.sub.R 2.20 min.

Example 28: (3-(2-phenylpropyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide

[0349] The title compound was obtained as a white solid reacting 5-amino-3-(2-phenylpropyl)-1,2,3-oxadiazol-3-ium chloride in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.66 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 7.71 (br d, J=8.3 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.34-7.31 (m, 4H), 7.26-7.21 (m, 2H), 4.76 (br d, J=8.1 Hz, 2H), 3.58-3.53 (m, 1H), 1.30 (d, J=7.0 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.17F.sub.3N.sub.4O.sub.2 390.13; found 391 (M+H).sup.+. HPLC t.sub.R 2.01 min.

Example 29: (3-(pyridin-3-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide

[0350] The title compound was obtained as a white solid reacting 5-amino-3-(pyridin-3-ylmethyl)-1,2,3-oxadiazol-3-ium chloride in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.71 (s, 1H), 8.80 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 8.00 (br d, J=7.9 Hz, 1H), 7.71 (br d, J=8.3 Hz, 1H), 7.51-7.41 (m, 2H), 7.21 (br d, J=7.7 Hz, 1H), 5.84 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.87 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.16H.sub.12F.sub.3N.sub.5O.sub.2 363.09; found 364 (M+H).sup.+. HPLC t.sub.R 1.42 min.

Example 38: (3-(1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide

[0351] The title compound was obtained as a white solid reacting 5-amino-3-(1-phenylethyl)-1,2,3-oxadiazol-3-ium chloride in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.69 (s, 1H), 8.23 (br s, 1H), 8.19 (s, 1H), 7.69 (br d, J=8.3 Hz, 1H), 7.61 (br d, J=6.2 Hz, 2H), 7.50-7.41 (m, 4H), 7.22 (br d, J=7.5 Hz, 1H), 6.16 (q, J=6.0 Hz, 1H), 2.01 (d, J=7.2 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.15F.sub.3N.sub.4O.sub.2 376.11; found 375 (MH).sup.. HPLC t.sub.R 1.95 min.

Example 46: (3-(3-bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide

[0352] The title compound was obtained as a light orange solid reacting 5-amino-3-(3-bromobenzyl)-1,2,3-oxadiazol-3-ium chloride in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (s, 1H), 8.27 (s, 1H), 8.21 (br s, 1H), 7.86 (br s, 1H), 7.72 (br d, J=8.3 Hz, 1H), 7.67 (br d, J=7.9 Hz, 1H), 7.59 (br d, J=7.9 Hz, 1H), 7.43 (br t, J=7.8 Hz, 2H), 7.22 (br d, J=7.7 Hz, 1H), 5.78 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.17H.sub.12BrF.sub.3N.sub.4O.sub.2 440.01; found 441 (M+H).sup.+. HPLC t.sub.R 2.07 min.

Example 47: (3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide

[0353] The title compound was obtained as a light-yellow solid reacting 5-amino-3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium chloride in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.22 (s, 1H), 8.21 (br s, 1H), 7.84 (br d, J=8.6 Hz, 2H), 7.72 (br d, J=8.8 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.38 (d, J=8.3 Hz, 2H), 7.22 (br d, J=7.7 Hz, 1H), 5.75 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.17H.sub.12F.sub.3IN.sub.4O.sub.2 488.00; found 489 (M+H).sup.+. HPLC t.sub.R 2.12 min.

Example 59: (3-((1R,2S)-2-phenylcyclopentyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0354] The title compound was obtained as a white solid reacting 5-amino-3-((1R,2S)-2-phenylcyclopentyl)-1,2,3-oxadiazol-3-ium chloride in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.70 (s, 1H), 8.26 (s, 1H), 8.25 (br s, 1H), 7.69 (br d, J=8.1 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.35-7.30 (m, 4H), 7.27-7.21 (m, 2H), 5.29-5.22 (m, 1H), 3.76-3.69 (m, 1H), 2.56-2.50 (m, 1H), 2.37-2.22 (m, 2H), 2.05-1.86 (m, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.27 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.19F.sub.3N.sub.4O.sub.2 416.15; found 417 (M+H).sup.+. HPLC t.sub.R 2.15 min.

Example 68: (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0355] The title compound was obtained as a white solid reacting (R)-5-amino-3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium chloride in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.24 (s, 2H), 7.70-7.67 (m, 3H), 7.57 (d, J=8.6 Hz, 2H), 7.43 (t, J=8.0 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 6.16 (q, J=7.0 Hz, 1H), 2.00-1.99 (m, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.27 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.14BrF.sub.3N.sub.4O.sub.2 454.03; found 453 (MH).sup.. HPLC t.sub.R2.13 min.

Example 69: (S)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0356] The title compound was obtained as a white solid reacting (S)-5-amino-3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium chloride in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.24 (s, 2H), 7.70-7.67 (m, 3H), 7.57 (d, J=8.6 Hz, 2H), 7.43 (t, J=7.9 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 6.16 (q, J=7.0 Hz, 1H), 2.00-1.99 (m, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.27 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.14BrF.sub.3N.sub.4O.sub.2 454.03; found 453 (MH).sup.. HPLC t.sub.R2.13 min.

Example 113: ((3-chlorophenyl)carbamoyl)(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0357] The title compound was obtained as a white solid reacting 1-chloro-3-isocyanatobenzene and 5-amino-3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium 2,2,2-trifluoroacetate in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.58 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 7.84 (br t, J=2.0 Hz, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.46 (br d, J=9.2 Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), 6.93 (dd, J.sub.1=7.9 Hz, J.sub.2=1.3 Hz, 1H), 5.85 (s, 2H), 3.94 (s, 3H), 2.39 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.19C.sub.1N.sub.6O.sub.3 450.12; found 449 (MH).sup.. HPLC t.sub.R 1.85 min.

Example 114: ((3-cyanophenyl)carbamoyl)(3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0358] The title compound was obtained as a beige solid reacting 3-isocyanatobenzonitrile and 5-amino-3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium 2,2,2-trifluoroacetate in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (s, 1H), 8.43 (s, 1H), 8.23 (s, 1H), 8.12 (br s, 1H), 7.81 (br d, J=8.1 Hz, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.43 (br t, J=8.0 Hz, 1H), 7.34 (d, J=7.7 Hz, 1H), 5.87 (s, 2H), 3.94 (s, 3H), 2.39 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.19N.sub.7O.sub.3 441.15; found 442 (M+H).sup.+. HPLC t.sub.R 1.65 min.

Example 115: (3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)(phenylcarbamoyl)amide

[0359] The title compound was obtained as a beige solid reacting isocyanatobenzene and 5-amino-3-(4-(2-methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium 2,2,2-trifluoroacetate in Step 3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.35 (br s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.69 (d, J=8.3 Hz, 2H), 7.61 (d, J=7.7 Hz, 2H), 7.54 (d, J=8.3 Hz, 2H), 7.21 (br t, J=7.9 Hz, 2H), 6.90 (t, J=7.3 Hz, 1H), 5.85 (s, 2H), 3.95 (s, 3H), 2.40 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.20N.sub.6O.sub.3 416.16; found 415 (MH).sup.. HPLC t.sub.R 1.61 min.

Example 15: (3-(1-Phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

##STR00020##

[0360] A suspension of 5-(trifluoromethyl)pyridin-3-amine (135.3 mg, 0.83 mmol) and TEA (0.23 mL, 1.67 mmol) in THF (5.4 mL) was treated with triphosgene (123.8 mg, 0.42 mmol). The reaction mixture was stirred for 10 min at rt. Diethyl ether (2 mL) was added to the mixture and the salt formed was filtered off to afford a clear solution of isocyanate in THF/ethyl ether that was stored under N.sub.2. A solution of Intermediate 3 (100 mg, 0.420 mmol) in THF was treated with sodium hydride (35 mg, 1.04 mmol, mineral oil 60%) and the mixture was stirred at rt for 15 min. After addition of the solution of isocyanate in THF/ethyl ether, the reaction mixture was stirred for 6 h.

[0361] After evaporation of the solvent under reduced pressure, the residue was purified by chromatography on silica gel (eluting with 1% of MeOH in DCM) to afford the title compound as a light beige solid (28 mg, 17%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.90 (br s, 1H), 8.89 (s, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 7.31-7.19 (m, 5H), 5.20-5.11 (m, 1H), 3.31 (m, 2H), 1.66 (d, J=4.0 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.21 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.16F.sub.3N.sub.5O.sub.2 391.13; found 392 (M+H).sup.+. HPLC t.sub.R 1.59 min.

[0362] Examples 16, 34, 55, 73 and 76 were synthesized according to the above procedure (Scheme 5) by reacting with the appropriate starting materials.

Example 16: (3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl) pyridin-2-yl)carbamoyl)amide

[0363] The title compound was obtained as a yellow solid reacting 4-(trifluoromethyl)pyridin-2-amine in Step 1. LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.16F.sub.3N.sub.5O.sub.2 391.13; found 392 (M+H).sup.+. HPLC t.sub.R 1.89 min.

Example 34: ((3-methoxy-5-(trifluoromethyl)phenyl)carbamoyl)(3-(1-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0364] The title compound was obtained as a white solid reacting 3-methoxy-5-(trifluoromethyl)aniline in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.62 (s, 1H), 8.34 (s, 1H), 7.74 (s, 1H), 7.48 (s, 1H), 7.32-7.20 (m, 5H), 6.76 (s, 1H), 5.17-5.10 (m, 1H), 3.78 (s, 3H), 3.32-3.29 (m, 2H), 1.66 (d, J=6.6 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.36 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.19F.sub.3N.sub.4O.sub.3 420.14; found 421 (M+H).sup.+. HPLC t.sub.R 2.04 min.

Example 55: (3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0365] The title compound was obtained as a white solid reacting 5-amino-3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium chloride in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.97 (br s, 1H), 8.91 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 8.48 (s, 1H), 8.27 (s, 1H), 7.84 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.6 Hz, 2H), 5.77 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.21 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.16H.sub.11F.sub.31N.sub.5O.sub.2 488.99; found 490 (M+H).sup.+. HPLC t.sub.R 2.00 min.

Example 73: (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0366] The title compound was obtained as a white solid reacting (R)-5-amino-3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium chloride in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.96 (br s, 1H), 8.89 (d, J=2.0 Hz, 1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H), 6.18 (q, J=7.0 Hz, 1H), 2.00 (d, J=7.0 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.22 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.17H.sub.13BrF.sub.3N.sub.5O.sub.2 455.02; found 455-457 (M+H).sup.+. HPLC t.sub.R 1.91 min.

Example 76: (S)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0367] The title compound was obtained as a light orange solid reacting (S)-5-amino-3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium chloride in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.96 (br s, 1H), 8.89 (d, J=2.2 Hz, 1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H), 6.18 (q, J=7.0 Hz, 1H), 2.00 (d, J=7.0 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.21 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.17H.sub.13BrF.sub.3N.sub.5O.sub.2 455.02; found 454-456 (MH).sup.. HPLC t.sub.R 1.93 min.

Example 17: (3-([1,1-Biphenyl]-4-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

##STR00021##

Step 1: 2-(([1,1-Biphenyl]-4-ylmethyl)amino)acetonitrile (Intermediate 8)

[0368] The title compound was prepared using the procedure reported for the synthesis of Intermediate 2 starting from (4-phenylphenyl)methanamine (400 mg, 2.18 mmol). The crude product was purified by chromatography on silica gel (eluting with 0-50% EtOAc in diethyl ether) to afford the title compound as a white solid (339 mg, 70%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.67-7.62 (m, 4H), 7.48-7.41 (m, 4H), 7.36 (t, J=8.0 Hz, 1H), 3.80 (br s, 2H), 3.62 (br d, J=4.0 Hz, 2H), 3.08 (br s, 1H).

Step 2: 3-([1,1-biphenyl]-4-ylmethyl)-5-amino-1,2,3-oxadiazol-3-ium chloride (Intermediate 9)

[0369] The title compound was prepared using the procedure reported for the synthesis of Intermediate 3 starting from Intermediate 8 (339 mg, 1.53 mmol). After filtration the title compound was obtained as a white powder (258 mg, 67%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (br s, 2H), 8.16 (s, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.69-7.66 (m, 4H), 7.48 (t, J=8.0 Hz, 2H), 7.41 (t, J=8.0 Hz, 1H), 5.96 (s, 2H).

Step 3: (3-([1,1-biphenyl]-4-ylmethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide (Example 17)

[0370] The title compound was prepared using the procedure reported for the synthesis of Example 1 starting from Intermediate 9 (50 mg, 0.200 mmol). After evaporation of the solvent under reduced pressure, the residue was purified by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). Fractions containing product were lyophilized to give the title compound as a white solid (30 mg, 35%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.71 (s, 1H), 8.24 (s, 1H), 8.21 (br s, 1H), 7.77-7.66 (m, 7H), 7.50-7.37 (m, 4H), 7.22 (d, J=8 Hz, 1H), 5.83 (s, 2H). .sup.19F-NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.17F.sub.3N.sub.4O.sub.2 438.13; found 437 (MH).sup.. HPLC t.sub.R2.2 min.

Example 24: (3-Benzyl-4-chloro-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide

##STR00022##

[0371] A solution of Example 6 (30 mg, 0.08 mmol) in chloroform (0.8 mL) was treated with Palau'Chlor (17.4 mg, 0.08 mmol) and the reaction mixture was stirred at rt for 6 h. After evaporation of the solvent under reduced pressure, the residue was purified by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). Fractions containing product were lyophilized to give the title compound as a light-yellow solid (16 mg, 49%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.78 (s, 1H), 8.15 (s, 1H), 7.80 (d, J=8 Hz, 1H), 7.48-7.43 (m, 6H), 7.24 (d, J=8 Hz, 1H), 5.83 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.24 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.17H.sub.12ClF.sub.3N.sub.4O.sub.2 396.06; found 397 (M+H).sup.+. HPLC t.sub.R 1.91 min.

Example 26: (3-(4-(Pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

##STR00023##

[0372] A solution of Example 19 (50 mg, 0.110 mmol), tetrakis(triphenylphosphine)palladium(0) (5.9 mg, 0.01 mmol), disodium carbonate (36.0 mg, 0.34 mmol) and pyrimidin-5-ylboronic acid (18.3 mg, 0.15 mmol) in dioxane (2 mL) and water (0.4 mL) in a sealed tube was heated at 80 C. for 2 h. After cooling the reaction mixture was filtered on a pad of solka floc and the filtrate was evaporated under reduced pressure. The residue was purified by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). Fractions containing product were lyophilized to give the title compound as a white solid (14 mg, 28%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.71 (br s, 1H), 9.21 (s, 1H), 9.17 (s, 2H), 8.24 (s, 1H), 8.20 (s, 1H), 7.91 (d, J=8 Hz, 2H), 7.75 (d, J=8 Hz, 2H), 7.72-7.69 (m, 1H), 7.43 (t, J=8 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 5.86 (s, 2H). .sup.13C NMR (101 MHz, DMSO-d.sub.6) 172.6, 159.0, 157.5, 154.9, 141.8, 134.9, 132.8, 132.5, 130.1, 129.5, 129.1, 127.7, 125.7, 121.3, 117.3, 113.7, 104.5, 55.5. .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.15F.sub.3N.sub.6O.sub.2 440.12; found 441 (M+H).sup.+. HPLC t.sub.R 1.62 min.

[0373] Examples 20, 21, 22, 23, 41, 48, 72, 74, 75, 77, 78, 93, 95, 96 and 97 were synthesized according to the above procedure (Scheme 8) by reacting with the appropriate starting materials.

Example 20: (3-(4-(thiophen-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3(trifluoromethyl) phenyl)carbamoyl)amide

[0374] The title compound was obtained as a white solid reacting thiophen-3-ylboronic acid in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.71 (s, 1H), 8.21 (br s, 2H), 7.95 (br s, 1H), 7.81 (br d, J=7.7 Hz, 2H), 7.72 (br d, J=8.3 Hz, 1H), 7.67-7.59 (m, 4H), 7.43 (t, J=7.9 Hz, 1H), 7.22 (br d, J=7.9 Hz, 1H), 5.80 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.15F.sub.3N.sub.4O.sub.2S 444.09; found 443 (MH).sup.. HPLC t.sub.R 2.12 min.

Example 21: (3-((2-methyl-[1,1-biphenyl]-4-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0375] The title compound was obtained as a white solid reacting o-tolylboronic acid in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.28 (s, 1H), 8.22 (br s, 1H), 7.73 (br d, J=8.1 Hz, 1H), 7.64 (br d, J=7.7 Hz, 2H), 7.44 (br d, J=7.2 Hz, 3H), 7.30-7.20 (m, 5H), 5.84 (s, 2H), 2.23 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.24H.sub.19F.sub.3N.sub.4O.sub.2 452.15; found 451 (MH).sup.. HPLC t.sub.R 2.29 min.

Example 22: (3-(4-(pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide

[0376] The title compound was obtained as a white solid reacting pyridin-3-ylboronic acid in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.92 (s, 1H), 8.60 (br d, J=4.6 Hz, 1H), 8.25 (s, 1H), 8.21 (br s, 1H), 8.11 (br d, J=7.9 Hz, 1H), 7.84 (br d, J=7.7 Hz, 2H), 7.72 (br d, J=7.9 Hz, 3H), 7.53-7.49 (m, 1H), 7.44 (br t, J=8.0 Hz, 1H), 7.22 (br d, J=7.7 Hz, 1H), 5.85 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.16F.sub.3N.sub.5O.sub.2 439.13; found 438 (MH).sup.. HPLC t.sub.R 1.45 min.

Example 23: (3-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0377] The title compound was obtained as a white solid reacting 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.69 (s, 1H), 8.19 (br s, 1H), 8.17 (br s, 2H), 7.89 (br s, 1H), 7.71 (br d, J=8.1 Hz, 1H), 7.65-7.63 (m, 2H), 7.56-7.54 (m, 2H), 7.42 (br t, J=8.0 Hz, 1H), 7.21 (br d, J=7.5 Hz, 1H), 5.74 (s, 2H), 3.86 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.17F.sub.3N.sub.6O.sub.2 442.14; found 441 (MH).sup.. HPLC t.sub.R 1.71 min.

Example 41: (3-(4-(2-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0378] The title compound was obtained as a white solid reacting (2-methoxypyrimidin-5-yl)boronic acid in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.71 (s, 1H), 8.97 (s, 2H), 8.23 (s, 1H), 8.21 (br s, 1H), 7.83 (br d, J=8.1 Hz, 2H), 7.71 (br d, J=8.1 Hz, 3H), 7.44 (br t, J=8.0 Hz, 1H), 7.22 (br d, J=7.7 Hz, 1H), 5.84 (s, 2H), 3.98 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.17F.sub.3N.sub.6O.sub.3 470.13; found 469 (MH).sup.. HPLC t.sub.R 1.82 min.

Example 48: (3-(4-(isoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide

[0379] The title compound was obtained as a white solid reacting isoxazol-4-ylboronic acid in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 9.51 (s, 1H), 9.21 (s, 1H), 8.21 (br s, 2H), 7.80 (br d, J=8.3 Hz, 2H), 7.71 (br d, J=9.2 Hz, 1H), 7.66 (br d, J=8.3 Hz, 2H), 7.43 (br t, J=7.9 Hz, 1H), 7.22 (br d, J=7.7 Hz, 1H), 5.80 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.14F.sub.3N.sub.5O.sub.3 429.10; found 428 (MH).sup.. HPLC t.sub.R 1.86 min.

Example 72: (R)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0380] The title compound was obtained as a white solid reacting pyrimidin-5-ylboronic acid and (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in Scheme 1) in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.65 (s, 1H), 9.14 (s, 1H), 9.10 (s, 2H), 8.20 (s, 1H), 8.17 (br s, 1H), 7.85 (br d, J=8.1 Hz, 2H), 7.72 (br d, J=8.1 Hz, 2H), 7.61 (br d, J=8.6 Hz, 1H), 7.36 (br t, J=7.9 Hz, 1H), 7.15 (br d, J=7.5 Hz, 1H), 6.17 (q, J=7.0 Hz, 1H), 1.99 (br d, J=7.0 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.27 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.17F.sub.3N.sub.6O.sub.2 454.14; found 453 (MH).sup.. HPLC t.sub.R 1.71 min.

Example 74: (S)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0381] The title compound was obtained as a white solid reacting pyrimidin-5-ylboronic acid and (S)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in Scheme 1) in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.65 (s, 1H), 9.14 (s, 1H), 9.10 (s, 2H), 8.20 (s, 1H), 8.17 (br s, 1H), 7.85 (br d, J=8.6 Hz, 2H), 7.72 (br d, J=8.3 Hz, 2H), 7.61 (br d, J=8.3 Hz, 1H), 7.36 (br t, J=7.4 Hz, 1H), 7.14 (br d, J=8.3 Hz, 1H), 6.17 (q, J=7.2 Hz, 1H), 1.99 (br d, J=7.0 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.27 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.17F.sub.3N.sub.6O.sub.2 454.14; found 453 (MH).sup.. HPLC t.sub.R 1.71 min.

Example 75: (R)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0382] The title compound was obtained as a white solid reacting pyrimidin-5-ylboronic acid and (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (prepared as reported in Scheme 1) in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.96 (br s, 1H), 9.22 (s, 1H), 9.18 (s, 2H), 8.89 (br d, J=2.0 Hz, 1H), 8.58 (br s, 1H), 8.47 (br s, 1H), 8.32 (s, 1H), 7.92 (br d, J=8.3 Hz, 2H), 7.79 (br d, J=8.3 Hz, 2H), 6.27 (q, J=7.0 Hz, 1H), 2.07 (br d, J=7.0 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.21 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.16F.sub.3N.sub.7O.sub.2 455.13; found 456 (M+H).sup.+. HPLC t.sub.R 1.49 min.

Example 77: (S)-(3-(1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0383] The title compound was obtained as a white solid reacting pyrimidin-5-ylboronic acid and (S)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (prepared as reported in Scheme 1) in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.89 (br s, 1H), 9.14 (s, 1H), 9.10 (s, 2H), 8.82 (br d, J=2.0 Hz, 1H), 8.50 (br s, 1H), 8.40 (br s, 1H), 8.25 (s, 1H), 7.85 (br d, J=8.3 Hz, 2H), 7.72 (br d, J=8.3 Hz, 2H), 6.19 (q, J=7.0 Hz, 1H), 1.99 (br d, J=7.0 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.22 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.16F.sub.3N.sub.7O.sub.2 455.13; found 456 (M+H).sup.+. HPLC t.sub.R 1.49 min.

Example 78: (3-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0384] The title compound was obtained as a white solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 7.72 (br d, J=8.1 Hz, 1H), 7.68 (br d, J=8.1 Hz, 2H), 7.50 (br d, J=8.1 Hz, 2H), 7.44 (br t, J=8.0 Hz, 1H), 7.22 (d, J=7.9 Hz, 1H), 5.83 (s, 2H), 2.41 (s, 3H), 2.24 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.18F.sub.3N.sub.5O.sub.3 457.14; found 458 (M+H).sup.+. HPLC t.sub.R 1.92 min.

Example 93: (3-(4-(5-methylpyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0385] The title compound was obtained as a beige solid reacting 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (s, 1H), 9.19 (s, 1H), 9.07 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.76-7.71 (m, 3H), 7.63 (br d, J=8.1 Hz, 2H), 7.44 (br t, J=7.5 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 5.88 (s, 2H), 2.33 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.17F.sub.3N.sub.6O.sub.2 454.14; found 455 (M+H).sup.+. HPLC t.sub.R 1.61 min.

Example 95: (3-(4-(1,5-dimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0386] The title compound was obtained as a white solid reacting (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.81 (s, 1H), 8.31 (br s, 2H), 7.81 (br d, J=8.6 Hz, 1H), 7.69 (br d, J=6.4 Hz, 3H), 7.58 (d, J=8.1 Hz, 2H), 7.53 (t, J=7.9 Hz, 1H), 7.31 (br d, J=7.2 Hz, 1H), 5.88 (s, 2H), 3.88 (s, 3H), 2.47 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.19F.sub.3N.sub.6O.sub.2 456.15; found 455 (MH).sup.. HPLC t.sub.R 1.81 min.

Example 96: (3-(4-(1,3-dimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0387] The title compound was obtained as a white solid reacting (1,3-dimethyl-1H-pyrazol-4-yl)boronic acid in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.71 (s, 1H), 8.21 (br s, 2H), 7.94 (s, 1H), 7.72 (br d, J=7.9 Hz, 1H), 7.58 (br d, J=8.1 Hz, 2H), 7.51 (br d, J=8.1 Hz, 2H), 7.44 (br t, J=8.1 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 5.77 (s, 2H), 3.79 (s, 3H), 2.30 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.19F.sub.3N.sub.6O.sub.2 456.15; found 455 (M+H).sup.+. HPLC t.sub.R 1.79 min.

Example 97: (3-(trifluoromethyl)phenyl)carbamoyl)(3-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0388] The title compound was obtained as a white solid reacting (1,3,5-trimethyl-1H-pyrazol-4-yl)boronic acid in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.26 (s, 1H), 8.21 (br s, 1H), 7.72 (br d, J=8.6 Hz, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.44 (br t, J=7.9 Hz, 1H), 7.35 (d, J=7.9 Hz, 2H), 7.22 (d, J=7.7 Hz, 1H), 5.80 (s, 2H), 3.70 (s, 3H), 2.22 (s, 3H), 2.13 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.21F.sub.3N.sub.6O.sub.2 470.17; found 469 (MH).sup.. HPLC t.sub.R 1.81 min.

Example 50: (3-(3-(Pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide

##STR00024##

[0389] The title compound was prepared using procedure reported for the synthesis of compound 26 starting from Example 46. The crude product was purified by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). Fractions containing product were lyophilized to give the title compound as a white solid (18.4 mg, 37%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (br s, 1H), 9.23 (s, 1H), 9.19 (s, 2H), 8.28 (s, 1H), 8.21 (br s, 1H), 8.09 (br s, 1H), 7.92 (d, J=7.7 Hz, 1H), 7.72-7.62 (m, 3H), 7.43 (t, J=8.0 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 5.85 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.15F.sub.3N.sub.6O.sub.2 440.12; found 439 (MH).sup.. HPLC t.sub.R 1.68 min.

[0390] Examples 51, 52, 53 and 94 were synthesized according to the above procedure (Scheme 9) by reacting with the appropriate starting materials.

Example 51: (3-(3-(pyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide

[0391] The title compound was obtained as a white solid reacting pyridin-3-ylboronic acid in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.96 (br d, J=1.8 Hz, 1H), 8.63 (dd, J.sub.1=4.8 Hz, J.sub.2=1.3 Hz, 1H), 8.28 (s, 1H), 8.21 (br s, 1H), 8.17 (br d, J=7.9 Hz, 1H), 8.02 (br s, 1H), 7.84 (br d, J=7.0 Hz, 1H), 7.71 (br d, J=7.9 Hz, 1H), 7.65-7.56 (m, 3H), 7.43 (t, J=7.9 Hz, 1H), 7.22 (br d, J=7.7 Hz, 1H), 5.85 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.16F.sub.3N.sub.5O.sub.2 439.13; found 438 (MH).sup.. HPLC t.sub.R 1.54 min.

Example 52: (3-(3-(1-methyl-1H-pyrazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0392] The title compound was obtained as a white solid reacting 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.21 (s, 1H), 8.20 (br s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.78 (br s, 1H), 7.71 (br d, J=8.3 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.46-7.37 (m, 3H), 7.22 (br d, J=7.7 Hz, 1H), 5.76 (s, 2H), 3.87 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.27 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.17F.sub.3N.sub.6O.sub.2 442.14; found 441 (MH).sup.. HPLC t.sub.R 1.77 min.

Example 53: (3-(3-(2-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0393] The title compound was obtained as a white solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.97 (s, 2H), 8.27 (s, 1H), 8.21 (br s, 1H), 8.00 (s, 1H), 7.83 (br d, J=6.4 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.62-7.60 (m, 2H), 7.43 (br t, J=7.9 Hz, 1H), 7.22 (br d, J=7.5 Hz, 1H), 5.83 (s, 2H), 3.98 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.17F.sub.3N.sub.6O.sub.3 470.13; found 469 (MH).sup.. HPLC t.sub.R 1.86 min.

Example 94: (3-(3-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0394] The title compound was obtained as a white solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid in Step 1 (K.sub.2CO.sub.3 in a mixture of MeOH/dioxane was used). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.64 (s, 1H), 8.21 (s, 1H), 8.13 (br s, 1H), 7.64 (br d, J=8.1 Hz, 1H), 7.57 (s, 1H), 7.51-7.49 (m, 2H), 7.43-7.40 (m, 1H), 7.36 (br t, J=7.9 Hz, 1H), 7.14 (br d, J=7.7 Hz, 1H), 5.76 (s, 2H), 2.35 (s, 3H), 2.18 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.18F.sub.3N.sub.5O.sub.3 457.14; found 456 (MH).sup.. HPLC t.sub.R 1.96 min.

Example 57: (3-(4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl) pyridin-3-yl)carbamoyl)amide

##STR00025##

[0395] The title compound was prepared using procedure reported for the synthesis of Example 26 starting from Example 55. The title compound was obtained after purification by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). Fractions containing product were lyophilized to give the title compound as a white solid (13 mg, 31%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.90 (br s, 1H), 9.15 (s, 1H), 9.11 (s, 2H), 8.83 (d, J=2.2 Hz, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.68 (d, J=8.3 Hz, 2H), 5.81 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.22 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.14F.sub.3N.sub.7O.sub.2 441.12; found 442 (M+H).sup.+. HPLC t.sub.R 1.41 min.

[0396] Examples 56, 58 and 67 were synthesized according to the above procedure (Scheme 10) by reacting with the appropriate starting materials.

Example 56: (3-((4-(morpholinomethyl)-[1,1-biphenyl]-4-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0397] The title compound was obtained as a white solid reacting 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.24 (s, 1H), 8.21 (br s, 1H), 7.77-7.65 (m, 7H), 7.46-7.40 (m, 3H), 7.22 (br d, J=7.9 Hz, 1H), 5.83 (s, 2H), 3.58 (br s, 4H), 3.50 (br s, 2H), 2.37 (br s, 4H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.27 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.28H.sub.26F.sub.3N.sub.5O.sub.3 537.20; found 536 (MH).sup.. HPLC t.sub.R 1.48 min.

Example 58: (3-(4-(2-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0398] The title compound was obtained as a white solid reacting (2-methoxypyrimidin-5-yl)boronic acid and (3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (prepared as reported for the synthesis of Example 15) in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.89 (br s, 1H), 8.90 (s, 2H), 8.83 (br d, J=1.8 Hz, 1H), 8.48 (br s, 1H), 8.40 (br s, 1H), 8.22 (s, 1H), 7.76 (br d, J=8.3 Hz, 2H), 7.64 (br d, J=8.3 Hz, 2H), 5.79 (s, 2H), 3.90 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.22 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.16F.sub.3N.sub.7O.sub.3 471.13; found 472 (M+H).sup.+. HPLC t.sub.R 1.58 min.

Example 67: (3-(4-(pyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0399] The title compound was obtained as a white solid reacting pyridin-4-ylboronic acid and (3-(4-iodobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (prepared as reported for the synthesis of Example 15) in Step 1. LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.15F.sub.3N.sub.6O.sub.2 440.12; found 439 (MH).sup.. HPLC t.sub.R 1.07 min.

Example 60: (3-(4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

##STR00026##

Step 1: (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Intermediate 10)

[0400] A solution of Example 19 (390 mg, 0.88 mmol) in dioxane (25 mL) was treated with bis(chloranyl)palladium cyclopentyl(diphenyl)phosphane ferrocene (32.8 mg, 0.04 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (246.9 mg, 0.97 mmol) and potassium acetate (260.3 mg, 2.65 mmol). The reaction mixture was refluxed for 18 h. After cooling down, it was quenched with water and extracted with EtOAc. The combined organic phase was washed with brine and dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The title compound was obtained after purification on RP (C18) silica gel (eluting with 10-40% MeCN in H.sub.2O) as a yellow solid (361 mg, 33%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.70 (br s, 1H), 8.18 (br s, 2H), 7.75 (d, J=7.7 Hz, 2H), 7.72 (br d, J=9.2 Hz, 1H), 7.56 (d, J=7.9 Hz, 2H), 7.43 (t, J=8.1 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 5.81 (s, 2H), 1.29 (s, 12H). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.24BF.sub.3N.sub.4O.sub.4 488.18; found 489 (M+H).sup.+. HPLC t.sub.R 2.24 min.

Step 2: (3-(4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 60)

[0401] The title compound was prepared using conditions reported for the synthesis of Example 26 using Intermediate 10 and 5-bromo-4-methylpyrimidine. The title compound was obtained after purification by RP (C18) chromatography (eluting with 10-45% MeCN in H.sub.2O). Fractions containing product were lyophilized to give the title compound as a white solid (16 mg, 34%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (br s, 1H), 9.05 (s, 1H), 8.62 (s, 1H), 8.29 (s, 1H), 8.21 (br s, 1H), 7.72 (d, J=8.3 Hz, 3H), 7.58 (d, J=8.1 Hz, 2H), 7.43 (t, J=7.9 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 5.86 (s, 2H), 2.45 (s, 3H). .sup.13C NMR (101 MHz, DMSO-d.sub.6) 171.5, 162.7, 157.9, 155.9, 155.0, 140.7, 135.5, 132.3, 131.1, 128.7, 128.4, 128.0, 124.6, 121.9, 120.2, 116.2, 112.6, 103.5, 54.4, 21.5. .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.17F.sub.3N.sub.6O.sub.2 454.14; found 455 (M+H).sup.+. HPLC t.sub.R 1.66 min.

[0402] Examples 39, 42, 61, 62, 63, 64, 79, 105 and 106 were synthesized according to the above procedure (Scheme 11) by reacting with the appropriate starting materials.

Example 39: (3-(4-(pyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide

[0403] The title compound was obtained as a white solid reacting 4-bromopyridine in Step 2. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.74 (br s, 2H), 7.92 (br s, 1H), 7.80 (br s, 1H), 7.76 (br d, J=8.1 Hz, 2H), 7.59-7.52 (m, 5H), 7.47 (br s, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.29 (br d, J=8.1 Hz, 1H), 5.57 (s, 2H). .sup.19F NMR (377 MHz, CDCl.sub.3) 62.71 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.16F.sub.3N.sub.5O.sub.2 439.13; found 438 (MH).sup.. HPLC t.sub.R 1.35 min.

Example 42: (3-(4-(pyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide

[0404] The title compound was obtained as a white solid reacting 2-iodopyrazine in Step 2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 9.30 (s, 1H), 8.75 (s, 1H), 8.65 (br d, J=2.4 Hz, 1H), 8.26-8.21 (m, 4H), 7.76-7.71 (m, 3H), 7.44 (t, J=7.9 Hz, 1H), 7.22 (br d, J=7.5 Hz, 1H), 5.88 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.15F.sub.3N.sub.6O.sub.2 440.12; found 439 (MH).sup.. HPLC t.sub.R 1.76 min.

Example 61: (3-(4-(pyridazin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide

[0405] The title compound was obtained as a white solid reacting 4-bromopyridazine in Step 2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 9.67 (s, 1H), 9.31 (br d, J=5.5 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.06-8.02 (m, 3H), 7.78 (br d, J=8.1 Hz, 2H), 7.72 (br d, J=8.1 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.22 (br d, J=7.9 Hz, 1H), 5.88 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.15F.sub.3N.sub.6O.sub.2 440.12; found 439 (MH).sup.. HPLC t.sub.R 1.54 min.

Example 62: (3-(4-(4-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0406] The title compound was obtained as a white solid reacting 5-bromo-4-methoxypyrimidine in Step 2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.66 (s, 1H), 8.74 (s, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 8.14 (br s, 1H), 7.66-7.59 (m, 5H), 7.37 (br t, J=8.1 Hz, 1H), 7.15 (br d, J=7.7 Hz, 1H), 5.77 (s, 2H), 3.90 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.17F.sub.3N.sub.6O.sub.3 470.13; found 469 (MH).sup.. HPLC t.sub.R 1.79 min.

Example 63: (3-(4-(2-methoxypyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0407] The title compound was obtained as a light-yellow solid reacting 4-bromo-2-methoxypyridine in Step 2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.65 (s, 1H), 8.18 (s, 1H), 8.17 (s, 1H), 8.14 (br s, 1H), 7.80 (br d, J=8.3 Hz, 2H), 7.65-7.62 (m, 3H), 7.36 (br t, J=8.0 Hz, 1H), 7.26 (dd, J.sub.1=5.5 Hz, J.sub.2=1.5 Hz, 1H), 7.15 (br d, J=7.7 Hz, 1H), 7.07 (s, 1H), 5.78 (s, 2H), 3.83 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.18F.sub.3N.sub.5O.sub.3 469.14; found 468 (MH).sup.. HPLC t.sub.R 1.98 min.

Example 64: (3-(4-(2-hydroxypyridin-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0408] The title compound was obtained as a white solid reacting 4-bromopyridin-2-ol in Step 2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.71 (br s, 1H), 9.80 (s, 1H), 8.33 (s, 1H), 8.28 (br s, 1H), 7.86 (br d, J=7.9 Hz, 2H), 7.82-7.74 (m, 3H), 7.55-7.49 (m, 2H), 7.30 (br d, J=7.5 Hz, 1H), 6.69 (br s, 1H), 6.59 (d, J=6.8 Hz, 1H), 5.92 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.16F.sub.3N.sub.5O.sub.3 455.12; found 454 (MH).sup.. HPLC t.sub.R 1.47 min.

Example 79: (S)-(3-(1-(4-(4-methylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0409] The title compound was obtained as a white solid reacting (S)-(3-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide and 5-bromo-4-methylpyrimidine in Step 2. LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.19F.sub.3N.sub.6O.sub.2 468.15; found 467 (MH).sup.. HPLC t.sub.R 1.75 min.

Example 105: (3-(4-(1,2-dimethyl-1H-imidazol-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0410] The title compound was obtained as a beige solid reacting 5-bromo-1,2-dimethyl-1H-imidazole in Step 2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.25 (s, 1H), 8.21 (br s, 1H), 7.73-7.64 (m, 3H), 7.52 (br d, J=7.9 Hz, 2H), 7.46-7.42 (m, 1H), 7.23-7.21 (m, 1H), 6.93 (s, 1H), 5.82 (s, 2H), 3.54 (s, 3H), 2.35 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.19F.sub.3N.sub.6O.sub.2 456.15; found 455 (MH).sup.. HPLC t.sub.R 1.31 min.

Example 106: (3-(4-(4-cyanopyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0411] The title compound was obtained as a beige solid reacting 5-bromopyrimidine-4-carbonitrile in Step 2. .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.14F.sub.3N.sub.7O.sub.2 465.12; found 466 (M+H).sup.+. HPLC t.sub.R 1.84 min.

Example 99: (R)-(3-(2-amino-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate

##STR00027## ##STR00028## ##STR00029##

Step 1: Methyl (R)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate (Intermediate 11)

[0412] To a suspension of ()-4-hydroxy-D-phenylglycine (5 g, 29.91 mmol) in methanol (30 mL) at 0 C., thionyl chloride (2.17 mL, 29.91 mmol) was added dropwise. The reaction mixture was stirred at reflux for 18 h, then cooled to rt and used as such. DIPEA (13 mL, 59.8 mmol) was then added dropwise followed by a solution of di-tert-butyl dicarbonate (7.18 g, 32.9 mmol) in methanol (12 mL) added dropwise over 40 min. The reaction mixture was stirred at rt overnight. Solvent was reduced to half the original volume and the resulting solution was poured into water (100 mL), forming a white precipitate that was collected by filtration. The crude was dried under vacuum pump overnight to afford the title compound as a white solid (7.15 g, 85%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.49 (s, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.61 (d, J=7.8 Hz, 1H), 6.71 (d, J=8.4 Hz, 2H), 5.06 (d, J=7.8 Hz, 1H), 3.59 (s, 3H), 1.38 (s, 9H). LCMS (ES.sup.+) m/z calculated for C.sub.14H.sub.19NO.sub.5 281.13; found 282 (M+H).sup.+. HPLC t.sub.R 1.62 min.

Step 2: tert-Butyl (R)-(2-hydroxy-1-(4-hydroxyphenyl)ethyl)carbamate (Intermediate 12)

[0413] A solution of Intermediate 11 (1.2 g, 4.27 mmol) in anhydrous THE (30 mL) was cooled to 5 C. 1 M Lithium aluminium hydride in THE (12.8 mL, 12.8 mmol) was added by dropwise slowly over 40 min, maintaining an internal reaction temperature of less than 15 C. The stirring was continued for 30 min, and then the reaction was carefully quenched with NH.sub.4C.sub.1 sat. sol. (2 mL) over 45 min, followed by 0.3 N HCl (2 mL). The resulting suspension was then filtered and rinsed with ethyl acetate, 1 N HCl was added to the filtrate to adjust the aqueous layer to pH=1. The organic extract was rinsed with water, brine, and dried over MgSO.sub.4. The aqueous phase was extracted additionally with EtOAc and the organic phase was treated as previously. The organic layers were combined and concentrated to give the title compound as a yellowish solid (927 mg, 95%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.21 (s, 1H), 7.06 (m, 3H), 6.67 (d, J=8.4 Hz, 2H), 4.68 (t, J=5.7 Hz, 1H), 4.41 (q, J=7.2 Hz, 1H), 3.42 (t, J=6.3 Hz, 2H), 1.36 (s, 9H). LCMS (ES.sup.+) m/z calculated for C.sub.13H.sub.19NO.sub.4 253.13; found 254 (M+H).sup.+. HPLC t.sub.R 1.26 min.

Step 3: (R)-4-(4-Hydroxyphenyl)oxazolidin-2-one (Intermediate 13)

[0414] A solution Intermediate 12 (927 mg, 3.66 mmol) in THE (11 mL) was cooled to 0 C., thionyl chloride (0.29 mL, 4.03 mmol) was added dropwise. After the addition the reaction mixture was stirred at rt overnight. Then, the reaction mixture was partially concentrated under reduced pressure. The residual slurry was stirred at rt and MTBE (10 mL) was added. The product started to crystallize out. The slurry was stirred for 15 min and filtered. The filter cake was washed with MTBE (55 mL). The solid was dried to afford the title compound as a red-brown powder (0.63 g, 95%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.48 (s, 1H), 8.05 (s, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 4.81 (t, J=8 Hz, 1H), 4.59 (t, J=8 Hz, 1H), 3.93 (dd, J.sub.1=8 Hz, J.sub.2=12 Hz, 1H). LCMS (ES.sup.+) m/z calculated for C.sub.9H.sub.9NO.sub.3 179.06; found 180 (M+H).sup.+. HPLC t.sub.R 0.81 min.

Step 4: (R)-4-(2-Oxooxazolidin-4-yl)phenyl trifluoromethanesulfonate (Intermediate 14)

[0415] To a slurry of Intermediate 13 (676 mg, 3.77 mmol) in acetonitrile (7.5 mL) was added dry pyridine (0.85 mL, 11.32 mmol). The mixture was stirred under a nitrogen atmosphere and trifluoromethanesulfonic anhydride (0.76 mL, 4.53 mmol) was added slowly maintaining the reaction temperature at 20 C. The reaction mixture was stirred at the same temperature for 30 min, followed by 30 min at rt. The solvent was removed under reduced pressure and the resulting oil was taken with DCM. The organic phase was washed with sat. sol. NaHCO.sub.3, brine and dried over Na.sub.2SO.sub.4, then concentrated under reduced pressure to give a dark red oil. The crude product was purified by chromatography on silica gel (eluent gradient from 100% DCM to 15% DCM/EtOAc) to yield the title compound (0.741 mg, 68%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8.24 (s, 1H), 7.56 (s, 4H), 5.03 (dd, J=8.2, 6.9 Hz, 1H), 4.69 (t, J=8.7 Hz, 1H), 4.04 (dd, J=8.6, 6.3 Hz, 1H). LCMS (ES.sup.+) m/z calculated for C.sub.10H.sub.8F.sub.3NO.sub.5S 311.01; found 312 (M+H).sup.+. HPLC t.sub.R 1.70 min.

Step 5: (R)-4-(4-(3,5-Dimethylisoxazol-4-yl)phenyl)oxazolidin-2-one (Intermediate 15)

[0416] A pressure vessel was charged with Intermediate 14 (220.5 mg, 0.71 mmol) and (3,5-dimethyl-1,2-oxazol-4-yl)boronic acid (149.8 mg, 1.06 mmol) in NMP (1 mL). Then, triphenylphosphane (29.7 mg, 0.11 mmol), palladium(II) acetate (0.69 mL, 0.02 mmol) and DIPEA (0.1 mL, 0.74 mmol) were added. The reaction mixture was refluxed in a closed vessel at 90 C. for 30 min. The cooled reaction mixture was diluted with DCM and the organic layer was washed with water, 5% citric acid, 3 N HCl and brine. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude was purified by chromatography on silica gel (eluent DCM/MeOH from 100% DCM to 9/1 DCM/MeOH) to give the title compound as a yellow solid (278 mg) that was used as such in the next synthetic step. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8.21 (s, 1H), 7.49-7.41 (m, 4H), 5.00 (dd, J=8.4, 6.6 Hz, 1H), 4.70 (t, J=8.6 Hz, 1H), 4.08 (dd, J=8.5, 6.4 Hz, 1H), 2.40 (s, 3H), 2.23 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.14H.sub.14N.sub.2O.sub.3 258.10; found 259 (M+H).sup.+. HPLC t.sub.R 1.41 min.

Step 6: tert-butyl (R)-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-hydroxyethyl)carbamate (Intermediate 16)

[0417] A mixture of Intermediate 15 (278 mg, 1.08 mmol), di-tert-butyl dicarbonate (470 mg, 2.15 mmol) and DMAP (39.5 mg, 0.32 mmol) in DCM/THF (1:1) (4 mL) was stirred at rt for 30 min. The reaction mixture was diluted with DCM (30 mL) and the organic phase was washed with water, brine and dried over Na.sub.2SO.sub.4. The organic phase was concentrated under reduced pressure to yield crude tert-butyl (R)-4-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-oxooxazolidine-3-carboxylate as a light-yellow foam (357 mg). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.22N.sub.2O.sub.5 358.15, found 359 (M+H).sup.+. HPLC t.sub.R 1.86 min. A mixture of this crude and potassium carbonate (298 mg, 2.16 mmol) in MeOH (3 mL) was sonicated for 5 min and then stirred at rt for 1 h. The reaction mixture was diluted with EtOAc and washed with small amounts of water. The combined aqueous layer was extracted with EtOAc. The organic layers were combined and washed with brine and evaporated to give the title compound (327 mg, 74% over three steps). .sup.1H NMR (300 MHz, DMSO-d.sub.6) 7.50-7.18 (m, 5H), 4.83 (br s, 1H), 4.58 (m, 1H), 3.53 (br d, J=3.4 Hz, 2H), 2.40 (s, 3H), 2.23 (s, 3H), 1.46-1.30 (m, 9H). LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.24N.sub.2O.sub.4 332.17; found 333 (M+H).sup.+. HPLC t.sub.R 1.72 min.

Step 7: (R)-2-((tert-Butoxycarbonyl)amino)-2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl methanesulfonate (Intermediate 17)

[0418] To a solution of Intermediate 16 (327 mg, 0.89 mmol) and TEA (0.18 mL, 1.33 mmol) in DCM (3 mL) at 0 C. was added dropwise a solution of methanesulfonyl chloride (0.082 mL. 1.07 mmol) in DCM (1 mL) over 5 min and then the mixture was stirred for 30 min at 0 C. The reaction mixture was washed with water, sat. sol. KHSO.sub.4 and brine. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to the title compound (341 mg, 93%) that was used as such in the next step. LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.26N.sub.2O.sub.6S 410.15; found 411 (M+H).sup.+. HPLC t.sub.R 1.93 min.

Step 8: tert-butyl (R)-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)carbamate (Intermediate 18)

[0419] In a flask were added Intermediate 17 (340 mg, 0.828 mmol) in DMF (0.25 M), potassium 1,3-dioxoisoindolin-2-ide (153 mg, 0.83 mmol) and TBAB (5.3 mg, 0.017 mmol) were added. The reaction was stirred at 60 C. for 4 h. Then water was added (10 mL) and the precipitated product was filtered, washed additionally with water and dried under vacuum to give the title compound as a light orange powder (264 mg, 69%). The crude was used as such in the next synthetic step. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 7.98-7.83 (m, 5H), 7.56-7.37 (m, 4H), 5.16-4.97 (m, 1H), 4.07-3.77 (m, 2H), 2.43 (s, 3H), 2.25 (s, 3H), 1.27 (s, 9H). LCMS (ES.sup.+) m/z calculated for C.sub.26H.sub.27N.sub.3O.sub.5 461.20; found 462 (M+H).sup.+. HPLC t.sub.R 2.16 min.

Step 9: (R)-2-(2-amino-2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)isoindoline-1,3-dione hydrochloride (Intermediate 19)

[0420] Intermediate 18 (260 mg, 0.572 mmol) was treated directly at rt with 4 N HCl in dioxane (1.2 mL). The reaction mixture was stirred at rt overnight. The resulting suspension was diluted with DCM (10 mL), sonicated, and filtered to give the title compound as light pink powder (108 mg, 47%). The crude was used as such in the next step. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8.69 (br s, 3H), 8.02-7.80 (m, 4H), 7.65 (d, J=8.3 Hz, 2H), 7.48 (d, J=8.3 Hz, 2H), 4.67 (br dd, J=7.9, 5.7 Hz, 1H), 4.23-4.04 (m, 1H), 4.02-3.87 (m, 1H), 2.39 (s, 3H), 2.21 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.19N.sub.3O.sub.3 361.14; found 362 (M+H).sup.+. HPLC t.sub.R 1.26 min.

Step 10: (R)-2-((1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)amino)acetonitrile (Intermediate 20)

[0421] To a suspension of Intermediate 19 (108 mg, 1.08 mmol) and DIPEA (0.18 mL, 1.03 mmol) in MeCN (2 mL), 2-bromoacetonitrile (0.038 mL, 0.54 mmol) was added. The reaction mixture was heated at 60 C. for 3 h and then it was concentrated under reduced pressure. The obtained oil was treated with small amount of water and extracted with EtOAc. The combined organic phase was washed additionally with water (33 mL) and brine, then dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain the title compound (117 mg, 100%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) 7.91-7.80 (m, 4H), 7.47-7.38 (m, 2H), 7.38-7.26 (m, 2H), 4.27-4.11 (m, 1H), 3.94-3.78 (m, 1H), 3.75-3.55 (m, 2H), 3.45-3.36 (m, 1H), 3.27-3.17 (m, 1H), 2.37 (s, 3H), 2.19 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.20N.sub.4O.sub.3 400.15; found 401 (M+H).sup.+. HPLC t.sub.R 1.85 min.

Step 11: (R)-5-amino-3-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 21)

[0422] Intermediate 20 (0.12 g, 0.29 mmol) was dissolved in DMSO (0.2 mL) and isopentyl nitrite (0.12 mL, 0.88 mmol) as added at rt. The reaction mixture was stirred at rt for 4 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give (R)N-(cyanomethyl)-N-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)nitrous amide as a yellow oil that was used directly in the next synthetic step. LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.19N.sub.5O 429.14, found 430 (M+H).sup.+. HPLC t.sub.R 1.99 min. The crude was treated directly with 4 N HCl (1.2 mL), allowed without stirring at rt for 4 h. The mixture was concentrated under reduced pressure and stripped several times with DCM and diethyl ether until a solid product was obtained. The crude was triturated with diethyl ether to give the title compound as a beige powder (125 mg, 91%) that was used as such in the next step. LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.20N.sub.5O.sub.4 430.15; found 430 (M+H).sup.+. HPLC t.sub.R 1.41 min.

Step 12: (R)-(3-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Intermediate 22)

[0423] A cold suspension (ice bath) of Intermediate 21 (40.99 mg, 0.08 mmol) in pyridine (1.5 mL) was treated directly with 1-isocyanato-3-(trifluoromethyl)benzene (0.05 mL, 0.39 mmol). After 10 min the reaction was quenched at 0 C. with water and the suspension was extracted with diethyl ether.

[0424] The organic phase was washed additionally with water, sat. sol. KHSO.sub.4 and brine, then was dried over Na.sub.2SO.sub.4, concentrated and stripped with DCM under reduced pressure to give the title compound as a solid (138 mg, 0.22 mmol) that was used as such in the next synthetic step. LCMS (ES.sup.+) m/z calculated for C.sub.31H.sub.23F.sub.3N.sub.6O.sub.5 616.17; found 617 (M+H).sup.+. HPLC t.sub.R 2.21 min.

Step 13: (R)-(3-(2-amino-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate (Example 99)

[0425] A solution of Intermediate 22 (0.086 g, 0.14 mmol) in ethanol (6 mL) was treated with hydrazine hydrate (0.14 mL, 2.8 mmol) at rt. The reaction was stirred at 65 C. for 1 h. The reaction was cooled to rt and a white precipitate was formed. The reaction was diluted with ethanol (5 mL) and the precipitate was filtered. The solution was concentrated under reduced pressure to give a light-yellow solid. The title compound was obtained after purification by chromatography on silica gel column using water DCM/MeOH 1% eluents. Fractions containing product were dried under reduced pressure and then lyophilized to give the title compound as a white solid (17.4 mg, 23%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.77 (s, 1H), 8.43 (s, 1H), 8.36-8.25 (m, 1H), 7.81-7.70 (m, 3H), 7.61-7.44 (m, 3H), 7.27 (d, J=7.7 Hz, 1H), 5.94 (dd, J=9.9, 4.6 Hz, 1H), 3.79 (dd, J=13.8, 10.0 Hz, 1H), 3.46-3.39 (m, 1H), 2.46 (s, 3H), 2.29 (s, 3H), 1.96 (br s, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.21F.sub.3N.sub.6O.sub.3 486.17; found 487 (M+H).sup.+. HPLC t.sub.R 2.73 min.

[0426] Examples 49, 54, 65, 66, 102 and 116 were synthesized according to the above procedure (Scheme 12) by reacting with the appropriate starting materials.

Example 49: (R)-(3-(1-amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate

[0427] The title compound was obtained as a white solid starting from Boc-D-Phenylalaninol following Scheme 12 (step 7-13). .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.76 (s, 1H), 8.58 (s, 1H), 8.16 (br s, 3H), 7.69 (br d, J=8.4 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.39-7.12 (m, 7H), 5.27-5.06 (m, 1H), 3.82-3.64 (m, 1H), 3.58-3.31 (m, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.18F.sub.3N.sub.5O.sub.2 405.14; found 406 (M+H).sup.+. HPLC t.sub.R 2.66 min.

Example 54: (S)-(3-(1-amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate

[0428] The title compound was obtained as a white solid starting from Boc-L-Phenylalaninol following Scheme 12 (step 7-13). .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.76 (s, 1H), 8.58 (s, 1H), 8.16 (br s, 3H), 7.69 (br d, J=8.4 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.37-7.10 (m, 7H), 5.27-5.06 (m, 1H), 3.82-3.64 (m, 1H), 3.56-3.28 (m, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.18F.sub.3N.sub.5O.sub.2 405.14; found 406 (M+H).sup.+. HPLC t.sub.R 2.67 min.

Example 65: (S)-(3-(1-([1,1-biphenyl]-4-yl)-3-aminopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate

[0429] The title compound was obtained as a white solid starting from (S)-tert-butyl (1-([1,1-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate following Scheme 12 (step 7-13). .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.21 (br s, 1H), 8.92 (br s, 1H), 8.26 (s, 1H), 8.21-8.05 (m, 4H), 7.76-7.57 (m, 5H), 7.53-7.40 (m, 3H), 7.38-7.25 (m, 4H), 5.37 (br d, J=6.6 Hz, 1H), 3.92-3.63 (m, 1H), 3.63-3.35 (m, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.25H.sub.22F.sub.3N.sub.5O.sub.2 481.17. found 482 (M+H).sup.+. HPLC t.sub.R 3.07 min.

Example 66: (R)-(3-(1-([1,1-biphenyl]-4-yl)-3-aminopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0430] The title compound was obtained as a white solid starting from (R)-tert-butyl (1-([1,1-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate following Scheme 12 (step 7-13). .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.23 (s, 1H), 8.94 (s, 1H), 8.26 (s, 1H), 8.20-8.04 (m, 3H), 7.74-7.58 (m, 5H), 7.55-7.39 (m, 3H), 7.37-7.26 (m, 4H), 5.38 (q, J=6.9 Hz, 1H), 3.91-3.66 (m, 1H), 3.61-3.32 (m, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.25H.sub.22F.sub.3N.sub.5O.sub.2 481.17; found 482 (M+H).sup.+. HPLC t.sub.R 3.08 min.

Example 102: (R)-(3-(2-amino-1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate

[0431] The title compound was obtained as a white solid following Scheme 12 and using pyrimidin-5-ylboronic acid in step 5. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.71 (s, 1H), 9.22 (s, 1H), 9.16 (s, 2H), 8.38 (s, 1H), 8.30-8.19 (m, 1H), 7.91 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 2H), 7.72-7.63 (m, 1H), 7.43 (br t, J=7.9 Hz, 1H), 7.22 (br d, J=8.2 Hz, 1H), 5.92 (dd, J=9.72, 4.58 Hz, 1H), 3.83-3.66 (m, 1H), 3.42-3.36 (m, 1H). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.18F.sub.3N.sub.7O.sub.2 469.43; found 470 (M+H).sup.+. HPLC t.sub.R 3.08 min.

Example 116: (S)-(3-(2-amino-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide formate

[0432] The title compound was obtained as a white solid starting from 4-hydroxy-L-phenylglycine and following Scheme 12. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.77 (s, 1H), 8.43 (s, 1H), 8.36-8.25 (m, 1H), 7.81-7.70 (m, 3H), 7.61-7.44 (m, 3H), 7.27 (d, J=7.7 Hz, 1H), 5.94 (dd, J=9.9, 4.6 Hz, 1H), 3.79 (dd, J=13.8, 10.0 Hz, 1H), 3.46-3.39 (m, 1H), 2.46 (s, 3H), 2.29 (s, 3H), 1.96 (br s, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.21F.sub.3N.sub.6O.sub.3 486.16; found 487 (M+H).sup.+. HPLC t.sub.R 2.73 min.

Example 88: (3-(4-(3,5-Dimethylisoxazol-4-yl)-3-methylbenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

##STR00030##

[0433] A solution of (3-(4-bromo-3-methylbenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Intermediate 23) (prepared as described in the synthesis of Example 6) (30.0 mg, 0.07 mmol), tripotassium phosphate (42.0 mg, 0.20 mmol), bis(chloranyl)palladium cyclopentyl(diphenyl)phosphane ferrocene (5.5 mg, 0.01 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (13.0 mg, 0.09 mmol) in a mixture of H.sub.2O/dioxane (1:10) (1.1 mL) was heated at 75 C. for 16 h. The reaction mixture was cooled at rt and filtered on a pad of solca flock. The excess of solvent was removed under reduced pressure to get a residue which was purified by chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to give the title compound (5 mg, 16%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (br s, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 7.71 (br d, J=8.3 Hz, 1H), 7.54 (s, 1H), 7.47-7.42 (m, 2H), 7.27-7.21 (m, 2H), 5.79 (s, 2H), 2.20 (s, 3H), 2.12 (s, 3H), 2.01 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.20F.sub.3N.sub.5O.sub.3 471.15; found 470 (MH).sup.. HPLC t.sub.R 2.03 min.

[0434] Examples 87, 100, 103, 104, 108, 109, 110, 117, 119, 120, 121 and 124 were synthesized according to the above procedure (Scheme 13) by reacting with the appropriate starting materials.

Example 87: (3-(3-methyl-4-(pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0435] The title compound was obtained as a white solid reacting pyrimidin-5-ylboronic acid in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 9.23 (s, 1H), 8.89 (s, 2H), 8.24 (s, 1H), 8.21 (br s, 1H), 7.72 (br d, J=8.6 Hz, 1H), 7.59 (s, 1H), 7.55 (br d, J=7.7 Hz, 1H), 7.46-7.42 (m, 2H), 7.23 (br d, J=7.7 Hz, 1H), 5.82 (s, 2H), 2.30 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.17F.sub.3N.sub.6O.sub.2 454.14; found 453 (MH).sup.. HPLC t.sub.R 1.78 min.

Example 100: (3-((5-(pyrimidin-5-yl)thiophen-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0436] The title compound was obtained as a white solid reacting pyrimidin-5-ylboronic acid and (3-((5-bromothiophen-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.49 (br s, 1H), 8.91 (s, 1H), 8.89 (s, 2H), 7.98 (s, 2H), 7.82 (br s, 1H), 7.66 (s, 1H), 7.49 (br d, J=7.9 Hz, 1H), 7.20 (br t, J=7.7 Hz, 1H), 6.99 (br d, J=7.2 Hz, 1H), 5.61 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.13F.sub.3N.sub.6O.sub.2S 446.08; found 445 (MH).sup.. HPLC t.sub.R 1.65 min.

Example 103: (3-((6-(pyrimidin-5-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0437] The title compound was obtained as a pale yellow solid reacting pyrimidin-5-ylboronic acid and (3-((6-bromopyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (br s, 1H), 9.47 (s, 2H), 9.28 (s, 1H), 8.97 (br s, 1H), 8.33 (br s, 1H), 8.26-8.19 (m, 3H), 7.72 (br d, J=8.3 Hz, 1H), 7.44 (br t, J=7.9 Hz, 1H), 7.22 (br d, J=7.7 Hz, 1H), 5.93 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.14F.sub.3N.sub.7O.sub.2 441.12; found 440 (MH).sup.. HPLC t.sub.R 1.51 min.

Example 104: (3-((6-(3,5-dimethylisoxazol-4-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0438] The title compound was obtained as a white solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid and (3-((6-bromopyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide (prepared as reported in the synthesis of Example 6) in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.89 (s, 1H), 8.34 (s, 1H), 8.22 (br s, 1H), 8.10 (br d, J=8.3 Hz, 1H), 7.72 (br d, J=8.6 Hz, 1H), 7.66 (br d, J=8.1 Hz, 1H), 7.44 (br t, J=7.9 Hz, 1H), 7.23 (br d, J=7.9 Hz, 1H), 5.88 (s, 2H), 2.58 (s, 3H), 2.39 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.17F.sub.3N.sub.6O.sub.3 458.13; found 457 (MH).sup.. HPLC t.sub.R 1.76 min.

Example 108: (3-((5-(pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0439] The title compound was obtained as a white solid reacting pyrimidin-5-ylboronic acid and (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl) amide (prepared as reported in the synthesis of Example 6) in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (br s, 1H), 9.26 (br s, 1H), 9.24 (br s, 2H), 9.06 (br s, 1H), 8.39 (dd, J.sub.1=8.0 Hz, J.sub.2=2.1 Hz, 1H), 8.24 (s, 1H), 8.20 (br s, 1H), 7.84 (br d, J=8.1 Hz, 1H), 7.74 (br d, J=7.9 Hz, 1H), 7.44 (br t, J=8.0 Hz, 1H), 7.22 (br d, J=7.5 Hz, 1H), 6.03 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.14F.sub.3N.sub.7O.sub.2 441.12; found 440 (MH).sup.. HPLC t.sub.R 1.49 min.

Example 109: (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0440] The title compound was obtained as a white solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid and (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide (prepared as reported in the synthesis of Example 6) in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (br s, 1H), 8.67 (br s, 1H), 8.25 (s, 1H), 8.21 (br s, 1H), 8.00 (dd, J=8.0 Hz, J.sub.2=2.1 Hz, 1H), 7.78-7.73 (m, 2H), 7.44 (br t, J=8.0 Hz, 1H), 7.22 (br d, J=7.7 Hz, 1H), 6.00 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.17F.sub.3N.sub.6O.sub.3 458.13; found 457 (MH).sup.. HPLC t.sub.R 1.76 min.

Example 110: (3-((4-(4-methylpyrimidin-5-yl)thiophen-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0441] The title compound was obtained as a white solid reacting 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine and (3-((4-bromothiophen-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.66 (s, 1H), 8.95 (s, 1H), 8.65 (s, 1H), 8.19 (s, 1H), 8.13 (br s, 1H), 7.89 (d, J=1.3 Hz, 1H), 7.68 (s, 1H), 7.65 (br s, 1H), 7.37 (br t, J=7.9 Hz, 1H), 7.16 (br d, J=7.7 Hz, 1H), 6.04 (s, 2H), 2.48 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.15F.sub.3N.sub.6O.sub.2S 460.09; found 459 (MH).sup.. HPLC t.sub.R 1.66 min.

Example 117: (3-((6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0442] The title compound was obtained as a white solid reacting tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and (3-((6-bromopyridin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) in Step 1, crude material from Step 1 was treated with HCl (4.0 M in dioxane) to get the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.74 (d, J=1.8 Hz, 1H), 8.64 (br s, 1H), 8.43 (br s, 2H), 8.27 (s, 1H), 8.22 (br s, 1H), 8.13 (s, 1H), 8.01-7.99 (m, 1H), 7.79 (br d, J=8.1 Hz, 1H), 7.71 (br d, J=8.6 Hz, 1H), 7.44 (br t, J=8.2 Hz, 1H), 7.22 (br d, J=8.1 Hz, 1H), 5.82 (s, 2H), 4.59-4.52 (m, 1H), 3.46-3.40 (m, 2H), 3.14-3.06 (m, 2H), 2.29-2.22 (m, 2H), 2.19-2.11 (m, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.24H.sub.23F.sub.3N.sub.8O.sub.2 512.19; found 511 (MH).sup.. HPLC t.sub.R 1.28 min.

Example 119: (3-((5-(isoindolin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0443] The title compound was obtained as a white solid reacting tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate and (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) in Step 1; crude material from Step 1 was treated with HCl (4 N in dioxane) to get the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.75 (br s, 1H), 9.47 (br s, 2H), 8.76 (br d, J=1.8 Hz, 1H), 8.26 (s, 1H), 8.22 (br s, 1H), 8.09 (dd, J.sub.1=8.1 Hz, J.sub.2=2.4 Hz, 1H), 7.81 (br d, J=7.9 Hz, 1H), 7.73 (br d, J=7.7 Hz, 1H), 7.56-7.50 (br m, 3H), 7.45 (br t, J=8.0 Hz, 1H), 7.23 (br d, J=7.5 Hz, 1H), 6.03 (s, 2H), 4.68-4.63 (m, 2H), 4.61-4.58 (m, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.24H.sub.19F.sub.3N.sub.6O.sub.2 480.15; found 479 (MH).sup.. HPLC t.sub.R 1.28 min.

Example 120: (3-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0444] The title compound was obtained as a white solid reacting tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) in Step 1, crude material from Step 1 was treated with HCl (4.0 N in dioxane) to get the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.90 (br d, J=1.8 Hz, 1H), 8.64 (br s, 1H), 8.39 (br s, 2H), 8.20 (br s, 1H), 8.17 (s, 1H), 8.12 (dd, J=8.1 Hz, J.sub.2=2.2 Hz, 1H), 8.09 (s, 1H), 7.72 (br d, J=8.1 Hz, 1H), 7.67 (br d, J=8.1 Hz, 1H), 7.44 (br t, J=8.0 Hz, 1H), 7.22 (br d, J=7.5 Hz, 1H), 5.91 (s, 2H), 4.57-4.50 (m, 1H), 3.75-3.69 (m, 1H), 3.46-3.39 (m, 2H), 3.15-3.06 (m, 2H), 2.27-2.22 (m, 2H), 2.17-2.10 (m, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.27 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.24H.sub.23F.sub.3N.sub.8O.sub.2 512.19; found 511 (MH).sup.. HPLC t.sub.R 1.20 min.

Example 121: (3-((5-(2-(aminomethyl)phenyl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0445] The title compound was obtained as a white solid reacting tert-butyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate and (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) in Step 1. crude material from Step 1 was treated with HCl (4.0 M in dioxane) to get the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.75 (s, 1H), 8.63 (br d, J=1.8 Hz, 1H), 8.26 (s, 1H), 8.22 (br s, 1H), 8.12 (br s, 3H), 7.98 (dd, J.sub.1=8.0 Hz, J.sub.2=2.3 Hz, 1H), 7.81-7.72 (m, 2H), 7.66 (br d, J=7.5 Hz, 1H), 7.59-7.50 (m, 2H), 7.45 (br t, J=8.0 Hz, 1H), 7.40 (br d, J=7.7 Hz, 1H), 7.23 (br d, J=7.2 Hz, 1H), 6.03 (s, 2H), 4.00-3.96 (m, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.19F.sub.3N.sub.6O.sub.2 468.15; found 467 (MH).sup.. HPLC t.sub.R 1.30 min.

Example 124: (3-((5-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0446] The title compound was obtained as a yellow solid reacting tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate and (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 6) in Step 1, crude material from Step 1 was treated with HCl (4.0 M in dioxane) to get the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (s, 1H), 9.58 (br s, 2H), 8.71 (br d, J=2.0 Hz, 1H), 8.20 (br s, 2H), 8.07 (s, 1H), 7.99 (dd, J.sub.1=8.1 Hz, J.sub.2=2.4 Hz, 1H), 7.75-7.71 (m, 2H), 7.44 (br t, J=7.9 Hz, 1H), 7.23 (br d, J=7.7 Hz, 1H), 5.96 (s, 2H), 4.72 (br s, 2H), 4.39 (br t, J=5.7 Hz, 2H), 3.71 (br t, J=5.6 Hz, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.19F.sub.3N.sub.8O.sub.2 484.16; found 483 (MH).sup.. HPLC t.sub.R 1.13 min.

Example 90: (3-(4-(2-Methoxy-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

##STR00031##

[0447] A solution of Intermediate 10 (30.0 mg, 0.07 mmol), tripotassium phosphate (42.0 mg, 0.20 mmol), bis(chloranyl)palladium cyclopentyl(diphenyl)phosphane ferrocene (5.5 mg, 0.01 mmol) and 5-bromo-2-methoxy-4-methylpyrimidine (26.8 mg, 0.13 mmol) in a mixture of H.sub.2O/dioxane (1:10) (1.1 mL) was heated at 75 C. for 40 min. The reaction mixture was cooled at rt and filtered on a pad of solca flock. The excess of solvent was removed under reduced pressure to get a residue which was purified by chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to give the title compound as a white solid (14 mg, 43%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.84 (br s, 1H), 8.53 (s, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 7.84-7.76 (m, 3H), 7.64 (d, J=7.9 Hz, 2H), 7.55 (br t, J=8.0 Hz, 1H), 7.33 (br d, J=7.5 Hz, 1H), 5.96 (s, 2H), 4.05 (s, 3H), 2.50 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.19F.sub.3N.sub.6O.sub.3 484.15; found 483 (MH).sup.. HPLC t.sub.R 1.98 min.

[0448] Examples 80, 81, 82, 83, 84, 85, 86, 89, 91, 92, 98, 101, 107, 111, and 112 were synthesized according to the above procedure (Scheme 14) by reacting with the appropriate starting materials.

Example 80: ((3-(trifluoromethyl)phenyl)carbamoyl)(3-(4-(4-(trifluoromethyl)pyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0449] The title compound was obtained as a white solid reacting 5-bromo-4-(trifluoromethyl)pyrimidine (using XPhos Pd G4 in THF) in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (s, 1H), 9.48 (s, 1H), 9.09 (s, 1H), 8.30 (s, 1H), 8.22 (br s, 1H), 7.73 (br d, J=8.1 Hz, 3H), 7.56 (br d, J=8.1 Hz, 2H), 7.44 (t, J=8.2 Hz, 1H), 7.23 (br d, J=7.9 Hz, 1H), 5.89 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F), 62.35 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.14F.sub.6N.sub.6O.sub.2 508.11; found 509 (M+H).sup.+. HPLC t.sub.R 2.42 min.

Example 81: (3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0450] The title compound was obtained as a beige solid reacting 5-bromo-4,6-dimethylpyrimidine (using XPhos Pd G4 in THF) in Step 1, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (br s, 1H), 8.89 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.73-7.70 (br m, 3H), 7.46-7.41 (m, 3H), 7.23 (br d, J=7.7 Hz, 1H), 5.87 (s, 2H), 2.18 (s, 6H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.19F.sub.3N.sub.6O.sub.2 468.15; found 467 (MH).sup.. HPLC t.sub.R 1.69 min.

Example 82: (R)-(3-(1-(4-(4-methylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0451] The title compound was obtained as a white solid reacting 5-bromo-4-methylpyrimidine and (R)-(3-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 60 starting from (R)-(3-(1-(4-bromophenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide prepared as reported in Scheme 4), XPhos Pd G4 in THE was used in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.66 (s, 1H), 8.99 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 8.18 (br s, 1H), 7.69 (br d, J=8.1 Hz, 2H), 7.62 (br d, J=7.8 Hz, 1H), 7.53 (br d, J=8.3 Hz, 2H), 7.37 (br t, J=8.0 Hz, 1H), 7.16 (br d, J=7.3 Hz, 1H), 6.21-6.16 (m, 1H), 2.39 (s, 3H), 2.00 (br d, J=7.5 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.19F.sub.3N.sub.6O.sub.2 468.15; found 467 (MH).sup.. HPLC t.sub.R 1.76 min.

Example 83: (3-(3-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0452] The title compound was obtained as a white solid reacting 5-bromo-4-methylpyrimidine and (3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 60 starting from Example 46), XPhos Pd G4 in THF was used in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 9.07 (s, 1H), 8.64 (s, 1H), 8.28 (s, 1H), 8.21 (br s, 1H), 7.75-7.58 (m, 5H), 7.44 (br t, J=8.1 Hz, 1H), 7.22 (br d, J=7.7 Hz, 1H), 5.85 (s, 2H), 2.47 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.17F.sub.3N.sub.6O.sub.2 454.14; found 453 (MH).sup.. HPLC t.sub.R 1.72 min.

Example 84: (3-(3-(4-methoxypyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0453] The title compound was obtained as a white solid reacting 5-bromo-4-methoxypyrimidine and (3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 60 starting from Example 46). XPhos Pd G4 in THF was used in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.82 (s, 1H), 8.63 (s, 1H), 8.25 (s, 1H), 8.21 (br s, 1H), 7.87 (s, 1H), 7.72-7.69 (m, 2H), 7.64-7.55 (m, 2H), 7.43 (br t, J=7.9 Hz, 1H), 7.22 (br d, J=7.7 Hz, 1H), 5.84 (s, 2H), 3.99 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.30 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.17F.sub.3N.sub.6O.sub.3 470.13; found 469 (MH).sup.. HPLC t.sub.R 1.82 min.

Example 85: (3-(4-(4-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0454] The title compound was obtained as a white solid reacting 3-bromo-4-methylpyridine, XPhos Pd G4 in THE was used in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (s, 1H), 8.45 (br d, J=5.0 Hz, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 8.22 (br s, 1H), 7.73 (br d, J=8.1 Hz, 1H), 7.69 (br d, J=8.3 Hz, 2H), 7.52 (br d, J=8.3 Hz, 2H), 7.44 (br t, J=8.1 Hz, 1H), 7.35 (br d, J=5.0 Hz, 1H), 7.22 (br d, J=7.7 Hz, 1H), 5.86 (s, 2H), 2.27 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.18F.sub.3N.sub.5O.sub.2 453.14; found 452 (MH).sup.. HPLC t.sub.R 1.37 min.

Example 86: (3-(4-(3-methylpyrazin-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0455] The title compound was obtained as a beige solid reacting 2-bromo-3-methylpyrazine; XPhos Pd G4 in THE was used in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (s, 1H), 8.58-8.55 (m, 2H), 8.30 (s, 1H), 8.21 (br s, 1H), 7.76-7.69 (m, 5H), 7.44 (br t, J=7.9 Hz, 1H), 7.22 (br d, J=7.7 Hz, 1H), 5.88 (s, 2H), 2.57 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.17F.sub.3N.sub.6O.sub.2 454.14; found 453 (MH).sup.. HPLC t.sub.R 1.76 min.

Example 89: (3-(4-(2-(2-hydroxyethoxy)-4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0456] The title compound was obtained as a yellow solid reacting 2-((5-bromo-4-methylpyrimidin-2-yl)oxy)ethan-1-ol in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.65 (s, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 8.14 (br s, 1H), 7.65-7.60 (m, 3H), 7.46 (br d, J=8.1 Hz, 2H), 7.37 (br t, J=7.8 Hz, 1H), 7.15 (br d, J=7.2 Hz, 1H), 5.78 (s, 2H), 4.84-4.80 (m, 1H), 4.29-4.26 (m, 2H), 3.68-3.64 (m, 2H), 2.31 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.24H.sub.21F.sub.3N.sub.6O.sub.4 514.16; found 513 (MH).sup.. HPLC t.sub.R 1.68 min.

Example 91: (3-(4-(4-cyclopropylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0457] The title compound was obtained as a white solid reacting 5-bromo-4-cyclopropylpyrimidine; XPhos Pd G4 in THE was used in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.99 (s, 1H), 8.55 (s, 1H), 8.30 (s, 1H), 8.22 (br s, 1H), 7.75-7.71 (m, 3H), 7.62 (br d, J=8.1 Hz, 2H), 7.44 (br t, J=7.9 Hz, 1H), 7.23 (br d, J=7.9 Hz, 1H), 5.88 (s, 2H), 2.06-1.98 (m, 1H), 1.16-1.10 (m, 2H), 1.06-1.02 (m, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.24H.sub.19F.sub.3N.sub.6O.sub.2 480.15; found 479 (MH).sup.. HPLC t.sub.R 1.94 min.

Example 92: (3-(4-(2-methylpyridin-3-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0458] The title compound was obtained as a white solid reacting 3-bromo-2-methylpyridine; XPhos Pd G4 in THE was used in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.66 (s, 1H), 8.40 (dd, J.sub.1=4.8 Hz, J.sub.2=1.8 Hz, 1H), 8.21 (s, 1H), 8.14 (br s, 1H), 7.65 (br d, J=8.8 Hz, 1H), 7.60 (br d, J=8.1 Hz, 2H), 7.55 (dd, J.sub.1=7.7 Hz, J.sub.2=1.5 Hz, 1H), 7.43 (br d, J=8.1 Hz, 2H), 7.37 (br t, J=8.0 Hz, 1H), 7.24 (dd, J.sub.1=7.7 Hz, J.sub.2=4.8 Hz, 1H), 7.15 (br d, J=7.5 Hz, 1H), 5.78 (s, 2H), 2.35 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.18F.sub.3N.sub.5O.sub.2 453.14; found 452 (MH).sup.. HPLC t.sub.R 1.34 min.

Example 98: (3-(4-(1,4-dimethyl-1H-imidazol-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0459] The title compound was obtained as a white solid reacting 5-bromo-1,4-dimethyl-1H-imidazole; XPhos Pd G4 in THE was used in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.30 (s, 1H), 8.22 (br s, 1H), 7.72 (br d, J=7.9 Hz, 1H), 7.67 (br d, J=8.1 Hz, 2H), 7.59 (s, 1H), 7.48 (br d, J=8.1 Hz, 2H), 7.44-7.42 (m, 1H), 7.22 (br d, J=7.7 Hz, 1H), 5.83 (s, 2H), 3.53 (s, 3H), 2.11 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.19F.sub.3N.sub.6O.sub.2 456.15; found 455 (MH).sup.. HPLC t.sub.R 1.31 min.

Example 101: (3-(3-methyl-4-(4-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0460] The title compound was obtained as a white solid reacting 5-bromo-4-methylpyrimidine and ((3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (prepared as reported in the synthesis of Example 60 starting from Intermediate 23) in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 9.08 (s, 1H), 8.53 (s, 1H), 8.28 (s, 1H), 8.22 (br s, 1H), 7.72 (br d, J=7.9 Hz, 1H), 7.59 (s, 1H), 7.52 (br d, J=8.1 Hz, 1H), 7.44 (br t, J=7.9 Hz, 1H), 7.31 (br d, J=7.7 Hz, 1H), 7.23 (br d, J=7.7 Hz, 1H), 5.82 (s, 2H), 2.23 (s, 3H), 2.08 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.19F.sub.3N.sub.6O.sub.2 468.15; found 467 (MH).sup.. HPLC t.sub.R 1.72 min.

Example 107: (3-(4-(4-fluoro-6-oxo-1,6-dihydropyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0461] The title compound was obtained as a light-pink solid reacting 5-bromo-4,6-difluoropyrimidine; XPhos Pd G4 in THE was used in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.65 (s, 1H), 8.16 (s, 1H), 8.13 (br s, 1H), 8.05 (br s, 1H), 7.66 (br d, J=8.8 Hz, 1H), 7.50 (br s, 4H), 7.36 (br t, J=7.8 Hz, 1H), 7.15 (br d, J=7.7 Hz, 1H), 5.73 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.27 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.14F.sub.4N.sub.6O.sub.3 474.11; found 473 (MH).sup.. HPLC t.sub.R 1.64 min.

Example 111: (3-(4-(4-methoxy-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0462] The title compound was obtained as a white solid reacting 5-bromo-4-methoxy-6-methylpyrimidine in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (s, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 8.22 (br s, 1H), 7.73 (br d, J=8.8 Hz, 1H), 7.65 (br d, J=8.1 Hz, 2H), 7.46-7.40 (m, 3H), 7.23 (br d, J=7.9 Hz, 1H), 5.84 (s, 2H), 3.84 (s, 3H), 2.21 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.19F.sub.3N.sub.6O.sub.3 484.15; found 483 (MH).sup.. HPLC t.sub.R 1.82 min.

Example 112: (3-(4-(4-(2-hydroxyethoxy)-6-methylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0463] The title compound was obtained as a white solid reacting 2-((5-bromo-6-methylpyrimidin-4-yl)oxy)ethan-1-ol in Step 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (s, 1H), 8.64 (s, 1H), 8.62 (br s, 1H), 8.32 (s, 1H), 8.22 (br s, 1H), 7.73 (br d, J=9.0 Hz, 1H), 7.64 (br d, J=8.1 Hz, 2H), 7.46-7.42 (m, 3H), 7.23 (br d, J=7.7 Hz, 1H), 5.85 (s, 2H), 4.36-4.31 (m, 2H), 3.62-3.58 (m, 2H), 2.22 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.24H.sub.21F.sub.3N.sub.6O.sub.4 514.16; found 513 (MH).sup.. HPLC t.sub.R 1.63 min.

Example 123: ((3-((5-(4-(2-(metheyliumyl(methyl)ammonio)ethoxy)-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide) (2,2,2-trifluoroacetate)

##STR00032##

Step 1: (3-((5-boronopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 122)

[0464] A solution of bis(chloranyl)palladium; cyclopentyl(diphenyl)phosphane ferrocene (5.6 mg, 0.01 mmol), (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Intermediate 24) (prepared as described in the synthesis of Example 6) (30.0 mg, 0.07 mmol), potassium acetate (20.0 mg, 0.20 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (34.5 mg, 0.14 mmol) in dioxane (7.0 mL) was heated at 75 C. for 30 min. The reaction mixture was cooled at rt and filtered on a pad of solca flock. The excess of solvent was removed under reduced pressure to afford the title compound (27.0 mg, 97%) as a brown oil which was used as such in the next step. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.75 (s, 1H), 8.21-8.18 (m, 3H), 7.74 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 5.94 (s, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.16H.sub.13BF.sub.3N.sub.5O.sub.4 407.10; found 408 (M+H).sup.+. HPLC t.sub.R 1.37 min.

Step 2: ((3-((5-(4-(2-(metheyliumyl(methyl)ammonio)ethoxy)-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide) (2,2,2-trifluoroacetate) (Example 123)

[0465] The title compound was prepared using same conditions reported for the synthesis of Example 90 using Example 122 (48 mg, 0.12 mmol) and 2-((5-bromo-6-methylpyrimidin-4-yl)oxy)-N,N-dimethylethan-1-amine (61 mg, 0.24 mmol). The title compound was obtained after purification on silica gel (eluting with 10% MeOH in DCM) and lyophilization from H.sub.2O/MeCN+0.1% TFA as a brown gummy (6.7 mg, 10%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.75 (s, 1H), 9.48 (br s, 1H), 8.75 (s, 1H), 8.63 (d, J=1.8 Hz, 1H), 8.23 (s, 1H), 8.21 (br s, 1H), 7.98 (dd, J.sub.1=8.1 Hz, J.sub.2=2.2 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.72 (br d, J=8.8 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.23 (d, J=7.7 Hz, 1H), 6.01 (s, 2H), 4.64-4.62 (m, 2H), 3.45-3.41 (m, 2H), 2.68 (s, 3H), 2.67 (s, 3H), 2.28 (s, 3H); .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.25H.sub.25F.sub.3N.sub.8O.sub.3 542.20; found 543 (M+H).sup.+. HPLC t.sub.R 1.20 min.

[0466] Examples 43 and 118 were synthesized according to the above procedure (Scheme 15) by reacting with the appropriate starting materials.

Example 43: (3-((5-(2-(2-(dimethylamino)ethoxy)-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0467] The title compound was obtained as a yellow solid reacting 2-((5-bromo-4-methylpyrimidin-2-yl)oxy)-N,N-dimethylethan-1-amine in Step 2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (s, 1H), 9.48 (br s, 1H), 8.68 (br d, J=1.8 Hz, 1H), 8.48 (s, 1H), 8.25 (s, 1H), 8.20 (br s, 1H), 8.05 (dd, J.sub.1=8.0 Hz, J.sub.2=2.3 Hz, 1H), 7.79-7.73 (m, 2H), 7.44 (t, J=7.9 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 6.01 (s, 2H), 4.43 (t, J=5.8 Hz, 2H), 2.66-2.63 (m, 2H), 2.40 (s, 3H), 2.22 (s, 6H); .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.25H.sub.25F.sub.3N.sub.8O.sub.3 542.20; found 541 (MH).sup.. HPLC t.sub.R 1.22 min.

Example 118: (3-((5-(1,4-dimethyl-1H-imidazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0468] The title compound was obtained as a white solid reacting 5-bromo-1,4-dimethyl-1H-imidazole in Step 2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 8.20 (br s, 1H), 8.00-7.97 (m, 1H), 7.77-7.68 (m, 3H), 7.47-7.42 (m, 1H), 7.24-7.22 (m, 1H), 6.00 (s, 2H), 3.56 (s, 3H), 2.13 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.18F.sub.3N.sub.7O.sub.2 457.15; found 456 (MH).sup.. HPLC t.sub.R 1.27 min.

Example 31: (S)-(3-(2-hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

##STR00033##

Step 1: (S)-2-((2-hydroxy-1-phenylethyl)amino)acetonitrile (Intermediate 25)

[0469] To a suspension of (S)-2-phenylglycinol (343 mg, 2.5 mmol) and N,N-diisopropylethylamine (0.52 mL, 3 mmol) in MeCN (4 mL), 2-bromoacetonitrile (0.12 mL, 1.67 mmol) was added at rt.

[0470] The reaction was stirred overnight at rt and then concentrated under reduced pressure. The obtained oil was treated with water (2 mL) and extracted with Et.sub.2O. The organic phase was washed with water (33 mL) and brine, then was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to obtain the title compound (268 mg, 91%) as an oil. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 7.43-7.16 (m, 5H), 5.02 (t, J=5.5 Hz, 1H), 3.84-3.76 (m, 1H), 3.75-3.65 (m, 1H), 3.54-3.35 (m, 2H), 3.25-3.11 (m, 1H), 2.99 (ddd, J=10.6, 4.6, 1.7 Hz, 1H). LCMS (ES.sup.+) m/z calculated for C.sub.10H.sub.12N.sub.2O 176.09; found 177 (M+H).sup.+. HPLC t.sub.R 1.35 min.

Step 2: (S)N-(cyanomethyl)-N-(2-hydroxy-1-phenylethyl)nitrous amide (Intermediate 26)

[0471] A cold mixture (ice bath) of Intermediate 25 (268 mg, 1.52 mmol) in 3 N hydrogen chloride (2.03 mL, 6.08 mmol) in ethanol (2 mL) was added dropwise to a stirred and cooled (ice-salt) solution of sodium nitrite (210 mg, 3.04 mmol) in water (1.5 mL). The reaction was warmed up until rt for 1 h. Then, it was added brine and extracted with Et.sub.2O. The organic phase was washed with water, brine and dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to yield the title compound as an oil that as used as such in the next synthetic step 1H NMR (300 MHz, DMSO-d.sub.6) 7.56-7.26 (m, 5H), 5.78 (dd, J=9.2, 5.1 Hz, 1H), 5.33 (dd, J=5.5, 5.0 Hz, 1H), 4.68-4.54 (m, 2H), 4.32-4.23 (m, 1H), 4.03 (dt, J=11.7, 5.0 Hz, 1H). HPLC t.sub.R20.25 min.

Step 3: (S)-5-amino-3-(2-hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 27)

[0472] Intermediate 26 was directly treated with 4 N HCl in dioxane (1.5 mL) at rt to give a yellowish solution. After 10 min the reaction mixture was diluted with Et.sub.2O (3 mL) and concentrated under reduced pressure. The crude was stripped with DCM and was dried under vacuum pump overnight to give the title compound (286 mg, 78% over two steps) as a white foam. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.73 (s, 2H), 8.22 (s, 1H), 7.71-7.53 (m, 2H), 7.52-7.41 (m, 3H), 6.21 (dd, J=9.3, 4.2 Hz, 1H), 5.77 (br s, 1H), 4.44 (dd, J=12.2, 9.4 Hz, 1H), 4.10 (dd, J=12.2, 4.3 Hz, 1H). LCMS (ES.sup.+) m/z calculated for C.sub.10H.sub.12N.sub.3O.sub.2.sup.+ Exact Mass: 206.09; found 206 [M]+. HPLC t.sub.R 1.44 min.

Step 4: (S)-(3-(2-hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide (Example 31)

[0473] Intermediate 27 (222 mg, 0.92 mmol) in dry methanol (3 mL) was cooled at 10 C. (ice-salt bath) and sodium acetate (82 mg, 1.01 mmol) was added. The mixture was stirred at the same temperature for 15 min and 1-isocyanato-3-(trifluoromethyl)benzene (0.13 mL, 0.92 mmol) was added. The reaction was stirred further at 10 C. for 1 hr and then was diluted with water. The precipitated product was filtered and washed with water. The crude was purified on silica gel eluting with DCM/MeOH 99.8:0.2 to obtain the title compound (140 mg, 39%) as white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 7.70 (br d, J=8.6 Hz, 1H), 7.66-7.56 (m, 2H), 7.54-7.36 (m, 4H), 7.22 (br d, J=7.7 Hz, 1H), 6.02 (dd, J=9.4, 4.2 Hz, 1H), 5.69 (br s, 1H), 4.52 (br t, J=10.7 Hz, 1H), 4.07 (br dd, J=11.9, 4.1 Hz, 1H). LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.15F.sub.3N.sub.4O.sub.3 392.11; found 393 (M+H).sup.+. HPLC t.sub.R 3.12 min.

[0474] Examples 30, 32, and 45 were synthesized according to the above procedure (Scheme 16) by reacting with the appropriate starting materials.

Example 30: (R)-(3-(2-hydroxy-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0475] The title compound was obtained as a white solid starting from (R)-2-phenylglycinol. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 7.70 (br d, J=8.4 Hz, 1H), 7.62 (dd, J=6.7, 2.9 Hz, 2H), 7.53-7.38 (m, 4H), 7.22 (d, J=7.8 Hz, 1H), 6.02 (dd, J=9.5, 4.2 Hz, 1H), 5.67 (t, J=5.5 Hz, 1H), 4.52 (ddd, J=12.0, 9.6, 5.8 Hz, 1H), 4.15-3.98 (m, 1H). LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.15F.sub.3N.sub.4O.sub.3 392.11; found 393 (M+H).sup.+. HPLC t.sub.R 3.11 min.

Example 32: (S)-(3-(1-hydroxy-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0476] The title compound was obtained as a white solid starting from Boc-L-Phenylalaninol. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.68 (s, 1H), 8.33 (s, 1H), 8.30-8.23 (m, 1H), 7.73-7.65 (m, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.34-7.16 (m, 6H), 5.89-5.16 (m, 1H), 5.10-4.94 (m, 1H), 4.05-3.94 (m, 1H), 3.93-3.84 (m, 1H), 3.34-3.27 (m, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.17F.sub.3N.sub.4O.sub.3 406.13; found 407 (M+H).sup.+. HPLC t.sub.R 3.20 min.

Example 45: (R)-(3-(1-amino-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0477] The title compound was obtained as a white solid starting from Boc-D-Phenylalaninol. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.68 (s, 1H), 8.34 (s, 1H), 8.30-8.25 (m, 1H), 7.74-7.65 (m, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.34-7.18 (m, 6H), 5.14-4.93 (m, 1H), 3.92-3.84 (m, 1H), 3.34-3.26 (m, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.17F.sub.3N.sub.4O.sub.3 406.13; found 407 (M+H).sup.+. HPLC t.sub.R 3.20 min.

Example 35: (3-(1-Phenylvinyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

##STR00034##

[0478] To an ice-cooled solution of Example 30 (20 mg, 0.05 mmol) in dry THF (0.25 mL, 0.003 mol) was added 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-14-sulfanamine (0.04 mL, 0.06 mmol) dropwise under nitrogen atmosphere. The reaction was stirred at 0 C. for 40 min. More 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-14-sulfanamine (0.04 mL, 0.06 mmol) was added and stirred for another 30 min. Then a second addition of 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-14-sulfanamine (0.07 mL) was done at 0 C. The reaction was stirred at 0 C. for 40 min and then was allowed to warm-up slowly overnight. The reaction mixture was quenched with NaHCO.sub.3 (0.3 mL, sat. sol.) and water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a yellow oil that was purified on silica gel column (eluent gradient from 100% petroleum ether to 70/30 petroleum ether/ethyl acetate) then reverse phase chromatography (eluent gradient 15-70% MeCN+0.1% HCOOH). The pure fractions were combined and lyophilized to afford the title compound (1.41 mg, 8%) as a yellow solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.81 (br s, 1H), 8.37-8.13 (m, 2H), 7.74 (br d, J=7.9 Hz, 1H), 7.66-7.37 (m, 6H), 7.23 (br d, J=7.4 Hz, 1H), 6.45-6.12 (m, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.15F.sub.3N.sub.4O.sub.3 392.11; found 393 (M+H).sup.+. HPLC t.sub.R 3.64 min.

(3-(3-phenylprop-1-en-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl) carbamoyl)amide (Example 36) and (S)-(3-(1-fluoro-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 37)

##STR00035##

[0479] To an ice-cooled solution of Example 32 (20 mg, 0.05 mmol) in dry THF (0.25 mL, 0.003 mol), 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-14-sulfanamine (0.22 mL, 0.3 mmol) was added dropwise. The reaction mixture was stirred for 40 min at 0 C. More 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-14-sulfanamine was added (0.22 mL, 0.3 mmol) and the reaction was stirred at 0 C. for 1 hr. Then potassium fluoride (2.9 mg, 0.05 mmol) was added, and the reaction was stirred at rt overnight. The next day the reaction was quenched by water and extracted with EtOAc. The organic layer was washed additionally with water, 1 N HCl and brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated to yield a yellow oil. The crude was purified by direct phase silica gel chromatography (eluent DCM+0.5% MeOH). The first eluted product was additionally purified by reverse phase chromatography (eluent gradient 10-70% MeCN+0.1% HCOOH) to yield (3-(3-phenylprop-1-en-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 36) (0.4 mg, 2%) as a white powder. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.91-9.58 (m, 1H), 8.46 (s, 1H), 8.26 (br s, 1H), 7.70 (br d, J=8.2 Hz, 1H), 7.52-7.15 (m, 7H), 6.28 (s, 1H), 5.75 (s, 1H), 4.13 (br s, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.15F.sub.3N.sub.4O.sub.2 388.11; found 389 (M+H).sup.+. HPLC t.sub.R 3.66 min.

[0480] The second eluted product was additionally purified by reverse phase chromatography (eluent gradient 10-70% MeCN+0.1% HCOOH) to yield (S)-(3-(1-fluoro-3-phenylpropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 37) (2.64 mg, 12%) as a white powder. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 7.70 (br d, J=8.71 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.36-7.19 (m, 6H), 5.65-5.39 (m, 1H), 5.18-5.03 (m, 1H), 5.01-4.86 (m, 1H), 3.45-3.34 (m, 2H); .sup.19F NMR (282 MHz, DMSO-d.sub.6) 224.60 (s, 1F) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.16F.sub.4N.sub.4O.sub.2 408.12; found 409 (M+H).sup.+. HPLC t.sub.R 3.62 min.

Example 44: (3-(2,2,2-trifluoro-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

##STR00036##

Step 1: 2-((2,2,2-trifluoro-1-phenylethyl)amino)acetonitrile (Intermediate 28)

[0481] A microwave vail was charged with 2-((2,2,2-trifluoro-1-phenylethyl)amino)acetonitrile (0.25 mg, 1.44 mmol), N,N-diisopropylethylamine (0.3 mL, 1.73 mmol) and 2-bromoacetonitrile (0.07 mL, 0.96 mmol) in MeCN (2 mL). The reaction mixture was heated under microwave irradiation for 90 min at 100 C.; then more DIPEA (300 uL) and 2-bromoacetonitrile (0.07 mL, 0.96 mmol) were added and the reaction was heated additionally for 30 min at 100 C., then was directly diluted with EtOAc and washed with small amount of water and brine. The organic phase was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give dark brown oil which was purified by chromatography on silica gel (eluent DCM 100%) to give the title compound (87 mg, 28%) was as a white powder. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 7.87-7.26 (m, 5H), 4.50 (q, J=7.7 Hz, 1H), 3.90 (br s, 1H), 3.75-3.61 (m, 1H), 3.56-3.44 (m, 1H). LCMS (ES.sup.+) m/z calculated for C.sub.10H.sub.9F.sub.3N.sub.2 214.07; found 215 (M+H).sup.+. HPLC t.sub.R 1.78 min.

Step 2: N-(cyanomethyl)-N-(2,2,2-trifluoro-1-phenylethyl)nitrous amide (Intermediate 29)

[0482] The title compound was prepared using the procedure described in Example 31, step 2 starting from intermediate 28. The obtained crude as a yellow oil was used as such in the next synthetic step. LCMS (ES.sup.+) m/z calculated for C.sub.10H.sub.8F.sub.3N.sub.3O 243.06; found 244 (M+H).sup.+. HPLC t.sub.R 1.91 min.

Step 3: 5-amino-3-(2,2,2-trifluoro-1-phenylethyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 30)

[0483] The title compound was prepared using the procedure described in Example 32, step 3 but heating at 90 C. for 10 min starting from intermediate 29. The impure crude product (30 mg) was obtained as a white solid and was used as such in the next synthetic step. LCMS (ES.sup.+) m/z calculated for C.sub.10H.sub.9F.sub.3N.sub.3O.sup.+ 244.07; found 244 [M]+. HPLC t.sub.R 1.09 min.

Step 4: (3-(2,2,2-trifluoro-1-phenylethyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl) phenyl)carbamoyl)amide (Example 44)

[0484] A mixture of Intermediate 30 (30 mg, 0.11 mmol) in pyridine (1 mL) was treated with 1-isocyanato-3-(trifluoromethyl)benzene (0.04 mL, 0.27 mmol) at 0 C. The reaction was stirred at RT for 20 min; then was diluted with DCM. The organic phase was washed with water, 1 N HCl and brine; the was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The title compound (0.62 mg, 1.25%) was obtained after purification by reverse phase chromatography (MeCN/H.sub.2O+0.1% HCOOH). Fractions containing product were lyophilized to give the title compound as a white powder. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.87 (s, 1H), 8.36 (s, 1H), 8.18 (s, 1H), 7.75 (br d, J=8.0 Hz, 3H), 7.67-7.50 (m, 4H), 7.46 (t, J=8.0 Hz, 1H), 7.25 (d, J=7.70 Hz, 1H). LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.12F.sub.6N.sub.4O.sub.2 430.09; found 431 (M+H).sup.+. HPLC t.sub.R 4.02 min.

Example 70: (S)-(3-(1-(1,1-biphenyl-4-yl)-3-acetamidopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

##STR00037##

[0485] To a solution of Example 65 (3.6 mg, 0.01 mmol) and sodium bicarbonate (0.3 mL, sat. sol.) in THF (0.5 mL) at 0 C., acetyl chloride (10 uL) was added. The reaction was stirred for 5 min at rt, then was diluted with EtOAc and the organic phase was washed with sat. sol. KHSO.sub.4 and brine.

[0486] The organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The product was dissolved in MeCN/water and after frizz-drying the title compound was obtained (2.3 mg, 40%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.70 (s, 1H), 8.47 (s, 1H), 8.21 (br t, J=5.6 Hz, 1H), 7.76-7.59 (m, 6H), 7.52-7.40 (m, 4H), 7.39-7.30 (m, 4H), 7.23 (br d, J=8.0 Hz, 1H), 5.12-4.93 (m, 1H), 3.89-3.76 (m, 1H), 3.74-3.60 (m, 1H), 1.79 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.27H.sub.24F.sub.3N.sub.5O.sub.3 523.18; found 524 (M+H).sup.+. HPLC t.sub.R 3.66 min.

Example 71: (R)-(3-(1-([1,1-biphenyl]-4-yl)-3-acetamidopropan-2-yl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0487] The title compound was synthesized according to the above procedure (Scheme 20) by reacting with the appropriate starting materials. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.70 (s, 1H), 8.47 (s, 1H), 8.21 (br t, J=5.6 Hz, 1H), 7.76-7.59 (m, 6H), 7.52-7.40 (m, 4H), 7.39-7.30 (m, 4H), 7.23 (br d, J=8.0 Hz, 1H), 5.12-4.93 (m, 1H), 3.89-3.76 (m, 1H), 3.74-3.60 (m, 1H), 1.79 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.27H.sub.24F.sub.3N.sub.5O.sub.3 523.18; found 524 (M+H).sup.+. HPLC t.sub.R 3.66 min.

Example 127: (3-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

##STR00038##

Step 1: 2-((4-bromobenzyl)amino)acetonitrile (Intermediate 31)

[0488] A suspension of (4-bromobenzyl)amine hydrochloride (10 g, 45 mmol) and DIPEA (31 mL, 180 mmol) in MeCN (70 mL) was treated with 2-bromoacetonitrile (3.4 mL, 49 mmol) and the reaction mixture was stirred at 60 C. for 4 h. After cooling the solvent was then removed under reduced pressure and the residue treated with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na.sub.2SO.sub.4, and evaporated under reduced pressure to get the title compound as a yellow oil (9.07 g, 90%). LCMS (ES.sup.+) m/z calculated for C.sub.9H.sub.9BrN.sub.2 223.99, found 225 (M+H).sup.+. HPLC t.sub.R 1.15 min.

Step 2: 5-amino-3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 32)

[0489] A solution of 2-[(4-bromophenyl)methylamino]acetonitrile (Intermediate 31, 9.07 g, 40.3 mmol) in THF (50 mL) was treated with tert-butyl nitrite (15.9 mL, 133 mmol) and stirred at rt for 30 min before being diluted with EtOAc, washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford a crude material which was dissolved in dioxane (10 mL), treated with 4 N HCl in dioxane (7.32 g, 201 mmol) and stirred at rt for 1 h. The excess of solvent was removed under reduced pressure and the resulted crude compound was titrated with Et.sub.2O to give the title compound as a white powder (10.5 g, 90%). LCMS (ES.sup.+) m/z calculated for C.sub.9H.sub.9BrClN.sub.3O 253.99 (parent), found 254 (M+H).sup.+. HPLC t.sub.R 0.85 min.

Step 3: (3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Intermediate 33)

[0490] A solution of bis(trichloromethyl)carbonate (101.8 mg, 0.34 mmol), [5-(trifluoromethyl)-3-pyridyl]amine (111.2 mg, 0.69 mmol) and DIPEA (178 mg, 1.4 mmol) in dry THE (2.6 mL) was stirred at rt for 20 minutes before being added dropwise to a stirring suspension of 3-[(4-bromophenyl)methyl]oxadiazol-3-ium-5-amine;hydrochloride (Intermediate 32, 100 mg, 0.34 mmol) in dry THE (2 mL) at 0 C. DIPEA (178 mg, 1.4 mmol) was added and the reaction mixture was stirred at rt for further 10 min before being diluted with water and extracted twice with EtOAc.

[0491] The organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to get a residue which was purified by flash chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to give the title compound as a white powder (148 mg, 98%). LCMS (ES.sup.+) m/z calculated for C.sub.16H.sub.11BrF.sub.3N.sub.5O.sub.2 441.00; found 440-442 (MH).sup.. HPLC t.sub.R 1.79 min.

Step 4: (3-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide. (Example 127)

[0492] A degassed suspension of (3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Intermediate 33, 25 mg, 0.06 mmol), Pd(dppf)Cl.sub.2 (4.1 mg, 0.006 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (15.9 mg, 0.11 mmol) and K.sub.3PO.sub.4 (36 mg, 0.17 mmol) in a mixture of dioxane (1 mL) and H.sub.2O (0.1 mL) was stirred at 75 C. for 1 h. After cooling the reaction mixture was filtered on a pad of solka floc and the filtrate was evaporated under reduced pressure to get a residue which was purified by flash chromatography on silica gel (eluting with 0-100% MeCN in water) to afford a pale-yellow solid (12 mg). The title compound was obtained after a further purification by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column) to give the title compound as a white solid (4.0 mg, 14%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.96 (br s, 1H), 8.91 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 8.47 (s, 1H), 8.33 (s, 1H), 7.65 (s, 1H), 7.61-7.52 (m, 2H), 7.50-7.47 (m, 1H), 5.85 (s, 2H), 2.43 (s, 3H), 2.25 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.17F.sub.3N.sub.6O.sub.3 458.13; found 459 (M+H).sup.+. HPLC t.sub.R 1.68 min.

[0493] Example 187 was synthesized according to the above procedure (Scheme 21) by reacting with the appropriate starting materials.

Example 187: (3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0494] The title compound was obtained as a pale yellow solid reacting 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.96 (br s, 1H), 8.91 (s, 2H), 8.55 (br s, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 7.65-7.56 (m, 3H), 7.42 (dd, J.sub.1=7.0 Hz, J.sub.2=1.7 Hz, 1H), 5.86 (s, 2H), 2.19 (s, 6H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.23 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.18F.sub.3N.sub.7O.sub.2 469.15; found 468 (MH).sup.. HPLC t.sub.R 1.45 min.

Example 130: (3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

##STR00039##

[0495] The title compound was prepared using the procedure reported for the synthesis of Example 127 starting from Intermediate 24 and 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine. The title compound was obtained as a white solid (458 mg, 31%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.75 (br s, 1H), 8.93 (s, 1H), 8.59 (d, J=1.8 Hz, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.97 (dd, J.sub.1=8.0 Hz, J.sub.2=2.3 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.74 (br d, J=8.5 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.23 (d, J=7.9 Hz, 1H), 6.04 (s, 2H), 2.21 (s, 6H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.18F.sub.3N.sub.7O.sub.2 469.15; found 470 (M+H).sup.+. HPLC t.sub.R 1.52 min.

[0496] Examples 129, 143, 170, 172, 181 and 159 were synthesized according to the above procedure (Scheme 22) by reacting Intermediate 24 with the appropriate boronic ester.

Example 129: (3-((5-(5-methylpyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0497] The title compound was obtained as a white solid reacting 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.75 (br s, 1H), 9.24 (s, 1H), 9.14 (d, J=0.8 Hz, 1H), 8.78 (dd, J.sub.1=2.3 Hz, J.sub.2=0.7 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.16 (dd, J.sub.1=8.1 Hz, J.sub.2=2.3 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.74 (d, J=8.9 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 6.05 (s, 2H), 2.34 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.16F.sub.3N.sub.7O.sub.2 455.13; found 454 (MH).sup.. HPLC t.sub.R 1.45 min.

Example 143: ((3-(trifluoromethyl)phenyl)carbamoyl)(3-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0498] The title compound was obtained as a beige solid reacting 1,3,5-trimenthyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.53 (s, 1H), 8.23-8.20 (m, 2H), 7.83 (br d, J=8.1 Hz, 1H), 7.75-7.69 (m, 2H), 7.44 (br t, J=7.9 Hz, 1H), 7.22 (br d, J=7.5 Hz, 1H), 5.96 (s, 2H), 3.72 (s, 3H), 2.24 (s, 3H), 2.14 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.20F.sub.3N.sub.7O.sub.2 471.16; found 470 (MH).sup.. HPLC t.sub.R 1.61 min.

Example 170: (3-((3,5-difluoro-[3,4-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0499] The title compound was obtained as a beige solid reacting (3,5-difluoro-4-pyridyl)boronic acid .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.75 (s, 1H), 8.81 (s, 1H), 8.73 (s, 2H), 8.30 (s, 1H), 8.20-8.18 (m, 2H), 7.85 (d, J=8.1 Hz, 1H), 7.74 (br d, J=8.3 Hz, 1H), 7.45 (br t, J=8.2 Hz, 1H), 7.23 (br d, J=7.5 Hz, 1H), 6.06 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.13F.sub.5N.sub.6O.sub.2 476.10; found 475 (MH).sup.. HPLC t.sub.R 1.74 min.

Example 172: (3-((2-chloro-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0500] The title compound was obtained as a beige solid reacting 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (br s, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.51 (dd, J.sub.1=4.8 Hz, J.sub.2=1.8 Hz, 1H), 8.26 (s, 1H), 8.21 (br s, 1H), 8.11 (dd, J.sub.1=8.1 Hz, J.sub.2=2.1 Hz, 1H), 8.01 (dd, J.sub.1=7.6 Hz, J.sub.2=1.6 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.74 (br d, J=8.6 Hz, 1H), 7.59-7.57 (m, 1H), 7.45 (br t, J=8.1 Hz, 1H), 7.23 (br d, J=7.9 Hz, 1H), 6.04 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.14ClF.sub.3N.sub.6O.sub.2 474.08; found 473 (MH).sup.. HPLC t.sub.R 1.74 min.

Example 181: (3-((5-(3,6-dimethoxypyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0501] The title compound was obtained as an off-white solid reacting 3,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.75 (s, 1H), 8.86 (d, J=2.1 Hz, 1H), 8.24-8.21 (m, 3H), 7.79-7.75 (m, 2H), 7.45-7.42 (m, 2H), 7.23 (d, J=7.6 Hz, 1H), 6.02 (s, 2H), 4.00 (s, 6H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.18F.sub.3N.sub.7O.sub.4 501.14; found 500 (MH).sup.. HPLC t.sub.R 1.76 min.

Example 159: (3-((2-methoxy-4-methyl-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0502] The title compound was obtained as a white solid reacting 2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.49 (d, J=1.5 Hz, 1H), 8.27 (s, 1H), 8.20 (br s, 1H), 8.09 (d, J=5.3 Hz, 1H), 7.86 (dd, J1=8.1 Hz, J.sub.2=2.2 Hz, 1H), 7.73-7.71 (m, 2H), 7.44 (t, J=8.0 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 7.01 (d, J=5.3 Hz, 1H), 6.00 (s, 2H), 3.76 (s, 3H), 2.08 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.19F.sub.3N.sub.6O.sub.3 484.15; found 483 (MH).sup.. HPLC t.sub.R 1.88 min.

Example 134: (3-((5-(2-methoxy-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

##STR00040##

[0503] A degassed solution of (3-((5-boronopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 122, 44.9 mg, 0.11 mmol) in dioxane (2.0 mL) and water (0.2 mL) was treated with 5-bromo-2-methoxy-4-methyl-pyrimidine (46 mg, 0.23 mmol), Pd(dppf)Cl.sub.2 (8.3 mg, 0.011 mmol), K.sub.3PO.sub.4 (72 mg, 0.34 mmol) and heated at 85 C. for 1 h. After cooling the mixture was diluted with EtOAc and filtered on a pad of cellulose. The excess of solvent was removed under reduced pressure. The title compound was obtained after purification by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column) to give the title compound as a creamy solid (9.5 mg, 16%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (s, 1H), 8.68 (s, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 8.20 (br s, 1H), 8.05 (dd, J1=8.1 Hz, J.sub.2=2.0 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.74 (br d, J=8.3 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.23 (br d, J=7.2 Hz, 1H), 6.02 (s, 2H), 3.95 (s, 3H), 2.41 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.18F.sub.3N.sub.7O.sub.3 485.14; found 484 (MH).sup.. HPLC t.sub.R 1.68 min.

[0504] Examples 131, 135, 138, 139, 148, 151, 155, 160, 162, 163, 164, 165, 179, 180, 177, 176, 175 and 132 were synthesized according to the above procedure (Scheme 23) by reacting Example 122 or analogous boronic acids with the appropriate starting materials.

Example 131: ((3-(trifluoromethyl)phenyl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0505] The title compound was obtained as a beige solid reacting 5-bromo-4-(trifluoromethyl)pyrimidine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (br s, 1H), 9.53 (s, 1H), 9.16 (s, 1H), 8.70 (br s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 8.08 (br d, J=7.9 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.75 (br d, J=8.3 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.23 (br d, J=8.8 Hz, 1H), 6.07 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F), 62.39 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.13F.sub.6N.sub.7O.sub.2 509.10; found 508 (MH).sup.. HPLC t.sub.R 1.79 min.

Example 135: (3-((5-(4-methoxy-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0506] The title compound was obtained as a beige solid reacting 5-bromo-4-methoxy-6-methyl-pyrimidine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.67 (br s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.21 (br s, 1H), 8.13 (s, 1H), 7.88 (br d, J=8.0 Hz, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.37 (t, J=8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 5.94 (s, 2H), 3.79 (s, 3H), 2.18 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.18F.sub.3N.sub.7O.sub.3 485.14; found 484 (MH).sup.. HPLC t.sub.R 1.62 min.

Example 138: (3-((2-methyl-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0507] The title compound was obtained as a beige solid reacting 3-bromo-2-methyl-pyridine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.75 (br s, 1H), 8.71 (br s, 2H), 8.27 (s, 1H), 8.21 (br s, 1H), 8.11-8.07 (m, 2H), 7.81 (br d, J=8.0 Hz, 1H), 7.74 (br d, J=7.9 Hz, 1H), 7.69-7.66 (m, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.23 (br d, J=7.9 Hz, 1H), 6.04 (s, 2H), 2.55 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.17F.sub.3N.sub.6O.sub.2 454.14; found 453 (MH).sup.. HPLC t.sub.R 1.22 min.

Example 139: (3-((4-methyl-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0508] The title compound was obtained as a beige solid reacting 3-bromo-4-methyl-pyridine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.75 (br s, 1H), 8.72 (br s, 1H), 8.65 (br s, 2H), 8.27 (s, 1H), 8.21 (br s, 1H), 8.09 (dd, J.sub.1=8.0 Hz, J.sub.2=1.9 Hz, 1H), 7.82 (br d, J=7.9 Hz, 1H), 7.75-7.70 (m, 2H), 7.45 (t, J=8.0 Hz, 1H), 7.23 (br d, J=7.7 Hz, 1H), 6.06 (s, 2H), 2.40 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.17F.sub.3N.sub.6O.sub.2 454.14; found 453 (MH).sup.. HPLC t.sub.R 1.27 min.

Example 148: (3-((5-(4-cyanopyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0509] The title compound was obtained as a creamy solid reacting 5-bromopyrimidine-4-carbonitrile. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.75 (br s, 1H), 9.48 (s, 1H), 9.35 (s, 1H), 8.95 (s, 1H), 8.36 (dd, J1=8.1 Hz, J.sub.2=2.2 Hz, 1H), 8.29 (s, 1H), 8.20 (br s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.74 (br d, J=8.1 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.23 (br d, J=7.9 Hz, 1H), 6.09 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.13F.sub.3N.sub.8O.sub.2 466.11; found 465 (MH).sup.. HPLC t.sub.R 1.65 min.

Example 151: (3-((5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0510] The title compound was obtained as a creamy solid reacting 4-bromo-3,5-dimethyl-1H-pyrazole. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (br s, 1H), 8.57 (s, 1H), 8.24 (s, 1H), 8.20 (br s, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.69 (br d, J=7.9 Hz, 1H), 7.44 (t, J=8.1 Hz, 1H), 7.23 (br d, J=7.5 Hz, 1H), 5.96 (s, 2H), 2.22 (s, 6H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.18F.sub.3N.sub.7O.sub.2 457.15; found 456 (MH).sup.. HPLC t.sub.R 1.49 min.

Example 155: (3-((5-(4-cyclopropylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0511] The title compound was obtained as a white solid reacting 5-bromo-4-cyclopropylpyrimidine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (br s, 1H), 9.03 (s, 1H), 8.77 (s, 1H), 8.62 (s, 1H), 8.27 (s, 1H), 8.21 (br s, 1H), 8.14-8.12 (m, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.23 (br d, J=7.6 Hz, 1H), 6.04 (s, 2H), 2.00-1.94 (m, 1H), 1.18-1.13 (m, 2H), 1.08-1.05 (m, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.18F.sub.3N.sub.7O.sub.2 481.15; found 480 (MH).sup.. HPLC t.sub.R 1.74 min.

Example 160: (3-((5-(pyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0512] The title compound was obtained as a creamy solid reacting 4-bromopyridazine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (br s, 2H), 9.36 (d, J=5.4 Hz, 1H), 9.15 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 8.20 (s, 1H), 8.13 (dd, J1=5.3 Hz, J.sub.2=2.3 Hz, 1H), 7.87-7.85 (m, 1H), 7.76-7.73 (m, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.23-7.22 (m, 1H), 6.05 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.14F.sub.3N.sub.7O.sub.2 441.12; found 440 (MH).sup.. HPLC t.sub.R 1.40 min.

Example 162: (3-((5-(4-methylpyridazin-3-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0513] The title compound was obtained as a beige solid reacting 3-bromo-4-methyl-pyridazine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (br s, 1H), 9.14 (d, J=5.3 Hz, 1H), 8.87 (d, J=1.6 Hz, 1H), 8.29 (s, 1H), 8.24 (dd, J.sub.1=7.9 Hz, J.sub.2=2.3 Hz, 1H), 8.21 (s, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.75 (br d, J=8.6 Hz, 1H), 7.71 (dd, J.sub.1=5.1 Hz, J.sub.2=0.8 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.23 (br d, J=7.9 Hz, 1H), 6.07 (s, 2H), 2.37 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.16F.sub.3N.sub.7O.sub.2 455.13; found 454 (MH).sup.. HPLC t.sub.R 1.46 min.

Example 163: (3-((3-methyl-[3,4-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0514] The title compound was obtained as an off-white solid reacting 4-bromo-3-methyl-pyridine hydrochloride. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (br s, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.56 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.05 (dd, J1=8.0 Hz, J.sub.2=2.3 Hz, 1H), 7.77-7.73 (m, 2H), 7.44 (t, J=8.0 Hz, 1H), 7.33 (d, J=5.0 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 6.03 (s, 2H), 2.27 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.17F.sub.3N.sub.6O.sub.2 454.14; found 453 (MH).sup.. HPLC t.sub.R 1.25 min.

Example 164: (3-((3-fluoro-[3,4-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0515] The title compound was obtained as an off-white solid reacting 4-bromo-3-fluoro-pyridine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (br s, 1H), 8.90 (s, 1H), 8.74 (d, J=2.3 Hz, 1H), 8.58 (d, J=4.9 Hz, 1H), 8.26-8.24 (m, 2H), 8.21 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.76-7.74 (m, 2H), 7.45 (t, J=8.1 Hz, 1H), 7.23 (d, J=7.9 Hz, 1H), 6.05 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.14F.sub.4N.sub.6O.sub.2 458.11; found 457 (MH).sup.. HPLC t.sub.R 1.65 min.

Example 165: (3-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0516] The title compound was obtained as an off-white solid reacting 5-bromo-1,4-dimethyl-pyrazole. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (br s, 1H), 8.69 (s, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 8.04 (dd, J1=8.2 Hz, J.sub.2=2.3 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.74 (br d, J=8.6 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.39 (s, 1H), 7.23 (d, J=7.6 Hz, 1H), 6.04 (s, 2H), 3.74 (s, 3H), 1.99 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.18F.sub.3N.sub.7O.sub.2 457.15; found 456 (MH).sup.. HPLC t.sub.R 1.66 min.

Example 179: (3-((5-(4-chloropyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0517] The title compound was obtained as an off-white solid reacting 4-chloro-5-iodopyrimidine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.75 (br s, 1H), 9.13 (s, 1H), 8.96 (s, 1H), 8.81-8.80 (m, 1H), 8.27 (s, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.19 (d, J=2.3 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 6.05 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.13ClF.sub.3N.sub.7O.sub.2 475.08; found 474 (MH).sup.. HPLC t.sub.R 1.63 min.

Example 180: (3-((5-(4,6-dichloropyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0518] The title compound was obtained as an off-white solid reacting 4,6-dichloro-5-iodopyrimidine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.76 (br s, 1H), 9.02 (s, 1H), 8.71 (d, J=1.8 Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 8.10 (dd, J.sub.1=8.1 Hz, J.sub.2=2.2 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.75 (br d, J=8.3 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 6.06 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.27 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.12C.sub.12F.sub.3N.sub.7O.sub.2 509.04; found 508 (MH).sup.. HPLC t.sub.R 1.78 min.

Example 177: ((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0519] The title compound was obtained as a white solid reacting 5-bromo-4-(trifluoromethyl)pyrimidine. .sup.1H NMR (600 MHz, DMSO-d.sub.6) 10.19 (s, 1H), 9.53 (s, 1H), 9.16 (s, 1H), 8.70 (d, J=2.0 Hz, 1H), 8.47 (d, J=5.6 Hz, 1H), 8.36 (s, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.08 (dd, J.sub.1=8.2 Hz, J.sub.2=2.3 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.72 (dd, J.sub.1=5.6 Hz, J.sub.2=1.6 Hz, 1H), 6.11 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 62.38 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.12F.sub.6N.sub.8O.sub.2 510.10; found 509 (MH).sup.. HPLC t.sub.R 1.54 min.

Example 176: (3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0520] The title compound was obtained as a white solid reacting 5-bromo-4,6-dimethyl-pyrimidine. .sup.1H NMR (600 MHz, DMSO-d.sub.6) 10.19 (br s, 1H), 8.94 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.47 (d, J=5.6 Hz, 1H), 8.37 (s, 1H), 8.20 (d, J=1.6 Hz, 1H), 7.97 (dd, J.sub.1=7.9 Hz, J.sub.2=2.3 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.72 (dd, J1=5.8 Hz, J.sub.2=1.8 Hz, 1H), 6.09 (s, 2H), 2.55 (s, 3H), 2.21 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 66.92 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.17F.sub.3N.sub.8O.sub.2 470.14; found 469 (MH).sup.. HPLC t.sub.R 1.26 min.

Example 175: (3-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0521] The title compound was obtained as a white solid reacting 5-bromo-1,4-dimethyl-1H-pyrazole. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.18 (br s, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.45 (d, J=5.6 Hz, 1H), 8.36 (s, 1H), 8.18 (d, J=1.6 Hz, 1H), 8.03 (dd, J1=8.0 Hz, J.sub.2=2.3 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.70 (dd, J1=5.6 Hz, J.sub.2=1.6 Hz, 1H), 7.38 (s, 1H), 6.06 (s, 2H), 3.73 (s, 3H), 1.98 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 66.92 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.17F.sub.3N.sub.8O.sub.2 458.14; found 457 (MH).sup.. HPLC t.sub.R 1.41 min.

Example 132: (3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0522] The title compound was obtained as a white solid reacting 5-bromo-4,6-dimethyl-pyrimidine. LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.17F.sub.3N.sub.8O.sub.2 470.14; found 469 (MH).sup.. HPLC t.sub.R 1.26 min.

Example 126: (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

##STR00041##

Step 1: (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Intermediate 35)

[0523] A solution of [5-(trifluoromethyl)-3-pyridyl]amine (74 mg, 0.46 mmol) and DIPEA (118 mg, 0.91 mmol) in dry THF (1.8 mL) was treated with triphosgene (68 mg, 0.23 mmol) and stirred at rt for 30 min before being cooled at 0 C. and treated dropwise with a suspension of 3-[(5-bromo-2-pyridyl)methyl]oxadiazol-3-ium-5-amine dihydrochloride (Intermediate 34, 75 mg, 0.23 mmol; prepared as described in the synthesis of Intermediate 24) and DIPEA (118 mg, 0.91 mmol) in dry THF (1 mL). The reaction mixture was stirred at rt for 5 min before being diluted with water and extracted with EtOAC (2). The organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give a residue which was purified by chromatography on silica gel (eluent gradient from 0% to 100% EtOAc in petroleum ether) to yield the title compound as a white powder (49 mg, 49%). LCMS (ES) m/z calculated for C.sub.15H.sub.81IBrF.sub.3N.sub.6O.sub.5 442.00; found 441-443 (MH).sup.. HPLC t.sub.R 1.61 min.

Step 2: (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Example 126)

[0524] A degassed suspension of [3-[(5-bromo-2-pyridyl)methyl]oxadiazol-3-ium-5-yl]-[[5-(trifluoromethyl)-3-pyridyl]carbamoyl]azanide (Intermediate 35, 20 mg, 0.045 mmol), Pd(dppf)Cl.sub.2 (3.3 mg, 0.006 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (12.7 mg, 0.09 mmol) and K.sub.3PO.sub.4 (28.7 mg, 0.14 mmol) in a mixture of dioxane (1 mL) and H.sub.2O (0.1 mL) was stirred at 75 C. for 1 h. After cooling the reaction mixture was filtered on a pad of solka floc and the filtrate was evaporated under reduced pressure to get a residue which was purified by flash chromatography on silica gel (eluting with 0-100% MeCN in water) to afford the title compound as a white solid (12.0 mg, 57%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.98 (br s, 1H), 8.92 (d, J=2.3 Hz, 1H), 8.67 (dd, J1=2.3 Hz, J.sub.2=0.6 Hz, 1H), 8.55 (t, J=2.0 Hz, 1H), 8.49-8.47 (m, 1H), 8.30 (s, 1H), 8.01 (dd, J1=8.1 Hz, J.sub.2=2.3 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 6.02 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.16F.sub.3N.sub.7O.sub.3 459.13; found 458 (MH).sup.. HPLC t.sub.R 1.52 min.

[0525] Examples 125, 128, 147, 150, 152, 153, 154, 156, 157, 158, 161, 166, 168 and 171 were synthesized according to the above procedure (Scheme 24) by reacting with the appropriate commercially materials.

Example 125: (3-((5-(pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0526] The title compound was obtained as a white solid reacting 5-pyrimidyl boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.98 (s, 1H), 9.25 (s, 2H), 9.06 (dd, J.sub.1=2.3 Hz, J.sub.2=0.7 Hz, 1H), 8.92 (d, J=2.4 Hz, 1H), 8.55 (br t, J=2.1 Hz, 1H), 8.48 (br d, J=1.0 Hz, 1H), 8.39 (dd, J1=8.1 Hz, J.sub.2=2.4 Hz, 1H), 8.29 (s, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.53 (br s, 1H), 6.05 (s, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.13F.sub.3N.sub.8O.sub.2 442.11; found 441 (MH).sup.. HPLC t.sub.R 1.21 min.

Example 128: (3-((5-(5-methylpyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0527] The title compound was obtained as a white solid reacting 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.99 (br s, 1H), 9.24 (s, 1H), 9.14 (d, J=0.9 Hz, 1H), 8.93 (d, J=2.3 Hz, 1H), 8.78 (dd, J1=2.3 Hz, J.sub.2=0.8 Hz, 1H), 8.55 (br t, J=2.0 Hz, 1H), 8.50-8.47 (m, 1H), 8.32 (s, 1H), 8.16 (dd, J1=8.1 Hz, J.sub.2=2.3 Hz, 1H), 7.84 (d, J=7.5 Hz, 1H), 6.07 (s, 2H), 2.35 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.15F.sub.3N.sub.8O.sub.2 456.13; found 455 (MH).sup.. HPLC t.sub.R 1.19 min.

Example 147: ((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)(3-((5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0528] The title compound was obtained as a white solid reacting 1,3,5-trimethyl-4-(tetramethyl-1,3,3-dioxaborolan-2-yl)-1H-pyrazole. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.98 (br s, 1H), 8.92 (d, J=2.3 Hz, 1H), 8.55 (br t, J=2.1 Hz, 1H), 8.52 (dd, J.sub.1=2.3 Hz, J.sub.2=0.8 Hz, 1H), 8.50-8.45 (m, 1H), 8.29 (s, 1H), 7.83 (dd, J.sub.1=8.1 Hz, J.sub.2=2.3 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 5.98 (s, 2H), 3.72 (s, 3H), 2.24 (s, 3H), 3.14 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.19F.sub.3N.sub.8O.sub.2 472.16; found 471 (MH).sup.. HPLC t.sub.R 1.37 min.

Example 150: (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)amide

[0529] The title compound was obtained as a yellow solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.76 (br s, 1H), 8.67-8.66 (m, 1H), 8.25 (s, 1H), 8.24-8.21 (m, 1H), 8.00 (dd, J1=8.1 Hz, J.sub.2=2.3 Hz, 1H), 7.79-7.75 (m, 2H), 7.38 (t, J=9.9 Hz, 1H), 6.00 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.16F.sub.4N.sub.6O.sub.3 476.12; found 475 (MH).sup.. HPLC t.sub.R 1.77 min.

Example 152: (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0530] The title compound was obtained as a white solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.18 (br s, 1H), 8.67 (s, 1H), 8.47 (d, J=5.4 Hz, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 8.01 (dd, J.sub.1=8.0 Hz, J.sub.2=1.7 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.71 (br d, J=4.8 Hz, 1H), 6.04 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 66.92 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.16F.sub.3N.sub.7O.sub.3 459.13; found 458 (MH).sup.. HPLC t.sub.R 1.49 min.

Example 153: (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)amide

[0531] The title compound was obtained as a white solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.93 (br s, 1H), 8.67 (s, 1H), 8.27 (s, 1H), 8.00 (dd, J1=7.9 Hz, J.sub.2=1.6 Hz, 1H), 7.90 (s, 1H), 7.78-7.74 (m, 2H), 7.13 (d, J=8.2 Hz, 1H), 6.02 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.54 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.16F.sub.4N.sub.6O.sub.3 476.12; found 475 (MH).sup.. HPLC t.sub.R 1.86 min.

Example 154: (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)thiazol-5-yl)carbamoyl)amide

[0532] The title compound was obtained as a white solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.19 (br s, 1H), 8.66 (s, 1H), 8.34 (s, 1H), 8.00 (dd, J1=8.0 Hz, J.sub.2=1.7 Hz, 1H), 8.77 (d, J=8.1 Hz, 1H), 7.52 (s, 1H), 6.05 (s, 2H), 2.43 (s, 3H), 2.26 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 58.95 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.14F.sub.3N.sub.7O.sub.3S 465.08; found 464 (MH).sup.. HPLC t.sub.R 1.60 min.

Example 156: (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-methyl-5-(trifluoromethyl)phenyl)carbamoyl)amide

[0533] The title compound was obtained as a white solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.65 (s, 1H), 8.67 (d, J=2.3 Hz, 1H), 8.24 (s, 1H), 8.01-7.98 (m, 2H), 7.77 (d, J=7.9 Hz, 1H), 7.58 (s, 1H), 7.05 (s, 1H), 5.99 (s, 2H), 2.44 (s, 3H), 2.32 (s, 3H), 2.26 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.23 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.19F.sub.3N.sub.6O.sub.3 472.15; found 471 (MH).sup.. HPLC t.sub.R 1.87 min.

Example 157: ((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0534] The title compound was obtained as a yellow solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid. .sup.1H NMR (600 MHz, DMSO-d.sub.6) 9.85 (s, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.34 (d, J=2.6 Hz, 1H), 8.27 (s, 1H), 8.00 (dd, J1=7.9 Hz, J.sub.2=2.3 Hz, 1H), 7.76 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.9 Hz, 1H), 6.01 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.39 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.16ClF.sub.3N.sub.6O.sub.3 492.09; found 491 (MH).sup.. HPLC t.sub.R 1.90 min.

Example 158: (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)amide

[0535] The title compound was obtained as a yellow solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.60 (br s, 1H), 8.67 (s, 1H), 8.23 (s, 1H), 8.16 (br s, 1H), 8.00 (dd, J.sub.1=8.1 Hz, J.sub.2=1.8 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.64 (br d, J=8.1 Hz, 1H), 7.27 (t, J=8.4 Hz, 1H), 5.99 (s, 2H), 2.44 (s, 3H), 2.35 (s, 3H), 2.26 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 60.34 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.19F.sub.3N.sub.6O.sub.3 472.15; found 471 (MH).sup.. HPLC t.sub.R 1.82 min.

Example 161: (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)amide

[0536] The title compound was obtained as a yellow solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.82 (s, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.37 (d, J=8.6 Hz, 1H), 8.25 (s, 1H), 8.00 (dd, J1=8.2 Hz, J.sub.2=2.3 Hz, 1H), 7.96 (t, J=8.1 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.42 (d, J=7.2 Hz, 1H), 6.04 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 66.60 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.16F.sub.3N.sub.7O.sub.3 459.13; found 458 (MH).sup.. HPLC t.sub.R 1.67 min.

Example 166: (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)thiazol-2-yl)carbamoyl)amide

[0537] The title compound was obtained as a white solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.85 (br s, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.40 (s, 1H), 8.01 (dd, J=7.9 Hz, J.sub.2=2.3 Hz, 1H), 7.92 (d, J=1.3 Hz, 1H), 7.78 (br d, J=7.9 Hz, 1H), 6.07 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 52.55 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.14F.sub.3N.sub.7O.sub.3S 465.08; found 464 (MH).sup.. HPLC t.sub.R 1.65 min.

Example 168: ((3-(difluoromethyl)phenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0538] The title compound was obtained as a white solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.61 (br s, 1H), 8.67 (dd, J.sub.1=2.2 Hz, J.sub.2=0.7 Hz, 1H), 8.20 (s, 1H), 8.02-7.97 (m, 2H), 7.77 (d, J=7.6 Hz, 1H), 7.67-7.64 (m, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.09-7.07 (m, 1H), 6.95 (s, 1H), 5.99 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.18F.sub.2N.sub.6O.sub.3 440.14; found 439 (MH).sup.. HPLC t.sub.R 1.55 min.

Example 171: (3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((4-(trifluoromethyl)pyrimidin-2-yl)carbamoyl)amide

[0539] The title compound was obtained as a white solid reacting (3,5-dimethylisoxazol-4-yl)boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.26 (s, 1H), 8.89 (d, J=4.9 Hz, 1H), 8.68 (d, J=2.1 Hz, 1H), 8.29 (s, 1H), 8.01 (dd, J.sub.1=8.0 Hz, J.sub.2=2.3 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.47 (d, J=5.0 Hz, 1H), 6.03 (s, 2H), 2.43 (s, 3H), 2.25 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 68.87 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.15F.sub.3N.sub.8O.sub.3 460.12; found 459 (MH).sup.. HPLC t.sub.R 1.34 min.

Example 133: (3-((5-(2-methoxy-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

##STR00042##

Step 1: (3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Intermediate 36)

[0540] A degassed suspension of Pd(dppf)Cl.sub.2 (6.6 mg, 0.009 mmol), (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Intermediate 35, 40 mg, 0.09 mmol), 4,4,4,4,5,5,5,5-octamethyl-2,2-bis(1,3,2-dioxaborolane) (45.8 mg, 0.18 mmol) and KOAc (26.6 mg, 0.27 mmol) in dry dioxane (1 mL) was stirred at 75 C. for 2 h before being cooled and filtered through a pad of Solca Floc. The filtrate was concentrated in vacuo to give a residue which was used for the next step without further purification.

Step 2: (3-((5-(2-methoxy-4-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Example 133)

[0541] A degassed suspension of (3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide (Intermediate 36, 44 mg, 0.09 mmol), Pd(dppf)Cl.sub.2 (6.6 mg, 0.01 mmol), 5-bromo-2-methoxy-4-methylpyrimidine (36.6 mg, 0.18 mmol) and K.sub.3PO.sub.4 (57.3 mg, 0.27 mmol) in a mixture of dioxane (1 mL) and H.sub.2O (0.1 mL) was stirred at 75 C. for 1 h. After cooling the reaction mixture was filtered on a pad of solka floc and the title compound was obtained after purification by RP-HPLC using water (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column) to give the title compound as a white solid (14 mg, 30%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.99 (br s, 1H), 8.93 (d, J=2.1 Hz, 1H), 8.68 (br s, 1H), 8.55 (br s, 1H), 8.50 (s, 1H), 8.49-8.45 (m, 1H), 8.30 (s, 1H), 8.08-8.04 (m, 1H), 7.78 (d, J=8.1 Hz, 1H), 6.04 (s, 2H), 3.95 (s, 3H), 2.41 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.17F.sub.3N.sub.8O.sub.3 486.14; found 485 (MH).sup.. HPLC t.sub.R 1.43 min.

[0542] Examples 136, 137, 140, 141, 144, 145, 149 and 178 were synthesized according to the above procedure (Scheme 25) by reacting intermediate 36 with the appropriate starting materials.

Example 136: (3-((5-(4-methoxy-6-methylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0543] The title compound was obtained as a white solid reacting 5-bromo-4-methoxy-6-methyl-pyrimidine. LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.17F.sub.3N.sub.8O.sub.3 486.14; found 385 (MH).sup.. HPLC t.sub.R 1.36 min.

Example 137: ((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)(3-((5-(4-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0544] The title compound was obtained as a white solid reacting 5-bromo-4-(trifluoromethyl)-pyrimidine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.98 (br s, 1H), 9.52 (s, 1H), 9.18 (s, 1H), 8.93 (d, J=2.3 Hz, 1H), 8.70 (d, J=2.1 Hz, 1H), 8.55 (br s, 1H), 8.48 (d, J=1.0 Hz, 1H), 8.32 (s, 1H), 8.08 (dd, J.sub.1=8.1 Hz, J.sub.2=2.2 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 6.09 (s, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.12F.sub.6N.sub.8O.sub.2 510.10; found 509 (MH).sup.. HPLC t.sub.R 1.55 min.

Example 140: (3-((5-(1,4-dimethyl-1H-imidazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0545] The title compound was obtained as a white solid reacting 5-bromo-1,4-dimethyl-imidazole. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.99 (br s, 1H), 8.92 (br s, 1H), 8.65 (br s, 1H), 8.55 (br s, 1H), 8.48 (br s, 1H), 8.30 (br s, 1H), 8.00-7.97 (m, 1H), 7.77-7.75 (m, 1H), 7.66 (s, 1H), 6.04 (s, 2H), 3.56 (s, 3H), 2.12 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.17F.sub.3N.sub.8O.sub.2 458.14; found 457 (MH).sup.. HPLC t.sub.R 0.94 min.

Example 141: (3-((2-methyl-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0546] The title compound was obtained as a white solid reacting 3-bromo-2-methyl-pyridine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.99 (br s, 1H), 8.93 (d, J=2.3 Hz, 1H), 8.66 (d, J=1.6 Hz, 1H), 8.55 (br t, J=2.3 Hz, 1H), 8.52 (dd, J1=4.8 Hz, J.sub.2=1.7 Hz, 1H), 8.48 (br s, 1H), 8.31 (s, 1H), 8.03 (dd, J1=8.0 Hz, J.sub.2=2.3 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.70 (dd, J1=7.8 Hz, J.sub.2=1.8 Hz, 1H), 7.36 (dd, J.sub.1=7.8 Hz, J.sub.2=5.1 Hz, 1H), 6.04 (s, 2H), 2.45 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.16F.sub.3N.sub.7O.sub.2 455.13; found 454 (MH).sup.. HPLC t.sub.R 0.99 min.

Example 144: (3-((5-(4-cyanopyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0547] The title compound was obtained as a white solid reacting 5-bromo-pyrimidine-4-carbonitrile. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.99 (br s, 1H), 9.48 (s, 1H), 9.36 (s, 1H), 8.94 (dd, J.sub.1=8.5 Hz, J.sub.2=2.3 Hz, 2H), 8.55 (br s, 1H), 8.48 (br s, 1H), 8.36 (dd, J.sub.1=8.1 Hz, J.sub.2=2.3 Hz, 1H), 8.33 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 6.11 (s, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.12F.sub.3N.sub.9O.sub.2 467.11; found 466 (MH).sup.. HPLC t.sub.R 1.40 min.

Example 145: (3-((5-(pyridazin-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0548] The title compound was obtained as a yellow solid reacting 4-bromo-pyridazine hydrobromide. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.98 (br s, 1H), 9.74 (dd, J.sub.1=2.5 Hz, J.sub.2=1.3 Hz, 1H), 9.36 (dd, J.sub.1=5.4 Hz, J.sub.2=1.2 Hz, 1H), 9.15 (d, J=1.8 Hz, 1H), 8.93 (d, J=2.3 Hz, 1H), 8.55 (br s, 1H), 8.50-8.47 (m, 2H), 8.30 (s, 1H), 8.13 (dd, J.sub.1=5.4 Hz, J.sub.2=2.5 Hz, 1H), 7.86 (d, J=8.1 Hz, 1H), 6.07 (s, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.19H.sub.13F.sub.3N.sub.8O.sub.2 442.11; found 441 (MH).sup.. HPLC t.sub.R 1.15 min.

Example 149: (3-((4-methyl-[3,3-bipyridin]-6-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0549] The title compound was obtained as a white solid reacting 3-bromo-4-methyl-pyridine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.99 (br s, 1H), 8.93 (d, J=2.3 Hz, 1H), 8.68-8.67 (m, 1H), 8.57-8.55 (m, 1H), 8.50-8.47 (m, 2H), 8.44 (s, 1H), 8.32 (s, 1H), 8.04 (dd, J.sub.1=8.0 Hz, J.sub.2=2.4 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.39 (d, J=5.0 Hz, 1H), 6.05 (s, 2H), 2.29 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.16F.sub.3N.sub.7O.sub.2 455.13; found 454 (MH).sup.. HPLC t.sub.R 1.04 min.

Example 178: (3-((5-(1,4-dimethyl-1H-pyrazol-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((5-(trifluoromethyl)pyridin-3-yl)carbamoyl)amide

[0550] The title compound was obtained as a white solid reacting 5-bromo-1,4-dimethyl-1H-pyrazole. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.99 (s, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 8.48 (s, 1H), 8.33 (s, 1H), 8.04 (dd, J.sub.1=8.1 Hz, J.sub.2=2.2 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.39 (s, 1H), 6.05 (s, 2H), 3.74 (s, 3H), 1.98 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.21 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.17F.sub.3N.sub.8O.sub.2 458.14; found 457 (MH).sup.. HPLC t.sub.R 1.40 min.

Example 167: (3-((5-(3,5-dimethylisoxazol-4-yl)pyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

##STR00043##

Step 1: 2-(((5-bromopyrimidin-2-yl)methyl)amino)acetonitrile (Intermediate 37)

[0551] A suspension of (5-bromopyrimidin-2-yl)-methanamine (500 mg, 2.7 mmol) in MeCN (1.9 mL) was treated with DIPEA (687 mg, 5.3 mmol) and 2-bromoacetonitrile (351 mg, 2.9 mmol) and stirred at 60 C. for 2 h before being cooled, diluted with EtOAC, washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get a residue which was purified by chromatography on silica gel (eluent gradient from 10% to 100% EtOAc in petroleum ether) to afford the title compound as an orange powder (410 mg, 68%). .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.97 (s, 2H), 3.93 (d, J=5.9 Hz, 2H), 3.72 (d, J=5.8 Hz, 2H), 3.14-3.12 (m, 1H). LCMS (ES.sup.+) m/z calculated for C.sub.7H.sub.7BrN.sub.4 225.99; found 226-228 (M+H).sup.+. HPLC t.sub.R 0.62 min.

Step 2: 5-amino-3-((5-bromopyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 38)

[0552] A solution of 2-[(5-bromopyrimidin-2-yl)methylamino]acetonitrile (Intermediate 37, 390 mg, 1.72 mmol) in THF (2.2 mL) was treated with nitrous acid-{tert}-butyl ester (530 mg, 5.15 mmol) and stirred at rt for 30 min before being diluted with EtOAc, washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford N-[(5-bromopyrimidin-2-yl)methyl]-N-(cyanomethyl)nitrous amide (440 mg, 100%) as a brown residue which was used without further purification in the following step. The resulting intermediate N-[(5-bromopyrimidin-2-yl)methyl]-N-(cyanomethyl)nitrous amide (440 mg, 1.72 mmol) was dissolved in dioxane (2.2 mL) and treated with trimethylsilyl trifluoromethanesulfonate (1.53 g, 6.87 mmol) and HCl (4 M in dioxane; 2.2 mL, 8.8 mmol). The resulting reaction mixture was stirred at rt for 1 h 30 min before being quenched with water and concentrated under reduced pressure to get a residue which was dissolved in a mixture of MeCN/water (1:1) and lyophilized. The title compound was obtained as a brown oily residue (1.68 g, 100%) and used in the following step without further purification. .sup.1H NMR (600 MHz, DMSO-d.sub.6) 9.57 (s, 2H), 9.10 (s, 2H), 8.10 (s, 1H), 6.22 (s, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.7H.sub.7BrClN.sub.5O 255.98 (parent); found 256-258 (M+H).sup.+. HPLC t.sub.R 0.46 min.

Step 3: (3-((5-bromopyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Intermediate 39)

[0553] A suspension of 5-amino-3-((5-bromopyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 38, 570 mg, 0.52 mmol) in anhydrous MeCN (1.5 mL) was treated at 0 C. with anhydrous pyridine (330 mg, 4.2 mmol) and 1-isocyanato-3-(trifluoromethyl)benzene (107 mg, 0.57 mmol) and stirred at rt for 5 minutes before being quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a crude product which was purified by chromatography on silica gel (eluent gradient from 10% to 100% EtOAc in petroleum ether) to afford the title compound as a pale-yellow powder (205 mg, 89%). .sup.1H NMR (600 MHz, DMSO-d.sub.6) 9.75 (s, 1H), 9.09 (s, 2H), 8.28 (s, 1H), 8.20 (s, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.23 (d, J=7.9 Hz, 1H), 6.12 (s, 2H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.15H.sub.10BrF.sub.3N.sub.6O.sub.2 442.00; found 441 (MH).sup.. HPLC t.sub.R 1.75 min.

Step 4: (3-((5-(3,5-dimethylisoxazol-4-yl)pyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Example 167)

[0554] A degassed suspension of (3-((5-bromopyrimidin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide (Intermediate 39, 30 mg, 0.068 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (19.1 mg, 0.14 mmol), Pd(dppf)Cl.sub.2 (5 mg, 0.0068 mmol) and K.sub.3PO.sub.4 (43.1 mg, 0.20 mmol) in a mixture of dioxane (1 mL) and water (0.1 mL) was heated at 80 C. for 1 h before being cooled at rt, diluted with EtOAc and washed with water and brine, dried over Na.sub.2SO.sub.4 and evaporated in vacuo. The title compound was obtained after purification by RP-HPLC using water and MeCN as eluents (C18 column) to give the title compound as a beige solid (18 mg, 56%). .sup.1H NMR (600 MHz, DMSO-d.sub.6) 9.75 (br s, 1H), 8.99 (s, 2H), 8.32 (s, 1H), 8.21 (s, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.23 (d, J=7.9 Hz, 1H), 6.20 (s, 2H), 2.47 (s, 3H), 2.28 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.16F.sub.3N.sub.7O.sub.3 459.13; found 458 (MH).sup.. HPLC t.sub.R 1.71 min.

[0555] Examples 169, 173, 174, 183 and 184 were synthesized according to the above procedure (Scheme 26) by reacting with the appropriate starting materials.

Example 169: (3-((5-(3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0556] The title compound was obtained as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.75 (br s, 1H), 9.00 (s, 1H), 8.90 (d, J=1.4 Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 7.73 (br d, J=8.1 Hz, 1H), 7.46-7.42 (m, 1H), 7.23 (br d, J=7.8 Hz, 1H), 6.07 (s, 2H), 2.62 (s, 3H), 2.42 (s, 3H). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.16F.sub.3N.sub.7O.sub.3 459.13; found 458 (MH).sup.. HPLC t.sub.R 1.76 min.

Example 173: (3-((6-(3,5-dimethylisoxazol-4-yl)pyridazin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0557] The title compound was obtained as a beige solid. .sup.1H NMR (600 MHz, DMSO-d.sub.6) 9.75 (s, 1H), 8.34 (s, 1H), 8.21 (s, 1H), 8.07-8.02 (m, 2H), 7.74 (d, J=8.6 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.23 (d, J=7.9 Hz, 1H), 6.20 (s, 2H), 2.61 (s, 3H), 2.41 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.16F.sub.3N.sub.7O.sub.3 459.13; found 458 (MH).sup.. HPLC t.sub.R 1.64 min.

Example 174: (3-((2-(3,5-dimethylisoxazol-4-yl)pyrimidin-5-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0558] The title compound was obtained as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (s, 1H), 9.10 (s, 2H), 8.37 (s, 1H), 8.23 (s, 1H), 7.72 (br d, J=8.1 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 5.88 (s, 2H), 2.77 (s, 3H), 2.52 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.29 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.20H.sub.16F.sub.3N.sub.7O.sub.3 459.13; found 458 (MH).sup.. HPLC t.sub.R 1.83 min.

Example 183: (3-((4,6-dimethyl-[5,5-bipyrimidin]-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0559] The title compound was obtained as a beige solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.77 (s, 1H), 8.96 (s, 3H), 8.36 (s, 1H), 8.21 (s, 1H), 7.76 (br d, J=8.3 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.23 (d, J=7.1 Hz, 1H), 6.23 (s, 2H), 2.25 (s, 6H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.17F.sub.3N.sub.8O.sub.2 470.14; found 469 (MH).sup.. HPLC t.sub.R 1.51 min.

Example 184: (3-((6-(4,6-dimethylpyrimidin-5-yl)pyridazin-3-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-(trifluoromethyl)phenyl)carbamoyl)amide

[0560] The title compound was obtained as a pale pink solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.77 (s, 1H), 9.02 (s, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 8.13 (d, J=8.6 Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 6.26 (s, 2H), 2.22 (s, 6H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 61.28 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.17F.sub.3N.sub.8O.sub.2 470.14; found 469 (MH).sup.. HPLC t.sub.R 1.43 min.

Example 142: ((3-cyclopropylphenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

##STR00044##

Step 1: (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-cyclopropylphenyl)carbamoyl)amide (Intermediate 40)

[0561] A mixture of 3-cyclopropylaniline (62 mg, 0.47 mmol) and diphosgene (280 mg, 1.4 mmol) in dry dioxane (9.3 mL) was heated at 60 C. for 20 h. After cooling the solvent was removed under reduced pressure. The obtained 1-cyclopropyl-3-isocyanato-benzene (53.2 mg, 0.334 mmol) and anhydrous pyridine (192 mg, 2.43 mmol) were added dropwise simultaneously at 0 C. to a stirred suspension of 3-[(5-bromo-2-pyridyl)methyl]oxadiazol-3-ium-5-amine dihydrochloride (Intermediate 34, 100 mg, 0.304 mmol) in anhydrous MeCN (0.9 mL) and the reaction mixture was stirred 5 min at rt before being quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give a crude product which was purified by chromatography on silica gel (eluent gradient from 5% to 100% EtOAc in petroleum ether) to afford the title compound as a yellow powder (86 mg, 68%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.24 (br s, 1H), 8.75 (s, 1H), 8.20 (dd, J.sub.1=8.3 Hz, J.sub.2=2.0 Hz, 1H), 8.13 (s, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.06 (t, J=7.9 Hz, 1H), 6.63 (d, J=7.7 Hz, 1H), 5.91 (s, 2H), 1.85-1.78 (m, 1H), 0.93-0.89 (m, 2H), 0.61-0.57 (m, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.18H.sub.16BrN.sub.5O.sub.2 413.05; found 412-414 (MH).sup.. HPLC t.sub.R 1.73 min.

Step 2: ((3-cyclopropylphenyl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide (Example 142)

[0562] A degassed suspension of (3-((5-bromopyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)((3-cyclopropylphenyl)carbamoyl)amide (Intermediate 40, 25 mg, 0.06 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (17 mg, 0.12 mmol), Pd(dppf)Cl.sub.2 (4.4 mg, 0.006 mmol) and K.sub.3PO.sub.4 (38 mg, 0.18 mmol) in a mixture of dioxane (1 mL) and water (0.1 mL) was heated at 80 C. for 1.5 h before being cooled at rt, diluted with EtOAc and washed with water and brine, dried over Na.sub.2SO.sub.4 and evaporated in vacuo to give a crude product which was purified by chromatography on silica gel (eluent gradient from 5% to 100% EtOAc in petroleum ether) to afford the title compound as a yellow powder (15.5 mg, 58%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.24 (br s, 1H), 8.67 (s, 1H), 8.17 (s, 1H), 8.00 (dd, J.sub.1=7.9 Hz, J.sub.2=2.0 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.06 (t, J=7.9 Hz, 1H), 6.63 (br d, J=7.5 Hz, 1H), 5.97 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H), 1.85-1.78 (m, 1H), 0.93-0.89 (m, 2H), 0.61-0.57 (m, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.22N.sub.6O.sub.3 430.18; found 429 (MH).sup.. HPLC t.sub.R 1.65 min.

[0563] Examples 182 and 146 were synthesized according to the above procedure (Scheme 27) by reacting the appropriate starting materials.

Example 182: ((3-cyclopropylphenyl)carbamoyl)(3-((5-(4,6-dimethylpyrimidin-5-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0564] The title compound was obtained as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.26 (br s, 1H), 8.94 (s, 1H), 8.59 (d, J=1.9 Hz, 1H), 8.21 (s, 1H), 7.97 (dd, J.sub.1=7.9 Hz, J.sub.2=2.2 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.07 (t, J=7.8 Hz, 1H), 6.63 (br d, J=7.8 Hz, 1H), 6.02 (s, 2H), 2.21 (s, 6H), 1.85-1.78 (m, 1H), 0.93-0.89 (m, 2H), 0.61-0.57 (m, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.24H.sub.23N.sub.7O.sub.2 441.19; found 440 (MH).sup.. HPLC t.sub.R 1.43 min.

Example 146: ((5-cyclopropylpyridin-3-yl)carbamoyl)(3-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)methyl)-1,2,3-oxadiazol-3-ium-5-yl)amide

[0565] The title compound was obtained as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.47 (br s, 1H), 8.67 (dd, J.sub.1=2.3 Hz, J.sub.2=0.7 Hz, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.23 (s, 1H), 8.00 (dd, J.sub.1=8.1 Hz, J.sub.2=2.3 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.73 (br t, J=2.1 Hz, 1H), 5.99 (s, 2H), 2.44 (s, 3H), 2.25 (s, 3H), 1.92-1.86 (m, 1H), 1.00-0.96 (m, 2H), 0.66-0.62 (m, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.21N.sub.7O.sub.3 431.17; found 430 (MH).sup.. HPLC t.sub.R 1.01 min.

Example 185: (3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

##STR00045##

Step 1: (3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Intermediate 41)

[0566] A mixture of triphosgene (204 mg, 0.69 mmol), 2-(trifluoromethyl)pyridine-4-amine (222 mg, 1.4 mmol) and DIPEA (0.48 mL, 2.7 mmol) in dry THF (5.3 mL) was stirred at rt for 1 h before being added dropwise to a stirring suspension of 5-amino-3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium chloride (Intermediate 32, 200 mg, 0.69 mmol) in dry THF (2.0 mL). The resulting mixture was treated with DIPEA (0.48 mL, 2.7 mmol) at 0 C. and stirred 5 min at rt before being diluted with water and extracted with EtOAc (2). The collected organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give a crude product which was purified by chromatography on silica gel (eluent gradient from 0% to 100% EtOAc in petroleum ether) to afford the title compound as a yellow powder (190 mg, 62%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.17 (s, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.31 (s, 1H), 8.20 (d, J=1.8 Hz, 1H), 7.70-7.67 (m, 3H), 7.57-7.53 (m, 2H), 5.81 (s, 2H). LCMS (ES.sup.+) m/z calculated for C.sub.16H.sub.11BrF.sub.3N.sub.5O.sub.2 441.00; found 440-442 (MH).sup.. HPLC t.sub.R 1.81 min.

Step 2: (3-(4-(4,6-dimethylpyrimidin-5-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Example 185)

[0567] A degassed suspension of (3-(4-bromobenzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide (Intermediate 41, 139 mg, 0.31 mmol), 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (149 mg, 0.63 mmol), Pd(dppf)Cl.sub.2 (23 mg, 0.03 mmol) and K.sub.3PO.sub.4 (200 mg, 0.94 mmol) in a mixture of dioxane (1 mL) and water (0.1 mL) was heated at 75 C. for 1 h before being cooled at rt, diluted with EtOAc and washed with water and brine, dried over Na.sub.2SO.sub.4 and evaporated in vacuo to give a crude product which was purified by chromatography on silica gel (C18 RP; eluent gradient from 5% to 100% MeCN in H.sub.2O) to afford a residue which was dissolved in EtOAc and washed with HCl (1N aqueous solution). The aqueous phase was neutralized with NaHCO.sub.3 (sat. aqueous solution) and extracted with EtOAc. The organic phase was dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to get the title compound (70.3 mg, 48%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.19 (s, 1H), 8.90 (s, 1H), 8.47 (d, J=5.6 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.72-7.68 (m, 3H), 7.42 (d, J=8.1 Hz, 2H), 5.91 (s, 2H), 2.18 (s, 6H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 66.93 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.18F.sub.3N.sub.7O.sub.2 469.15; found 468 (MH).sup.. HPLC t.sub.R 1.43 min.

[0568] Examples 186, 189, 188, 190 and 191 were synthesized according to the above procedure (Scheme 28) by reacting with the appropriate starting materials.

Example 186: (3-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0569] The title compound was obtained as a white solid by reacting (3,5-dimethylisoxazol-4-yl)boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.18 (br s, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 7.68 (br d, J=8.3 Hz, 3H), 7.50 (br d, J=8.1 Hz, 2H), 5.87 (s, 2H), 2.41 (s, 3H), 2.24 (s, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 66.93 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.21H.sub.17F.sub.3N.sub.6O.sub.3 458.13; found 457 (MH).sup.. HPLC t.sub.R 1.68 min.

Example 189: (R)-(3-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0570] The title compound was obtained as a white solid by reacting (3,5-dimethylisoxazol-4-yl)boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.17 (br s, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.38 (s, 1H), 8.23 (br d, J=1.6 Hz, 1H), 7.71 (br d, J=8.3 Hz, 2H), 7.66 (br dd, J.sub.1=5.5 Hz, J.sub.2=1.6 Hz, 1H), 7.50 (br d, J=8.2 Hz, 2H), 6.25 (q, J=7.0 Hz, 1H), 2.41 (s, 3H), 2.24 (s, 3H), 2.06 (d, J=7.0 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 66.92 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.19F.sub.3N.sub.6O.sub.3 472.15; found 471 (MH).sup.. HPLC t.sub.R 1.77 min.

Example 188: (R)-(3-(1-(4-(4,6-dimethylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0571] The title compound was obtained as a white solid by reacting 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.18 (br s, 1H), 8.89 (s, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.41 (s, 1H), 8.24 (br d, J=1.6 Hz, 1H), 7.74 (br d, J=8.3 Hz, 2H), 7.67 (br dd, J.sub.1=5.5 Hz, J.sub.2=1.8 Hz, 1H), 7.43 (br d, J=8.3 Hz, 2H), 6.29 (q, J=7.1 Hz, 1H), 2.18 (s, 6H), 2.08 (d, J=7.0 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 66.92 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.20F.sub.3N.sub.7O.sub.2 483.16; found 482 (MH).sup.. HPLC t.sub.R 1.52 min.

Example 190: (S)-(3-(1-(4-(4,6-dimethylpyrimidin-5-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0572] The title compound was obtained as a white solid by reacting 4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.18 (br s, 1H), 8.90 (s, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.41 (s, 1H), 8.24 (br d, J=1.9 Hz, 1H), 7.74 (br d, J=8.3 Hz, 2H), 7.67 (br dd, J.sub.1=5.6 Hz, J.sub.2=1.9 Hz, 1H), 7.43 (br d, J=8.3 Hz, 2H), 6.29 (q, J=6.9 Hz, 1H), 2.18 (s, 6H), 2.08 (d, J=7.1 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 66.92 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.23H.sub.20F.sub.3N.sub.7O.sub.2 483.16; found 482 (MH).sup.. HPLC t.sub.R 1.51 min.

Example 191: (S)-(3-(1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)-1,2,3-oxadiazol-3-ium-5-yl)((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)amide

[0573] The title compound was obtained as a pale yellow solid by reacting (3,5-dimethylisoxazol-4-yl)boronic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.17 (br s, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.38 (s, 1H), 8.23 (br d, J=1.8 Hz, 1H), 7.71 (br d, J=8.3 Hz, 2H), 7.66 (br dd, J.sub.1=5.5 Hz, J.sub.2=1.9 Hz, 1H), 7.50 (br d, J=8.4 Hz, 2H), 6.26 (q, J=6.8 Hz, 1H), 2.41 (s, 3H), 2.24 (s, 3H), 2.06 (d, J=7.1 Hz, 3H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) 66.92 (s, 3F). LCMS (ES.sup.+) m/z calculated for C.sub.22H.sub.19F.sub.3N.sub.6O.sub.3 472.15; found 471 (MH).sup.. HPLC t.sub.R 1.77 min.

Biology

ZIKV Protease Expression and Purification The sequence coding for NS2B (aa 49-95, R95A) and NS3 (aa 1-170, R29G) were synthesized (GenScript, Piscataway, New Jersey, United States), cloned in pET15b vector downstream the sequence for 6His tag and fused by a not cleavable linker (G4SG4). The protease was expressed in E. coli BL21 (DE3) cells: bacteria were grown in LB medium at 37 C. up to 0.8 O.D. 600, then the temperature was lowered to 20 C. and protein expression induced with 0.5 mM IPTG (cat. N. 15502, Sigma Aldrich) for 18 h. Cells were collected by centrifugation (4000g, 4 C. for 30 min), then re-suspended (7 ml/g of cell paste) in lysis buffer (25 mM Tris pH 8.0, 100 mM NaCl, 5% glycerol) supplemented with 0.7 mg/ml of lysozyme (cat. N. 16876, Sigma Aldrich) and 25 U/ml of benzonase (cat. N. E1014, Sigma Aldrich). After incubating at 25 C. for 30 min, cells were homogenized at 800 bars by PANDA homogenizer (GEA) then cell extract was cleared by centrifugation (32914g, 4 C., 1 h), brought to 500 mM NaCl then loaded on 1 ml HisTrap HP column (cat. N. 17-52407-01, Cytiva, Sweden) equilibrated in 25 mM Tris pH 8.5, 500 mM NaCl, 5% glycerol. After three wash steps at 20, 30 and 50 mM imidazole, recombinant protein was eluted by a linear gradient up to 350 mM imidazole (cat. N. 1202, Sigma Aldrich). Fractions containing ZIKV protease were pooled and treated with 2 mM TCEP (cat. N. C4706, Sigma Aldrich) at 4 C. for 40 min, then concentrated threefold on Vivaspin 20, 3 KDa cut off device (cat. N. Z614610-48EA, Sigma Aldrich) and loaded on HiLoad 16/60 Superdex 75 column (cat. N. 28989333, Cytiva, Sweden) using 25 mM Tris pH 8.5, 5% glycerol and 1 mM DTT (cat. N. A2948, PanReac AppliChem) as mobile phase. Monomer peak fractions were collected, divided in small aliquots and frozen in liquid nitrogen.

DEN2V Protease Expression and Purification

[0574] The expression of DEN2V serine protease was performed as previously described (Acta Cryst. (2006). F62, 157-162), with few changes. The sequence coding for NS2B (aa 1394-1440, Uniprot Q91H74) and NS3 (aa 1476-1660, Uniprot Q91H74) were synthesized (GenScript, Piscataway, New Jersey, United States), cloned in pET15b vector downstream the sequence for 6His tag and fused by a not cleavable linker (G4SG4). The protease was expressed in E. coli BL21 (DE3) cells: bacteria were grown in MDG minimal not inducing medium at 25 C. for 24 h, with shaking at 300 RPM. Then the bacterial starter culture was diluted 1:20 in ZYM-5052 auto-inducing medium and let grow for additional 24 h at 25 C. with 200 RPM. Cells were collected by centrifugation (4000g, 4 C. for 30 min), then re-suspended (7 ml/g of cell paste) in lysis buffer (20 mM Tris pH 8.5, 50 mM NaCl, 5% glycerol) supplemented with 0.7 mg/ml of lysozyme (cat. N. 16876, Sigma Aldrich) and 25 U/ml of benzonase (cat. N. E1014, Sigma Aldrich). After incubating at 25 C. for 30 min, cells were homogenized at 800 bar by PANDA homogenizer (GEA) then cell extract was cleared by centrifugation (32914g, 4 C., 1 h), brought to 500 mM NaCl and loaded on 5 ml HisTrap HP column (cat. N. 17525501, Cytiva, Sweden) equilibrated in 20 mM Tris pH 8.5, 500 mM NaCl, 5% glycerol. After two wash steps at 10 and 20 mM imidazole, recombinant protein was eluted by a linear gradient up to 440 mM imidazole (cat. N. 1202, Sigma Aldrich). Fractions containing DEN2V protease were pooled, concentrated threefold on Vivaspin 20, 3 KDa cut off device (cat. N. Z614610-48EA, Sigma Aldrich) and loaded on HiLoad 16/60 Superdex 75 column (cat. N. 28989333, Cytiva, Sweden) using 20 mM Tris pH 8.5, 50 mM NaCl, 5% glycerol as mobile phase. Monomer peak fractions were collected, divided in small aliquots and frozen in liquid nitrogen.

JEV Protease Expression and Purification

[0575] The expression of JEV serine protease was performed as previously described (PLoS ONE 7(5): e36872), with few changes. The sequence coding for NS2B (aa 51-95, JEV genotype III strain JaOArS 982, Genebank accession number: M18370) and NS3 (aa 1-180, JEV genotype III strain JaOArS 982, Genebank accession number: M18370) were synthesized (GenScript, Piscataway, New Jersey, United States), cloned in pET15b vector downstream the sequence for 6His tag and fused by a cleavable linker derived from NS2B sequence (aa 121-131). The protease was expressed in E. coli BL21 (DE3) cells: bacteria were grown in MDG minimal not inducing medium at 25 C. for 24 h, with shaking at 300 RPM. Then the bacterial starter culture was diluted 1:20 in ZYM-5052 auto-inducing medium and let grow for additional 24 h at 25 C. with 200 RPM. Cells were collected by centrifugation (4000g, 4 C. for 30 min), then re-suspended (7 ml/g of cell paste) in lysis buffer (25 mM Tris pH 8.5, 100 mM NaCl, 5% glycerol) supplemented with 0.7 mg/ml of lysozyme (cat. N. 16876, Sigma Aldrich) and 25 U/ml of benzonase (cat. N. E1014, Sigma Aldrich). After incubating at 25 C. for 30 min, cells were homogenized at 800 bars by PANDA homogenizer (GEA) then cell extract was cleared by centrifugation (32914g, 4 C., 1 h), brought to 500 mM NaCl then loaded on 5 ml HisTrap HP column (cat. N. 17525501, Cytiva, Sweden) equilibrated in 25 mM Tris pH 8.5, 500 mM NaCl, 5% glycerol. After two wash steps at 10 and 30 mM imidazole, recombinant protein was eluted by a linear gradient up to 500 mM imidazole (cat. N. 1202, Sigma Aldrich). Fractions containing JEV protease were pooled then treated with 2 mM TCEP (cat. N. C4706, Sigma Aldrich) at 4 C. for 40 min, finally concentrated threefold on Vivaspin 20, 3 KDa cut off device (cat. N. Z614610-48EA, Sigma Aldrich) and loaded on HiLoad 16/60 Superdex 75 column (cat. N. 28989333, Cytiva, Sweden) using 25 mM Tris pH 9.0, 5% glycerol, 1 mM TCEP as mobile phase. Monomer peak fractions were collected, divided in small aliquots and frozen in liquid nitrogen.

ZIKV Protease Inhibition Assay

[0576] The enzyme inhibition assay was performed in 384-well flat bottom black polystyrene microplates (cat. N. 781900, Greiner,) in a reaction volume of 20 l. ZIKV NS2B-G4SG4-NS3 serine protease (MGSSHHHHHHSSGLVPRGSHMVDMYIERAGDITWEKDAEVTGNSPRLDVALDESGDF SLVEDDGPPMAGGGGSGGGGSGALWDVPAPKEVKKGETTDGVYRVMTRGLLGSTQV GVGVMQEGVFHTMWHVTKGSALRSGEGRLDPYWGDVKQDLVSYCGPWKLDAAWD GHSEVQLLAVPPGERARNIQTLPGIFKTKDGDIGAVALDYPAGTSGSPILDKCGRVIGLY GNGVVIKNGSYVSAITQGRR; SEQ. ID. No. 1) (1.25 nM) was incubated with increasing inhibitor concentrations (0.097-100 M or 0.0009-1 M for the most active compounds) in assay buffer (50 mM Tris-HCl, pH 8.5, 1% glycerol, 1 mM CHAPS, 1% DMSO) for 10 minutes at 25 C. 10 M of Bz-Nle-KRR-AMC substrate (cat. N. 4055312, Bachem) was added and the reaction mixture incubated for additional 30 minutes at 25 C. Product formation was evaluated by fluorescence measurement (excitation 360 nm, emission 465 nM), using a SPARK TM10 Tecan instrument. Results were analysed using Prism (GraphPad, San Diego, CA) and Vortex software (Dotmatics, Bioshops Stortford, UK). Dose-response curves were fitted by four-parameter logistic regression.

DEN2V Protease Inhibition Assay

[0577] The enzyme inhibition assay was performed in 384-well flat bottom black polystyrene microplates (cat. N. 781900, Greiner,) in a reaction volume of 20 l. DEN2V NS2B-G4SG4-NS3 serine protease (MGSSHI-HHIHHHSSGLVPRGSHMADLELERAADVRWEEQAEISGSSPILSITISED GSMSIKNEEEEQTLGGGGSGGGGAGVLWDVPSPPPVGKAELEDGAYRIKQKGILGYSQI GAGVYKEGTFHTMWHVTRGAVLMHKGKRIEPSWADVKKDLISYGGGWKLEGEWKE GEEVQVLALEPGKNPRAVQTKPGLFKTNTGTIGAVSLDFSPGTSGSPIVDKKGKVVGLY GNGVVTRSGAYVSAIAQTEKSIEDNPEIEDDIFRK; SEQ ID No 2) (10 nM) was incubated with increasing inhibitor concentrations (0.097-100 M or 0.0009-1 M for the most active compounds) in assay buffer (50 mM Tris-HCl, pH 8.5, 1% glycerol, 1 mM CHAPS, 1% DMSO) for 10 minutes at 25 C. 15 M of Bz-Nle-KRR-AMC substrate (cat. N. 4055312, Bachem) was added and the reaction mixture incubated for additional 30 minutes at 25 C. Product formation was evaluated by fluorescence measurement (excitation 360 nm, emission 465 nM), using a SPARK TM10 Tecan instrument. Results were analyzed using Prism (GraphPad, San Diego, CA) and Vortex software (Dotmatics, Bioshops Stortford, UK). Dose-response curves were fitted by four-parameter logistic regression.

WNV Protease Inhibition Assay

[0578] The enzyme inhibition assay was performed in 384-well flat bottom black polystyrene microplates (cat. N. 781900, Greiner,) in a reaction volume of 20 l. West Nile Virus (WNV) NS2B-NS3 protease (R&D, cat. N. 2907-SE-020) (2 nM) was incubated with increasing inhibitor concentrations (0.097-100 M or 0.0009-1 M for the most active compounds) in assay buffer (50 mM Tris-HCl, pH 9.0, 30% glycerol, 1% DMSO) for 10 minutes at 25 C. 10 M of pERTKR-AMC substrate (R&D, cat. N. ES013) was added and the reaction mixture incubated for additional 30 minutes at 25 C. Product formation was evaluated by fluorescence measurement (excitation 360 nm, emission 465 nM), using a SPARK TM10 Tecan instrument. Results were analyzed using Prism (GraphPad, San Diego, CA) and Vortex software (Dotmatics, Bioshops Stortford, UK). Dose-response curves were fitted by four-parameter logistic regression.

JEV Protease Inhibition Assay

[0579] The enzyme inhibition assay was performed in 384-well flat bottom black polystyrene microplates (cat. N. 781900, Greiner,) in a reaction volume of 20 l. Japanese encephalitis virus (JEV)-NS2B-NS3 protease (600 nM) was incubated with increasing inhibitor concentrations (0.097-100 M or 0.009-1 M for the most active compounds) in assay buffer (50 mM Tris-HCl, pH 9.0, 0.1% BSA, 0.1% Triton X-100, 1% DMSO) for 10 minutes at 25 C. 10 M of Pyr-RTKR-AMC substrate (Bachem, cat. N.4018149) was added and the reaction mixture incubated for additional 120 minutes at 25 C. Product formation was evaluated by fluorescence measurement (excitation 360 nm, emission 465 nM), using a SPARK TM10 Tecan instrument. Results were analyzed using Prism (GraphPad, San Diego, CA) and Vortex software (Dotmatics, Bioshops Stortford, UK). Dose-response curves were fitted by four-parameter logistic regression.

ZIKV Replicon Generation

[0580] To construct the subgenomic replicon we used the Natal RGN isolate of Asian lineage (GenBank: KU527068.1). In the replicon, the coding sequences of structural genes were removed with the exception of 31 amino acids at the N-terminus of the capsid protein fused with 32 amino acids at the C-terminus of the E protein. These sequences were retained to preserve the correct processing and translocation of NS1 and of the non-structural polyprotein across the endothelium reticulum membrane. An EMCV IRES was placed after the stop codon of the polyprotein. The IRES drives the translation of a downstream fusion protein consisting of a luciferase (Nano-Luc) gene followed by the ubiquitin gene (UBI), and the neomycin phosphotransferase resistance gene (NEO). This fusion protein is required for reporting purposes and to confer resistance to G-418. The sub-genomic replicon was transcribed as RNA via an upstream T7 promoter and transfected in Vero cells. The stable cell line used for the ZIKV replication assay was generated via selection with G-418.

ZIKV Replication Inhibition Assay and Cell Viability Assay

[0581] A green monkey cell line (Vero) with a stable ZIKV replicon was grown and maintained in Dulbecco's modified eagle's medium (DMEM) with high glucose and pyruvate (GIBCO #41966) completed with 10% fetal bovine serum (FBS) (Gibco #10270), 1% Penicillin Streptomycin (10 mg/ml) (Gibco #14140). 0.760 g/mL G418 solution (Sigma-Aldrich, Cat 4727894001) were used to maintain the ZIKV replication in the cells. The day of the experiment, compounds previously dissolved in 100% dimethyl sulfoxide (DMSO, Sigma-Aldrich, D5879-1L) were transferred to a 384 black plate (Greiner #781086) using an acoustic system (ATS-100 EDC). Compounds were tested in dose response. 50 M of mycophenolic acid (Sigma-Aldrich, M3536) was used in as positive control for the ZIKV replication assay while 32 M of Gambogic Acid (Sigma-Aldrich, G8171) was used as positive control for the cell viability assay. In both cases, in the negative control wells were added with 0.5% DMSO. 8000 cells/well were plated on the compound containing plates in 40 L growth medium. 72 h after the treatment at 37 C., 5% CO.sub.2 and 90% humidity, 20 L Nano-Glo (Promega #N1150) were added to reveal the NanoLuc signal, while 20 L CellTiter-Glo (Promega #G7573) were added to determine the cell viability. The luminescent signal for both assays was detected reading the plate on the Envision plate reading 10 minutes post detection reagent addition (luminescence was measured at 0.5 sec/well). Data were normalized between 0 and 100% inhibition (negative control and positive control respectively). For EC.sub.50 determinations, the dose-response was fitted with a 4-p logistic regression approach using the Dotmatics Studies software.

Results

[0582] The exemplified compounds described herein were tested in the assays described above. Results from IC.sub.50 calculation for inhibition of ZIKV protease and replicon and for the inhibition of Dengue Virus, West Nile Virus proteases are reported in the following Table 1, using the following letter codes: [0583] A: IC.sub.50 or EC.sub.50 lower than 0.1 M; B: IC.sub.50 or EC.sub.50 from 0.1 M to 1 M; C: IC.sub.50 or EC.sub.50 from 1 M to 20 M; D: IC.sub.50 or EC.sub.50 higher than 20 M; n.a.: not available.

TABLE-US-00001 Zika Zika Dengue WNV JEV Protease Replicon Protease Protease Protease Ex Structure IC.sub.50 (nM) EC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM) 1 [00046] C C n.a. n.a. n.a. 2 [00047] C D n.a. n.a. n.a. 3 [00048] C D n.a. n.a. n.a. 4 [00049] C C n.a. n.a. n.a. 5 [00050] C B n.a. C C 6 [00051] B C C C C 7 [00052] C C n.a. n.a. n.a. 8 [00053] C D n.a. n.a. n.a. 9 [00054] B C n.a. n.a. n.a. 10 [00055] B C n.a. n.a. n.a. 11 [00056] C D n.a. n.a. n.a. 12 [00057] C D n.a. n.a. n.a. 13 [00058] B C n.a. n.a. n.a. 14 [00059] C D n.a. n.a. n.a. 15 [00060] C C n.a. n.a. n.a. 16 [00061] D D n.a. n.a. n.a. 17 [00062] B B n.a. n.a. n.a. 18 [00063] B C n.a. n.a. n.a. 19 [00064] B B n.a. A C 20 [00065] A B n.a. n.a. n.a. 21 [00066] A B C n.a. C 22 [00067] B B C B C 23 [00068] B B C B n.a. 24 [00069] C D n.a. n.a. n.a. 25 [00070] C C n.a. n.a. n.a. 26 [00071] A B C B C 27 [00072] B C n.a. n.a. C 28 [00073] B B n.a. C C 29 [00074] C C n.a. B B 30 [00075] C C n.a. n.a. C 31 [00076] C D n.a. n.a. n.a. 32 [00077] C C n.a. n.a. n.a. 33 [00078] D D n.a. n.a. n.a. 34 [00079] D D n.a. n.a. n.a. 35 [00080] C C n.a. n.a. n.a. 36 [00081] C D n.a. n.a. n.a. 37 [00082] C D n.a. n.a. n.a. 38 [00083] B C n.a. n.a. C 39 [00084] A B n.a. B C 40 [00085] C C n.a. C n.a. 41 [00086] A B n.a. A C 42 [00087] A B n.a. B C 43 [00088] B B C n.a. n.a. 44 [00089] C D C C n.a. 45 [00090] C C n.a. C n.a. 46 [00091] A C C B C 47 [00092] A B C B C 48 [00093] A B C B C 49 [00094] C D D n.a. n.a. 50 [00095] A B C B C 51 [00096] A B n.a. B C 52 [00097] A B C B C 53 [00098] A B C B C 54 [00099] C D n.a. n.a. n.a. 55 [00100] A B C B n.a. 56 [00101] C C C B n.a. 57 [00102] A A n.a. A n.a. 58 [00103] A B n.a. A n.a. 59 [00104] B B C C n.a. 60 [00105] A A C A B 61 [00106] A A n.a. A C 62 [00107] A B C A C 63 [00108] A B n.a. B C 64 [00109] A B C A n.a. 65 [00110] C C C n.a. n.a. 66 [00111] C C C n.a. n.a. 67 [00112] A B n.a. B n.a. 68 [00113] C C n.a. C n.a. 69 [00114] B B n.a. C n.a. 70 [00115] D D n.a. n.a. n.a. 71 [00116] D D n.a. n.a. n.a. 72 [00117] B B C B n.a. 73 [00118] B C n.a. C n.a. 74 [00119] A B C A n.a. 75 [00120] A B C A n.a. 76 [00121] B B n.a. n.a. n.a. 77 [00122] A B C n.a. n.a. 78 [00123] A A C n.a. n.a. 79 [00124] A A C n.a. n.a. 80 [00125] A A D n.a. n.a. 81 [00126] A A B n.a. n.a. 82 [00127] B B C n.a. n.a. 83 [00128] B B C n.a. n.a. 84 [00129] A B C n.a. n.a. 85 [00130] A A C n.a. n.a. 86 [00131] A B C n.a. n.a. 87 [00132] A B C n.a. n.a. 88 [00133] A A B n.a. n.a. 89 [00134] A B C n.a. n.a. 90 [00135] A A B n.a. n.a. 91 [00136] A B B n.a. n.a. 92 [00137] A A B n.a. n.a. 93 [00138] A A C n.a. n.a. 94 [00139] A B C n.a. n.a. 95 [00140] A B C n.a. n.a. 96 [00141] A B C n.a. n.a. 97 [00142] A A B n.a. n.a. 98 [00143] A B C n.a. n.a. 99 [00144] A A C n.a. n.a. 100 [00145] A B C n.a. n.a. 101 [00146] A A C n.a. n.a. 102 [00147] B B C n.a. n.a. 103 [00148] A B C n.a. B 104 [00149] A A C n.a. n.a. 105 [00150] A B C n.a. n.a. 106 [00151] A B C n.a. n.a. 107 [00152] A C C n.a. n.a. 108 [00153] A B C n.a. n.a. 109 [00154] A A C n.a. n.a. 110 [00155] B B C n.a. n.a. 111 [00156] A A B n.a. n.a. 112 [00157] A A C n.a. n.a. 113 [00158] A B C n.a. n.a. 114 [00159] C C n.a. n.a. n.a. 115 [00160] C C n.a. n.a. n.a. 116 [00161] B B C n.a. n.a. 117 [00162] B C C n.a. n.a. 118 [00163] A B C n.a. n.a. 119 [00164] A B C n.a. n.a. 120 [00165] A C C n.a. n.a. 121 [00166] A B C n.a. n.a. 122 [00167] C D n.a. n.a. n.a. 123 [00168] B B C n.a. n.a. 124 [00169] A B C n.a. n.a. 125 [00170] B B C B n.a. 126 [00171] A A C A n.a. 127 [00172] B B C B n.a. 128 [00173] B C C B n.a. 129 [00174] A B C A n.a. 130 [00175] A A C A n.a. 131 [00176] A A C A n.a. 132 [00177] B B C B n.a. 133 [00178] B B C B n.a. 134 [00179] A A C A n.a. 135 [00180] A A C A n.a. 136 [00181] B B C B n.a. 137 [00182] A A C A n.a. 138 [00183] A A n.a. A n.a. 139 [00184] A A n.a. A n.a. 140 [00185] B C n.a. B n.a. 141 [00186] B B n.a. A n.a. 142 [00187] B B n.a. B n.a. 143 [00188] A B n.a. A n.a. 144 [00189] B C n.a. A n.a. 145 [00190] B C n.a. B n.a. 146 [00191] B B n.a. B n.a. 147 [00192] A B n.a. A n.a. 148 [00193] A B n.a. A n.a. 149 [00194] B B n.a. B n.a. 150 [00195] A A n.a. B n.a. 151 [00196] A B n.a. B n.a. 152 [00197] B A n.a. A n.a. 153 [00198] A A n.a. B n.a. 154 [00199] B B n.a. B n.a. 155 [00200] A B n.a. B n.a. 156 [00201] B B n.a. C n.a. 157 [00202] A B n.a. C n.a. 158 [00203] A A n.a. B n.a. 159 [00204] A A n.a. B n.a. 160 [00205] A B n.a. A n.a. 161 [00206] C C n.a. C n.a. 162 [00207] A A n.a. A n.a. 163 [00208] A A n.a. B n.a. 164 [00209] A A n.a. B n.a. 165 [00210] A A n.a. B n.a. 166 [00211] A A n.a. B n.a. 167 [00212] A A n.a. B n.a. 168 [00213] B B n.a. B n.a. 169 [00214] B B n.a. B n.a. 170 [00215] A A n.a. B n.a. 171 [00216] C C n.a. C n.a. 172 [00217] A A n.a. B n.a. 173 [00218] A A n.a. A n.a. 174 [00219] B B n.a. C n.a. 175 [00220] A A n.a. A n.a. 176 [00221] B B n.a. A n.a. 177 [00222] A B n.a. A n.a. 178 [00223] A A n.a. B n.a. 179 [00224] A C n.a. A n.a. 180 [00225] A C n.a. A n.a. 181 [00226] A A n.a. B n.a. 182 [00227] B B n.a. B n.a. 183 [00228] A A n.a. B n.a. 184 [00229] B B n.a. B n.a. 185 [00230] A A C A C 186 [00231] A A C A C 187 [00232] B C n.a. B n.a. 188 [00233] A A n.a. A n.a. 189 [00234] A B n.a. B n.a. 190 [00235] B B n.a. A n.a. 191 [00236] B B n.a. B n.a.