HETEROSUBSTITUTED PYRIDINE DERIVATIVES AS <i>PDE 4</i> INHIBITORS

Abstract: The invention encompasses the novel compound of Formula (I) useful in the treatment of diseases, including asthma, by raising the level of cyclic adenosine-3',5'-monophosphate (cAMP) through the inhibition of phosphodiesterase IV (PDE 4) or a pharmaceutically acceptable salt or hydrate thereof. The invention also encompasses pharmaceutical compositions and methods for treatment.

Description: TITLE OF THE INVENTION HETEROSUBSTΓΓUTED PYR « IDINE DERIVATIVES AS PDE 4 INHIBITO ' RS BACKGROUND OF THE INVENTION This invention relates to compounds and pharmaceutical compositions containing such compounds useful for treating diseases by raising the level of cyclic adenosme-3 ',5 -monophosphate (cAMP) through the inhibition of phosphodiesterase IV (PDE 4). Many hormones and neurotransmitters modulate tissue function by elevating intra-cellular levels of 3 ',5 -cyclic adenosme monophosphate (cAMP). The cellular levels of cAMP are regulated by mechanisms which control synthesis and breakdown. The synthesis of cAMP is controlled by adenyl cyclase which may be directly activated by agents such as forskohn or indirectly activated by the binding of specific agonists to cell surface receptors which are coupled to adenyl cyclase. The breakdown of cAMP is controlled by a family of phosphodiesterase (PDE) isoenzymes, which also control the breakdown of guanosme 3',5'-cyclιc monophosphate (cGMP). To date, nine members of the family have been descπbed (PDE 1-9) the distribution of which varies from tissue to tissue. This suggests that specific inhibitors of PDE isoenzymes could achieve differential elevation of cAMP in different tissues, [for reviews of PDE distribution, structure, function and regulation, see Beavo & Reifsnyder (1990) TIPS, 11. 150-155, Nicholson et al (1991) TIPS, 12. 19-27 and Houslay et al (1998) Adv. Pharmacol. 44. 225-342]. The availability of PDE isotype selective inhibitors has enabled the role of PDEs in a vaπety of cell types to be investigated. In particular it has been established that PDE 4 controls the breakdown of cAMP in many inflammatory cells, for example, basophils (Peachell P.T. et al, (1992) J. Immunol. 148 2503-2510) and " eosinophils (Dent G. et al., (1991) Br. J Pharmacol 103 1339-1346) and that inhibition of this isotype is associated with the inhibition of cell activation. Furthermore, elevation of cAMP in airway smooth muscle has a spasmolytic effect. Consequently PDE 4 inhibitors are currently being developed as potential anti- lnflammatory drugs particularly for the prophylaxis and treatment of asthma, by achieving both anti-inflammatory and bronchodilator effects The application of molecular cloning to the study of PDEs has revealed that for each isotype there may be one or more isoforms. For PDE 4, it is has been shown that there are four isoforms (A, B, C and D) each coded for by a separate gene in both rodents (Swinnen JN. et al., (1989) Proc. Νatl. Acad. Sci. USA 86 5325- 5329) and man (Bolger G. et al., (1993) Mol. Cell Biol. 13 6558-6571). The existence of multiple PDE 4s raises the prospect of obtaining inhibitors that are selective for individual isoforms, thus increasing the specificity of action of such inhibitors. This assumes that the different PDE 4 isoforms are functionally distinct. Indirect evidence in support of this comes from the selective distribution of these isoforms in different tissues (Swinnen et al., 1989; Bolger et al , 1993, Obernolte R. et al., (1993) Gene 129 239-247, ibid) and the high degree of sequence conservation amongst isoforms of different species. To date full length cDΝAs for human PDE 4A, B, C and D (Bolger et al., 1993 ibid; Obernolte et al., 1993 ibid; Mclaughlin M. et al., (1993) J. Biol Chem. 268 6470-6476, Owens et al (1997) Cell Signal., 9: 575-585) and rat PDE 4A, B and D (Davis R. et al., (1989) Proc Νatl Acad. Sci. USA 86 3604-3608, Swinnen JN et al , (1991) J. Biol Chem. 266 18370-18377), have been reported, enabling functional recombinant enzymes to be produced by expression of the cDΝAs in an appropriate host cell. These cDΝAs have been isolated by conventional hybridisation methods The design of PDE 4 inhibitors for the treatment of inflammatory diseases such as asthma, has met with limited success to date. Many of the PDE 4 inhibitors which have been synthesised have lacked potency and/or inhibit more than one type of PDE isoenzyme in a non-selective manner. PDE 4 inhibitors that are relatively potent and selective for PDE 4, are reported to be emetic as well Indeed this side effect has been so universal that experts have expressed their belief that the emesis expeπenced upon administration of a PDE 4 inhibitor, may be mechanism based One object of the present invention is to provide heterosubstituted pyndmes deπvatives that are inhibitors of PDE 4 at concentrations at which they have little or no inhibitory action on other PDE isoenzymes. These compounds inhibit the human recombinant PDE 4 enzyme and also elevate cAMP in isolated leukocytes The compounds thus prevent, alleviate or reduce inflammation the lungs, such as that induced by carrageenan, platelet-activating factor (PAF), ιnterleukm-5 (IL-5) or antigen challenge The compounds also suppress the hyperresponsiveness of airway smooth muscle seen in inflammed lungs. Another object of the present invention is to provide compounds that have good oral activity and that at orally effective doses, exhibit a reduced incidence of the side-effects associated with known PDE 4 inhibitors, such as rohpram The compounds of the invention are therefore of use in medicine, especially the prophylaxis and treatment of asthma and other inflammatory conditions SUMMARY OF THE INVENTION A compound represented by formula I: I or a pharmaceutically acceptable salt or hydrate thereof wherein: Y represents N or N-oxide; RI and R^ are independently selected from- H, Cι_6alkyl and haloCi-6 alkyl, R3 and R4 are independently selected from H and Ci-βalkyl, or R3 and R4 attached to the same carbon atom are taken together and represent a carbonyl oxygen atom, or R3 and R4 attached to different carbon atoms considered in combination with the carbon atoms to which they are attached along with any intervening atoms and represent a saturated 5, 6 or 7 membered carbocychc πng, R5 IS present or absent, when present, R^ represents a member selected from the group consisting of: H, Ci-6alkyl, C(O)Cι_6alkyl, C(O)Arl, CO 2 Ci-6alkyl, CO 2 Aτl, or an oxide oxygen atom, the alkyl portions of which are optionally substituted with 1-3 halo, hydroxy, Ci_4 alkyl or with one aryl group selected from phenyl, thienyl, thiazolyl, pyndyl and naphthyl; or R5 is taken in combination with one R group that is present, and represents along with the R3 group and any intervening atoms a 5-6 membered heterocyclic ring, or R-> is taken with a substituent on Ar* and represents a 5-6 membered heterocyclic ring fused to Ar^ ; when R5 is absent, the dotted line represents a bond and the carbon atom to which it is attached does not contain an R group; R6 and R7 are independently selected from the group consisting of: H, halo, Ci-6alkyl, haloCι_6alkyl and CN; n represents an integer of from 0-6; each Arl is independently selected from the group consisting of: (a) thienyl, (b) thiazolyl, (c) pyridyl, (d) phenyl and (e) naphthyl, each Arl being optionally substituted with 1-3 members selected from the group consisting of: (I) halo, (2) Cι~6alkoxy, (3) Cι_7alkylthio, (4) CN, (5) Ci. 6 alkyl, (6) Ci-βhydroxyalkyl, (7) -CO2H, -CO 2 Ci-6alkyl, (8) NH(SO2Me), N(SO2Me)2, (9) SO2Me, (10) NO 2 , (II) Cι_6alkenyl, (12) halo Ci-6 alkyl, and (13) NH 2 , and when Ar represents a phenyl or naphthyl group with two or three substituents, two such substituents may be considered in combination and represent a 5 or 6 membered fused lactone ring. Pharmaceutical compositions and methods of treatment are also included. DETAILED DESCRIPTION OF THE INVENTION The present invention includes compounds represented by formula I: as well as pharmaceutically acceptable salts and hydrates thereof wherein: Y represents N or N-oxide; RI and R^ are independently selected from: H, Cι_6alkyl and haloC 1-6 alkyl, R3 and R^ are independently selected from H and Cι_6alkyl, or R and R^ attached to the same carbon atom are taken together and represent a carbonyl oxygen atom, or R and R^ attached to different carbon atoms considered in combination with the carbon atoms to which they are attached along with any intervening atoms and represent a saturated 5, 6 or 7 membered carbocyclic ring, R5 is present or absent; when present, R^ represents a member selected from the group consisting of: H, Ci-6alkyl, C(O)Cι_6alkyl, C(O)Arl, CO 2 Ci-6alkyl, CO 2 Arl, or an oxide oxygen atom, the alkyl portions of which are optionally substituted with 1-3 halo, hydroxy, C]-4 alkyl or with one aryl group selected from phenyl, thienyl, thiazolyl, pyridyl and naphthyl; or R5 is taken in combination with one R group that is present, and represents along with the R group and any intervening atoms a 5-6 membered heterocyclic ring, or R-> is taken with a substituent on Ar ' and represents a 5-6 membered heterocyclic ring fused to Ar^ ; when R5 is absent, the dotted line represents a bond and the carbon atom to which it is attached does not contain an R group; R6 and R7 are independently selected from the group consisting of: H, halo, Ci-6alkyl, haloCι_6alkyl and CN; n represents an integer of from 0-6; each Arl is independently selected from the group consisting of: (a) thienyl, (b) thiazolyl, (c) pyridyl, (d) phenyl and (e) naphthyl, each Arl being optionally substituted with 1-3 members selected from the group consisting of: (I) halo, (2) Ci-6alkoxy, (3) Ci-7alkylthio, (4) CN, (5) Ci-βalkyl, (6) Ci-6hydroxyalkyl, (7) -CO2H, -CO2Ci-6alkyl, (8) NH(SO2Me), N(SO2Me)2, (9) SO2Me, (10) NO2, (I I) Ci_6alkenyl, (12) halo Ci_6 alkyl, and (13) NH 2 , and when Ar^ represents a phenyl or naphthyl group with two or three substituents, two such substituents may be considered in combination and represent a 5 or 6 membered fused lactone ring. The following definitions pertain to the terms used herein unless otherwise indicated. Halo is intended to include F, Cl, Br and I. HaloCι-6 alkyl refers to an alkyl group having 1-9 halo groups attached. Examples include -CH2F, -CHF2 , -CF3 ? -CH2CH2F , -CHFCH2F , -CF 2 CH F , -CF2CHF2 and -CF2CF3. Alkyl groups include straight or branched alkyl groups having 1-7 carbon atoms, and cyclic alkyl groups having from 3-7 carbon atoms. Cycloalkyl groups with alkyl substituent groups attached are also included. Examples of C]. ζalkyl groups include methyl, ethyl, propyl, 2-propyl, s- and t-butyl. butyl, pentyl, hexyl, 1,1-dιmethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl Examples of C i -βalkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Likewise, Ci-7alkylthιo is intended to include alkylthio groups of from 1 to 7 carbon atoms of a straight, branched or cyclic configuration Examples of alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc By way of illustration, the propylthio group signifies -SCH CH 2 CH3 Preferred values of Rl and R^ are Ci-6 alkyl and haloCi-6alkyl. More preferred values are selected from the group consisting of CH3, CH2F, CHF2, CF3 and most preferrably CHF2- Within this subset, all other variables are as originally defined. Preferred values of n are 0, 1, 2 and 3 More preferred values are 0 and 1. Within these subsets, all other vaπables are as originally defined. Preferred values of Ar are phenyl and naphthyl. More preferred is phenyl. Within these subsets, all other vaπables are as originally defined Preferred values of R and R are H and methyl Within this subset, all other variables are as originally defined When present, R~ > may represent a member selected from the group consisting of. H, Ci-6alkyl, C(O)Cι_6alkyl, C(O)Arl, CO 2 H, CO 2 Ci-6alkyl, CO 2 Arl, or an oxide oxygen atom, the alkyl portions of which are optionally substituted with 1-3 halo, hydroxy, C1-.4 alkyl or aryl groups. Alternatively, R^ is taken in combination with one of the R groups that is present, and represents along with the R group and any intervening atoms a 5- 6 membered πng, or R^ IS taken with a substituent on Arl and represents a 5-6 membered ring fused to Ar^ . An example of R-> taken in combination with one R3 group is shown below: An example of R taken in combination with a substituent on Arl [ s shown below: As shown above, the ring represented by R5 m combination w '!"» one R group or a substitutent on Arl j s heterocyclic, containing 1 nitrogen atom, and can be 5-7 membered. An example of a compound wherein R5 IS absent and the dotted line represents a bond, and the carbon atom to which it is attached does not contain an R3 group is shown below: Preferably R^ is present and represents a member selected from the group consisting of H, Cι_6alkyl, C(O)Ci-6alkyl or CO 2 C 6 alkyl, the alkyl portions of which are optionally substituted with 1-3 halo, hydroxy, Ci-4 alkyl groups or with one phenyl, thienyl, thiazolyl, pyπdyl or naphthyl group Within this subset, all other variables are as originally defined Preferably R6 and R7 represent H or C ι_6alkyl More preferably R6 and R7 represent H Within these subsets, all other variables are as originally defined Preferably Y is in the 4 position relative to the point of attachment to the ethylene moiety Preferably the N shown in the pyπdyl πng is in the 3 position relative to the point of attachment to the ethylene moiety A subset of compounds that is of particular interest is defined with respect to formula I wherein R 1 and R 2 are Cι_6alkyl or haloCι_6alkyl, n is 0, 1, 2 or 3, AX IS phenyl or naphthyl, R and R4 are H and methyl, R5 IS present and represents a member selected from the group consisting of H, Ci_6alkyl, C(O)Cι_6alkyl or CO 2 Cι_6 alkyl, the alkyl portions of which aie optionally substituted with 1-3 halo, hydroxy, C1-.4 alkyl groups or with one phenyl, thienyl, thiazolyl, pyπdyl or naphthyl group, R6 and R7 represent H or Cι_-όalkyl, Y is in the 4 position relative to the point of attachment to the ethylene moiety; and the N shown in the pyridyl ring is in the 3 position relative to the point of attachment to the ethylene moiety. More particularly, the subset is defined as above wherein R6 and R7 represent H. Further, the subset is as defined above, wherein R* and R 2 are CHF 2 , Even more particularly, the subset is as defined above wherein RI and R 2 are CHF2; n is 0 or 1 ; R 3 and R 4 are H and Arl 1S phenyl. Examples of compounds of the invention are disclosed below: 1. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(benzylamιno)3- pyπdyl]ethyl Jpyndine, 2. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(5)-(l- phenylethylamιno)3-pyπdyl]ethyl Jpyπdine, 3. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(R)-(l- phenylethylamιno)3-pyπdyl]ethyl Jpyndine, 4. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-(4- fluorophenyl)ethylamιno]3-pyπdyl Jethyl Jpyπdine, 5. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-(4- fluorophenyl)ethylamιno]3-pyπdyl Jethyl Jpyπdine-N-oxide, 6. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(benzylamιno)3- pyπdyljethyl Jpyπdine-N-oxide, 7. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(S)-(l- phenylethylamιno)3-pyπdyl]ethyl }pyπdme-N-oxιde, 8. 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(R)-(l- phenylethylamιno)3-pyπdyl]ethyl Jpyπdine-N-oxide, 9 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(2- phenylethylamιno)3-pyrιdyl]ethyl Jpyπdιne-N-oxιde, 10. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[2-(2- pyπdyl)ethylamιno]3-pyndyl Jethyl Jpyπdine-N-oxide, 11. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(l-methyl-l- phenylethylamιno)3-pyπdyl]ethyl}pyπdme-N-oxιde, 12. (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6- ( 1 -methyl- 1 -phenylethylamιno)3-pyπdyl]ethyl }pyndιne-N-oxιde, 13. (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6- (1 -methyl- l-phenylethylamιno)3-pyπdyl]ethyl}pyπdιne-N-oxιde, 14 (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6- ( 1 -methyl- l-phenylethylamιno)3-pyπdyl-N-oxιde]ethyl Jpyπdine-N-oxide, 15. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[(2- pyπdyl)methylamιno]3-pyndyl Jethyl }pyπdme-N-oxιde, 16. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[(2-pyπdyl-N- oxιde)methylammo]3-pyπdyl Jethyl Jpyπdine-N-oxide, 17. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(R)-(l- phenylpropylamιno)3-pyπdyl]ethyl }pyπdιne-N-oxιde, 18 (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6- ( 1 -methyl- 1 -phenylethylamιno)3-pyπdyl]ethyl Jpyπdine, 19. (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6- (1 -methyl- l-phenylethylammo)3-pyπdyl]ethyl Jpyndine, 20. (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6- ( 1 -methyl- l-phenylethylamιno)3-pyπdyl-N-oxιde]ethyl Jpyπdine, 21. (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [l-methyl-l-(4-fluorophenyl)ethylamιno]3-pyndyl Jethyl Jpyπdine-N-oxide, 22. (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [ l-methyl-l-(4-tolyl)ethylamιno]3-pyπdyl Jethyl }pyπdιne-N-oxιde, 23. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{ 6-[l-methyl-l-(4- benzyloxyphenyl)ethylamιno]3-pyπdyl Jethyl Jpyπdine-N-oxide, 24. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(4- hydroxyphenyl)ethylamιno]3-pyπdyl Jethyl Jpyπdine-N-oxide, 25. (Enantιomer-l)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{ 6- [1 -methyl- l-(3-tolyl)ethylammo]3-pyπdyl Jethyl }pyπdιne-N-oxιde, 26. (Enantιomer-l)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [1 -methyl- l-(3-fluorophenyl)ethylamιno]3-pyπdyl Jethyl }pyndιne-N-oxιde, 27. (Enantιomer-l)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [1 -methyl- l-(3-bromophenyl)ethylamιno]3-pyπdyl Jethyl Jpyndιne--V-oxιde, 28 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(2- pyndyl)ethylamιno]3-pyπdyl Jethyl }pyndιne-N-oxιde, 29 4- { 2-[3 ,4-Bιs(dιfluoromethoxy)phenyl]-2- { 6- [ 1 -methyl- 1 -(2- pyndyl-N-oxιde)ethylamιno]3-pyndyl Jethyl Jpyπdine-N-oxide, 30 (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [1 -methyl- l-(4-chlorophenyl)ethylamιno]3-pyπdyl Jethyl }pyndme-N-oxιde, 31 (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [ 1 -methyl- l-(4-chlorophenyl)ethylamιno]3-pyπdyl Jethyl }pyπdιne-N-oxιde, 32 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(2- tolyl)ethylamιno]3-pyπdyl Jethyl }pyπdme-N-oxιde, 33 (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [ 1 -methyl- l-(4-methylsulfonylphenyl)ethylamιno]3-pyπdyl Jethyl Jpyπdine-N-oxide, 34 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(4- tπfluoromethylphenyl)ethylamιno]3-pyπdyl Jethyl }pyπdme-N-oxιde, 35 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(3,4- dιfluorophenyl)ethylammo]3-pyπdyl Jethyl Jpyndine-N-oxide, 36 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l,l-dιmethyl-2- (4-fluorophenyl)ethylamιno]3-pyndyl Jethyl Jpyndine-N-oxide, 37 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[2-(4- fluorophenyl)ethylamιno]3-pyπdyl Jethyl Jpyπdine-N-oxide, 38 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{ 6-[l-methyl-l-(3,5- dιfluorophenyl)ethylammo]3-pyndyl Jethyl Jpyπdine-N-oxide 39 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl] 2-{6-[l-methyl-l-(2,4- dιfluorophenyl)ethylamιno]3-pyπdyl Jethyl Jpyndine-N-oxide, 40 (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6- (4-fluorobenzylamιne)3-pyπdyl]ethyl }pyndιne-N-oxιde, 41 (Enantιomer-2)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6- (4-fluorobenzylamιne)3-pyπdyl]ethyl }pyπdιne-N-oxιde, 42 (Enantιomer-l)-4-{ 2-[3.4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [l-methyl-l-(4-ethylphenyl)ethylammo]3-pyπdyl Jethyl Jpyndine-N-oxide, 43 4- { 2- [3 ,4-Bι s(dιfl uoromethoxy)phenyl]-2- [6-(2,4- dιfluorobenzylamιne)3-pyπdyl]ethyl }pyπdιne-N-oxιde, 44 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[4- fluorophenylamιdo]3-pyπdyl Jethyl Jpyndine, 45. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[4- fluorophenylamιdo]3-pyπdyl Jethyl Jpyndine-N-oxide, 46. (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{ 6- [4-fluorophenylamιdo]3-pyndyl Jethyl Jpyπdine-N-oxide, 47. (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6- ( 1 -methyl- l-thιazolylethylamιno)3-pyπdyl]ethyl }pyπdιne-N-oxιde, 48. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(4- dιfluoromethoxyphenyl)ethylammo]3-pyπdyl Jethyl Jpyndine-N-oxide, 49. (Enantιomer-2)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6- ( 1 -methyl- l-phenylethylamιno)3-pyπdyl]ethy] Jpyndιne-N-oxιde hydromethanesulfonate, 50. 4- { 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{ 6-[ 1 -ethyl- 1 -(4- fluorophenyl)propylammo]3-pyπdyl Jethyl Jpyπdine-N-oxide, 51. (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [4-methylphenylamιdo]3-pyndyl Jethyl Jpyndine-N-oxide, 52. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[2-methyl-2-(4- fluorophenyl)propylamιno]3-pyndyl Jethyl Jpyπdine-N-oxide, 53. (Enantιomer-l)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-j 6- [l,l-dιmethyl-2-(4-fluorophenyl)ethylamιno]3-pyndyl Jethyl Jpyndine-N-oxide, 54. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-methyl-/V- benzylamιno)3-pyndyl]ethyl Jpyndine, 55 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N,N- dιbenzylamιno)3-pyndyl]ethyl Jpyndine, 56. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-methyl--V- benzylamιno)3-pyπdyl]ethyl Jpyndme-N-oxide, 57. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-methyl-N- benzylamιno)3-pyπdyl]ethyl Jpyndine-N-oxide hydrochlonde, 58. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-methyl-N-2- phenylethylammo)3-pyndyl]ethyl }pyndιne-N-oxιde, 59 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-ethyl-N- benzylammo)3-pyndyl]ethyl Jpyndιne-N-oxιde, 60. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-/-propyl-N- benzylammo)3-pyndyl]ethyl Jpyndme-N-oxide, 61. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-tert-butyl-N- benzylamιno)3-pyndyl]ethyl Jpyndine-N-oxide, 62. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N-4- chlorobenzylammo)3-pyndyl]ethyl}pyndιne-N-oxιde, 63. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N-3- methoxybenzylamιno)3-pyndyl]ethyl}pyπdme-N-oxιde, 64. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-[N-methyl-N-(3- pyπdyl)methylamιno]3-pyπdyl Jethyl Jpyπdine-N-oxide, 65. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N-2- methylbenzylamιno)3-pyndyl]ethyl Jpyndme-N-oxιde, 66. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-[N-methyl-N-(2- naphthyl)methylamιno]3-pyπdyl Jethyl Jpyndine-N-oxide, 67. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-2- hydroxyethyl-N-benzylammo)3-pyndyl]ethyl Jpyπdιne-N-oxιde, 68. 4-{2-[3,4-Bιsfdιfluoromethoxy)phenyl]-2-| 6-(N-methyl-N-4- methoxyphenylamιno)3-pyπdyl]ethyl Jpyndine, 69. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-| 6-(N-methyl-N-4- methoxyphenylamιno)3-pyπdyl]ethyl }pyπdιne-N-oxιde, 70. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N-(S)- l-phenylethylammo)3-pyπdyl]ethyl Jpyndine, 71. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenylJ-2- 6-(N-methyl-N-(S)- l-phenylethylamιno)3-pyπdyl]ethyl Jpyndme-N-oxide, 72. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N-(R)- l-phenylethylammo)3-pyndyl]ethyl }pyridine-N-oxide, 73. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N- phenylamιno)3-pyndyl]ethyl }pyndme-iV-oxιde, 74. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-hydroxyl-N- benzylamιno)3-pyndyl]ethyl Jpyndme-N-oxide, 75. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-ethyl-N-(R)-l- phenylethylammo)3-pyndyl]ethyl }pyndιne-N-oxιde, 76. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-ethyl-N-(S)-l- phenylethylamιno)3-pyπdyl]ethyl Jpyπdine-N-oxide, 77. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-[N-methyl-N-(3- pyndyl-N-oxιde)methylamιno]3-pyπdyl Jethyl Jpyndine-N-oxide, 78. (Enantιomer-2)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [methoxy(4-fluorophenyl)methanιmιne]3-pyπdyl Jethyl }pyndιne--V-oxιde, 79. (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6- (N-methyl-4-fluorophenylamιdo)3-pyπdyl]ethyl Jpyπdιne-N-oxιde, 80. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-benzyl tnfluoroacetamιdo)3-pyndyl]ethyl Jpyndine, 81. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-benzyl acetamιdo)3-pyπdyl]ethyl }pyndιne-N-oxιde, 82. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l- phenyl)ethyl-N-(tert-butyloxycarbonyl)amιno]3-pyπdyl Jethyl Jpyndine-N-oxide, 83. (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [N-(l-methyl-l-phenyl)ethyl-N-(tert-butyloxycarbonyl)amιno]3- pyndyl Jethyl Jpyndme-N-oxide, 84 (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [N-(l -methyl- l-phenyl)ethyl-N-(benzyloxycarbonyl)amιno]3-pyπdyl Jethyl Jpyndine, 85. (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [N-(l-methyl-l-phenyl)ethyl-N-(benzyloxycarbonyl)amιno]3-pyndyl Jethyl Jpyπdine, 86. (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [N-( 1 -methyl- l-(4-methylphenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyπdyl Jethyl Jpyndine, 87. (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [N-(l-methyl-l-(4-methylphenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyndyl Jethyl Jpyndine, 88. (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [N-(l -methyl- l-(4-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyπdyl Jethyl Jpyπdine, 89. (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{ 6- [N-(l -methyl- l-(4-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amιno] 3- pyπdyl Jethyl Jpyndine, 90 (Enantιomer-l)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [N-(l -methyl- l-(3-methylphenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyπdyl Jethyl Jpyπdine, 91 (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [N-(l -methyl- l-(3-methylphen yl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyπdyl Jethyl Jpyπdine, 92 (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [N-( 1 -methyl- l-(3-bromophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyπdyl Jethyl Jpyndine, 93 (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [N-(l-methyl-l-(3-bromophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyπdyl Jethyl Jpyndine, 94. (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [N-(l -methyl- l-(3-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyπdyl Jethyl Jpyndine, 95 (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [N-(l-methyl-l-(3-fluorophenyl))ethyl-N-(benzyloxycarbonyl)ammo]3- pyndyl Jethyl Jpyndine, 96. (Enantιomer-l)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [N-(l,l-dιmethyl-2-(4-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyridyl Jethyl Jpyπdine-N-oxide, 97. (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [N-(l,l-dιmethyl-2-(4-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyπdyl Jethyl Jpyndine-N-oxide, 98. 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l,l-dιmethyl- 2-(4-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3-pyπdyl-N- oxide Jethyl Jpyndme-N-oxide, 99. (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluororr, hoxy)phenyl]-2-{ 6- [N,N-dι(4-fluorobenzamιde)]3-pyndyl Jethyl Jpyπdιne-/V-oxιde, 100 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l,2,3,4- tetrahydroιsoqumohne]3-pyπdyl Jethyl Jpyndme-N-oxide. 101. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(l- amιnoιndane)3-pyndyl]ethyl }pyπdιne-N-oxιde, 102 (Dιastereomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [(R)-l-amιnoιndane]3-pyπdyl Jethyl Jpyndme-N-oxide, 103. (Dιastereomer-2)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [(R)-l-amιnomdane]3-pyndyl Jethyl Jpyndine-N-oxide, 104. (Dιastereomer-3)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [(S)-l-amιnomdane]3-pyndyl Jethyl Jpyπdine-N-oxide, 105 (Di astereomer-4)-4- { 2- [3 ,4-Bι s(dιf 1 uoromethoxy)phenyl ] -2- { 6- [(S)-l-amιnoιndane]3-pyndyl Jethyl Jpyndme-N-oxide, 106. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(2- phenylpyrohdme)3-pyπdyl]ethyl Jpyndme-N-oxide, 107. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-(4- fluorophenyl)cyclopentylamιno]3-pyndyl Jethyl Jpyndme-N-oxide, and 108. 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(2- amιnoιndane)3-pyπdyl]ethyl}pyπdιne-N-oxιde., As used herein, the terms "Enantιomer-1" , "Enamtιomer-2" , "Dιastereomer-1" and "Dιastereomer-2" refer to the order of separation when puπfied using HPLC. The compounds descnbed herein contain one or more asymmetπc centers and may thus give nse to diastereomers and optical isomers The present invention is meant to include all such possible isomers and diastereomers as well as their racemic and resolved, enantiomeπcally pure forms and pharmaceutically acceptable salts thereof. The invention also encompasses a pharmaceutical composition that is compπsed of a compound of formula I combination with a pharmaceutically acceptable earner. Preferably the composition is compnsed of a pharmaceutically acceptable earner and a non-toxic therapeutically effective amount of compound of formula I as descnbed above. Moreover, within this preferred embodiment, the invention encompasses a pharmaceutical composition for the treatment or prevention of disease by inhibition of PDE 4, resulting in an elevation of cAMP, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of formula I as descnbed above. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts denved from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly prefeπed are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of pnmary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange res s, such as arginine, beta e, caffeine, cho ne, N,N-dιbenzylethylenedιamme, diethylamine, 2- diethylaminoethanol, 2-dιmethylamιnoethanol, ethanolamme, ethylenediam e, N- ethylmorpho ne, N-ethylpipeπdine, glucam e, glucosamme, histidine, hydrabamine, isopropylamine, lysine, methylglucam e, morphohne, piperazine, pipendme, polyamme resins, procaine, punnes, theobromine, tnethylamine, tnmethylamine, tπpropylamine, tromethamine, and the like. It will be understood that references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts. The compounds of formula I are selective and potent inhibitors of PDE 4. The biological activity and utility of the compounds may be demonstrated as descnbed herein. The compounds according to the invention are thus of particular use in the prophylaxis and treatment of human diseases where an unwanted inflammatory response or muscular spasm (for example bladder or alimentary smooth muscle spasm) is present and where elevation of the cAMP levels may be expected to prevent or alleviate the disease or condition. Particular uses to which the compounds of the invention may be put include the prophylaxis and treatment of asthma, especially inflammed lung associated with asthma, cystic fibrosis, in the treatment of inflammatory airway disease, chronic bronchitis, eos ophilic granuloma, psonasis and other benign and malignant proliferative skin diseases, endotoxic shock, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthπtis, chronic glomerulonephπtis, atopic dermatitis, urticaria, adult respiratory distress syndrome, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arteπal restenosis and atherosclerosis. The compounds of the invention also suppress neurogemc inflammation. They are, therefore, analgesic, antitussive and antihyperalgesic in inflammatory diseases associated with irritation and pain. The compounds also elevate cAMP in lymphocytes and thereby suppress unwanted lymphocyte activation in immune-based diseases such as rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease. The compounds also reduce gastnc acid secretion and therefore can be used to treat conditions associated with hypersecretion of gastnc acid. The compounds also suppress cytokine synthesis by inflammatory cells in response to immune or infectious stimulation They are, therefore, useful in the treatment of bactenal, fungal or viral induced sepsis and septic shock in which cytokines such as tumour necrosis factor (TNF) are key mediators. The compounds of the invention also suppress inflammation and pyrexia due to cytokines and are, therefore, useful in the treatment of inflammation and cytokine-mediated chronic tissue degeneration which occurs in diseases such as rheumatoid or osteo-arthπtis. The over-production of cytokines such as TNF in bactenal, fungal or viral infections or diseases such as cancer, leads to cachexia and muscle wasting. Compounds of the invention ameliorate these symptoms as well. The compounds of the invention elevate cAMP in certain areas of the bram and thereby counteract depression and memory impairment. Compounds of the invention suppress cell proliferation in certain tumour cells and can be used, therefore, to prevent tumour growth and invasion of normal tissues. For the prophylaxis or treatment of disease the compounds may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which compnses a compound of formula (1) together with one or more pharmaceutically acceptable earners, excipients or diluents. For the treatment or prevention of any of the diseases or conditions descnbed herein, the compounds of formula I may be administered orally, topically, parenterally, by inhalation spray or rectally in formulations containing conventional non-toxic pharmaceutically acceptable earners, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular and intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle sheep, dogs, cats, etc., the compounds of the invention are useful for the treatment of humans. Oral pharmaceutical compositions containing the active ingredient are typically in the form of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, colonng agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubπcatmg agents, for example, magnesium stearate, steaπc acid or talc The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer penod For example, a time delay matenal such as glyceryl monostearate or glyceryl distearate may be employed They may also be coated by the technique described in the U.S Patent 4,256,108, 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release In hard gelatin capsules, the active ingredient is typically mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. In soft gelatin capsules, the active ingredient is typically mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active matenal in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl-cellulo* methylcellulose, hydroxy-propylmethycellulose, sodium alginate, polyvmyl-pynohdone, gum tragacanth and gum acacia, dispersing or wetting agents may be a naturally-occurπng phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters denved from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters denved from fatty acids and hexitol anhydπdes, for example polyethylene sorbitan monooleate The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more colonng agents, one or more flavoπng agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavonng agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above Additional excipients, for example sweetening, flavonng and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion The oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydπdes, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavounng agents Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and colonng agents. The pharmaceutical compositions may be in the form of a steπle injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The steπle injectable preparation may also be a steπle injectable solution or suspension in a non-toxic parenteral ly-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloπde solution. In addition, sterile, fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglyceπdes. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Compounds of formula I may also be administered in the form of suppositoπes for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at normal body temperature and will therefore melt to release the drug Examples of such materials include cocoa butter and polyethylene glycols. For topical use. creams, ointments, jellies, solutions or suspensions, containing the compound of Formula I are employed. (For purposes of this application, topical application also includes mouth washes and gargles.) Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day. The amount of active ingredient that may be combined with the carrier mateπals to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of earner matenal which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 1 mg to about 500 mg of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg. It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the seventy of the particular disease undergoing therapy. The compounds of the invention can be synthesized using the general synthesis schemes provided below It will be apparent to one skilled m the art that similar methodology could be used to prepare the enantiomers or the racemates of the illustrated compounds The following abbreviations have the indicated meanings: ALKYL GROUP ABBREVIATIONS SCHEME 1 The preparation of bromopyndine intermediate 1 is shown in Scheme 1. Monolithiation of 2,5-dιbromopyndιne followed by the addition 3,4- bιs(dιfluoromethoxy)benzaldehyde as found in U S Pat No 5,710,170 gave the secondary alcohol which was subsequently oxidized to the corresponding ketone with an oxidizing agent such as Mnθ2 SCHEME 1 SCHEME 2 The preparation of bromopyndine intermediate 2 and 3 is shown in Scheme 2. The secondary alcohol II was converted to the corresponding chloride III using a chloπnating agent such as thionyl chlonde in the presence of a base. This chloπde was condensed with the a-anion of ethyl 4-pyndyl acetate, affording the ester IV which upon hydrolysis with a base such as lithium hydroxide, followed by acidification with an acid such as hydrochlonc acid afforded the decarboxylated intermediate 2. Oxidation of the pyπdme to the pyπdine-N-oxide 3 was done with an oxidizing agent such as MMPP SCHEME 3 The general method for the preparation of substituted alcohols is presented in Scheme 3. Esteπfication of a suitable carboxylic acid V under Fisher's conditions followed by dialkylation of the methyl ester VI with a base such as LHMDS and a suitable alkylating agent, afforded the corresponding gem-α,α- disubstituted ester VII. This intermediate is converted to the alcohol VIII by reduction with a reducing agent such as lithium aluminum hydnde. SCHEME 3 LiHMDS Alkyl Iodide XI Ra represents a substituent group attached to Arl, wherein Ar* represents phenyl. Up to 3 R a groups may be present. The alkyl iodide provides the source for R and R4, which can be the same or different. SCHEME 4 Scheme 4 is presenting the preparation of the substituted am e XIX. Nitrile XVI was dialkylated with a base such as NaHMDS and an alkylating agent such as methyl iodide followed by hydrolysis of the cyanide XVII to the coπespond g amide XVIII. Finally, reduction of the amme with a reducing agent such as borane dimethyl sulfide gave access to the amine XIX. SCHEME 4 XVI XVII XVIII XIX SCHEME 5 The general transformation for the preparation of gem-disubstituted benzylamine XX is shown in Scheme 5. A suitable benzonitnle was treated with an excess of methyl organocenum reagent to produce the desired substituted amine Xla. SCHEME 5 Xla SCHEME 6 Substituted amine Xlb was prepared according to the sequence presented in Scheme 6 Phenol XXa was first converted to a difluoromethoxy group with an alkylatng agent such as methyl 2-chloro-2.2-dιfluoroacetate and a base such as potassium carbonate This intermediate XXb was then treated with an excess of methyl organocenum leagent to afford the amine Xlb. SCHEME 6 XXa XXb Xlb SCHEME 7 Scheme 7 is presenting the general method of preparation of 6-amιno- 3-pyndyl denvatives of formula Ik and Ij. Bromopyndines 2 or 3 were coupled with a suitable secondary amme in the presence of copper (I) iodide. In the case of more hindered or non-reactive ammes, the intermediate 2 was preferred as starting matenal in order to avoid extensive reduction of the N-oxide The pyπdine Ij was then oxidized to the pyπdme-N-oxide Ik with an oxidizing agent such as MMPP SCHEME 7 SCHEME 8 The synthesis of 6-ammo-3-pyπdyl deπvatives of formula II to Io is shown in Scheme 8 Bromopyndine 2 was coupled with a suitable primary amine in the presence of copper (I) iodide. Protection by acylation afforded Im R D represents alkyl, haloalkyl, aralkyl or aryl. Oxidation of this amide Im with an oxidizing agent such as MMPP followed by the hydrolysis of the protecting group with a base such as lithium hydroxide, gave access to the desired free amine pyndιne-/V-oxιde In In the case where the amine was protected as a tnfluoroacetamide, the MMPP oxidation lead to the direct formation of hydroxylamine pyπdine-N-oxide Io SCHEME 8 Io SCHEME 9 Scheme 9 is presenting an alternative route for the preparation of 6- amino-3-pyridyl derivatives of formula In and Ip. The coupling of a suitable amme with the bromopyridme intermediate 1 was performed with Cul. The resulting ammo ketone XXIX was then protected as a suitable carbamate, the ketone XXX was reduced to the secondary alcohol XXXI with a reducing agent such as sodium borohydπde and then converted to the corresponding chlonde XXXII with a chlonnating agent such as thionyl chlonde and a base. This chloπde was condensed with the α-anion of ethyl 4-pyπdyl acetate, affording the ester XXXIII which upon hydrolysis with a base such as lithium hydroxide, followed by acidification with an acid such as hydrochloπc acid afforded the decarboxylated intermediate Ip. Oxidation of the pyndine to the pyndme-N-oxide was done with an oxidizing agent such as MMPP and finally the carbamate protecting group was removed under hydrogenolysis condition (For CBZ protecting group) or in the presence of a Lewis acid such as tπmethylsilyl iodide and a base such as dι-tert-butylpyπdιne. SCHEME 9 XXIX SCHEME 9 -Cont.) XXXIII IP In SCHEME 10 In Scheme 10 another approach is presented for the synthesis of 6- ammo-3-pyπdyl denvatives of formula Iq to Is. The amine functionality was introduced by a copper (I) coupling of intermediate 2 with a benzylic amme such as α- methyl benzylamine followed by the deprotection of the benzylic residue with an acid such as tπfluoroacetic acid to access the aminopyπdme XXXIV. This amine was heated in a suitable dimethyl acetal and the resulting lmme XXXV was then treated with a nucleophile such as methyl Gπgnard to access the gem-dimethyl denvative Iq The 4-pyndyl-N-oxιde Is was obtained by a sequence of protection of the amine with tπfluoroacetic anhydnde, oxidation with an oxidizing agent such as MMPP and deprotection of the amme with a base such as lithium hydroxide. SCHEME 10 SCHEME 10 (ConU SCHEME 11 Scheme 11 is presenting the preparation of different amide denvatives of formula It and lu to Iw starting with the aminopyπdine XXXIV. In the presence of a suitable acylating agent the mono and bis-amide were obtained. The coπesponding N-oxide derivatives Iv and Iw were prepared by oxidation with an oxidizing agent such as MMPP followed by the mono hydrolysis of the bis-amide Iv to give the mono-amide pyπdme-N-oxide Iw. SCHEME 11 SCHEME 12 In Scheme 12 the synthesis of ! uenvatives of foπnula Ij and Ik, starting from hindered secondary amines, is shown The coupling of a suitable amme with the bromopyndine intermediate 1 was performed with Cul. The resulting ammo ketone XXXVI was reduced to the secondary alcohol XXXVII with a reducing agent such as sodium borohydπde and then converted to the corresponding chloπde XXXVIII with a chlonnating agent such as thionyl chloπde and a suitable base This chloride was condensed with the α-anion of ethyl 4-pyndyl acetate, affording the ester XXXIX which upon hydrolysis with a base such as lithium hydroxide, followed by acidification with an acid such as hydrochloric acid afforded the decarboxylated intermediate Ij Oxidation of the pyndine to the pyπdιne-/V-oxιde Ik was done with an oxidizing agent such as MMPP. SCHEME 12 XXXVI SCHEME 12 (CONT.) Ik SCHEME 13 In Scheme 13 the treatment of a suitable amide Iw with a base such as sodium hydride and an alkylating agent such as methyl iodide afforded the N-methyl amide ly and the imine Ix from O-alkylation. SCHEME 13 SCHEME 14 In Scheme 14 a suitable amine II was protected as a carbamate in the presence of a suitable chloroformate or a dicarbonate. SCHEME 14 ip SCHEME 15 In Scheme 15 several derivatives of formula II and Iz were obtained starting from the same intermediate Ipχ. Oxidation of this compound lead to the formation of the mono-pyridine-N-oxide Iz and the bis-pyridine-N-oxide XL which were both deprotected with a reducing agent such as Pd/C under an hydrogen atmosphere to afford respectively the free pyridine Ilχ and a mixture of mono and the bis-N-oxide XLII and XLI. Simple deprotection of carbamate Ipχ produced the free amine Ilj. SCHEME 15-Cont - XL Iz H 2 H 2 Pd/C Pd/C (Degussal XLI XLII SCHEME 16 In Scheme 16 the amine II was alkylated by reductive amination of acetic acid in the presence of an excess of a reducing agent such as sodium borohydnde Oxidation of the pyndine Ij with an oxidizing agent such as MMPP lead to the pyπdme-N-oxide Ik SCHEME 16 II ij Ik Representative compounds are shown in the tables below. Λ Unless specified, all the compounds are racemic mixture. b (S) stereoisomer. C (R) stereoisomer. pure. e (N)-oxιde of the 2, 5-dιsubstιtuted pyndine. f(R, S) mixture. SMeSO3H salt. α Unless specified, all the compounds are racemic mixture. ^Hvdrochloπde salt (2HC1). C (S) stereoisomer. d (R) stereoisomer e Optιcally puu (N)-oxιde of the 2,5- disubstituted pyndine. TABLE 3 TABLE 4 Ex Isomer 101 Racemic TABLE 5 Ex 106 TABLE 6 Ex 107 TABLE 7 Ex 108 TABLE 9 Y' m R 3a R 4a n R 3b R 4b Ra O 0 - - 0 - - 4-(tnfluoromethoxy) TABLE 12 Y' m R 3a R 4a R 3b R 4b Ra O 7-(trifluoro methoxy) TABLE 13 ASSAYS DEMONSTRATING BIOLOGICAL ACTIVITY LPS AND FMLP-INDUCED TNF-α AND LTB4 ASSAYS IN HUMAN WHOLE BLOOD Whole blood provides a protein and cell-πch milieu appropπate for the study of biochemical efficacy of anti-inflammatory compounds such as PDE 4- selective inhibitors. Normal non-stimulated human blood does not contain detectable levels of TNF-α and LTB4. Upon stimulation with LPS, activated monocytes expresss and secrete TNF-a up to 8 hours and plasma levels remain stable for 24 hours. Published studies have shown that inhibition of TNF-α by increasing intracellular cAMP via PDE 4 inhibition and/or enhanced adenylyl cyclase activity occurs at the transcriptional level. LTB4 synthesis is also sensitive to levels of intracellular cAMP and can be completely inhibited by PDE 4-selectιve inhibitors. As there is little LTB4 produced during a 24 hour LPS stimulation of whole blood, an additional LPS stimulation followed by fMLP challenge of human whole blood is necessary for LTB4 synthesis by activated neutrophils. Thus, using the same blood sample it is possible to evaluate the potency of a compound on two surrogate markers of PDE 4 activity in the whole blood. Fresh blood was collected in heparmized tubes by venipuncture from healthy human volunteers (male and female). These subjects had no apparent inflammatory conditions and had not taken any NSAIDs for at least 4 days prior to blood collection. Five hundred μL aliquots of blood were pre-incubated with either 2μL of vehicle (DMSO) or 2μL test compound at varying concentrations for 15 minutes at 37 C. This was followed by the addition of either lOμL vehicle (PBS) as blanks or lOμL LPS (lμg/ml final concentration, Sigma Chem, #L-2630 from E. coli, serotype 0111:B4; diluted in 0.1% w/v BSA (in PBS)). After 24 hours of incubation at 37 C, another lOμL of PBS (blank) or lOμL of LPS (lμg/ml final concentration) was added to blood and incubated for 30 minutes at 37 C The blood was then challenged with either lOμL of PBS (blank) or lOμL of fMLP (lμM final concentration, Sigma Chem #F-3506; diluted in 1% w/v BSA (in PBS)) for 15 minutes at 37 C. The blood samples were centnfuged at 1500xg for 10 minutes at 4 C to obtain plasma. A 50μL aliquot of plasma was mixed with 200μL methanol foi protein precipitation and centnfuged as above. The supernatant was assayed for LTB4 using an enzyme immunoassay kit (Cayman Chemicals #520111) according to the manufacturer's procedure TNF-α was assayed m diluted plasma (in PBS) using an ELISA kit (Cistron Biotechnology) according to manufacturer's procedure ANTI- ALLERGIC ACTIVITY IN VIVO Compounds of the invention have been tested for effects on an IgE- mediated allergic pulmonary inflammation induced by inhalation of antigen by sensitised guinea pigs Guinea pigs were initially sensitised to ovalbumin under mild cyclophosphamide-mduced immunosuppression, by mtrapentoneal injection of antigen in combinations with aluminium hydroxide and pertussis vaccine Booster doses of antigen were given two and four weeks later and at six weeks, animals were challenged with aerosohsed ovalbum whilst under cover of an intrapeπtoneally administered anti-histamine agent (mepyramme) After a further 48h, bronchial alveolar lavages (BAL) were performed and the numbers of eosmophils and other leukocytes in the BAL fluids were counted The lungs were also removed for histological examination for inflammatory damage Administration of compounds of the Examples (0 001-10mg/kg I p or p o ), up to three times dunng the 48h following antigen challenge, lead to a significant reduction in the eosinophiha and the accumulation of other inflammatory leukocytes There was also less inflammatory damage in the lungs of animals treated with compounds of the Examples SPA BASED PDE ACTIVITY ASSAY PROTOCOL Compounds which inhibit the hydrolysis of cAMP to AMP by the type-IV cAMP-specific phosphodiesterases were screened in 96-well plate format as follows: In a 96 well-plate at 30°C was added the test compound (dissolved in 2 3 μl DMSO), 188 ml of substrate buffer containing [2,8- H] adenosme 3 ',5 '-cyclic phosphate (cAMP, 100 nM to 50 μM), 10 mM MgCl2, 1 mM EDTA, 50 mM Tπs, pH 7.5. The reaction was initiated by the addition of 10 ml of human recombinant PDE- IV (the amount was controlled so that -10% product was formed m 10 min.). The reaction was stopped after 10 mm. by the addition of 1 mg of PDE-SPA beads (Amersham). The product AMP generated was quantified on a Microbeta 96-well plate counter. The signal in the absence of enzyme was defined as the background. 100% activity was defined as the signal detected in the presence of enzyme and DMSO with the background subtracted. Percentage of inhibition was calculated accordingly. IC50 value was approximated with a non-linear regression fit using the standard 4-parameter/multιple binding sites equation from a ten point titration. IC50 values shown in Table 7 were determined with 100 nM cAMP using the punfied GST fusion protein of the human recombinant phosphodiesterase IVa (met-248) produced from a baculovιrus/Sf-9 expression system. TABLE 14 In Vitro Potency of some representative PDE 4 Inhibitors. The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise: (1) all operations were earned out at room or ambient temperature, that is, at a temperature m the range 18-25°C; evaporation of solvent was earned out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) with a bath temperature of up to 60°C; the course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only, melting points are uncorrected and 'd' indicates decomposition; the melting points given are those obtained for the mateπals prepared as described; polymorphism may result in isolation of mateπals with different melting points in some preparations; the structure and puπty of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data; yields are given for illustration only, when given, NMR data is in the form of delta (δ) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent, conventional abbreviations used for signal shape are s. singlet; d doublet, t tπplet, m. multiplet; br. broad; etc.: in addition "Ar" signifies an aromatic signal, chemical symbols have their usual meanings; the following abbreviations have also been used v (volume), w (weight), b.p. (boiling point), m.p (melting point), L (lιter(s)), mL (millihters), g (gram(s)), mg (mιllιgrams(s)), mol (moles), mmol (mil moles), eq (equιvalent(s)). EXAMPLE 1 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(BENZYLAMINO)3- P YRID YL]ETHYL } PYRIDINE The intermediate 2 (942 mg, 2.0 mmol) was dissolved in 5 mL of benzylamine and Cul (79 mg, 0.4 mmol) was added in one portion. The resulting red- brown solution was stirred at 100 °C for 12 h, cooled down to room temperature, quenched with 1 mL of concentrated NH4OH and stiπed for 15 minutes. The mixture was diluted with ethyl acetate and a saturated aqueous solution of NaHCO3. The layers were separated, the organic phase was washed with brine, dned over MgSO4 and concentrated under reduced pressure. The residue was purified by distillation (1 mm Hg, 75 ° C) to remove most of the benzylamine, and by flash chromatography on silica gel (Gradient 80% ethyl acetate/hexane to 100% ethyl acetate) to afford the title compound (712 mg, 72%). !H NMR (500 MHz, Acetone-d6) δ 8.37 (s, 2H), 7.95 (s, IH), 7.42 (dd, IH), 7.37-7.14 (m, 10H), 6.94 (t, IH), 6.92 (t, IH), 6.48 (d, IH), 6.12 (t, IH), 4.52 (d, 2H), 4.36 (t, IH), 3.39 (d, 2H). EXAMPLE 2 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(S)-(l- PHENYLETHYLAMINO)3-PYRID YLJETHYL } PYRIDINE Following the procedure descnbed in Example 1 but substituting (S)-l- phenylethylamme at 160 °C for benzylamine at 100 °C, the title compound was obtained as an oil (368 mg, 55%). !H NMR (400 MHz, Acetone-d6) δ 8.36 (s, 2H), 7 88 (s, IH), 7 42- 7.11 (m, 1 IH), 6.92 (t, IH), 6.90 (t, IH), 6 40 (dd, IH), 6.09 (s, IH), 4.99 (m, IH), 4.37-4.28 (m, IH), 3.36 (d, 2H), 1.45 (d, 3H). EXAMPLE 3 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(R)-(l- PHENYLETHYLAMINO)3-PYRID YLJETHYL } PYRIDINE Following the procedure descnbed in Example 1 but substituting (R)- 1-phenylethylamιne at 160 °C for benzylamine at 100 °C, the title compound was obtained as an oil (444 mg, 54%). *H NMR (400 MHz, Acetone-d6) δ 8.34 (s, 2H), 7.90 (d, IH), 7.40- 7.10 (m, 11H), 6.90 (t, IH), 6.88 (t, IH), 6.38 (dd, IH), 6.1 (s, IH), 5.00 (m, IH), 4.32 (m, IH), 3.37 (d, 2H), 1.45 (d, 3H). EXAMPLE 4 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[l-(4- FLUOROPHEN YL)ETHYLAMINO] 3-P YRID YL } ETHYL } PYRIDINE Following the procedure descnbed in Example 1 but substituting (±)-l- (4-fluorophenyl)ethylamme at 150 °C for benzylamine at 100 °C, the title compound was obtained as an oil (280 mg, 46%). l H NMR (500 MHz, Acetone-d6) δ 8.35 (s, 2H), 7.92 (d, IH), 7.45- 7.35 (m, 2H), 7.32 (s, IH), 7.28-7.18 (m, 2H), 7.12 (s, 2H), 7.09-6.98 (m, 2H), 6.92 (t, large J, IH), 6.90 (t, large J, IH), 6.40 (dd, IH), 6.09 (s, IH), 5.05-4.96 (m, IH), 4.38-4.29 (m, IH), 3.38 (d, 2H), 1.47 (d, 3H) EXAMPLE 5 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[l-(4- FLUOROPHENYL)ETHYLAMl.NO]3-PYRIDYL}ETHYL}PYRIDINE-N-OXIDE Step 1 4-{2-r3,4-Bis(difluoromethoxv)phenvll-2-|6-rN-l-(4-fluorophenyl)ethyl trifluoroacetamidel3-pyridyl ) ethyl } pyridine To a 0 °C solution of 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[l- (4-fluorophenyl)ethylamino]3-pyridyl Jethyl }pyridine from Example 3 above (100 mg, 0.189 mmol) in 2 mL of CH2CI2, was added 0.03 mL of pyridine (0.378 mmol) followed by 0.04 mL of TFAA (0.284 mmol). The ice bath was removed and the reaction was stirred at room temperature for 1 h. 2 mL of toluene were added and the volatile were removed under reduced pressure. The residue was purified by flash chromatography on silica gel (Gradient 80% ethyl acetate/hexane to 100% ethyl acetate) to afford 100 mg (85%) of the trifluoroacetamide. Step 2 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[N-l-(4-fluorophenyl)ethyl trifluoroacetamide]3-pyridyl } ethyl }pyridine-Ν-oxide To a 0 °C solution of trifluoroacetamide from Step 1 above (100 mg, 0.16 mmol) in 2.0 mL of CH2CI2, was added 30 mg of NaHCO3 followed by 33 mg (0.19 mmol) of 80% MCPBA. The mixture was stiπed 1 h at 0 C, 2 h at room temperature and directly purified by flash chromatography on silica gel (20% EtOH/ethyl acetate + 3% Et3N) to afford 95 mg (93%) of the trifluoroacetamide-N- oxide. Step 3 4-{2-13.4-Bis(difluoromethoxy)phenyl1-2-| 6-ri-(4-fluorophenyl)ethylaminol3- pyndyl Jethyl }pyndιne-N-oxιde The tπfluoroacetamide-N-oxide from Step 2 above (95 mg, 0.148 mmol) was dissolved in a mixture of THF/MeOH/H2θ (1.5 mL/0 5 mL/0.15 mL) followed by the addition of 0.15 mL of a 2 N LiOH solution. The reaction was stirred 15 minutes at room temperature and rotovaped down with several portion of MeOH (Coevaporation). The residue was directly punfied by flash chromatography on silica gel (30% EtOH/acetone + 3% Et3N) to afford the title compound (78 mg, 96%). l H NMR (500 MHz, Acetone-dό) δ 8.00-7 92 (m, 2H), 7.90 (d, IH), 7.45-7.35 (m, 3H), 7.32 (s, IH), 7.27-7 19 (m, 2H), 7.18-7.11 (m, 2H), 7.06-6 98 (m, 2H), 6.93 (t, large J, IH), 6.90 (t, large J, IH), 6.42 (dd, IH), 6 18 (s, IH), 5.05-4 96 (m, IH), 4.31-4.24 (m, IH), 3.40-3.30 (m, 2H), 1 46 (d, 3H). EXAMPLE 6 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(BENZYLAMINO)3- PYRID YL]ETH YL } PYRIDINE-N-OXIDE Step 1 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-benzyl acetamιde)3- pyndyllethyl jpyndine To a solution of 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6- (benzylamιno)3-pyndyl]ethyl Jpyπdine from Example 1 (100 mg, 0.2 mmol) in 3 mL of 1,2-dιchloroethane, was added 0 077 mL (0.95 mmol) of pyπdme followed by 0.056 mL (0.6 mmol) of acetic anhydnde. The solution was stirred at reflux for 16 h, cooled down to room temperature, quenched with water and diluted with CH2CI2 The layers were separated and the organic phase was washed with bnne, dπed over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Gradient 100% ethyl acetate to 10% EtOH/ethyl acetate) to afford 29 mg (27%) of acetamide Step 2 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-benzyl acetamιde)3- pyndyllethyl Jpyndme-Ν-oxide To a solution of acetamide from Step 1 above (29 mg, 0.054 mmol) m a mixture of 2.0 mL of CH2CI2 and 0.2 mL of MeOH, was added 20 mg (0.032 mmol) of 80% MMPP. The mixture was stirred 2 days at room temperature and directly puπfied by flash chromatography on silica gel (Gradient 100% ethyl acetate + 3% Et3N to 40% EtOH ethyl acetate + 3% Et3N) to afford 29 mg (95%) of acetamide -N-oxide. Step 3 4-{2-[3,4-Bis(difluoromethoxy phenyll-2-[6-(benzylamino)3-pyndyllethyl Jpyndine- N -oxide The acetamide-N-oxide from Step 2 above (10 mg, 0.018 mmol) was dissolved m a mixture of THF/MeOH/H2θ (0 5 mL/0 15 mL/0.05 mL) followed by the addition of 0.054 mL of a 2 N LiOH solution. The reaction was stirred 5 h at 60 °C and rotovaped down with several portion of MeOH (Coevaporation). The residue was directly punfied by flash chromatography on silica gel (Gradient 100% ethyl acetate + 3% Et3N to 30% EtOH/ethyl acetate + 3% Et3N) to afford the title compound as an oil (6.3 mg, 70%). iH NMR (500 MHz, Acetone-d6) δ 7.96-7.92 (m, 3H). 7.42 (dd, IH), 7.36-7.31 (m, 3H), 7.30-7.23 (m, 4H), 7.20 (d, IH), 7.16 (d, 2H), 6 94 (t, IH), 6.91 (d, tH), 6.50 (d, 1H),4 53 (d, 2H), 4 32 (t, IH), 3 40 (d, 2H). EXAMPLE 7 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(S)-(l- PHENYLETHYLAMINO)3-PYRIDYL]ETHYL } PYRIDINE-N-OXIDE Following the procedures descnbed in Example 5 but substituting 4- {2-[3,4-bιs(dιfluoromethoxy)phenyl]-2-[6-(S)-(l-phenylethylamιno)3- pyπdyflethyl Jpyπdine (Example 2) for 4-{2-[3,4-bιs(dιfluoromethoxy)phenyl]-2-{6- [l-(4-fluorophenyl)ethylamιno]3-pyπdyl Jethyl Jpyndine (Example 4), the title compound was obtained as a foam (143 mg). iH NMR (500 MHz, Acetone-d6) δ 7.93-7.87 (m, 3H), 7.40-7.34 (m, 3H), 7.32 (s, IH), 7.29-7.11 (m, 7H), 6.93 (dt, IH), 6.88 (t, IH), 6.41 (dd. IH), 6.13 (brs, IH), 5.00 (m, IH), 4.30 (m, IH), 3.35 (dd, 2H), 1.46 (d, 3H). EXAMPLE 8 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(R)-(l- PHENYLETHYLAMINO)3-PYRIDYL]ETHYL}PYRIDINE-N-OXIDE Following the procedures descnbed in Example 5 but substituting 4- {2-[3,4-bιs(difluoromethoxy)phenyl]-2-[6-(R)-(l-phenylethylamιno)3- pyndyljethyl jpyridine (Example 3) for 4-{2-[3,4-bιs(dιfluoromethoxy)phenyl]-2-{6- [l-(4-fluorophenyl)ethylamιno]3-pyπdyl}ethyl }pyndme (Example 4), the title compound was obtained as a foam (176 mg). ! H NMR (500 MHz, Acetone-d6) δ 7.96 ( , 2H), 7.89 (dd, IH), 7.37 (d, 3H), 7.32 (s, IH), 7.29-7.13 (m, 7H), 6.93 (dt, IH), 6.89 (t, IH), 6.42 (dd, IH), 6.21 (brs, IH), 5.00 (m, IH), 4.30 (m, IH), 3.39 (dd, 2H), 1.48 (d, 3H). EXAMPLE 9 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(2- PHENYLETHYLAMINO)3-PYRIDYL]ETHYL } PYRIDINE-N-OXIDE The intermediate 3 (130 mg, 0.267 mmol) was dissolved in 2 mL of phenethylamine and Cul (10 mg, 0.053 mmol) was added in one portion. The resulting red-brown solution was stirred at 100 °C for 2 h and 6 h at 160 °C, cooled down to room temperature, quenched with 1 mL of concentrated NH4OH and stirred for 15 minutes. The mixture was diluted with ethyl acetate and a saturated aqueous solution of NaHCO3. The layers were separated, the organic phase was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative silica gel plate (1% NH4OH/9% MeOH/90% CH2CI2) to afford 108 mg of 80% pure compound (61%). l H NMR (500 MHz, Acetone-d6) δ 8.00-7.91 (m, 3H), 7.45-7.13 (m, 11H), 6.97 (t, large J, IH), 6.94 (t, large J, IH), 6.45 (d, IH), 5.84 (t, IH), 4.33 (t, IH), 3.59-3.49 (m, 2H), 3.39 (d, 2H), 2.87 (t, 2H). EXAMPLE 10 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[2-(2- P YRIDYL)ETHYLAMINO] 3-PYRIDYL JETHYL } PYRIDINE-N-OXIDE The intermediate 3 (250 mg, 0.513 mmol) was dissolved in 2 mL of 2- (2-aminoethyl)pyridine and Cul (20 mg, 0.103 mmol) was added in one portion. The resulting red-brown solution was stiπed at 100 ° C for 3 h, cooled down to room temperature, quenched with 1 mL of concentrated NH4OH and stirred for 15 minutes. The mixture was diluted with ethyl acetate and a saturated aqueous solution of NaHCO3. The layers were separated, the organic phase was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative silica gel plate (1% NH4OH/9% MeOH/90% CH2CI2) to afford the title compound as an oil (114 mg, 42%). H NMR (500 MHz, Acetone-d6) δ 8.50 (d, IH), 7.95 (d, 3H), 7.65 (t, IH), 7.40 (dd, IH), 7.35 (s, IH), 7.30-7.13 (m, 6H), 6.96 (t, large J, IH), 6.91 (t, large J, IH), 6.44 (d, IH), 5.85 (t, IH), 4.32 (t, IH), 3.67 (t, 2H), 3.39 (d, 2H), 3.01 (t, 2H). EXAMPLE 11 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(l-METHYL-l- PHENYLETHYLAMINO)3-PYRIDYL]ETHYL } PYRIDINE-N-OXIDE Step 1 ■ 3.4-Bιs(dιfluoromethoxy)phenyll-16-(l-methvl-l-phenylethylamιno)3- pyndyllmethanone The intermediate 1 ( 6.86 g, 17.4 mmol) was dissolved in 10 mL of cumylamine and Cul (331 mg, 1.74 mmol) was added in one portion The resulting red-brown solution was stirred at 140 °C for 15 h, cooled down to room temperature, quenched with 5 mL of concentrated NH4OH and stirred for 30 minutes. The mixture was diluted with ethyl acetate and a saturated aqueous solution of NaHCO3. The layers were separated, the organic phase was washed with bnne, dned over MgSO4 and concentrated under reduced pressure. The residue was purified by distillation (15 mm Hg, 125 ° C) to remove most of the cumylamine, and by flash chromatography on silica gel (Gradient 25% to 30% ethyl acetate/hex ane) to afford 6.9 g (89%) of amino ketone. Step 2 [3,4-Bιs(dιfluoromethoxy)phenyl]-{6-[N-(l-methyl-l-phenyl)ethyl-N; (benzyloxycarbonyl)amιnol3-pyndyl Jmethanone To a solution amino ketone from Step 1 above (12 g, 26.7 mmol) in 150 mL of dioxane was added 14 mL (80.1 mmol) of -Pr2ΝEt followed by 7 64 mL (53.5 mmol) of benzyl chloroformate The resulting solution was stiπed 16 h at room temperature, quenched with a saturated solution of NaHCO3 and diluted with ethyl acetate. The layers were separated and the organic phase was washed with bnne, dned over MgSO4 and concentrated under reduced pressure. The residue was used directly for the next step without any further puπfication. Step 3 [3,4-Bιs(dιfluoromethoxy)phenyl]-{6-[N-(l -methyl- l-pheny ethyl-N; (benzyloxycarbonyl)amιno13-pyπdylJmethanol To a 0 °C solution of ketone (26.7 mmol) from Step 2 above in 120 mL of a 5 : 1 mixture of THF MeOH, was added slowly 2.0 g (53.5 mmol) of ΝaBH4 The resulting solution was stirred 30 minutes at room temperature, quenched with a saturated aqueous NH4CI solution and diluted with ethyl acetate The organic layer was washed with bnne, dned over MgSO4 and concentrated under reduced pressure The residue was punfied by flash chromatography on silica gel (Gradient 40% to 50% Ethyl acetate/hexane) to afford 14 9 g (95 % for 2 steps) of alcohol Step 4 4-{ l-Carbethoxy-2-[3,4-bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l- phenvl)ethyl-N-(benzyloxycarbonyl)amιnol3-pyπdyl Jethyl Jpyndine To a 0 °C solution of pyndine (6 19 mL, 76 5 mmol) in 150 mL of toluene was added 2 78 mL (38 2 mmol) of SOCI2 followed by a solution of the alcohol from Step 3 above (14 9 g, 25 5 mmol) in 100 mL of toluene The solution was stirred 1 h at 0 °C followed by the addition of the enolate generated as follow to a solution of ethyl 4-pyndyl acetate (21 1 g, 127 5 mmol) and HMPA (22 2 mL, 127 5 mmol) in 250 mL of THF, was slowly added 255 mL (127 5 mmol) of a 0 5 M solution of KHMDS in toluene and the resulting solution was stirred 30 minutes at 0 °C The resulting cloudy solution was stirred 2 h, quenched with a saturated aqueous ΝH4CI solution and diluted with ethyl acetate/saturated NaHCO3 solution The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over MgSO4 and concentrated under reduced pressure The residue was used directly for the next step without any punfication Step 5 4- { 2-[3 ,4-bιs(dιfluoromethoxy)phenyl]-2- { 6-[N-( 1 -methyl- 1 -phenyl)ethyl-N- (benzyloxycarbonyl)ammol3-pyndvI Jethyl Jpyndine To a solution of the crude ester from Step 4 above in a mixture of THF/ MeOH/ water (570 mL/190 mL/190 mL), was added 190 mL (382 mmol) of a 2 Ν solution of LiOH The resulting solution was stiπed at 65 °C for 3 h, cooled down to room temperature followed by the addition of 204 mL of a 2 0 Ν HC1 solution The resulting mixture was rotovaped down to evaporate MeOH and the aqueous residue was diluted with ethyl acetate The aqueous layer was extracted with ethyl acetate and the combined organic layer were washed with water and bnne, dned over MgSO4 and concentrated under reduced pressure The residue was punfied by flash chromatography on silica gel (Gradient 80% Ethyl acetate/hexane to 100% ethyl acetate) to afford 13 5 g (80%) of pyndme Step 6 4-{2-[3,4-bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-phenyl)ethyl-N- (benzyloxycarbonyl)amιno]3-pyπdyl Jethyl Jpyπdine-Ν-oxide To a solution of pyπdme from Step 5 above (3.74 g, 5.66 mmol) in a CH2Cl2/MeOH mixture (180 mL/18 mL) was added 4.2 g (8.5 mmol) of MMPP in one portion. The resulting solution was stiπed at room temperature for 5 h and punfied directly by flash chromatography on silica gel (Gradient 100% CH2CI2 to 5% MeOH/CH2Cl2 to 5% (10% ΝH4θH/MeOH)/CH2Cl2) to afford 4 g of contaminated carbamate pyπdine-N-oxide. Step 7 4- { 2-r3.4-Bιs(dιfluoromethoxy)phenyl1-2-[6-( l -methyl- l-phenylethylamιno)3- pyπdyllethyl Jpyndine-N-oxide To a solution of carbamate pyπdine-N-oxide from Step 6 above (5.66 mmol) in 60 mL of EtOH, was added 1.0 g of 10% Pd/C and the resulting mixture was purged 3 times with H2 and stiπed under atmospheric pressure of H2 for 4 h. The reaction was then filtered on ce te and the volatile were removed under reduced pressure. The residue was purified by flash chromatography on silica gel (Gradient 3% to 8% MeOH/CH2Cl2 to 10% (10% NH4OH/MeOH)/CH2Cl2) to afford the title compound as an oil (1.7 g, 55% for 2 steps) ! H NMR (500 MHz, Acetone-d6) δ 7 91 (d, 2H), 7.81 (s, IH), 7 45 (d, 2H), 7.31-7.13 (m, 7H), 7.10 (d, 2H), 6.93 (t, large J, IH), 6 90 (t, large J, IH), 6.15 (dd, IH), 5.94 (s, IH), 4.22 (t, IH), 3.38-3.26 (m. 2H), 1.67 (s, 6H). EXAMPLE 12 (ENANTIOMER- 1 )-4- { 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-( 1 - METHYL- 1 -PHENYLETHYLAMINO)3-PYRID YLJETHYL } PYRIDINE-N-OXIDE The title compound was obtained by resolution of racemic 4-{2-[3,4- Bιs(dιfluoromethoxy)phenyl]-2-[6-(l -methyl- 1-phen ylethylamιno)3- pyndyljethyl Jpyπdine-N-oxide (Example 11) on chiral column: preparative chiralpak AD, 35% --PrOH/hexane, 75 mL/mm. Example 12 is the fast eluting enantiomer with a retention time on analytical chiralpak AD of 10 minutes (50% /-PrOH/hexane, 1.0 l R NMR (500 MHz, Acetone-d6) δ 7.91 (d, 2H), 7.81 (s, IH), 7.45 (d, 2H), 7.31-7.13 (m, 7H), 7.10 (d, 2H), 6.93 (t, large J, IH), 6.90 (t, large J, IH), 6.15 (dd, IH), 5.94 (s, IH), 4.22 (t, IH), 3.38-3.26 (m, 2H), 1.67 (s, 6H). EXAMPLE 13 (ENANTIOMER-2)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(l- METHYL-l-PHENYLETHYLAMINO)3-PYRIDYL]ETHYL}PYRIDINE-N-OXIDE The title compound was obtained by resolution of racemic 4-{2-[3,4- Bιs(dιfluoromethoxy)phenyl]-2-[6-(l-methyl-l-phenylethylamιno)3- pyndyljethyl Jpyndine-N-oxide (Example 11) on chiral column: preparative chiralpak AD, 35% /-PrOH/hexane, 75 mL/mm. Example 13 is the slow elut g enantiomer with a retention time on analytical chiralpak AD of 15 minutes (50% /-PrOH/hexane, !H NMR (500 MHz, Acetone-d6) δ 7.91 (d, 2H). 7.81 (s, IH), 7.45 (d, 2H), 7.31-7.13 (m, 7H), 7.10 (d, 2H), 6.93 (t, large J, IH), 6.90 (t, large J, IH), 6.15 (dd, IH), 5.94 (s, IH), 4.22 (t, IH), 3.38-3.26 (m, 2H), 1 67 (s, 6H). EXAMPLE 14 (ENANTIOMER-2)-4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(l- METHYL- 1 -PHENYLETHYLAMINO)3-PYRIDYL-N- OXIDEJETHYL } PYRIDINE-N-OXIDE The title compound was obtained as a side product of Example 11 Step 6 (overoxidation) and Step 7 (deprotection of the bis-N-oxide) to afford 710 mg of the title compound as a foam. !H NMR (500 MHz, Acetone-d6 + D2O) δ 8.17 (s, IH), 8.08 (d, 2H), 7.38 (d, 2H), 7.33 (d, 2H), 7.30-7.25 (m, 3H), 7.22-7.16 (m, 3H), 7.04 (d, IH), 6.88 (t, IH), 6.85 (t, IH), 6.00 (d, IH), 4.37 (t, IH), 3.40 (d, 2H). 1.66 (s, 3H), 1.66 (s, 3H) EXAMPLE 15 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[(2- PYRIDYL)METHYLAMINO]3-PYRIDYL}ETHYL}PYRIDINE-N-OXIDE Following the procedure described in Example 10 but substituting 2- (amιnomethyl)pyπdιne at 120 °C for 2-(2-aminoethyl)pyridine at 100 ° C, the title compound was obtained as an oil (145 mg, 50%) contaminated with 10% of starting matenal. *H NMR (500 MHz, Acetone-d6) δ 8.50 (d, IH), 7.94 (d, 3H), 7.68 (t, IH), 7.45 (dd. IH), 7 39-7.12 (m, 7H), 6.96 (t, large J, IH), 6.92 (t, large J, IH), 6.57 (d, IH), 6 35 (t, IH), 4.60 (s, 2H), 4.32 (t, IH), 3.45-3.32 (m, 2H). EXAMPLE 16 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[(2-PYRIDYL-N- OXIDE)METHYLAMINO] 3-PYRIDYL J ETHYL } PYRIDINE-N-OXIDE Step l 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyll-2-16-[(2-pyπdyl)methylamιnoJ3- pyπdyl Jethyl Jpyndine The intermediate 2 (540 mg, 1.15 mmol) was dissolved in 3 mL of 2- (amιnomethyl)pyπdιne and Cul (22 mg, 0.115 mmol) was added in one portion The resulting red-brown solution was stiπed at 120 °C for 15 h, cooled down to room temperature, quenched with 1 mL of concentrated NH4OH and stirred for 15 minutes The mixture was diluted with ethyl acetate and a saturated aqueous solution of NaHCO3. The layers were separated, the organic phase was washed several times with water and with bnne, dried over MgSO4 and concentrated under reduced pressure. The residue was punfied by flash chromatography on silica gel (20% EtOH/ethyl acetate) to afford 480 mg (84%) of ammo pyπdme. Step 2 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(2-pyπdyl)methyl tnfluoroacetamιdel3-pyπdyl Jethyl Jpyndine To a 0 °C solution of 4-{2-[3,4-Bis(difluoromethoxy)phenylJ-2-{6-[(2- pyndyl)methylamιno]3-pyπdyl Jethyl Jpyπdme from Step 1 above (480 mg, 0.963 mmol) in 10 mL of CH2CI2, was added 0.156 mL of pyndine (1.93 mmol) followed by 0 204 mL of TFAA (1 44 mmol). The solution was stirred 2 h at 0 °C, the reaction was diluted with CH2CI2 and quenched with saturated aqueous solution of ΝaHC03 The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with brine, dned over MgSO4 and concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (Gradient 5% to 10% EtOH/ethyl acetate) to afford the 394 mg (69%) of the tnfluoroacetamide. Step 3 4-| 2-[3,4-Bιs(dιfluoromethoxy)phenyl1-2-{6-l(2-pyπdyl-N-oxιde)methylamιnol3- pyπdyl J ethyl J pyπdine-N-oxide To a 0 °C solution of trifluoroacetamide from Step 2 above (390 mg, 0.656 mmol) in 6.0 mL of CH2CI2, was added 300 mg of NaHCO3 followed by 425 mg (1 97 mmol) of 80% MCPBA. The mixture was stiπed 2 h at room temperature and directly punfied by flash chromatography on silica gel (20% EtOH/ethyl acetate + 3% Et3N) to afford 280 mg (81%) of the unprotected bis-N-oxide. J H NMR (500 MHz, Acetone-d6) δ 8.20 (d, III) 7.93 (d, 3H), 7.47 (dd, IH), 7.39-7.12 (m, 8H), 6.95 (t, large J, IH), 6 91 (t, large J, IH), 6.60 (d, IH), 6.42 (s, IH), 4.66 (s, 2H), 4.33 (t, IH), 3.45-3.32 (m, 2H) EXAMPLE 17 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(R)-(l- PHENYLPROPYLAMINO)3-PYRIDYLJETHYL}PYRIDINE-N-OXIDE Step 1 4-{2-r3,4-Bιs(dιfluoromethoxv)phenvl1-2-[6-(R)-(l-phenylpropylammo)3- pyndyllethyl Jpyndine Following the procedures described in Example 1 but substituting (R)- 1-phenylpropylamιne at 160 °C for benzylamine at 100 °C, the title compound was obtained as an oil (90 mg, 20%). Step 2 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-(R)-l-phenylpropyl tπfluoroacetamιde)3-pyndyl1ethyl Jpyndine The procedure for the protection of the ammo group descnbed in Example 5, Step 1 was applied using the product of Step 1 above as starting matenal. The tnfluoroacetamide was obtained as an oil (70 mg, 66%). Step 3 4-{2-[3,4-Bιs(dιfluoromethoxy)phenylJ-2-[6-(V-(R)-l-phenylpropyl trιfluoroacetamιde)3-pyπdyllethyl )pyrιdιne-Ν-oxιde The procedure for the oxidation of the pyndine descnbed in Example 5, Step 2 was applied using the product of Step 2 above as starting material. The pyndine-N-oxide was obtained as an oil (65 mg, 90%) Step 4 4-{2-[3,4-Bιs(dιfluoromethoxv)phenyll-2-[6-(R)-(l-phenylpropylammo)3- pyndyljethyl Jpyndine-N-oxide The procedure for the deprotection of the amino group described in Example 5, Step 3 was applied using the product of Step 3 above as starting matenal. The title compound was obtained as an oil (50 mg, 91%). ! H NMR (500 MHz, Acetone-d6) δ 7 97-7.85 (m, 3H), 7.40-7 10 (m, 11H), 6 94 (t, large J, IH), 6.90 (t, large J, IH), 6 43 (d, IH), 6.22 (s, IH), 4.76 (q, IH), 4.30-4.23 (m, IH), 3.40-3.29 (m, 2H), 1 90-1.72 (m, 2H), 0.9 (t, 3H) EXAMPLE 18 (EN ANTIOMER- 1 )-4- { 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-( 1 - METHYL- 1 -PHENYLETHYLAMINO)3-PYRID YLJETHYL } PYRIDINE Step 1 (Enantιomer-l)-4-{ 2-[3,4-bιs(dιfluoromethoxy)phenyll-2-{ 6-[N-(l-methyl-l- phenyl)ethyl-N-(benzyloxycarbonvI)amιno13-pyπdyl Jethyl Jpyndme The carbamate of Example 11 Step 5 was resolved on a preparative column chiralpak AD, 20% /-PrOH/hexane, 100 mL/min and was obtained as the fast elut g enantiomer (4.2 g, retention time 39 mm). Step 2 (Enantiomer- 1)-4-{ 2-[3,4-bιs(dιfluoromethoxy)phenyl]-2- { 6-[N-( 1 -methyl- 1- phenyl)ethyl-N-(benzyloxycarbonyl)ammoJ3-pyrιdyl Jethyl Jpyπdine-Ν-oxide The procedure for the oxidation of the pyndine descnbed in Example 11, Step 6 was applied using the product of Step 1 above as starting matenal and 4 g of pyπdme-Ν-oxide was obtained as an oil. Step 3 (Enantιomer-l)-4-{2-r3,4-Bιs(dιfluoromethoxy)phenyl1-2-[6-(l-methyl-l- phenylethylammo)3-pyndylJethyl Jpyndine The procedure for the deprotection of the amino group descnbed in Example 11, Step 7 was applied using the product of Step 3 above as starting matenal The title compound was obtained as a side product of overreduction of the Ν-oxide iH ΝMR (500 MHz, Acetone-d6) δ 8.35 (d, 2H), 7.83 (s, IH), 7.45 (d, 2H), 7.31-7.13 (m, 7H), 7.10 (d, 2H), 6.92 (t, large J, IH), 6 90 (t, large J, IH), 6.15 (d, IH), 5.95 (s, IH), 4.28 (t, IH), 3.38-3.27 (m, 2H), 1 67 (s, 6H). EXAMPLE 19 (ENANTIOMER-2)-4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(l- METHYL- 1 -PHENYLETHYLAMINO)3-PYRID YLJETHYL } PYRIDINE Step 1 (Enantιomer-2)-4-{2-[3,4-bιs(dιfluoromethoxy)phenylJ-2-{6-[N-(l-methyl-l- phenvl)ethvl-N-(benzy1oxycarbonyl)amιnol3-pyndyl Jethyl Jpyndine The carbamate of Example 11, Step 5 was resolved on a preparative column chiralpak AD, 20% / ' -PrOH hexane, 100 mL/mm and was obtained as the slow eluting enantiomer (4.2 g, retention time 52 mm). Step 2 (Enantιomer-2)-4-{ 2-r3,4-Bιs(dιfluoromethoxv)phenyl1-2-r6-(l-methyl-l- phenylethylamιno)3-pyndyl1ethyl Jpyndine The procedure for the deprotection of the amino group descnbed in Example 11, Step 7 was applied using the product of Step 1 above as starting matenal. The ammo pyndine was obtained as a foam (2.8 g, 90%). iH ΝMR (500 MHz, Acetone-dό) δ 8.35 (d, 2H), 7 83 (s, IH), 7.45 (d, 2H), 7 31-7.13 (m, 7H), 7.10 (d, 2H), 6.92 (t, large J, IH), 6.90 (t, large J, IH), 6.15 (d, IH). 5 95 (s, IH), 4.28 (t, IH), 3.38-3 27 (m, 2H), 1.67 (s, 6H) EXAMPLE 20 (EΝ AΝTIOMER-2)-4- { 2-[3 ,4-BIS (DIFLUOROMETHOX Y)PHENYL] -2- [6-( 1 - METHYL- 1 -PHENYLETHYLAMINO)3-PYRIDYL-N-OXIDE]ETHYL } PYRIDINE To a solution of (enantιomer-2)-4-{ 2-[3,4- bιs(dιfluoromethoxy)phenyl]-2-[6-(l-methyl-l-phenylethylamιno)3-pyndyl-N- oxιde]ethyl }pyndme-N-oxιde (Example 14) (100 mg, 0 144 mmol) in 3 mL of MeOH 60 mL, was added 153 mg of 10% Pd/C (Degussa type) and the resulting mixture was purged 3 times with H2 and stiπed under atmosphenc pressure of H2 for 15 h. The reaction was then filtered on ce te and the volatile were removed under reduced pressure. The residue was punfied by flash chromatography on silica gel (Gradient 10% to 15% EtOH/CH2Cl2) to afford the title compound as an oil (26 mg, 34%) II - iH NMR (300 MHz, Acetone-d6) δ 8.35 (d, 2H), 8.14 (s, IH), 7.47- 7.11 (m, 10H), 6.98-6.86 (m, IH), 6.94 (t, IH), 6.90 (m, IH), 5 96 (d, IH), 4.40 (t, IH), 3.4 (d, 2H), 1.7 (s, 6H). EXAMPLE 21 (ENANTIOMER-l)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[l- METHYL- 1 -(4-FLUOROPHENYL)ETHYLAMINOJ 3- P YRID YL } ETHYL } PYRIDINE-N-OXIDE Step 1 1 -methyl- l-(4-fluorophenyl)ethylamme Dry CeCl3 (17.7 g, 72 mmol) was refluxed 1 h in THF The suspension was cooled down to -45 ° C followed by the addition of 51 mL of 1.4 M solution of MeLi in E-2O over 5 minutes. The resulting mixture was stiπed 1 h at -60 °C and 2 9 g (24 mmol) of 4-fluorobenzonitrile were added This heterogeneous solution was allowed to warm up to room temperature over 3 h, cooled down to -40 °C, quenched with 50 mL of cone NH4OH and stirred overnight at room temperature. The supernatant was decanted and the solid residue was washed 3 times with CH2CI2. The combined organic layers were dned over MgSO4 and concentrated under reduced pressure. The residue was punfied by flash chromatography on silica gel (Gradient 20% EtOH/hexane to 3% Et3N/ethyl acetate) to afford 2.0 g (54%) of amine. Step 2-8 Following the procedures descnbed in Examp - 1 1 but substituting 1- methyl-l-(4-fluorophenyl)ethylamme from Step 1 above for cumylamine and by resolution of the carbamate of Step 5 (Preparative chiralpak AD, 30% /-PrOH/hexane, 65 mL/min, fast eluting enantiomer 34 mm), the title compound was obtained as a foam (110 mg). !H NMR (400 MHz, Acetone-d6) δ 7.91 (d, 2H), 7 80 (s, IH), 7.50- 7.42 (m, 2H), 7.32-7.29 (m, 4H), 7 10 (d, 2H), 7.05-6.95 (m, 2H). 6 92 (t, large J, IH), 6.90 (t, large J, IH), 6.20 (d, IH), 5.99 (s, IH), 4.24 (t, IH), 3 40-3 25 (m, 2H). 1.67 (s, 6H) EXAMPLE 22 (ENANTIOMER-l)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[l- METHYL-l-(4-TOLYL)ETHYLAMINOJ3-PYRIDYL}ETHYL}PYRIDINE-N- OXIDE Following the procedures descnbed in Example 11 but substituting 1- methyl-l-(4-tolyl)ethylamιne (Prepared as in Example 21, Step 1) for cumylamine and by resolution of the carbamate of Step 5 (Preparative chiralpak AD, 30% / ' - PrOH/hexane, 65 mL/mm, fast elut g enantiomer 32 mm), the title compound was obtained as a foam (728 mg). ! H NMR (500 MHz, Acetone-d6) δ 7.91 (d, 2H), 7.82 (d, IH), 7.33- 7.28 (m, 3H), 7.28-7.20 (m, 3H), 7.12-7 04 (m, 4H), 6.93 (t, IH), 6 90 (t, IH), 6.12 (d, IH), 5.88 (s, IH), 4.23 (t, IH), 3.37-3.26 (m, 2H), 2.27 (s. 3H), 1.64 (s, 3H), 1.63 (s, 3H). EXAMPLE 23 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[l-METHYL-l-(4- BENZYLOXYPHEN YL)ETHYLAMINO] 3-PYRIDYL J ETHYL } PYRIDINE-N- OXIDE Step 1 (4-benzyloxy)benzonitrile Benzyl bromide (11.5 mL, 96.5 mmol) was added dropwise to a solution of potassium carbonate (17.4g, 126 mmol) and 4-cyanophenol (10.0 g, 83 9 mmol) in 140 mL of DMF. The reaction mixture was stirred for 2 h, poured into 1.5 L of water and extracted with ethyl acetate. The combined organic layers were washed with 25% NH4OAC solution, water, and bnne, dned over MgSO4 and concentrated under reduced pressure. The crude yellow solid obtained was triturated in 10% ethyl acetate/hexane and after filtration 16.3 g (93%) of white crystals were obtained. Step 2 1 -methyl- l-(4-benzy]oxyphenyl)ethylamιne Following the procedures described in Example 21, Step 1 but substituting (4- benzyloxy)benzonιtπle from Step 1 above for 4-fluorobenzonιtπle, the amme was obtained 68% yield as white crystals. Step 3-9 Following the procedures described in Example 11 but substituting 1- methyl-l-(4-benzyloxyphenyl)ethylamιne for cumylamine, the title compound was obtained as a foam (23 mg). H NMR (500 MHz, Acetone-d6) δ 7.92 (d, 2H), 7.82 (d, IH), 7.48 (d, 2H), 7.40-7.29 (m, 6H), 7.29-7.20 (m, 3H), 7.10 (d, 2H), 6.94 (t, IH), 6.92 (d, 2H), 6.90 (t, IH), 6.13 (d, IH), 5.86 (s, IH), 5.08 (s, 2H), 4.23 (t, IH), 3.42-3.27 (m, 2H), 1.65 (s, 3H), 1 64 (s, 3H). EXAMPLE 24 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[l-METHYL-l-(4- HYDROXYPHENYL)ETHYLAM--NO]3-PYRIDYL}ETHYL}PYRIDINE-N- OXIDE The title compound was obtained as a side product of Example 23, Steps 9 (13 mg). ! H NMR (500 MHz, Acetone-d6) δ 8.55 (s, IH), 7.95 (d, 2H), 7 78 (s, IH), 7.32 (s, IH), 7.27-7.11 (m, 7H), 6.95 (t, IH), 6.90 (t, IH), 6.67 (d, 2H), 6 10 (d, IH), 5.81 (brs, IH), 4.27 (t, IH), 3.42-3.28 (m, 2H), 1.65 (s, 3H), 1.60 (s, 3H). EXAMPLE 25 (ENANTIOMER- 1)-4-{2-[3, 4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[l- METHYL-l-(3-TOLYL)ETHYLAMINO]3-PYRIDYL}ETHYL}PYRIDINE-N- OXIDE Following the procedures descnbed in Example 11 but substituting 1- methyl-l-(3-tolyl)ethylamιne (Prepared as in Example 21, Stepl) for cumylamine and by resolution of the carbamate of Step 5 (Preparative chiralpak AD, 70% i- PrOH/hexane, 60 mL/min, fast eluting enantiomer 36 mm), the title compound was obtained as an oil (160 mg). !H NMR (400 MHz, Acetone-d6) δ 7.91 (d, 2H), 7.82 (d, IH), 7.28- 7.18 (m, 6H), 7.17-7.05 (m, 3H), 6.98 (d, IH), 6 93 (t, IH), 6.90 (t, IH), 6.13 (d, IH), 5.88 (brs, IH), 4.23 (t, IH), 3.37-3.27 (m, 2H), 2.27 (s, 3H), 1.65 (s, 6H). EXAMPLE 26 (ENANTIOMER-l)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[l- METHYL- 1 -(3-FLUOROPHENYL)ETHYLAMINO]3- PYRIDYL } ETHYL } PYRIDINE-N-OXIDE Following the procedures descnbed in Example 11 but substituting 1- methyl-l-(3-fluorophenyl)ethylamme (Prepared as in Example 35, Step 1-4) for cumylamine and by resolution of the carbamate of Step 5 (Preparative chiralpak AD, 30% /-PrOH/hexane, 73 mL/m , fast elutmg enantiomer 19 mm), the title compound was obtained as an oil (150 mg). l H NMR (400 MHz, Acetone-d6) δ 7.91 (d, 2H), 7.79 (s, IH), 7.33- 7.16 (m, 7H), 7.10 (d, 2H), 6.93-6.89 (m, IH), 6.93 (t, IH), 6.91 (t, IH), 6.26 (d, IH), 6.05 (s, IH), 4.23 (t, IH), 3.32 (t, 2H), 1.68 (s, 6H) EXAMPLE 27 (ENANTIOMER- 1 )-4- { 2- [3 ,4-BIS(DIFLUOROMETHOXY)PHENYL]-2- { 6- [ 1 - METHYL- 1 -(3-BROMOPHENYL)ETHYLAMINO]3- PYRIDYL JETHYL } PYRIDINE-N-OXIDE Following the procedures described in Example 11 but substituting 1- methyl-l-(3-bromophenyl)ethylamιne (Prepared as in Example 35, Stepl-4) for cumylamine and by resolution of the carbamate of Step 5 (Preparative chiralpak AD, 30% /-PrOH/hexane, 70 mL/min, fast eluting enantiomer, retention time 11 minute on analytical HPLC: 1 mL/min, 30% /-PrOH/hexane), the title compound was obtained iH NMR (500 MHz, Acetone-d6) δ 7.94 (d, 2H), 7.77 (s, IH), 7.60 (s, IH), 7.42 (d, IH), 7.30 (m, 3H), 7.22 (m, 3H), 7.09 (d, 2H), 6.93 (t, IH), 6.90 (t, IH), 6.30 (d, IH), 6.12 (s, IH), 4.22 (t, IH), 3.33 (m, 2H), 1.67 (s, 6H). EXAMPLE 28 4-{ 2-[3,4-BIS(D-FLUOROMETHOXY)PHENYLJ-2-{6-[l-METHYL-l-(2- PYRID YL)ETHYLAMINO]3-PYRIDYL J ETHYL } PYRIDINE-N-OXIDE Following the procedures descnbed in Example 11 but substituting 1- methyl- l-(2-pyπdyl)ethylamιne (Prepared as in Example 21, Step 1) for cumylamine, the title compound was obtained as an oil (40 mg). !H NMR (400 MHz, Acetone-d6) δ 8 48 (d, IH), 7.91 (d, 2H), 7.79 (d, IH), 7.63 (m, IH), 7.45 (d, IH), 7.34 (dd, IH), 7.31 (s, IH), 7.26 (dd, IH), 7.22 (d, IH), 7.16-7.10 ( , 3H), 6.91 (t, IH), 6.91 (t, IH), 6.31 (d, IH), 6.26 (brs, IH), 4.24 (t, IH), 3.39-3.28 (m, 2H). EXAMPLE 29 4- { 2-[3 ,4-BIS (DIFLUOROMETHOXY)PHEN YLJ-2- { 6- [ 1 -METHYL- 1 -(2- PYRIDYL-N-OXIDE)ETHYLAMINO]3-PYRIDYLJETHYL}PYRlDINE-N-OXIDE The title compound (82 mg) was obtained as a side product of Example 28, Steps 6 (overoxidation) !H NMR (400 MHz, Acetone-d6) δ 8.56 (d, IH), 8.13 (s, IH), 7.93 (d, 2H), 7.75-7.70 (m, IH), 7.58 (s, IH), 7.44 (d, IH), 7 32 (s, IH), 7.32-7.24 (m, 3H), 7.16 (d, 2H), 6.97 (dd, IH), 6.95 (t, IH), 6.92 (t, IH), 5.99 (d, IH), 4.35 (t, IH), 3.39 (d, IH), 1.71 (s, 6H) EXAMPLE 30 (ENANTIOMER-l)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[l- METHYL- 1 -(4-CHLOROPHEN YL)ETHYLAMINO]3- PYRIDYL JETHYL} PYRIDINE-N-OXIDE Following the procedures descnbed in Example 11 but substituting 1- methyl-l-(4-chlorophenyl)ethylamιne (Prepared as in Example 21, Step 1) for cumylamine and by resolution of the carbamate of Step 5 (Preparative chiralpak AD, 30% /-PrOH/hexane, 70 mL/mm, fast eluting enantiomer 27 mm), the title compound was obtained as an oil (35 mg). l H NMR (400 MHz, Acetone-d6) δ 7 92 (dd, 2H), 7.79 (d, IH), 7.44 (dd, 2H), 7.23-7 34 (m, 6H), 7.11 (d, 2H), 6.94 (t, IH), 6.91 (t, IH), 6.26 (dd, IH), 6.03 (brs, IH), 4.24 (t, IH), 3.27-3 37 (m, 2H), 1.67 (s, 6H). EXAMPLE 31 (ENANTIOMER-2)-4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[l- METHYL- 1 -(4-CHLOROPHENYL)ETHYLAMINO]3- PYRIDYL JETHYL } PYRIDINE-N-OXIDE Following the procedures descnbed in Example 11 but substituting 1- methyl-l-(4-chlorophenyl)ethylamιne (Prepared as in Example 21, Step 1) for cumylamine and by resolution of the carbamate of Step 5 (Preparative chiralpak AD, 30% /-PrOH/hexane, 70 mL/min, fast eluting enantiomer 35 mm), the title compound was obtained as an oil (65 mg). iH NMR (400 MHz, Acetone-d6) δ 7 92 (dd, 2H), 7.79 (d, IH), 7 44 (dd, 2H), 7.23-7 34 (m, 6H), 7 11 (d, 2H), 6.94 (t, IH), 6 91 (t, IH), 6.26 (dd, IH), 6.03 (brs, IH), 4.24 (t, IH), 3.27-3.37 (m, 2H), 1 67 (s, 6H) EXAMPLE 32 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYLJ-2-{6-[l-METHYL-l-(2- TOLYL)ETHYLAMINO]3-PYRIDYL } ETHYL } PYRIDINE-N-OXIDE Following the procedures described in Example 11 but substituting 1- methyl-l-(2-tolyl)ethylamιne (Prepared as in Example 21 , Step 1) for cumylamine, the title compound was obtained as an oil (300 mg) iH NMR (400 MHz, Acetone-d6) δ 7 92 (d, 2H), 7 80 (s, IH), 7 46 (d, IH), 7 29 (s, IH), 7.25-7 14 (m, 4H), 7.13-7.05 ( , 3H), 7 03 (d, IH), 6 93 (t, IH). 6.90 (t, IH), 6.05 (d, IH), 5.83 (brs, IH), 4.20 (t, IH), 3 36-3 24 (m, 2H), 2 41 (s, 3H), 1 75 (s, 6H) EXAMPLE 33 (ENANTIOMER-l)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[l- METHYL- 1 -(4-METHYLSULFONYLPHENYDETHYLAMI-NOJ3- P YRID YL } ETHYL } PYRIDINE-N-OXIDE Step 1 (Enantiomer- l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-(6-ammo-3 : pyndyl)ethyl Jpyndine To a 0 °C solution of (Enantiomer-l)-4-{ 2-[3,4- bιs(dιfluoromethoxy)phenyl]-2-[6-( 1 -methyl- 1 -phenylethylamιno)3- pyndyljethyl Jpyπdme from Example 18 (590 mg, 1.12 mmol) in 4 mL of CH2CI2, was added 4 mL of TFA and the resulting solution was stirred 45 minutes at room temperature. The reaction mixture was then coevaporated with toluene under reduced pressure and the residue was diluted with ethyl acetate and with a saturated aqueous solution of N-1HCO3. The layers were separated, the organic phase was washed with bnne, dned over MgSO4 and concentrated under reduced pressure. The residue was punfied by flash chromatography on silica gel (Gradient 10% to 20% E-OH/CH2O2) to afford 439 mg (96%) of aminopyndine as a white foam. Step 2 l-(4-methylthιophenyl)-l,l-dιmethoxy ethane To a solution of (4-methylthιo)acetophenone (1 0 g, 6 01 mmol) in 10 mL of MeOH, was added 35 mL of methyl orthoformate followed by 30 mg (0.16 mmol) of /7-toluenesulfonιc acid. The solution was stirred at 70 ° C for 17 h, cooled down to room temperature and diluted with Et2θ The organic layer was washed with a saturated aqueous solution of NaHCO3 and with bnne, dned over MgSO4 and concentrated under reduced pressure. The ketal was used directly for the next step without any further punfication. Step 3 (Enantiomer- 1)-4-{ 2-r3,4-Bιs(dιfluoromethoxy)phenylJ-2-{6-rmethyl(4- methylthιophenyl)methanιmιne1-3-pyπdyl Jethyl Jpyπdme The aminopyndine from Step 1 above (210 mg, 0 516 mmol) was dissolved in 810 mg (3.82 mmol) of l-(4-methylthιophenyl)-l,l-dιmethoxy ethane from Step 2 above and the resulting mixture was heated at 120 ° C for 1.5 h. The solution was cooled down to room temperature and punfied directly by flash chromatography on silica gel (Gradient 5% to 10% EtOH/CH2θ2) to afford 200 mg (69%) of imine. Step 4 (Enantiomer- 1)-4-{ 2-r3,4-Bιs(dιfluoromethoxy)phenylJ-2-{ 6-ri-methyl-l-(4- methylthiophenyl )ethylamιno13-pyndyl Jethyl Jpyndine To a 0 °C solution of imine from Step 3 above (200 mg, 0.36 mmol) in 4 mL of CH2CI2, was added 1.2 mL (3 6 mmol) of a 3.0 M solution of MeMgBr in ether. The solution was stirred 2 h at room temperature and quenched with saturated aqueous solution of NH4CI. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with bnne, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Gradient 5% to 7% EtOH/CH2Cl2) to afford 172 mg (69%) of amine. Step 5 (Enantιomer-l)-4-{2-[3,4-Bιs(difluoromethoxy)phenylJ-2-{6-[N-l-methyl-l-(4- methylthιophenyl)ethyl trifluoroacetamideJ3-pyridyl Jethyl Jpyπdme To a 0 ° C solution of amine from Step 4 above (172 mg, 0.3 mmol) in 3 mL of CH2CI2, was added 0.05 mL (0.6 mmol) of pyndine followed by 0.063 mL (0.45 mmol) of TFAA. The resulting solution was stiπed 3 h at room temperature, quenched with an aqueous solution of ΝaHC03 and diluted with ethyl acetate The organic layer was washed with brine, dned over MgSO4 and concentrated under reduced pressure. The residue was punfied by flash chromatography on silica gel to afford 131 mg (66%) of trifluoroacetamide. Step 6 (Enantιomer-l)-4-{ 2-[3,4-Bιs(difluoromethoxy)phenyl]-2-{6-[N-l-methyl-l-(4- methylsulfonylphenyl)ethyl tπfluoroacetamιdeJ3-pyπdyl Jethyl Jpyπdine-Ν-oxide To a 0 °C solution of trifluoroacetamide from Step 5 above ( 131 mg, 0.196 mmol) 3 mL of CH2CI2, was added 131 mg of ΝaHC03 followed by 169 mg (0.784 mmol) of 80% MCPBA. The solution was stiπed and allowed to warm up to room temperature over 5 h. The reaction was directly punfied by flash chromatography on silica gel to afford 140 mg (100%) of methyl sulfone pyπdine-N- oxide. Step 7 (Enantιomer-l)-4-{ 2-r3,4-Bιs(dιfluoromethoxy)phenyl1-2-{ 6-[l-methyl-l-(4- methylsulfonylphenyl)ethylamino13-pyndyl Jethyl Jpyndine-N-oxide The tnfluoroacetamide from Step 6 above (140 mg, 0.196 mmol) was dissolved in a mixture of THF/MeOH/H2θ (2.0 mL/0.7 mL/0.2 mL) followed by the addition of 0.196 mL of a 2 N LiOH solution. The reaction was stirred 1 h at room temperature and rotovaped down with several portion of MeOH (Coevaporation). The residue was directly punfied by flash chromatography on silica gel (Gradient 6% to 8% MeOH/CH2Cl2 and 10%(10%NH4OH/MeOH)/CH2Cl2) to afford the title compound as an oil (110 mg, 92%). !H NMR (400 MHz, Acetone-d6) δ 7.92 (d, 2H), 7.82 (d, 2H), 7.74- 7.63 (m, 3H), 7.39-7.18 (m, 4H), 7.14-7.05 (m, 2H), 6.92 (t, large J, IH), 6 90 (t, large J, IH), 6.40 (d, IH), 6.25 (s, IH), 4.22 (t, IH), 3.40-3.24 (m, 2H), 3.10 (s, 3H), 1.71 (s, 3H), 1.69 (s, 3H). EXAMPLE 34 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[l-METHYL-l-(4- TRIFLUOROMETHYLPHENYL)ETHYLAMINO] 3- PYRID YL } ETHYL } PYRIDINE-N-OXIDE Step 1-6 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-l-methyl-l-(4- trιfluoromethvlphenvl)ethvl-N-(benzvloxvcarbonvl)amιnoJ3-pyndyl Jethyl Jpyπdme- Ν-oxide Following the procedures described in Example 11 , Step 1 to 6 but substituting 1 -methyl- l-(4-tπfluoromethylphenyl)ethylamιne for cumylamine, the corresponding benzyloxycarbamate was obtained (207 mg). Step 7 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(4- tπfluoromethylphenyl)ethylamιno13-pyndyl Jethyl }pyrιdιne-Ν-oxιde To a 0 °C solution of benzyloxycarbamate (207 mg, 0.28 mmol) in 6 mL of CH3CN, was added 0.62 mL (2.8 mmol) of 2,6-dι-t-butylpyndιne followed by 0.2 mL (1.4 mmol) of TMSI. The resulting solution was stirred 1.25 h at room temperature and quenched with a solution of NH4OAC The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with Na2S2θ3 and bnne, dried over MgSO4 and concentrated under reduced pressure. The residue was punfied by flash chromatography on silica gel (10% MeOH/CHCl3) to afford the title compound as a foam (130 mg, 76%). !H NMR (500 MHz. Acetone-d6) δ 7.92 ( , 2H), 7.76 (d, IH), 7 64 (d, 2H), 7.59 (d, 2H), 7.33 (dd, IH), 7 29 (s, IH), 7.21 (m, 2H), 7.11 (d, 2H), 6 93 (t, IH), 6.90 (t, IH), 6 33 (d, IH), 6.21 (s, IH), 4.23 (t, IH), 3.32 (m, 2H), 1.70 (s, 3H), 1.69 (s, 3H). EXAMPLE 35 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{ 6-[l-METHYL-l-(3,4- DIFLUOROPHENYL)ETHYLAMINO]3-PYRIDYL}ETHYL}PYRIDINE-N- OXIDE Step 1 Methyl 2-(3,4-dιfluorophenyl)ethanoate Difluorophenylacetic acid was dissolved in methanol (solution concentration IM) under nitrogen atmosphere. To this limpid solution was added 1.5eq of thionyl chlonde on a 10 minutes peπod. Reaction was completed after 90 minutes when stirnng at room temperature. The product was concentrated in vacuo to afford quantitatively the ester as a limpid yellow oil which was used for the next step without further purification. Step 2 Methyl 2-methyl-2-(3,4-dιfluorophenyl)propιonate Crude ester from Step 1 above was dissolved in dry THF (solution concentration 0.4M) under argon atmosphere and cooled down at 0 ° C (cracked ice bath). 2.5eq of a commercial 2.0M / THF solution of NaHMDS was slowly added and the resulting pale yellow solution was stiπed for 30 minutes. Neat methyl iodide (lOeq) was added to the solution at 0 °C which was then allowed to warm up at room temperature. TLC (eluent: 15% Et2θ / Hexane) showed no more starting matenal left after 60 minutes. Reaction was neutralized by using a saturated aqueous solution of NH4CI and it was extracted 3 times with Et2θ. Combined organic extracts were washed with water and with a 5% Na2S2θ3 aqueous solution, then it was dned over MgSO4. There was about 25% of monoalkylated product (more polar on TLC than the dialkylated product) even if reaction time was prolonged over a week end. To completly convert into the desired dialkylated product, the isolated crude oil was reconducted in the same reaction conditions as above. The crude orange oil was purified by flash-chromatography using 8% Et2θ / Hexane as eluent or by distillation under reduced pressure (rotavap pump) to afford the title compound in 74% yield for 2 steps. Step 3 2-Methyl-2-(3,4-dιfluorophenyl)propιonιc acid Saponification of ester from Step 3 above was performed by using a mixed solution of MeOH/ THF / NaOH 5.0N in a 2: 1 :2 ratio. The mixture was stirred overnight at room temperature. The organic solvents were evaporated and the aqueous portion was neutralized at 0 °C with HC1 5. ON with formation of a white precipitate as a consequence. Extractions with EtOAc followed by usual brine washings and MgSO4 treatment of the organic extracts afforded quantitatively the desired acid which was used as such for the next step without further purification Step 4 1 -Methyl- 1 -(3 ,4-dιfluorophenyl)eth ylamine To a flame-dned flask containing the acid from Step 3 above in toluene (solution concentration 0.4M) under nitrogen atmosphere was added 4eq of tnethylamme and 1.5eq of (PhO)2P(O)N3. This solution was stirred at room temperature for 2 hours. The reaction was neutralized with a solution of KH2PO4 0.5M (pH 4) and extracted 3 times witH Et2θ. Combined organic extracts were washed with bnne and dned over MgSO4. Purification by flash-chromatography using Et2θ/ Hexane as eluent with a 15%20% gradient afforded the azide in 85% yield. This azide was diluted in toluene (solution concentration 2.3M) and refluxed for 60 minutes. The solvent was removed to afford quantitatively the coπesponding isocyanate. A slight excess of concentrated HC1 was added and the pale yellow solution was warmed at 80 °C for a few minutes. A white solid slowly appeared (protonated amine) and a large excess of water was added. Neutralization with NaOH 10 ON ant extraction of the aqueous portion with Et2θ followed by usual MgSO4 treatment afforded the amine in 59% yield. Step 5-11 Following the procedures descnbed in Example 11 but substituting 1- methyl-l-(3,4-dιfluorophenyl)ethylamme from Step 4 above for cumylamine, the title compound was obtained as an oil (110 mg). iH NMR (400 MHz, Acetone-d6) □ 7.91 (d, 2H), 7.78 (d, IH), 7.14-7.38 (m, 7H), 7.10 (d, 2H), 6.93 (t, IH), 6.90 (t, IH), 6.32 (d, IH), 6.07 (s, IH), 4.22 (t, IH), 3.27-3.39 (m, 2H), 1.66 (s, 6H). EXAMPLE 36 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[l,l-DIMETHYL-2-(4- FLUOROPHENYL)ETHYLAMINO]3-PYRIDYL}ETHYL}PYRIDINE-N-OXIDE Following the procedures described in Example 11 but substituting l ,l-dιmethyl-2-(4-fluorophenyl)ethylamme for cumylamine, the title compound was obtained as an oil (95 mg). l U NMR (400 MHz, Acetone-d6) [ I 8.02 (d, IH), 7.97 (dd, 2H), 7.36- 7.40 (m, 2H), 7.34 (dd, IH), 7.27 (d, IH), 7.20 (d, 2H), 6.98 (t, IH), 6.95 (t, IH), 6.97-7.03 (m, 2H), 6.90-6.95 (m, 2H), 6.44 (d, IH), 5.31 (brs, IH), 4.33 (t, IH), 3.42 (dd, 2H), 3.23 (dd, 2H), 1.34 (s, 3H), 1.32 (s, 3H). EXAMPLE 37 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[2-(4- FLUOROPHENYL)ETHYLAMINO] 3-PYRID YL } ETHYL } PYRIDINE-N-OXIDE Following the procedure described in Example 10 but substituting 2- (4-fluorophenyl)ethylamιne at 120 °C for 2-(2-amιnoethyl)pyridine at 100 °C, the title compound was obtained as a yellow foam (147 mg, 44%). iH NMR (500 MHz, Acetone-d6) 7 97 (m. 3H), 7.41 (dd, IH), 7.37 (s, IH), 7.30-7.20 (m, 4H), 7.19 (m, 2H), 7.02 (m, 2H), 6.98 (t, IH), 6.93 (t, IH), 6.45 (d, IH), 5.87 (bit, IH), 4.33 (t, IH), 3.52 (m, 2H), 3.39 (m, 2H), 2.85 (t, 2H). EXAMPLE 38 4- { 2-[3 ,4-BIS (DIFLUOROMETHOXY)PHEN YL] -2- { 6-[ 1 -METHYL- 1 -(3 ,5- D-FLUOROPHENYL)ETHYLAMINO]3-PYRIDYLJETHYL}PYRIDINE-N- OXIDE Following the procedures described in Example 11 but substituting 1- methyl-l-(3,5-dιfluorophenyl)ethylamme (Prepared as in Example 35, Step 1-4) for cumylamine, the title compound was obtained as an oil (120 mg). !H NMR (400 MHz, Acetone-d6) D 7.93 (d, 2H), 7.78 (d, IH), 7.28- 7 38 (m, 2H), 7.02-7.24 (m, 6H), 6.94 (t, IH), 6.91 (t, IH), 6.77 (tt, IH), 6.38 (d, IH), 6.27 (brs, IH), 4.23 (t, IH), 3.25-3.41 (m, 2H), 1.67 (s, 6H). EXAMPLE 39 4- { 2- [3 ,4-BIS(DIFLUOROMETHOXY)PHEN YL]-2- { 6- [ 1 -METHYL- 1 -(2,4- DIFLUOROPHENYL)ETHYLAMINO] 3-PYRIDYL } ETHYL } PYRIDINE-N- OXIDE Step 1-6 4-{2-[3 . 4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-l-methyl-l-(2,4- dιfluorophenyl.ethyl-N-(benzyloxycarbonyl)ammo,3-pyπdyl Jethyl Jpyπdme-Ν-oxide Following the procedures described in Example 11, Step 1 to 6 but substituting 1 -methyl- l-(2,4-dιfluorophenyl)ethylamme (Prepared as in Example 35, Step 1-4) for cumylamine, the coπesponding benzyloxycarbamate was obtained. Step 7 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(2,4- dιfluorophenyl)ethylamιnol3-pyndyl Jethyl Jpyπdine-Ν-oxide The procedure for the deprotection of the amino group described in Example 34, Step 7 was applied using the product of Step 6 above as starting material. The title compound was obtained as an oil (90 mg, ( " ' ->) *H ΝMR (400 MHz, Acetone-d6) D 7 91 (d, 2H), 7 77 (s, IH), 7.43 (q, IH), 7 36 (dd, IH), 7.30 (s. IH), 7.26-7.21 (m, 2H), 7.11 (d. 2H), 6.93 (t, IH), 6.91 (t, IH), 6.89-6 83 (m, 2H), 6 43 (d, IH), 6.07 (s, IH), 4.23 (t, IH), 3.37-3.27 (m, 2H), 1.75 (s, 6H). EXAMPLE 40 (EΝAΝTIOMER-l)-4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHEΝYL]-2-[6-(4- FLUOROBENZYLAMINE)3-PYRIDYL]ETHYL } PYRIDINE-N-OXIDE Following the procedure descnbed in Example 10 but substituting 4- fluorobenzylamme at 130 °C for 2-(2-aminoethyl)pyridine at 100 °C, the racemic title compound was obtained as a yellow solid (57%). This racemic mixture was then resolved by preparative HPLC (Chiralpak AD, 40% / ' -PrOH/hexane, 60 mL/min) to afford 47 mg of the title compound as the fast eluting enantiomer. ! H NMR (500 MHz, Acetone-d6) 3 7.94 (m, 3H), 7.42 (dd, IH), 7.37 (m, 3H), 7.27 (dd, 2H), 7.17 (d, 2H), 7.03 (t, 2H), 6.96 (t, IH), 6.91 (t, IH), 6.49 (d, IH), 6.23 (t, IH), 4.50 (m, 2H), 4.32 (t, IH), 3.44-3.33 (m, 2H). EXAMPLE 41 (ENANTIOMER-2)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(4- FLUOROBENZYLAMINE)3-PYRIDYL]ETHYL } PYRIDINE-N-OXIDE Following the procedure descnbed in Example 10 but substituting 4- fluorobenzylamine at 130 °C for 2-(2-aminoethyl)pyridine at 100 °C, the racemic title compound was obtained as a yellow solid (57%). This racemic mixture was then resolved by preparative HPLC (Chiralpak AD, 40% /-PrOH/hexane, 60 mL/min) to afford 49 mg of the title compound as the slow eluting enantiomer. l U NMR (500 MHz, Acetone-d6) -T 7.94 (m, 3H), 7.42 (dd, IH), 7.37 (m, 3H), 7.27 (dd, 2H), 7.17 (d, 2H), 7.03 (t, 2H), 6.96 (t, IH), 6.91 (t, IH), 6 49 (d, IH), 6.23 (t, IH), 4.50 (m, 2H), 4.32 (t, IH), 3.44-3.33 (m, 2H). EXAMPLE 42 (ENANTIOMER- 1 )-4- { 2- [3 ,4-BIS(DIFLUOROMETHOXY)PHENYL] -2- { 6-[ 1 - METHYL-l-(4-ETHYLPHENYL)ETHYLAMINO]3- PYRIDYL JETHYL } PYRIDINE-N-OXIDE Step 1 Following the procedure descnbed in Example 33 but substituting 1- (4-ethylphenyl)-l,l-dιmethoxy ethane for l-(4-methylthιophenyl)-l,l-dιmethoxy ethane, the title compound was obtained as a gum (19 mg). l R NMR (500 MHz, Acetone-d6) -T 7.91 (d, 2H), 7.82 (d, IH), 7.35 (d, 2H), 7.30 (s, IH), 7.28-7.20 (m, 3H), 7.11 (m, 4H), 6.93 (t, IH), 6.90 (t, IH), 6.14 (d, IH), 5.89 (s, IH), 4.22 (t, IH), 3.38-3.27 (m, 2H), 2.58 (q, 2H), 1.65 (s, 6H), 1.18 (t, 3H). EXAMPLE 43 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(2,4- DIFLUOROBENZYLAMINE)3-PYRIDYL]ETHYL } PYRIDINE-N-OXIDE Following the procedure descnbed in Example 10 but substituting 2,4- difluorobenzylamine at 130 °C for 2-(2-aminoethyl)pyridine at 100 ° C. the title compound was obtained as a white foam (71 mg, 56%). !H NMR (500 MHz, Acetone-d6) δ 7.95 (m, 3H), 7.48-7.39 (m, 2H), 7.35 (s, IH), 7.26 (dd, 2H), 7.17 (d, 2H), 7.00-6.86 (m, 2H), 6.96 (t, IH), 6.91 (t, IH), 6.52 (d, IH), 6.29 (t, IH), 4.55 (m, 2H), 4.32 (t, IH), 3.42-3.31 (m, 2H). EXAMPLE 44 4- { 2- [3 ,4-BIS (DIFLUOROMETHOX Y)PHEN YL] -2- [6-(4- FLUOROPHENYLAMIDO)3-PYRIDYL]ETHYL}PYRIDINE To a solution of 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-(6-amιno-3- pyπdyl)ethyl Jpyndine (205 mg. 0 5 mmol) (Racemate of Example 33, Step 1) in 3 mL of THF, was added 0.26 mL (1.51 mmol) of z-Pr2NEt followed by 0 15 mL ( 1.25 mmol) of 4-fluorobenzoyl chloπde The reaction was stirred 30 minutes at room temperature, quenched with a 25% aqueous solution of NH4OAC and diluted with ethyl acetate. The organic layer was washed with bnne, dried over MgSO4 and concentrated under reduced pressure The residue was punfied by flash chromatography on silica gel (Gradient 60% to 80% ethyl acetate/toluene) to afford the title compound as a foam (40 mg, 15%). l H NMR (500 MHz, Acetone-d6) δ 8.37 (d, 2H), 8 29 (d, IH), 8.24 (d, IH), 8.17-8.12 (m, 2H), 7 87 (dd, IH), 7.42 (s, IH), 7.36 (dd, IH), 7.31-7 10 (m, 5H), 6.95 (t, IH), 6.93 (t, IH), 4 60 (t, IH), 3.52 (d, 2H). EXAMPLE 45 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[4- FLUOROPHENYLAMIDO]3-PYRIDYLJETHYLJPYRIDINE-N-OXIDE Step 1 4-{ 2-r3,4-Bιs(dιfluoromethoxy)phenyll-2-(6-ammo-3-pyndyl)ethyl Jpyndιne-N-oxιde To a 0 °C solution of benzyloxycarbamate from Example 1 1 , Step 6 (328 mg, 0.485 mmol) in 2 mL of 1,2-dιchloroethane, was added 2 mL of TFA The resulting solution was stirred 16 h at 70 ° C, cooled down to room temperature and rotovaped down to dryness. The residue was dissolved in ethyl acetate, washed with a solution of 5% NaHCO3, dried over MgSO4 and concentrated under reduced pressure. The residue was punfied by flash chromatography on silica gel (Gradient 10% MeOH/CHCl3 to 10%(10%NH4OH/MeOH)/CHCl3) to afford the corresponding aminopyπdine as a brown gum (139 mg, 68%). Step 2 4-{ 2-J3,4-Bιs(dιfluoromethoxy)phenyl]-2-{ 6-J4-fluorophenylamιdo13- pyridyl Jethyl Jpyndme-N-oxide To a solution of 4-{ 2-[3,4-bιs(dιfluoromethoxy)phenyl]-2-(6-arnmo-3- pyridyl)ethyl }pyndme-N-oxide (38 mg, 0 089 mmol) from Step 1 above in 1.5 mL of THF, was added 0.022 mL (0 27 mmol) of pyndine followed by 0 013 mL (0.089 mmol) of 4-fluorobenzoyl chlonde The reaction was stirred 1 h at room temperature, quenched with a 25% aqueous solution of NH4OAC and diluted with ethyl acetate The organic layer was washed with bnne, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Gradient 100% ethyl acetate to 5% EtOH/CH2Cl2 to 10% E-OH/CH2CI2) to afford the title compound as an oil (10 mg, 20%) !H NMR (400 MHz, Acetone-d6) δ 9.70 (s, IH), 8 30-8.22 ( , 2H), 8 15 (dd, 2H), 7.98 (d, 2H), 7 88 (dd, IH), 7.42 (s, IH), 7 37 (d, IH), 7 31-7.25 (m, 3H), 7.21 (d, 2H), 6.96 (t, IH), 6 94 (t. IH), 4.55 (t, IH), 3 51 (d, 2H) EXAMPLE 46 (ENANTIOMER- 1 )-4- { 2- [3 ,4-BIS(DIFLUOROMETHOXY)PHENYL] -2- { 6- [4- FLUOROPHENYLAMIDO] 3-P YRID YL } ETHYL } PYRIDINE-N-OXIDE Step 1 (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[NN-dιi4 I fluorobenzamιde)13-pyπdyl Jethyl Jpyndine To a solution of (enantiomer- 1)-4-[2-[3,4- bιs(dιfluoromethoxy)phenyl]-2-(6-amιno-3-pyπdyl)ethyl]pyπdme (205 mg, 0.5 mmol) from Example 33, Step 1 in 3 mL of THF, was added 0 26 mL (1.51 mmol) of z-PnΝEt followed by 0.15 mL (1 25 mmol) of 4-fluorobenzoyl chlonde The reaction was stiπed 30 minutes at room temperature, quenched with a 25% aqueous solution of NH4OAC and diluted with ethyl acetate. The organic layer was washed with bnne, dned over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Gradient 60% to 80% ethyl acetate/toluene) to afford the bis amide as a foam (230 mg, 70%). Step 2 (Enantιomer-l)-4-{2-13,4-Bιs(dιfluoromethoxv)phenyn-2-J 6-rN.N-dι(4- fluorobenzamιde)]3-pyndyl Jethyl Jpyndine-Ν-oxide To a solution of bis amide from Step 1 above (220 mg, 0.338 mmol) in a mixture of 5 mL of CH2CI2 and 0.5 mL of MeOH, was added MMPP (167 mg, 0.338 mmol) in one portion. The mixture was stiπed 3.5 h at room temperature, quenched with water and diluted with CH2CI2. The organic layer was washed with bnne, dried over MgSO4 and concentrated under reduced pressure. The residue was punfied by flash chromatography on silica gel (Gradient 5% to 10% EtOH/CH2θ2) to afford the corresponding Ν-oxide as a white foam (164 mg, 73 %). Step 3 (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[4- fluorophenylamιdol3-pyndyl Jethyl Jpyπdine-Ν-oxide To a solution of bis amide pyπdme-Ν-oxide from Step 2 above (116 mg, 0.17 mmol) in a mixture of THF/MeOH/water (5 mL/1.5 mL/0.5 ml 1 was added 0434 mL of 2 Ν LiOH. The resulting solution was stiπed 10 minute-, at room temperature and diluted with water/ethyl acetate. The organic layer was washed with brine, dned over MgSO4 and concentrated under reduced pressure. The residue was punfied by flash chromatography on silica gel (Gradient 100% ethyl acetate to 10% EtOH/CH2Cl2) to afford the title compound as a white foam (86 mg, 92 %) l H ΝMR (400 MHz, Acetone-d6) δ 9.70 (s, IH), 8.30-8.22 (m, 2H), 8.15 (dd, 2H), 7.98 (d, 2H), 7.88 (dd, IH), 7.42 (s, IH), 7 37 (d, IH), 7.31-7.25 (m, 3H), 7.21 (d, 2H), 6.96 (t, IH), 6.94 (t, IH), 4.55 (t, IH), 3 51 (d, 2H). EXAMPLE 47 (ENANTIOMER-l)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(l- METHYL- 1 -THIAZOLYLETHYLAMINO)3-PYRIDYL]ETHYL J PYRIDINE-N- OXIDE Following the procedure descnbed in Example 33 but substituting 1- thιazolyl-l,l-dιmethoxy ethane for l-(4-methylthιophenyl)-l,l-dιmethoxy ethane, the title compound was obtained as a viscous oil (102 mg) { n NMR (400 MHz, Acetone-d6) δ 7 91 (d, 2H), 7 80 (s, IH), 7.58 (d, IH), 7.41-7.37 (m, 2H), 7.32 (s, IH), 7.27 (dd, IH), 7.22 (d, IH), 7 10 (d, 2H), 6.94 (t, IH), 6.91 (t, IH), 6.42 (d, IH), 6.31 (s, IH), 4.26 (t, IH), 3.40-3.29 (m, 2H), 1.77 (s, 3H), 1.75 (s, 3H). EXAMPLE 48 4- { 2- [3 ,4-BIS (DIFLUOROMETHOXY)PHEN YL] -2- { 6- [ 1 -METHYL- 1 -(4- D_FLUOROMETHOXYPHENYL)ETHYLAMINO]3- PYRID YL } ETHYL } PYRIDINE-N-OXIDE Step 1 4-dιfluoromethoxybenzonιtnle To a solution of 4-hydroxybenzonιtπle (4.76 g, 40 mmol) in 150 mL of DMF was added 5.52 g (40 mmol) of K2CO3. The mixture was heated at 95 °C and 5.27 mL (50 mmol) of ClCF2CO2Me was added slowly over 10 minutes. The reaction was stiπed at 95 °C for 15 minutes and a 1.5 mL portions of ClCF2CO2Me were added until no changes were observed by TLC. The reaction was stirred overnight at room temperature diluted with water (300 mL) and extracted with Et2θ. The combined organic layers were washed with brine, dned over MgSO4 and concentrated under reduced pressure. The residue was punfied by flash chromatography on silica gel (30% ethyl acetate/hexane) to afford the corresponding nitπle as a white solid (3.0 g, 44%). Step 2 1 -methyl- 1 -(4-dιfluoromethoxyphenyl)eth ylamine Following the procedure described in Example 21, Step 1 but substituting 4-dιfluoromethoxybenzonιtπle from Step 1 above for 4- fluorobenzonitπle, 1.96 g (59%) of the amine were obtained. Step 3-8 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-l-methyl-l-(4- dιfluoromethoxyphenvl)ethvl-N-(benzvloxycarbonvl)amιno]3-pyπdyl Jethyl Jpyndme- Ν-oxide Following the procedures descnbed in Example 11 , Step 1 to 6 but substituting 1 -methyl- l-(4-dιfluoromethoxyphenyl)ethylamme for cumylamine, the coπesponding benzyloxycarbamate was obtained (411 mg). Step 9 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(4- dιfluoromethoxyphenyl)ethylamιno]3-pyπdyl Jethyl }pyrιdιne-Ν-oxιde The procedure for the deprotection of the amino group descnbed in Example 34, Step 7 was applied using the product of Step 8 above as starting matenal. The title compound was obtained as an oil (200 mg, 68%). [ R NMR (400 MHz, Acetone-d6) δ 7 90 (d, 2H), 7 77 (s, IH), 7.46 (d, 2H), 7.31-7.21 (m, 4H), 7.12-7.04 (m, 4H), 7.00 (t, IH). 6 94 (t, IH), 6 91 (t, IH), 6.25 (d, IH), 6.02 (brs, IH), 4.22 (t, IH), 3.38-3 26 (m, 2H), 1 68 (s, 3H), 1.66 (s, 3H) EXAMPLE 49 (ENANTIOMER-2)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(l- METHYL- 1 -PHENYLETHYLAMINO)3-PYRIDYL]ETHYL } PYRIDINE-N-OXIDE HYDROMETHANESULFONATE To a solution of (enantιomer-2)-4-{2-[3,4- bιs(dιfluoromethoxy)phenyl]-2-[6-( 1 -methyl- 1 -phenylethylammo)3- pyπdyl]ethylJpyndιne-N-oxιde from Example 13 (1.0 g, 1.85 mmol) in a mixture of 45 mL of Et2θ and 4 5 mL of dioxane, was added slowly 3.21 mL (1.66 mmol) of a 0.517 M solution of methanesulfonic acid in Et2θ resulting in the formation of a white precipitate The supernatant was removed with a syringe and the solid residue was washed 2 times with dry Et2θ under inert atmosphere and pumped under high vacuum. *H NMR (500 MHz, Acetone-d6) δ 9.40 (s, IH), 7.98 (d, 2H), 7.92 (s, IH), 7.72 (d, IH), 7.47 (d, 2H), 7.40-7.23 (m, 6H), 7.19 (d, 2H), 6.92 (t, large J, IH), 6.91 (t, large J, IH), 6.26 (d, IH), 4.48 (t, IH), 3.46 (d, 2H), 2 66 (s, 3H), 1.71 (s, 6H) EXAMPLE 50 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[l-ETHYL-l-(4- FLUOROPHENYL)PROPYLAMINO]3-PYRIDYL}ETHYL}PYRIDINE-N-OXIDE Step 1-6 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-l-ethyl-l-(4-fluorophenyl)propyl-N- (benzyloxycarbonvl)amιno]3-pyndyl Jethyl Jpyndme-Ν-oxide Following the procedures descnbed in Example 11, Step 1 to 6 but substituting l-ethyl-l-(4-fluoropheny])propylamιne for cumylamine, the coπesponding benzyloxycarbamate was obtained (710 mg). Step 7 4-{2-[3.4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-ethyl-l-(4- fluorophenyl)propylamιno]3-pyndyl Jethyl )pyrιdιne-Ν-oxιde To a 0 °C solution of benzyloxycarbamate (695 mg. 0 96 mmol) in 20 mL of CH3CN, was added 2.2 mL (9.86 mmol) of 2,6-dι-t-butylpyndιne followed by 0.7 mL (4 93 mmol) of TMSI. The resulting solution was stiπed 1.25 h at room temperature and quenched with a solution of NH4OAC. Layers were separated and the aqueous phase was extracted with ethyl acetate. Combined organic layers were washed with Na2S2θ3 and brine, dned over MgSO4 and concentrated under reduced pressure. The residue was punfied by flash chromatography on silica gel (Gradient 5% to 10% E-OH/CHCI3) to afford the title compound as a foam (281 mg, 50%) *H NMR (500 MHz, Acetone-d6) δ 7.90 (d, 2H), 7 79 (d, IH). 7.42 (dd, 2H), 7 30-7.20 (m, 4H), 7 10-7.00 (m, 4H), 6.93 (t, IH), 6.90 (t, IH), 6.21 (d, IH), 5 70 (s, IH), 4.21 (t, IH), 3.38-3.25 (m, 2H), 2.24-2.15 (m, 2H), 2.00-1.90 (m, 2H), 0.68 (t, 6H) EXAMPLE 51 (ENANTIOMER- 1 )-4- { 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2- { 6-[4- METHYLPHEN YLAMIDO] 3-P YRID YL } ETHYL } PYRIDINE-N-OXIDE Following the procedures described in Example 46 but substituting 4- methylbenzoyl chlonde for 4-fluorobenzoyl chlonde, the title compound was obtained as a white foam (82 mg). H NMR (400 MHz, Acetone-d6) δ 8.27 (dd, 2H), 7.99-7.93 (m, 4H), 7.85 (dd, IH), 7.42 (s. IH), 7.37-7.31 (m, 3H), 7.28 (d, IH), 7.20 (d, 2H), 6.97 (t, IH), 6.93 (t, IH), 4.55 (t, IH), 3.50 (d, 2H), 240 (s, 3H). EXAMPLE 52 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[2-METHYL-2-(4- FLUOROPHENYL)PROPYLAMINO]3-PYRBDYLJETHYLJPYRIDINE-N-OXIDE Step 1 2-Methyl-2-(4-fluorophenyl)propιonιtnIe To a 0 °C solution of 4-fluorophenylacetonitrile (37 mmol) in 80 mL of THF was added 83 mmol of a 1.0 M solution of NaHMDS in THF. The solution was stirred 35 miutes at 0 °C and 112 mmol od Mel were added. The reaction was stiπed overnight at room temperature and quenched at 0 °C with a saturated solution of NH4CI. The aqueous layer was extracted with Et2θ and the combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure The residue was punfied by flash chromatography on silica gel ( 10% Et2θ/hexane) to afford 5.44 g (89%) of alkylated propduct Step 2 2-Methyl-2-(4-fluorophenyl)propylamιde To a solution of nitπle (8.74 g, 54 mmol) from Step 1 above was added 44 mL of H2SO4 and the solution was stirred at 80 °C for 30 minutes. The reaction was cooled down to 0 °C and water was added followed by an 8 N KOH solution (pH 8-9) The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dned over MgSO4 and concentrated under reduced pressure The residue was punfied by flash chromatography on silica gel (Gradiant 50% to 60% ethyl acetate/hexane) to afford the amide as a white solid (54%) Step 3 2-methyl-2-(4-fluorophenyl)propylamιne To a solution of amide from Step 2 above (5.2 g, 29 mmol) in 80 mL of THF, was added 22 mL (44 mmol) of a BH3HDMS solution. The reaction was refluxed for 9 h, cooled down to 0 ° C and quenched slowly with 20 mL of 6 N HCl. The solution was stirred 1 h at room temperature, refluxed for 30 minutes, cooled down to 0 °C and neutralized with 4.2 g of NaOH. The aqueous layer was extracted with Et2θ and the combined organic layers were washed with bnne, dned over MgSO4 and concentrated under reduced pressure. The residue was punfied by flash chromatography on silica gel (40% MeOH/CH2Cl2) to afford 2.06 g (43%) of amme. Step 4-9 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-2-methyl-2-(4-fluorophenyl)propyl- N-(benzvloxycarbonvI)amιno]3-pyπdyl Jethyl Jpyπdine-Ν-oxide Following the procedures descnbed in Example 11, Step 1 to 6 but substituting 2-methyl-2-(4-fluorophenyl)propylamιne (From Step 4 above) at 80 ° C for cumylamine at 140 °C, the coπesponding benzyloxycarbamate was obtained. Step 10 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[2-methyl-2-(4- fluorophenyl)propylamιno]3-pyπdyl Jethyl Jpyndine-Ν-oxide The procedure for the deprotection of the ammo group descnbed m Example 24, Step 7 was applied using the product of Step 9 above as starting matenal. The title compound was obtained as an oil (52 mg, 46%). *H ΝMR (400 MHz, Acetone-d6) δ 7.93 (d, IH), 7.91 (s, IH), 7.46-7.43 (m, 2H), 7.36-7.33 (m, 2H), 7.28-7.23 (m, 2H), 7.15 (d, 2H), 7.03 (t, 2H), 6.95 (t, IH), 6.92 (t, IH), 6.41 (d, IH), 5.32 (t, IH), 4.23 (t, IH), 3.57 (d, 2H), 3.38 (dd, 2H), 1.33 (s, 6H). EXAMPLE 53 (ENANTIOMER- 1 )-4- { 2- [3 ,4-BIS (DIFLUOROMETHOXY)PHEN YL] -2- { 6-[ 1 , 1 - DIMETHYL-2-(4-FLUOROPHENYL)ETHYLAMINO]3- PYRID YL } ETHYL } PYRIDINE-N-OXIDE Step 1-6 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-l ,l-dιmethyl-2-(4- fluorophenyl)ethyl-N-(benzyloxycarbonyl)amιno]3-pyπdyl Jethyl Jpyπdme-Ν-oxide Following the procedures described in Example 11, Step 1 to 6 but substituting l,l-dιmethyl-2-(4-fluorophenyl)ethylamιne for cumylamine, the coπesponding benzyloxycarbamate was obtained (315 mg) Step 7 (Enantiomer- l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l,l-dιmethyl-2-(4- fluorophenyl)ethylammo]3-pyπdyl Jethyl Jpvπdine-Ν-oxide The procedure for the deprotection of the amino group described in Example 34, Step 7 was applied using the product of Step 6 above as starting material. The title compound was obtained as an oil (210 mg, 82%). l H ΝMR (400 MHz, Acetone-d6) δ 8.02 (d, IH), 7.97 (dd, 2H), 7.36- 7 40 (m, 2H), 7.34 (dd, IH), 7.27 (d, IH), 7 20 (d, 2H), 6 98 (t, IH), 6.95 (t, IH), 6.97-7.03 (m, 2H), 6.90-6.95 (m, 2H), 6.44 (d, IH), 5.31 (bis, IH), 4 33 (t, IH), 3.42 (dd, 2H), 3.23 (dd, 2H), 1.34 (s, 3H), 1.32 (s, 3H) EXAMPLE 54 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHEΝYL]-2-[6-(N-METHYL-N- BEΝZYLAMIΝO)3-PYRIDYL]ETHYL}PYRIDIΝE The intermediate 2 (100 mg, 0.212 mmol) was dissolved in 3 mL of N- methylbenzylamine and 200 mg of Cul were added in one portion. The resulting solution was stiπed at 150 ° C for 6 h, 100 mg of Cul were added and the reaction was stiπed for 16 h. The solution was cooled down to room temperature, quenched with 1 mL of concentrated ΝH4OH and stiπed for 15 minutes The mixture was diluted with ethyl acetate and a saturated aqueous solution of NaHCO3 The layers were separated, the organic phase was washed with brine, dned over MgSO4 and concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (20% acetone/CH2Cl2) to afford the title compound (75 g, 71%). *H NMR (500 MHz, Acetone-d6) δ 8.37 (s, 2 H), 8.07 (s, 1 H), 7.52 (d, 1 H), 7.40-7.13 (m, 10 H), 6.95 (t, large J, 1 H), 6.90 (t, large J, 1 H), 6.56 (s, 1 H), 4.8 (s, 2 H), 4.40 (t, 1 H), 3.42 (d, 2 H), 3.00 (s, 3 H). EXAMPLE 55 4-{2-[3,4-BIS(D--FLUOROMETHOXY)PHENYL]-2-[6-(N,N-DIBENZYLAMINO)3- PYRIDYL]ETHYL } PYRIDINE Following the procedures described in Example 54 but substituting dibenzylamine for N-methylbenzylamme, the title compound was obtained (48 mg, 38%). l H ΝMR (500 MHz, Acetone-d6) δ 8.40 (s, 2 H), 8.08 (s, 1 H), 7.47 (d, 1 H), 7.40-7.13 (m, 15 H), 6.92 (t, large J, 1 H), 6.90 (t. large J, 1 H), 6.50 (s, 1 H), 4.8 (s, 4 H), 4.40 (t, 1 H), 3.45-3.35 (m, 2 H). EXAMPLE 56 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHEΝYL]-2-[6-(N-METHYL-N- BEΝZYLAMIΝO)3-PYRIDYL]ETHYL } PYRIDINE-N-OXIDE The intermediate 3 (220 mg, 0.467 mmol) was dissolved in 5 mL of N- methylbenzylamme and Cul (100 mg, 0.53 mmol) was added in one portion The resulting solution was stiπed at 150 ° C for 16 h, cooled down to room temperature, quenched with 1 mL of concentrated ΝH4OH and stiπed for 15 minutes The mixture was diluted with ethyl acetate and a saturated aqueous solution of NaHCO3. The layers were separated, the organic phase was washed with bnne, dned over MgSO4 and concentrated under reduced pressure. The residue was punfied by distillation (1 mm Hg, 100 ° C) to remove most of the N-methylbenzylamine, and by flash chromatography on silica gel (40% EtOH/ethyl acetate) to afford the title compound (150 mg, 61%). IH ΝMR (500 MHz, Acetone-d6) δ 8.05 (s, 1 H), 7.98 (d, 2 H), 7.50 (d, 1 H), 7 37 (s, 1 H), 7.30-7.15 (m, 9 H), 6.95 (t, large J, 1 H), 6.90 (t, large J, 1 H), 6 57 (d, 1 H), 4.8 (s, 2 H), 4.35 (t, 1 H), 3.56 (d, 2 H), 3.00 (s, 3 H). EXAMPLE 57 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(N-METHYL-N- BEΝZYLAMIΝO)3-PYRIDYL]ETHYL}PYRIDIΝE-Ν-OXIDE HYDROCHLORIDE To a solution of 4-{ 2-[3,4-bιs(dιfluoromethoxy)phenyl]-2-[6-(N- methyl-N-benzylamιno)3-pyridyl]ethyl}pyndιne-Ν-oxιde from Example 56 (150 mg, 0.284 mmol) in 3 mL of dioxane was added 0.57 mL (0.568 mmol) of a 1 N solution of HCl in dioxane. The solution was stiπed at room temperature for 30 minutes and the formation of a gum was observed. The heterogeneous mixture was sonicated and the dioxane was removed under reduced pressure. The residue was washed 2 times with dry ether and pumped under high vacuum to afford the title compound as a yellow solid (160 mg, 94%) iH NMR (500 MHz, Acetone-d6) δ 8 78 (d, 2 H), 8.15 (s, 1 H), 8.08 (d, 1 H), 7 95 (d, 2 H), 7.52 (s, 1 H), 7.45-7.25 (m, 7 H), 7.19 (d, 1 H), 6.99 (t, large J, 1 H), 6.92 (t, large J, 1 H), 5.08 (s, 2 H), 4 85 (t, 1 H), 3.89 (d, 2 H), 3.42 (s, 3 H). EXAMPLE 58 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(N-METHYL-N-2- PHEΝYLETHYLAMIΝO)3-PYRID YL]ETHYL } PYRIDINE-N-OXIDE Following the procedures descnbed in Example 56 but substituting N- methylphenethylamme for N-methylbenzylamine, the title compound was obtained (40 mg, 18%). iH ΝMR (500 MHz, Acetone-d6) δ 8.07 (s, 1 H), 7.98 (d, 2 H), 7.53 (dd, 1 H), 7 40 (s, 1 H), 7.33-7.14 (m, 9 H), 6.99 (t, large J, 1 H), 6.94 (t, large J, 1 H), 6.55 (d, 1 H), 4.38 (t, 1 H), 3.8-3.68 (m, 2 H), 3 44 (d, 2 H), 2 95 (s, 3 H), 2.92- 2.79 (m, 2 H). EXAMPLE 59 4-{2-[3,4-BIS(D_FLUOROMETHOXY)PHEΝYL]-2-[6-(N-ETHYL-N- BEΝZYLAMIΝO)3-PYRIDYL]ETHYL}PYRIDIΝE-Ν-OXIDE Following the procedures described in Example 56 but substituting N- ethylbenzylam e for N-methylbenzylamine, the title compound was obtained (40 mg, 18%). EXAMPLE 60 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(NJ-PROPYL-N- BEΝZYLAMIΝO)3-PYRIDYL]ETHYL J PYRIDINE-N-OXIDE Following the procedures descnbed in Example 56 but substituting N- 2-propylbenzylamme for N-methylbenzylamine, the title compound was obtained (41 mg, 18%). iH ΝMR (400 MHz, Acetone-d6) δ 8.06 (s, 1 H), 7.95 (d, 2 H), 7.49 (dd, 1 H), 7.40-7.15 (m, 10 H), 6.96 (t, large J, 1 H), 6.92 (t, large J, 1 H), 6.51 (d, 1 H), 4.75 (s, 2 H), 4.35 (t, 1 H), 3.55 (d, 2 H), 2.68-2.51 (m, 1 H), 1.15-1.02 (m, 6 H). EXAMPLE 61 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHEΝYL]-2-[6-(N-rEEr-BUTYL-N- BΕΝZYLAMIΝO)3-PYRIDYL]ΕTHYL}PYRIDIΝΕ-Ν-OXIDΕ Following the procedures descnbed in Example 56 but substituting N- terf-butylbenzylamme for N-methylbenzylamine, the title compound was obtained (35 mg, 15%). EXAMPLE 62 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHEΝYL]-2-[6-(N-METHYL-N-4- CHLOROBEΝZYLAMIΝO)3-PYRIDYL]ETHYL}PYRIDIΝE-Ν-OXIDE Following the procedures descnbed in Example 56 but substituting N- methyl-4-chlorobenzylamme for N-methylbenzylamine, the title compound was obtained (140 mg, 65%). iH ΝMR (500 MHz, Acetone-d6) δ 8.4 (s, 2 H), 8.07 (s, 1 H), 7.53 (d, 1 H), 7.41-7.13 (m, 9 H), 6.96 (t, large J, 1 H), 6.94 (t, large J, 1 H), 6.57 (d, 1 H), 4.78 (s, 2 H), 4.41 (t, 1 H), 3.41 (d, 2 H), 3.00 (s, 3 H). EXAMPLE 63 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHEΝYL]-2-[6-(N-METHYL-N-3- METHOXYBEΝZYLAMIΝO)3-PYRBDYL]ETHYLJPYRIDIΝE-Ν-OXIDE Following the procedures descnbed in Example 56 but substituting N- methyl-3-methoxybenzylamιne at 180 °C for N-methylbenzylamme at 150 °C. the title compound was obtained. l U NMR (500 MHz, Acetone-d6) δ 8.45 (s, 2 H), 8.05 (s, 1 H), 7.51 (d, 1 H), 7.37 (s, 1 H). 7.32-7.15 (m, 5 H), 6.92 (t, large J, 1 H), 6.90 (t, large J, 1 H), 6.88-6.75 (m, 3 H), 6.57 (d, 1 H), 4.75 (s, 2 H), 4.40 (t, 1 H), 3.71 (s, 3 H), 3.41 (d, 2 H), 3.00 (s, 3 H). EXAMPLE 64 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[N-METHYL-N-(3- PYRID YL)METHYLAMIΝO] 3 -PYRIDYL } ETHYL } PYRIDINE-N-OXIDE Following the procedures described in Example 56 but substituting N- methyl-(3-pyridyl)methylamine for N-methylbenzylamine, the title compound was obtained (90 mg, 42%). *H ΝMR (500 MHz, Acetone-d6) δ 8.47 (s, 1 H), 8.42 (d, 1 H), 8.08 (s, 1 H), 7.97 (d, 2 H), 7.62-7.51 (m, 2 H), 7.39 (s, 1 H), 7.33-7.14 (m, 5 H), 6.96 (t, large J, 1 H), 6.94 (t, large J, 1 H), 6.60 (d, 1 H), 4.82 (s, 2 H), 4.37 (t, 1 H), 3.41 (d, 2 H), 3.02 (s, 3 H). EXAMPLE 65 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHEΝYL]-2-[6-(N-METHYL-N-2- METHYLBEΝZYLAMIΝO)3-PYRID YL]ETHYL } PYRIDINE-N-OXIDE Following the procedures described in Example 56 but substituting N- methyl-2-methylbenzylamine for N-methylbenzylamine, the title compound was obtained (105 mg, 47%). ! H ΝMR (500 MHz, Acetone-d6) δ 8.05 (s, 1 H), 7.96 (d, 2 H), 7.50 (d, 1 H), 7.39 (s, 1 H), 7.33-7.04 (m, 7 H), 6.97 (t. large J, 1 H), 6.95 (d, 1 H), 6.92 (t, large J, 1 H), 6.54 (d, 1 H), 4.73 (s, 2 H), 4.35 (t, 1 H), 3.40 (d, 2 H), 3.00 (s, 3 H), 2.27 (s, 3 H). EXAMPLE 66 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHEΝYL]-2-{ 6-[N-METHYL-N-(2- ΝAPHTHYL)METHYLAMIΝO]3-PYRIDYL JETHYL } PYRIDINE-N-OXIDE Following the procedures described in Example 56 but substituting N- methyl-2-naphthylamine at 100 °C for N-methylbenzylamine at 150 °C. the title compound was obtained (47 mg, 19%). Ϊ H NMR (300 MHz, Acetone-d6) δ 8 09 (d, 1 H), 8.00 (d, 2 H), 7.59- 7.15 (m, 13 H), 7.00 (t, large J, 1 H), 6 92 (t, large J, 1 H), 6.58 (d, 1 H), 5.25 (s, 2 H), 4.40 (t, 1 H), 3.42 (d, 2 H), 3.02 (s, 3 H). EXAMPLE 67 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(N-2-HYDROXYETHYL-N- BEΝZYLAMIΝO)3-PYRIDYL]ETHYLJPYRIDIΝE-Ν-OXIDE Following the procedures descnbed in Example 56 but substituting N- benzylethanolamine for N-methylbenzylamine, the title compound was obtained (76 mg, 34%). l H ΝMR (300 MHz, Acetone-d6) δ 8 08 (d, 1 H), 7.96 (d, 2 H), 7 70 (dd, 1 H), 7.50-7.13 (m, 10 H), 6.96 (t, large J. 1 H), 6.94 (t, large J, 1 H), 6 70 (d, 1 H), 4.49 (t, 1 H), 4.32 (t, 2 H), 3.80 (s, 2 H), 3.46 (d, 2 H), 2.90 (t, 2 H). EXAMPLE 68 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHEΝYL]-2-[6-(N-METHYL-N-4- METHOXYPHEΝYLAMIΝO)3-PYRID YL]ETHYL } PYRIDINE Step 1 J3,4-Bιs(dιfluoromethoxy)phenyn-[6-(N-methyl--V-4-methoxyphenylamιno)3- pyπdyllmethanone The intermediate 1 ( 197 mg, 0.5 mmol) was dissolved in 2 g of N-methyl-4- methoxyanihne and Cul (20 mg, 0 1 mmol) was added in one portion The resulting solution was stiπed at 100 ° C for 6 h, cooled down to room temperature, quenched with 8 drops of concentrated ΝH4OH and stiπed for 30 minutes. The mixture was diluted with ethyl acetate and a saturated aqueous solution of NaHCO3. The layers were separated, the organic phase was washed with bnne, dned over MgSO4 and concentrated under reduced pressure. The residue was puπfied by distillation (1 mm Hg, 200 °C) to remove most of the N-methyl-4-methoxyanιlιne, and by flash chromatography on silica gel (20% ethyl acetate/hexane) to afford 223 mg (100%) of ammo ketone. Step 2 13,4-Bιs(dιfluoromethoxy)phenyn-r6-(N-methy]-N-4-methoxyphenylammo)3- pyndyllmethanol To a 0 °C solution of ketone (225 mg, 0.5 mmol) from Step 1 above in 6 mL of a 5 : 1 mixture of THF • MeOH, was added slowly 38 mg (1.0 mmol) of ΝaBF-4 The resulting solution was stirred 30 minutes at room temperature, quenched with a saturated aqueous NH4CI solution and diluted with ethyl acetate. The organic layer was washed with bnne, dned over MgSO4 and concentrated under reduced pressure The residue was used directly for the next step without any punfication Step 3 4-{ l-Carbethoxy-2-r3,4-bis(difluoromethoxy)phenyll-2-[6-(N-methyl-N-4- methoxyphenylamιno)3-pyπdyllethyl Jpyndme To a 0 °C solution of alcohol from Step 2 above (121 mg, 0.27 mmol) in 3 mL of toluene was added 0.113 mL (0.65 mmol) of z-Pr2ΝEt followed by 0.024 mL (0.32 mmol) of SOCI2. The solution was stiπed 1 h at 0 ° C followed by the addition of the enolate generated as follow: to a solution of ethyl 4-pyndyl acetate (178 mg, 1 08 mmol) and HMPA (0.188 mL, 11 08 mmol) in 4 mL of THF, was slowly added 2.2 mL (1.08 mmol) of a 0.5 M solution of KHMDS in toluene and the resulting solution was stirred 10 minutes at room temperature The resulting cloudy solution was stiπed 25 minutes, quenched with a saturated aqueous NH4CI solution and diluted with ethyl acetate/saturated NaHCO3 solution Tht aqueous layer was extracted with ethyl acetate and the combined organic layer weie washed with water and brine, dned over MgSO4 and concentrated under reduced pressure. The residue was used directly for the next step without any punfication. Step 4 4-{ 2-|3,4-Bιs(dιfluoiOmethoxy)phenyl1-2-J6-(N-methyl-N-4-methoxyphenylamιno)3- pyridyllethyl Jpyndine To a solution of the crude ester from Step 3 above in a mixture of THF/ MeOH/ water (4.5 mL. 1.5 mL/1.5 mL), was added 1.6 mL (3.24 mmol) of a 2 Ν solution of LiOH. The resulting solution was stirred at 65 °C for 3 h, cooled down to room temperature followed by the addition of 3.4 mL of a 1.0 Ν HCl solution. The resulting mixture was rotovaped down to evaporate MeOH and the aqueous residue was diluted with ethyl acetate The aqueous layer was extracted with ethyl acetate and the combined organic layer were washed with water and bnne, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Gradient 70% Ethyl acetate/hexane to 100% ethyl acetate) to afford 67 mg (47%, 2 steps) of the title compound. ! H NMR (500 MHz, Acetone-d6) δ 8.37 (s, 2H), 8.09 (s, IH), 7.37 (dd, IH), 7.35 (s, IH), 7.28 (dd, IH), 7.24 (d, IH), 7.19-7.12 (m, 4H), 6.99-6.94 (m, 2H), 6.93 (t, IH), 6.90 (t, IH), 6.27 (d, IH), 4.41 (t, IH), 3.8 (s, 3H), 3.40 (d. 2H), 3.30 (s, 3H). EXAMPLE 69 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(N-METHYL-N-4- METHOXYPHENYLAMINO)3-PYRIDYL]ETHYL} PYRIDINE-N-OXIDE To a solution of 4-{2-[3,4-bιs(dιfluoromethoxy)phenyl]-2-[6-(N- methyl-N-4-methoxyphenylammo)3-pyπdyl]ethyl Jpyndine from Example 112 (60 mg, 0.11 mmol) in a mixture of 3.0 mL of CH2CI2 and 0.3 mL MeOH, was added 84 mg (0 136 mmol) of 80% MMPP. Reaction was stirred for 24 h at room temperature, quenched with a saturated solution of NaHCO3 and diluted with ethyl acetate. The organic layer was then washed with bnne, dned over MgSO4 and concentrated under reduced pressure. The residue was punfied by flash chromatography on silica gel (Gradient 40% to 50% EtOH/ethyl acetate) to afford 27 mg (45%) of the title compound. *H NMR (500 MHz, Acetone-d6) δ 8.09 (d, IH), 7 95 (d, 2H), 7.37 (m, 2H), 7.30 (dd, IH), 7.25 (d, IH), 7.22-7.13 (m, 4H), 6.97 (d, 2H), 6.94 (t. IH), 6.91 (t, IH), 6.28 (d, IH), 4.39 (t, IH), 3.82 (s, 3H), 3.41 (d, 2H), 3.32 (s, 3H). EXAMPLE 70 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(N-METHYL-N-(S)-l- PHENYLETHYLAMINO)3-PYRIDYL]ETHYL J PYRIDINE Following the procedures described in Example 68 but substituting (S)- N-methyl- 1-phenylethylamιne for /V-methyl-4-methoxyanιlme, the title compound was obtained (54 mg). iH ΝMR (500 MHz, Acetone-d6) δ 8.37 (s, 2H), 8.08 (s, IH), 7.55 (m, IH), 7 40-7.16 (m, 10H), 6.94 (t, IH), 6.91 (t, IH), 6.56 (d, IH), 6 14 (q, IH), 4.42 (t, IH), 3 44 (d, 2H), 2.68 (s, 3H), 1.50 (d, 3H). - I l l - EXAMPLE 71 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(N-METHYL-N-(5)- 1 - PHENYLETHYLAMINO)3-PYRIDYL]ETHYL } PYRIDINE-N-OXIDE The procedure for the oxidation of the pyndine group described in Example 69 was applied using the product of Example 70 above as starting matenal The title compound was obtained as an oil (14.6 mg, 27%). ! H NMR (500 MHz, Acetone-d6) δ 8.08 (s, IH), 7.95 (d, 2H), 7.54 (m, IH), 7.37 (s, IH), 7.33-7.17 (m, 10H), 6.95 (t, IH), 6.91 (t, IH), 6.57 (d, IH), 6.15 (q, IH), 4.38 (t, IH), 3 42 (d, 2H), 2.69 (s, 3H), 1.5 (d, 3H). EXAMPLE 72 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(N-METHYL-N-(R)-l- PHENYLETHYLAMINO)3-PYRIDYL]ETHYL } PYRIDINE-N-OXIDE Step 1-4 4-{ 2-13,4-Bιs(dιfluoromethoxv)phenyl1-2-f6-(N-methvl-N-(R)-l-phenylethylamιno)3- pyπdyllethyl Jpyndine Following the procedures described in Example 68 but substituting (R)-N-methyl-l-phenylethylamιne for N-methyl-4-methoxyanιlιne, 600 mg of the pyndine were obtained Step 5 4-{ 2-r3,4-Bιs(dιfluoromethoxv)phenvl1-2-16-(Ν-methvl-Ν-(R)-l-phenylethylamιno)3- pyndyllethyl Jpyndine-N-oxide The procedure for the oxidation of the pyndine group described in Example 69 was applied using the product of Step 4 above as starting matenal. The title compound was obtained as an oil (50 mg, 8%) EXAMPLE 73 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(N-METHYL-N- PHENYLAMINO)3-PYRIDYL]ETHYL}PYRIDINE-N-OXIDE Step 1-4 4-{ 2- 3,4-Bιs(dιfluoromethoxy)phenyl1-2-[6-(N-methyl-N-phenylammo)3- pyndyllethyl Jpyndine Following the procedures described in Example 68 but substituting N- methyl-anilme for N-methyl-4-methoxyanιhne, 278 mg of pyndine were obtained as Step 5 4-{ 2-r3,4-Bιs(dιfluoromethoxy)phenyl1-2-[6-(Ν-methyl-Ν-phenylammo)3- pyndyllethyl Jpyndine-N-oxide The procedure for the oxidation of the pyndine group descnbed in Example 69 was applied using the product of Step 4 above as starting matenal. The title compound was obtained as a foam (156 mg, 56%). !H NMR (500 MHz, Acetone-dό) δ 8.13 (d, IH), 7.95 (d, 2H), 7.44- 7.35 (m, 4H), 7.30 (dd, IH), 7.27-7.16 (m, 6H), 6.95 (t, IH), 6.92 (t, IH), 6.46 (d, IH), 4 40 (t, IH), 3.42 (d, 2H), 3 39 (s, 3H) EXAMPLE 74 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(N-HYDROXYL-N- BENZYLAMINO)3-PYRIDYL]ETHYL}PYRIDINE-N-OXIDE To a solution of 4-{2-[3,4-bιs(dιfluoromethoxy)phenyl]-2-[6-(N- benzyl tπfluoroacetamιde)3-pyπdyl]ethyl Jpyπdine (Example 124) (60 mg, 0.10 mmol) in a mixture of 3.0 mL of CH2CI2 and 0.3 mL MeOH, was added 94 mg (0.152 mmol) of 80% MMPP. Reaction was stirred for 24 h at room temperature and was purified directly by flash chromatography on silica gel (50% EtOH/ethyl acetate + 3% Et3N) to afford 29 mg (55%) of the title compound !H NMR (500 MHz, Acetone-d6) δ 8 19 (s, IH), 7.96 (d, 2H), 7.55- 7.45 (m, IH), 7.40 (s, IH), 7.37-7.14 (m, 9H), 6 97 (t, large J, IH), 6.91 (t, large J, IH), 6 62 (d, IH), 4.55 (d, 2H), 4.40 (t, IH), 3 43 (d, 2H). EXAMPLE 75 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(N-ETHYL-N-(R)-l- PHENYLETHYLAMINO)3-PYRIDYL]ETHYL } PYRIDINE-N-OXIDE Step 1 4-{2-r3,4-Bιs(dιfluoromethoxv)phenyl]-2-16-(N-ethyl-N-(R)-l-phenylethylamιno)3- pyndyllethyl Jpyndine To a 90 ° C solution of 4-{2-[3,4-bιs(difluoromethoxy)phenyl]-2-[6- (R)-(l-phenylethylamιno)3-pyndyl]ethyl Jpyπdine from Example 3 (150 mg, 0.29 mmol) in 2 0 mL of acetic acid, was added several 25 mg portion of NaBF-4 until TLC analysis showed no more starting material The mixture was cooled to room temperature and poured into a 2 : 1 mixture of CH2CI2 /NaOH 5 M. The layers were separated and the aqueous phase was extracted with CH2C12- The combined organic layers were diluted with ethyl acetate, washed with brine, dned over MgSO4 and concentrated under reduced pressure. The residue was punfied by flash chromatography on silica gel (70% ethyl acetate/hexane) to afford 125 mg (80%) of the pyndine. Step 2 4-{ 2-r3,4-Bιs(dιfluoromethoxv)phenvl1-2-f6-(N-ethvl-N-(R)-l-phenylethylammo)3- pyπdyllethyl Jpyndme-N-oxide To a solution of pyndine from Step 1 above (12"> mg, 0.232 mmol) in a mixture of 7.0 mL of CH2CI2 and 0.7 mL MeOH, was added 143 mg (0.232 mmol) of 80% MMPP. Reaction was stirred for 24 h at room temperature and was punfied directly by flash chromatography on silica gel (Gradient ethyl acetate + 3% Et3N to 30% EtOH/ethyl acetate + 3% Et3N) to afford 35 mg (27%) of the title compound. iH NMR (500 MHz, Acetone-d6) δ 8.10 (s, IH), 7.97 (d, 2H), 7.55- 7.49 (m, IH), 7.39 (s, IH), 7.33-7.15 (m, 9H), 6.97 (t, large J, IH), 6.91 (t, large J, IH), 6 54 (d, IH), 6.10 (q, IH), 4.38 (t, IH), 3 47-3 27 (m, 3H), 3.25-3.15 (m, IH), 1.54 (d, 3H), 0.98 (t, 3H). EXAMPLE 76 4- { 2- [3 ,4-BIS(DIFLUOROMETHOXY)PHENYL] -2-[6-(N-ETHYL-N-(S)- 1 - PHEN YLETHYLAMINO)3-PYRID YL]ETHYL } PYRIDINE-N-OXIDE Following the procedures described in Example 75 but substituting 4- { 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(S)-(l-phenylethylamιno)3- pyπdyflethyl Jpyndine (Example 2) for 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6- (R)-(l-phenylethylammo)3-pyndyl]ethyl Jpyπdine, the title compound was obtained as an oil (53 mg). !H NMR (500 MHz, Acetone-d6) δ 8.10 (t, IH), 7.97 (d, 2H), 7.55- 7.49 (m, IH), 7.39 (s, IH), 7.33-7.15 (m, 9H), 6.97 (t, large J, IH), 6.92 (t, large J, IH), 6 54 (d, IH), 6.10 (q, IH), 4.38 (t, IH), 3 47-3.27 ( , 3H), 3.25-3.15 (m, IH), 1.54 (d, 3H). 0.97 (t, 3H) EXAMPLE 77 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[N-METHYL-N-(3- PYRID YL-N-OXIDE)METHYLAMINO]3-PYRID YL } ETHYL } PYRIDINE-N- OXIDE Following the procedures descnbed in Example 74 but substituting 4- {2-[3,4-bιs(dιfluoromethoxy)phenyl]-2-{6-[N-methyl-N-(3-pyπdyl)methylammo]3- pyndyl Jethyl Jpyndme-N-oxide (Example 64) for 4-{ 2-[3,4- bιs(dιfluoromethoxy)phenyl]-2-[6-(N-benzyl tπfluoroacetamιde)3- pyπdyl]ethyl Jpyndine, the title compound was obtained (10 mg, 35%) !H NMR (500 MHz, Acetone-d6) δ 8 09-7.97 (m. 4H), 7.60-7.54 (m, 2H), 7.39 (s, IH), 7.33-7.29 (m, 2H), 7.25 (d, IH), 7.21-7.15 (m, 3H), 6.97 (t, large J, IH), 6 93 (t, large J, IH), 6.63 (d, IH), 4.80 (s, 2H), 4 38 (t, IH), 3 47-3.40 (m, 2H), 3.06 (s, 3H) EXAMPLE 78 (ENANTIOMER-2)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6- [METHOXY(4-FLUOROPHENYL)METHANPMINE]3- PYRID YL } ETHYL } PYRIDINE-N-OXIDE To a solution of (Enantιomer-l)-4-{ 2-[3,4- bιs(dιfluoromethoxy)phenyl]-2-{ 6-[4-fluorophenylamιdo]3-pyπdyl Jethyl Jpyπdine-N- oxide trom Example 46 (20 mg, 0 037 mmol) m 1.0 mL of DMF. was added 2 mg (0.04 mmol) of 60% NaH followed by 0.004 mL (0.055 mmol) of Mel. The reaction was stirred 1 h at room temperature, quenched with a 25% NH4OAC solution and diluted with ethyl acetate. The organic phase was washed with brine, dned over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on preparative plate (20% E-OH/CH2CI2) to afford 3.8 mg (19%) of the title compound. !H NMR (500 MHz, Acetone-d6) δ 8.34 (d, IH), 7.95 (d, 2H), 7.65 (dd, IH), 7.37 (s, IH), 7.32-7.26 (m, 4H), 7.16 (d, 2H), 7.05-6.98 (m, 3H), 6.95 (t, IH), 6.94 (t, IH), 4.55 (t, IH), 3.47 (dd, 2H), 3.42 (s, 3H). EXAMPLE 79 (ENANTIOMER- 1 )-4- { 2-[3 ,4-BIS(DIFLUOROMETHOX Y)PHENYL] -2- [6-(N- METHYL-4-FLUOROPHENYLAMIDO)3-PYRIDYL]ETHYL}PYRIDINE-N- OXIDE To a solution of (enantιomer-l)-4-{2-[3,4- bis(dιfluoromethoxy)phenyl]-2-{ 6-[4-fluorophenylamιdo]3-pyπdyl Jethyl }pyπdιne-N- oxide from Example 46 (20 mg, 0.037 mmol) in 1.0 mL of DMF, was added 2 mg (0.04 mmol) of 60% NaH followed by 0.004 mL (0.055 mmol) of Mel. The reaction was stirred 1 h at room temperature, quenched with a 25% NH4OAC solution and diluted with ethyl acetate. The organic phase was washed with bnne. dned over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on preparative plate (20% EtOH/CH2Cl2) to afford 5.5 mg (27%) of the title compound. *H NMR (500 MHz, Acetone-d6) δ 8.40 (d, IH), 8.29 (m, 2H), 8.06 (d, IH), 7.96 (d, 2H), 7.76 (dd, IH), 7.43 (s, IH), 7.34 (dd, IH), 7.29 (d, IH), 7.22 (d, 2H), 7.13-7.08 (m, 2H), 6.96 (t, IH), 6.94 (t. IH), 4.44 (t, IH), 3.88 (s, 3H), 3.55- 3.40 (m, 2H). EXAMPLE 80 4- { 2- [3 ,4-BIS (DIFLUOROMETHOX Y)PHEN YL] -2- [6-(N-BENZYL TRIFLUORO ACETAMIDO)3-PYRIDYL]ETHYL } PYRIDINE The procedure for the protection of the amme with a TFA group descnbed in Example 5, Step 1 was applied using 4-{2-[3,4- bιs(dιfluoromethoxy)phenyl]-2-[6-(benzylammo)3-pyπdyl]ethyl Jpyπdine (Example 1). The tnfluoroacetamide was obtained as an oil (200 mg, 50%). EXAMPLE 81 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(N-BENZYL ACETAMIDO)3-PYR-DYL]ETHYL } PYRIDINE-N-OXIDE Step 1 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-benzyl acetamιdo)3- pyπdyllethyl Jpyndine To a solution of 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6- (benzylamιno)3-pyπdyl]ethyl Jpyπdme from Example 1 (100 mg, 0.2 mmol) in 3 mL of 1,2-dιchloroethane, was added 0.077 mL (0.96 mmol) of pyndine followed by 0.012 mg (0.1 mmol) of DMAP and 0.056 mL (0.6 mmol) of acetic anhydnde. The solution was stiπed 24 h at reflux, quenched with water and diluted with CH2C12- The organic layer was washed with bnne, dned over MgSO4 and concentrated under reduced pressure. The residue was punfied by chromatography on silica gel (Gradient 100% ethyl acetate to 10% EtOH/ethyl acetate) to afford 29 mg (27%) of the acetamide. Step 2 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-benzyl acetamιdo)3- pyπdyllethyl Jpyndme-N-oxide The procedure for the oxidation of the pyndine group descnbed in Example 74 was applied using the product of Step 1 above as starting matenal. The title compound was obtained as an oil (29 mg, 95%). iH NMR (500 MHz, Acetone-d6) δ 8.42 (d, IH), 7.94 (d, 2H), 7.82 (dd, IH), 7.42 (s, IH), 7.34 (dd, 2H), 7.28-7.13 (m, 8H), 6.95 (t, IH), 6.93 (t, IH), 5.09 (s, 2H), 4.56 (t, IH), 3.55-3.42 (m, 2H), 2.00 (s, 3H). EXAMPLE 82 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[N-(l-METHYL-l- PHENYL)ETHYL-N-(rERE-BUTYLOXYCARBONYL)AMINO]3- PYRID YL } ETHYL } PYRIDINE-N-OXIDE Step 1 [3,4-Bιs(dιfluoromethoxy)phenyll-<6-lN-(l-methyl-l-phenyl)ethyl-N-(tert- butyloxycarbonyl)3-pyridyl )methanone To a solution of amino ketone from Example 11, Step 1 (467 mg, 1.04 mmol) in 5.0 mL of dioxane, was added 0.218 mL (1.25 mmol) of z-Pr2ΝEt followed by 272 mg (1.25 mmol) of di-tert-butyl dicarbonate and a few crystal of DMAP The solution was stirred 24 h at 60 °C, cooled down to room temperature, quenched with a saturated solution of NaHCO3 and diluted with ethyl acetate. The organic layer was washed with bnne, dried over MgSO4 and concentrated under reduced pressure. The residue was punfied by chromatography on silica gel (Gradient 15% to 30% ethyl acetate/hexane) to afford 440 mg (77%) of the BOC deπvative. Step 2 J3,4-Bιs(dιfluoromethoxy)phenyl1-| 6-[N-(l-methyl-l-phenyl)ethyl-N-(terr- butyloxycarbonyl)3-pyndyl Jmethanol The procedure for the reduction of the ketone descnbed in Example 11, Step 3 was applied using the product of Step 1 above as startin g material The alcohol obtained was used directly for the next step without any punfication Step 3 4-{ l-Carbethoxy-2-[3,4-bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l- phenyl)ethyl-N-(tgrt-butyloxvcarbonvl)ammo]3-pyndyl Jethyl Jpyndine The procedure for the alkylation with ethyl 4-pyndylacetate descnbed in Example 11, Step 4 was applied using the product of Step 2 above as starting matenal The ethyl ester obtained was used directly for the next step without any punfication. Step 4 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{ 6-[Ν-(l-methyl-l-phenyl)ethyl-Ν-(tert- butyloxycarbonyl)amιno]3-pyπdyl Jethyl Jpyπdme The procedure for the hydrolysis/decarboxylation descnbed in Example 11 , Step 5 was applied using the product of Step 3 above as starting matenal. The protected aminopyndine was obtained as an oil (95 mg, 20% for 4 steps). Step 5 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{ 6-[N-(l-methyl-l-phenyl)ethyl-N-(tert- butyloxvcarbonyl)amιno]3-pyridyl Jethyl Jpyndine-N-oxide The procedure for the oxidation of the pyndine group described in Example 11, Step 6 was applied using the product of Step 4 above as starting matenal. The title compound was obtained as an oil (70 mg, 86%). *H NMR (500 MHz, Acetone-d6) δ 8.51 (d, IH), 7 95 (d, 2H), 7.88 (dd, IH), 7.68 (d, 2H), 7.45 (s, IH), 7.39 (d, 2H), 7.21-7.16 (m, 3H), 6.97 (t, large J, IH), 6.95 (t, large J, IH), 4.63 (t, IH), 3.58-3.50 (m, 2H), 1.49 (s, 3H), 1.48 (s, 3H), 1.07 (s, 9H). EXAMPLE 83 (EN ANTIOMER-2)-4- { 2- [3 ,4-BIS(DIFLUOROMETHOXY)PHEN YL] -2- { 6-[N-( 1 - METHYL- 1 -PHENYL)ETHYL-N-(7ERr-BUTYLOXYCARBONYL)AMINO]3- PYRIDYLJETHYLJPYRIDINE-N-OXIDE The procedure for protection of the amine descnbed in Example 82, Step 1 was applied using the product of Example 13 as starting matenal. The title compound was obtained as a foam (150 mg, 63%). !H NMR (500 MHz, Acetone-d6) δ 8.51 (d, IH), 7.95 (d, 2H), 7.88 (dd, IH), 7.68 (d, 2H), 7.45 (s, IH), 7.39 (d, 2H), 7.21-7.16 (m, 3H), 6.97 (t, large J, IH), 6.95 (t, large J, IH), 4.63 (t, IH), 3.58-3.50 (m, 2H), 1.49 (s, 3H), 1.48 (s, 3H), 1.07 (s, 9H). EXAMPLE 84 (ENANTIOMER-l)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{ 6-[N-(l- METHYL-l-PHENYL)ETHYL-N-(BENZYLOXYCARBONYL)AMINO]3- P YRID YL } ETHYL J PYRIDINE 4.2 g of the title compound was obtained by resolution of 9.0 g of racemic 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-phenyl)ethyl-N- (benzyloxycarbonyl)amιno]3-pyπdyl Jethyl Jpyπdine (Example 11, Step 5) on chiral column: preparative chiralpak AD, 20% / ' -PrOH/hexane, 100 mL/min. Example 84 is the fast elutmg enantiomer with a retention time of 39 minutes. iH NMR (400 MHz, Acetone-d6) δ 8.50 (d, IH), 8.32 (d, 2H), 7.90 (dd, IH), 7.69 (d, 2H), 7.49-7.35 (m, 3H), 7.33-7.25 (m, 3H), 7.22-7.10 (m, 7H), 6.98-6.88 (m, IH), 6.94 (t, large J, 2H), 4.89-4.79 (m, 2H), 4.65 (t, IH), 3.60-3.46 (m, 2H), 1.52 (s, 6H). EXAMPLE 85 (ENANTIOMER-2)-4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[N-(l- METHYL-l-PHENYL)ETHYL~N-(BENZYLOXYCARBONYL)AMINO]3- PYRIDYLJETHYLJPYRIDINE 4.2 g of the title compound was obtained by resolution of 9.0 g of racemic 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l -methyl- l-phenyl)ethyl-N- (benzyloxycarbonyl)ammo]3-pyπdyl Jethyl Jpyπdme (Example 11 , Step 5) on chiral column: preparative chiralpak AD, 20% /-PrOH/hexane, 100 mL/mm. Example 85 is the slow elutmg enantiomer with a retention time of 52 minutes. l R NMR (400 MHz, Acetone-d6) δ 8.50 (d, IH), 8.32 (d, 2H), 7.90 (dd, IH), 7.69 (d, 2H), 7.49-7.35 (m, 3H), 7.33-7.25 (m, 3H), 7.22-7.10 (m, 7H), 6.98-6.88 (m, IH), 6.94 (t, large J, 2H), 4.89-4.79 (m, 2H), 4 65 (t, IH), 3.60-3.46 (m, 2H), 1.52 (s, 6H). EXAMPLE 86 (ENANTIOMER-l)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[N-(l- METHYL- 1 -(4-METHYLPHENYL))ETHYL-N- (BENZYLOXYCARBONYL)AMINO]3-PYRIDYL}ETHYL}PYRIDINE Step 1-5 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(4-methylphenyl))ethyl- N-(benzyloxycarbonyl)amιno13-pyndyl Jethyl Jpyndine Following the procedures descnbed in Example 11, Step 1-5 but substituting 1 -methyl- l-(4-tolyl)ethylamιne for cumylamine, 2.91 g of racemic carbamate were obtained as a white foam. Step 6 (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(4- methylphenyl))ethyl-N-(benzyIoxycarbonyl)amιno13-pyπdyl Jethyl Jpyndine The carbamate from Step 5 above was resolved by HPLC (Preparative chiralpak AD, 30% / ' -PrOH/hexane, 65 mL/min), to afford 1 26 g of the title compound as the fast eluting enantiomer (32 mm). *H NMR (500 MHz, Acetone-d6) δ 8.50 (d, IH), 8.32 (d, 2H), 7.89 (dd, IH), 7.55 (d, 2H), 7.47 (s, IH), 7.42 (d, IH), 7.38 (dd. IH), 7.29 (d, IH), 7.21- 7.08 (m, 7H), 6.96 (t, 2H), 6.96-6.92 (m, 2H), 4.84 (m, 2H), 4 64 (t, IH), 3.58-3.49 (m, 2H), 2.29 (s, 3H), 1.49 (s, 6H). EXAMPLE 87 (ENANTIOMER-2)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[N-(l- METHYL- 1 -(4-METHYLPHENYL))ETHYL-N- (BENZYLOX YC ARBONYL) AMINO]3-PYRID YL } ETHYL } PYRIDINE Step 1-5 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(4-methylphenyl))ethyl- N-(benzyloxycarbonyl)amino13-pyridyl Jethyl Jpyndine Following the procedures descnbed in Example 11 , Step 1-5 but substituting 1 -methyl- 1 -(4-tolyl )ethylamιne for cumylamine, 2 91 g of racemic carbamate were obtained as a white foam. Step 6 (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(4- methvlphenvl))ethyl-N-(benzyloxvcarbonyl)amιno13-pyπdyl Jethyl Jpyndine The carbamate from Step 5 above was resolved by HPLC (Preparative chiralpak AD, 30% / ' -PrOH/hexane, 65 mL/mm), to afford 1.26 g of the title compound as the slow eluting enantiomer (39 mm). iH NMR (500 MHz, Acetone-d6) δ 8.50 (d, IH), 8.32 (d, 2H), 7.89 (dd, IH), 7.55 (d, 2H), 7 47 (s, IH), 7 42 (d, IH), 7.38 (dd, IH), 7.29 (d, IH), 7.21- 7.08 (m, 7H), 6.96 (t, 2H), 6.96-6.92 (m, 2H), 4.84 (m, 2H), 4.64 (t, IH), 3.58-3.49 (m, 2H), 2.29 (s, 3H), 1.49 (s, 6H) EXAMPLE 88 (ENANTIOMER-l)-4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[N-(l- METHYL- 1 -(4-FLUOROPHENYL))ETHYL-N- (BENZYLOXYC ARBONYL) AMINO]3-PYRID YL } ETHYL } PYRIDINE Step 1-5 4-{2-[3,4-Bis(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(4-fluorophenyl))ethyl- N-(benzy]oxycarbonyl)amino]3-pyridyl Jethyl Jpyndine Following the procedures described in Example 11, Step 1-5 but substituting (4-fluorophenyl)ethylamine for cumylamine, 3.4 g of racemic carbamate were obtained as a white foam. Step 6 (Enantiomer-l)-4-{2-[3,4-Bιs(difluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(4- fluorophenyl))ethyl-N-(benzyloxycarbonyl)ammo]3-pyridyI Jethyl Jpyndine The carbamate from Step 5 above was resolved by HPLC (Preparative chiralpak AD, 30% /-PrOH/hexane, 65 mL/min), to afford 1.35 g of the title compound as the fast eluting enantiomer (34 min). iH NMR (500 MHz, Acetone-d6) δ 8.52 (s, IH), 8.32 (d, 2H), 7.90 (dd, IH), 7.74-7.68 (m, 2H), 7.49-7.41 (m, 2H), 7.40-7.36 (m, IH), 7.30 (d, IH), 7.22-7.12 (m, 6H), 7.08-6.95 (m, 3H), 6.95 (t, large J, 2H), 4.90-4.80 (m. 2H), 4.65 (t, IH), 3.60-3.47 (m, 2H), 1.50 (s, 6H). EXAMPLE 89 (ENANTIOMER-2)-4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{ 6-[N-(l- METH YL- 1 -(4-FLUOROPHEN YL))ETHYL-N- (BENZYLOXYC ARBONYL) AMINO] 3 -PYRIDYL J ETHYL } PYRIDINE Step 1-5 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(4-fluorophenyl))ethyl- N-(benzyloxycarbonyl)amino13-pyridyl Jethyl Jpyndine Following the procedures descnbed in Example 11, Step 1-5 but substituting (4-fluorophenyl)ethylamine for cumylamine, 3.4 g of racemic carbamate were obtained as a white foam. Step 6 (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(4- fluorophenyl))ethyl-N-(benzyloxycarbonyl)amιnol3-pyndyl Jethyl Jpyndme The carbamate from Step 5 above was resolved by HPLC (Preparative chiralpak AD, 30% z-PrOH/hexane, 65 m-Umin), to afford 1.9 g of the title compound as the slow elutmg enantiomer (39 mm). *H NMR (500 MHz, Acetone-d6) δ 8.52 (s, IH), 8.32 (d, 2H), 7.90 (dd, IH), 7.74-7.68 (m, 2H), 7 49-7.41 (m, 2H), 7.40-7.36 (m, IH), 7.30 (d, IH), 7.22-7.12 (m, 6H), 7.08-6.95 (m, 3H), 6.95 (t, large J, 2H), 4 90-4.80 (m, 2H), 4.65 (t, IH), 3.60-3.47 (m, 2H), 1.50 (s, 6H) EXAMPLE 90 (ENANTIOMER-l)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[N-(l- METHYL- 1 -(3-METHYLPHEN YL))ETHYL-N- (BENZYLOXYC ARBONYL)AMINO]3-PYRID YL } ETHYL } PYRIDINE Step 1-5 4- { 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{ 6-[N-( 1 -methyl- 1 -(3-methylphenyl))ethyl- N-(benzyloxycarbonyl)amιno13-pyndyl Jethyl Jpyndine Following the procedures descnbed in Example 11, Step 1-5 but substituting l-methyl-l-(3-tolyl)ethylamme for cumylamine, 700 mg of racemic carbamate were obtained as a white foam. Step 6 (Enantiomer- 1 )-4- { 2-[3 ,4-Bιs(dιfluoromethoxy)phenyl ]-2- { 6- [N-( 1 -methyl- 1 -(3- methylphenyl))ethyl-N-(benzyIoxycarbonyl)amιno]3-pyndyl Jethyl Jpyndme The carbamate from Step 5 above was resolved by HPLC (Preparative chiralpak AD, 70% /-PrOH/hexane, 60 mL/min), to afford 345 mg of the title compound as the fast eluting enantiomer (36 mm) iH NMR (400 MHz, Acetone-d6) δ 8 50 (d, IH), 8.32 (d, 2H), 7.90 (dd, IH), 7.50-7.40 (m, 4H), 7.39 (dd, IH), 7.29 (d, IH), 7.20-7.10 (m, 6H), 7.05 (d, IH), 7.0 (m, 2H), 6.95 (d, 2H), 4.85 (m, 2H), 4.65 (t, IH), 3 55 (m, 2H), 2.32 (s, 3H), 1.51 (s, 6H). EXAMPLE 91 (ENANTIOMER-2)-4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[N-(l- METHYL- 1 -(3-METHYLPHENYL))ETHYL-N- (BENZYLOXYCARBONYL)AMINO]3-PYRIDYL JETHYL} PYRIDINE Step 1-5 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(3-methylphenyl))ethyl- N-(benzvloxvcarbonyl)ammo13-pyπdyl Jethyl Jpyndine Following the procedures descnbed in Example 11, Step 1-5 but substituting 1 -methyl- l-(3-tolyl)ethylamιne for cumylamine, 700 mg of racemic carbamate were obtained as a white foam Step 6 (Enantιomer-2)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l -methyl- 1 -(3- methy]phenvl))ethyl-N-(benzyloxycarbonyl)amιno13-pyndyl Jethyl Jpyndme The carbamate from Step 5 above was resolved by HPLC (Preparative chiralpak AD, 70%> /-PrOH/hexane, 60 mL/min), to afford 325 mg of the title compound as the slow eluting enantiomer (44 mm). iH NMR (400 MHz, Acetone-d6) δ 8.50 (d, IH), 8.32 (d, 2H), 7.90 (dd, IH), 7 50-7.40 (m, 4H), 7.39 (dd, IH), 7 29 (d, IH), 7.20-7.10 (m, 6H), 7.05 (d, IH), 7.0 (m, 2H), 6.95 (d, 2H), 4.85 (m, 2H), 4 65 (t, IH), 3.55 (m. 2H), 2.32 (s, 3H), 1.51 (s, 6H) EXAMPLE 92 (ENANTIOMER-l)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[N-(l- METHYL- 1 -(3-BROMOPHENYL))ETHYL-N- (BENZYLOXYCARBONYL)AMINO]3-PYRIDYL} ETHYL J PYRIDINE Step 1-5 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(3-bromophenyl))ethyl- N-(benzyloxycarbonyl)ammo]3-pyndyl Jethyl Jpyndine Following the procedures descnbed in Example 11, Step 1-5 but substituting 1 -methyl- l-(3-bromophenyl)ethylamιne for cumylamine, the racemic carbamate was obtained as a foam. Step 6 (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(3- bromophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3-pyndyl Jethyl Jpyndine The carbamate from Step 5 above was resolved by HPLC (Preparative chiralpak AD, 30% /-PrOH/hexane, 70 mL/min, fast eluting enantiomer, retention time 11 minute on analytical HPLC: 1 mL/min, 30% /-PrOH/hexane) to afford 270 mg of the title compound. !H NMR (400 MHz, Acetone-d6) δ 8 54 (d, IH), 8.33 (dd, 2H), 7.93 (m, IH), 7.92 (d, IH), 7.70 (d, IH), 7.47 (s, IH), 7 45 (d, IH), 7.38 (td, 2H), 7.32- 7.20 (m, 6H), 7.15 (d, 2H), 6.99 (m, IH), 6.97 (t, IH), 6.96 (t, IH), 4 87 (dd, 2H), 4 66 (t, IH), 3.55 (m, 2H), 1.52 (s, 6H). EXAMPLE 93 (ENANTIOMER-2)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[N-(l- METHYL- 1 -(3-BROMOPHEN YL))ETHYL-N- (BENZYLOXYCARBONYL)AMINO]3-PYRIDYLJETHYLJPYRIDINE Step 1-5 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(3-bromophenyl))ethyl- N-(benzyloxycarbonyl)amino]3-pyndyl Jethyl Jpyndine Following the procedures described in Example 11, Step 1-5 but substituting 1 -methyl- l-(3-bromophenyl)ethylamιne for cumylamine, 700 mg of racemic carbamate were obtained as a foam. Step 6 (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(3- bromophenyl))ethyl-N-(benzyloxycarbonyl)amιno13-pyndyl Jethyl Jpyndine The carbamate from Step 5 above was resolved by HPLC (Preparative chiralpak AD, 30% /-PrOH/hexane, 70 mL/min, slow elutmg enantiomer, retention time 13 mmute on analytical HPLC: 1 mL/m , 30% /-PrOH/hexane) to afford 160 mg of the title compound. H NMR (400 MHz, Acetone-d6) δ 8.54 (d, IH), 8.33 (dd, 2H), 7.93 (m, IH), 7.92 (d, IH), 7.70 (d, IH), 7.47 (s. IH), 7.45 (d, IH), 7.38 (td, 2H), 7.32- 7.20 (m, 6H), 7.15 (d, 2H), 6.99 (m, IH), 6.97 (t, IH), 6.96 (t, IH), 4.87 (dd, 2H), 4.66 (t, IH), 3.55 (m, 2H), 1.52 (s, 6H). EXAMPLE 94 (ENANTIOMER- 1 )-4- { 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2- { 6-[N-( 1 - METHYL- 1 -(3-FLUOROPHENYL))ETHYL-N- (BENZYLOXYCARBONYL)AMINO]3-PYRIDYL}ETHYL}PYRIDINE Step 1-5 4-{2-[3.4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(3-fluorophenyl))ethyl- N-(benzvloxycarbonyl)ammol3-pyrιdyl Jethyl Jpyndine Following the procedures descnbed in Example 11, Step 1-5 but substituting 1 -methyl- l-(3-fluorophenyl)ethylamme for cumylamine, the racemic carbamate was obtained as a foam. Step 6 (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(3- The carbamate from Step 5 above was resolved by HPLC (Preparative chiralpak AD, 30% /-PrOH/hexane, 73 mL/mm), to afford 427 mg of the title compound as the fast eluting enantiomer (19 mm). H NMR (400 MHz, Acetone-d6) δ 8.53 (d, IH), 8.32 (d, 2H), 7.91 (dd, IH), 7.52-7.45 (m, 4H), 7.39-7.28 (m, 4H), 7.21-7.14 (m, 5H). 6.98-6.91 (m, 2H), 6 95 (t, 2H), 4.86 (s, 2H), 4.66 (t, IH), 3.59-3.4 (m, 2H), 1.51 (s, 6H). EXAMPLE 95 (ENANTIOMER-2)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{ 6-[N-(l- METHYL- 1 -(3-FLUOROPHENYL))ETHYL-N- (BENZYLOXYC ARBONYL) AMINO] 3-PYRID YL JETHYL } PYRIDINE Step 1-5 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(3-fluorophenyl))ethyl- N-(benzvloxycarbonyl)amιno13-pyndyl Jethyl Jpyndme Following the procedures described in Example 11, Step 1-5 but substituting l-methyl-l-(3-fluorophenyl)ethylamme for cumylamine, the racemic carbamate was obtained as a foam. Step 6 (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l-(3- fluorophenvl))ethyl-N-(benzyloxvcarbonvl)amιno]3-pyndyl Jethyl Jpyndine The carbamate from Step 5 above was resolved by HPLC (Preparative chiralpak AD, 30% /-PrOH/hexane, 73 mL/mm), to afford 200 mg of the title compound as the slow eluting enantiomer (29 mm). !H NMR (400 MHz, Acetone-d6) δ 8.53 (d, IH), 8.32 (d, 2H), 7.91 (dd, IH), 7.52-7.45 (m, 4H), 7.39-7.28 (m, 4H), 7.21-7 14 (m, 5H), 6.98-6 91 (m, 2H), 6.95 (t, 2H), 4.86 (s, 2H), 4.66 (t, IH), 3.59-3.4 (m, 2H), 1.51 (s, 6H) EXAMPLE 96 (ENANTIOMER-l)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{ 6-[N- ( 1 , l-DIMETHYL-2-(4-FLUOROPHENYL))ETHYL-N- (BENZYLOXYC ARBONYL) AMINO]3-PYRIDYL } ETHYL } PYRIDINE-N-OXIDE Step 1-6 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l,l-dιmethyl-2-(4- fluorophenyl))ethyl-N-(benzyloxycarbonvl)ammo13-pyndyl Jethyl Jpyndme-N-oxide Following the procedures descnbed in Example 11, Step 1-6 but substituting l,l-dιmethyl-2-(4-fluorophenyl)ethylamme for cumylamine, the racemic carbamate was obtained as a foam Step 7 (Enantiomer- 1)-4-{ 2-[3, 4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-( 1,1 -dιmethyl-2-(4- fluorophenyl))ethyl-N-(benzv]oxycarbonyl)amιno]3-pyrιdyl Jethyl Jpyπdine-N-oxide The carbamate from Step 6 above was resolved by HPLC (Preparative chiralpak AD, 23% / ' -PrOH/hexane, 60 mL/min), to afford 35 mg of the title compound as the fast eluting enantiomer with a retention time of 16 minutes on analytical HPLC (Chiralpak AD, 1 mL/mm, 23% /-PrOH/hexane). *H NMR (400 MHz, Acetone-d6) δ 8.33 (d, IH), 8.30 (dd, 2H), 7 62 (dd, IH), 7.38 (s, IH), 7.33-7.25 (m, 5H), 7.13 (m, 4H), 7.07 (dd, 2H), 6.96 (dt, 2H), 6.93 (t, IH), 6.92 (t, IH), 6.16 (d, IH), 5.03 (dd, 2H), 4.53 (t, IH), 3.43 (m, 2H), 3.32 (bis, 2H), 1.20 (brs, 6H) EXAMPLE 97 (ENANTIOMER-2)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[N- (l,l-DIMETHYL-2-(4-FLUOROPHENYL))ETHYL-N- (BENZYLOXYCARBONYL)AMINO]3-PYRIDYLJETHYL}PYRIDINE-N-OXIDE Step 1-6 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l,l-dιmethyl-2-(4- fluorophenyl))ethyl-N-(benzyloxycarbonvl)ammo]3-pyndyl Jethyl Jpyndine-N-oxide Following the procedures described in Example 11, Step 1-6 but substituting l,l-dιmethyl-2-(4-fluorophenyl)ethylamιne for cumylamine, the racemic carbamate was obtained as a foam Step 7 (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l,l-dιπιethyl-2-(4- fluorophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3-pyπdyl Jethyl Jpyndme-N-oxide The carbamate from Step 6 above was resolved by HPLC (Preparative chiralpak AD, 23% /-PrOH/hexane, 60 mL/min), to afford 11 mg of the title compound as the fast elut g enantiomer with a retention time of 19 minutes on analytical HPLC (Chiralpak AD, 1 mL/min, 23% /-PrOH/hexane). iH NMR (400 MHz, Acetone-d6) δ 8.33 (d, IH). 8.30 (dd, 2H), 7.62 (dd, IH), 7.38 (s, IH), 7.33-7.25 (m, 5H), 7 13 (m, 4H), 7.07 (dd, 2H), 6.96 (dt, 2H), 6.93 (t, IH), 6.92 (t, IH), 6.16 (d, IH), 5.03 (dd, 2H), 4.53 (t, IH), 3.43 (m, 2H), 3.32 (brs, 2H), 1.20 (brs, 6H). EXAMPLE 98 4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{ 6-[N-( 1 J-DIMETHYL^-^- FLUOROPHENY OETHYL-N- BENZYLOXYCARBONYL^MINO -PYRlDYL- N-OXIDE } ETHYL J PYRIDINE-N-OXIDE This pyndine bis-N-oxide (33 mg) was obtained as a side product of the oxidation of 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l,l-dιmethyl-2-(4- fluorophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3-pyndyl Jethyl Jpyndme. EXAMPLE 99 (ENANTIOMER-2)-4-{ 2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[N,N- DI(4-FLUOROBENZAMIDE)]3-PYR-DYL}ETHYL}PYRIDINE-N-OXIDE Following the procedures described in Example 46, Step 1-2 the title compound was obtained as a foam (164 mg). iH NMR (500 MHz, Acetone-d6) δ 8.26 (d, IH), 7.93-7.89 (m, 3H), 7.85-7.80 (m, 4H), 7.49 (d, IH), 7.38 (s, IH), 7.31 (dd, IH), 7.27 (d, IH), 7.22-7.16 (m, 4H), 7.13 (d, 2H), 6.95 (t, IH), 6.94 (t, IH), 4.57 (t, IH), 3.51-3.42 (m, 2H). EXAMPLE 100 4-{ 2-[3,4-BIS(DDFLUOROMETHOXY)PHENYL]-2-{ 6-[ 1 ,2,3,4- TETR AHYDROISOQUINOLINE] 3 -PYRIDYL } ETHYL } P YRIDINE-N-OXIDE Following the procedures described in Example 56 but substituting 1,2,3,4-tetrahydroisoquinoline at 100 °C for N-methylbenzylamme at 150 ° C, the title compound was obtained (117 mg, 53%). *H ΝMR (300 MHz, Acetone-d6) δ 8.10 (d, IH), 7.92 (d, 2H), 7.58 (dd, IH), 7.38 (s, IH), 7.32-7.10 (m, 8H), 6.96 (t, large J, IH), 6.91 (t, large J, IH). 6.77 (d, IH), 4.64 (s, 2H), 4.39 (t, IH), 3.80 (t, 2H), 3.42 (d, 2H), 2.90 (t, 2H). EXAMPLE 101 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(l-AMINOINDANE)3- P YRID YL]ETHYL } PYRIDINE-N-OXIDE Step l 4-{2-[3,4-Bis(difluoromethoxv)phenvll-2-r6-(l-aminomdane)3-pyndyl]ethyl Jpyndine Following the procedures descnbed in Example 1 but substituting (±)- 1-amιnomdane at 160 °C for benzylamine at 100 °C, 537 mg (76%) of the pyridine were obtained as an oil. Step 2 4-{2-r3,4-Bιs(dιfluoromethoxv)phenvl]-2-{6-[N-(l-mdanyl) tπfluoroacetamιde13- pyπdyl Jethyl Jpyndine The procedure for the protection of the amme descnbed in Example 5, Step 1 was applied using the product of Step 1 above as starting matenal The tnfluoroacetamide was obtained as an oil (122 mg, 65%). Step 3 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[/V-(l-ιndanyl) tπfluoroacetamιde]3- pyridyl Jethyl Jpyπdine-Ν-oxide The procedure for the oxidation of the pyndine described in Example 5, Step 2 was applied using the product of Step 2 above as staπ '. « material The Ν- oxide was obtained as an oil (117 mg, 92%). Step 4 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(l-amιnoιndane)3- pyπdyllethyl Jpyndine-Ν-oxide The procedure for the deprotection of the amine descnbed in Example 5, Step 3 was applied using the product of Step 3 above as starting material. The title compound was obtained as an oil (104 mg, 100%) l H ΝMR (500 MHz, Acetone-d6) δ 7 98 (m, 3H), 7 44 (dd, IH), 7.38 (s, IH), 7.32 (d, IH), 7.26 (d, IH), 7.24-7 07 (m, 5H), 6.98 (t, IH), 6.94 (t, IH), 6.56 (d, IH), 6.05 (d, IH), 5.52 (q, IH), 4.37 (t, IH), 3.41 (m, 2H), 2.96-2 88 (m, IH), 2.84-2.76 (m, IH), 2.56-2.48 (m, IH), 1 84-1.75 (m, IH) EXAMPLE 102 (DIASTEREOMER-l)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[(R)- 1-AMINO--NDANE13-PYR-DYLJETHYLJPYRIDINE-N-OX-DE Step 1 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[(R)-l-ammomdane]3- pyπdyl Jethyl Jpyndine Following the procedures descnbed in Example 1 but substituting (R)- 1-ammoιndane at 160 °C for benzylamine at 100 °C, 6.6 g (84%) of pyridine were obtained as an oil Step 2 (Diastereomer-l)-4-{ 2-r3,4-Bis(difluoromethoxy)phenyll-2-{ 6-[(R)-l-ammoindane13- pyridyl Jethyl Jpyndme The optically pure 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[(R)-l- amιnoιndane]3-pyndyl Jethyl Jpyπdine was obtained by resolution of the racemic product of Step 1 above on chiral column: preparative chiralpak AD, 35% EtOH/hexane, 50 mL/mm. 1.65 g of the resolved compound were obtained as the fast elutmg enantiomer (34 minutes) Step 3 (Dιastereomer-l)-4-{2-13,4-Bιs(dιfluoromethoxv)phenyl]-2-{6-[N-((R)-l-ιndanyl) trιfluoroacetamιdel3-pyπdyl Jethyl Jpyndine The procedure for the protection of the amine descnbed in Example 5, Step 1 was applied using the product of Step 2 above as starting material The tnfluoroacetamide was obtained as an oil (555 mg, 86%) Step 4 (Dιastereomer-l)-4-{ 2-13,4-Bιs(dιfluoromethoxv)phenvl1-2-16-rN-((R)-l-ιndanyl) tnfluoroacetamιde]3-pyndyl Jethyl Jpyndme-Ν-oxide The procedure for the oxidation of the pyndine descnbed in Example 5, Step 2 was applied using the product of Step 3 above as starting matenal. The Ν- oxide was obtained as an oil (510 mg, 89%) Step 5 (Dιastereomer-l)-4-{ 2-13,4-Bιs(dιfluoromethoxy)phenyl1-2-{ 6-[(R)-l-amιnoιndane]3- pyπdyl Jethyl Jpyndme-N-oxide The procedure for the deprotection of the amme described in Example 5, Step 3 was applied using the product of Step 4 above as starting material The title compound was obtained as an amorphous solid (454 mg, 100%) l ll NMR (500 MHz, Acetone-d6) δ 7 98 (m, 3H), 7 44 (dd, IH), 7.38 (s, IH), 7 32 (d, IH), 7.26 (d, IH), 7.24-7.07 (m, 5H), 6.98 (t, IH), 6.94 (t, IH), 6.56 (d, IH), 6 05 (d, IH), 5.52 (q, IH), 4 37 (t, IH), 3 41 (m, 2H), 2 96-2 88 (m, IH), 2.84-2 76 (m, IH), 2 56-2.48 (m, IH), 1.84-1.75 (m, IH) EXAMPLE 103 (DIASTEREOMER-2)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6-[(R)- 1-AMINOINDANEJ3-PYRIDYLJETHYLJPYR1DINE-N-OX-DE Step 1 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[(R)-l-ammoιndane]3- pyndyl Jethyl Jpyndine Following the procedures descnbed in Example 1 but substituting (R)- 1-amιnoιndane at 160 °C for benzylamine at 100 °C, 6 6 g (84%) of the pyridine were obtained as an oil Step 2 (Dιastereomer-2)-4-| 2-J3,4-Bιs(dιfluoromethoxy)phenyl1-2-{ 6-[(R)-l-ammoιndane]3- pyndyl Jethyl Jpyndine The optically pure 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[(R)-l- amιnomdane]3-pyndyl Jethyl Jpyπdine was obtained by resolution of the racemic product of Step 1 above on chiral column: preparative chiralpak AD, 35% EtOH/hexane, 50 mL/mm 1 66 g of the resolved compound were obtained as the slow eluting enantiomer (47 minutes) Step 3 (Dιastereomer-2)-4-{2-r3,4-Bιs(dιfluoromethoxv)phenvll-2-{6-lN-((R)-l-ιndanyl) trιfluoroacetamιde]3-pyndyl Jethyl Jpyndine The procedure for the protection of the amine descnbed in Example 5, Step 1 was applied using the product of Step 2 above as starting matenal. The tnfluoroacetamide was obtained as an oil (463 mg, 76%). Step 4 (Dιastereomer-2)-4-{ 2-13,4-Bιs(difluoromethoxy)phenyll-2-{ 6-JN-((R)-l-ιndanyl) tnfluoroacetamιdel3-pyridyl Jethyl Jpyndine-Ν-oxide The procedure for the oxidation of the pyπdme descnbed in Example 5, Step 2 was applied using the product of Step 3 above as starting material. The Ν- oxide was obtained as an oil (454 mg, 95%). Step 5 (Dιastereomer-2)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{ 6-J(E)-l-amιnomdanel3- pyndyl Jethyl Jpyndine-Ν-oxide The procedure for the deprotection of the amme descnbed in Example 5, Step 3 was applied using the product of Step 4 above as starting material. The title compound was obtained as an amorphous solid (413 mg, 100%). !H ΝMR (500 MHz, Acetone-d6) δ 7.98 (m, 3H), 7.44 (dd, IH), 7.38 (s, IH), 7.32 (d, IH), 7.26 (d, IH), 7.24-7.07 (m, 5H), 6.98 (t, IH), 6.94 (t, IH), 6.56 (d, IH), 6.05 (d, IH), 5.52 (q, IH), 4.37 (t, IH), 3.41 (m, 2H), 2.96-2.88 (m, IH), 2.84-2.76 (m, IH), 2.56-2.48 (m, IH), 1.84-1.75 (m, IH). EXAMPLE 104 (DIASTEREOMER-3)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHEΝYL]-2-{6-[(S)- l-AMINOINDANE]3-PYRIDYL JETHYL} PYRIDINE-N-OXIDE Step 1 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[(S)-l-amιnomdane]3- pyndyl Jethyl Jpyndme Following the procedures described in Example 1 but substituting (S)- 1-amιnoιndane at 160 ° C for benzylamine at 100 ° C. 2.0 g (67%) of the pyridine were obtained as an oil. Step 2 (Dιastereomer-3)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyll-2-{6-r(5)-l-amιnoιndanel3- pyndyl Jethyl Jpyndine The optically pure 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[(S)-l- ammomdane]3-pyπdyl Jethyl Jpyndme was obtained by resolution of the racemic product of Step 1 above on chiral column: preparative chiralpak AD, 35% EtOH/hexane, 50 mL/min. 500 mg of the resolved compound were obtained as the fast eluting enantiomer (37 minutes). Step 3 (Dιastereomer-3)-4-{ 2-13,4-Bιs(dιfluoromethoxy)phenyll-2-{6-[N-((S)-l-ιndanyl) tnfluoroacetamιde]3-pyπdyl Jethyl Jpyndme The procedure for the protection of the amine descnbed in Example 5, Step 1 was applied using the product of Step 2 above as starting matenal. The tnfluoroacetamide was obtained as an oil (447 mg, 75%) Step 4 (Dιastereomer-3 -4-{ 2-r3,4-Bιs(dιfluoromethoxv)phenvl1-2-{6-lN-((5)-l-ιndanyl) trιfluoroacetamιde]3-pyndyl Jethyl Jpyndine-Ν-oxide The procedure for the oxidation of the pyndine descnbed in Example 5, Step 2 was applied using the product of Step 3 above as starting matenal The Ν- oxide was obtained as an amorphous solid (417 mg. 91%). Step 5 (Dιastereomer-3)-4-{2-J3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[(S)-l-amιnoιndane]3- pyndyl Jethyl Jpyndine-Ν-oxide The procedure for the deprotection of the amine descnbed in Example 5, Step 3 was applied using the product of Step 4 above as starting material. The title compound was obtained as an amorphous solid (371 mg, 100%). iH ΝMR (500 MHz, Acetone-d6) δ 7.98 (m, 3H), 7.44 (dd, IH), 7 38 (s, IH), 7.32 (d, IH), 7 26 (d, IH), 7.24-7.07 (m, 5H), 6.98 (t, IH), 6.94 (t, IH), 6.56 (d, IH), 6.05 (d, IH), 5.52 (q, IH), 4.37 (t, IH), 3.41 (m, 2H), 2.96-2.88 (m, IH), 2.84-2.76 ( , IH), 2.56-2 48 (m, IH), 1.84-1.75 (m, IH). EXAMPLE 105 (DIASTEREOMER-4)-4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-{6- [(5)- 1 - AMINOIND ANE] 3 -PYRIDYL } ETHYL } PYRIDINE-N-OXIDE Step 1 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[(S)-l-aminoindane]3- pyridyl Jethyl } pyridine Following the procedures described in Example 1 but substituting (S)- 1-aminoindane at 160 °C for benzylamine at 100 °C, 2.0 g (67%) of the pyridine were obtained as an oil. Step 2 (Diastereomer-4)-4-{2-r3.4-Bis(difluoromethoxy)phenyl1-2-{ 6-r(S)-l-aminoindane]3- pyridyl Jethyl J pyridine The optically pure 4-{2-[3,4-bis(difluoromethoxy)phenyl]-2-{6-[(S)-l- aminoindane]3-pyridyl Jethyl Jpyridine was obtained by resolution of the racemic product of Step 1 above on chiral column: preparative chiralpak AD, 35% EtOH hexane, 50 mUmin. 502 mg of the resolved compound were obtained as the fast eluting enantiomer (47 minutes). Step 3 (Diastereomer-4)-4-{ 2-13,4-Bis(difluoromethoxy)phenyl1-2-{ 6-rN-((S)-l-indanyl) trifluoroacetamide]3-pyridyl Jethyl Jpyridine The procedure for the protection of the amine described in Example 5, Step 1 was applied using the product of Step 2 above as starting material. The trifluoroacetamide was obtained as an oil (461 mg, 78%). Step 4 (Diastereomer-4)-4-{2-13,4-Bis(difluoromethoxy)phenvll-2-{6-JN-((S)-l-indanyl) trifluoroacetamide13-pyridyl Jethyl Jpyridine-Ν-oxide The procedure for the oxidation of the pyridine described in Example 5, Step 2 was applied using the product of Step 3 above as starting material. The Ν- oxide was obtained as an amorphous solid (435 mg, 92%). Step 5 (Dιastereomer-4)-4-{ 2-r3,4-Bιs(dιfluoromethoxy)phenvl1-2-{6-r(S)-l-ammoιndane]3- pyndyl Jethyl Jpyndine-N-oxide The procedure for the deprotection of the amme described in Example 5, Step 3 was applied using the product of Step 4 above as starting matenal. The title compound was obtained as an amorphous solid (395 mg, 100%). *H NMR (500 MHz, Acetone-d6) δ 7.98 (m, 3H), 7.44 (dd, IH), 7.38 (s, IH), 7 32 (d, IH), 7.26 (d, IH), 7.24-7 07 (m, 5H), 6.98 (t, IH), 6 94 (t, IH), 6.56 (d, IH), 6.05 (d, IH), 5.52 (q, IH), 4.37 (t, IH), 3 41 (m, 2H), 2.96-2 88 (m, IH), 2.84-2.76 ( , IH), 2.56-2.48 (m, IH), 1.84-1.75 (m, IH). EXAMPLE 106 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-[6-(2- PHENYLPYROLIDINE)3-PYRID YL]ETHYL } PYR-DINE-N-OXIDE Step 1 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(2-phenylpyrolιdme)3- pyndyl] ethyl Jpyndine Following the procedures descnbed in Example 1 but substituting 2- phenylpyrohdme at 160 °C for benzylamine at 100 °C, 484 mg (70%) of the pyridine were obtained as an oil. Step 2 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(2-phenylpyrohdme)3- pyndyflethyl Jpyndme-N-oxide To a solution of pyndine from Step 1 above (480 mg, 0.89 mmol) in a mixture of 10.0 mL of CH2CI2 and 1.0 mL MeOH, was added 332 mg (0.54 mmol) of 80% MMPP. The reaction was stirred for 24 h at room temperature and was punfied directly by flash chromatography on silica gel (Gradient 100% acetone + 3% Et3N to 30% EtOH/acetone + 3% E-3N) to afford 210 mg (43%) of the title compound. IH NMR (500 MHz, Acetone-d6) δ 8.35 (d, 2H), 8.00 (t, IH), 7.43- 7.31 (m, 2H), 7.30-7.11 (m, 9H), 6 94 (td, IH), 6 90 (td, IH), 6.20 (dd, IH), 5.00- 4.92 (m, IH), 4.40-4.32 (m, IH), 3.84-3.77 (m, IH), 3 64-3.55 (m, IH), 3.40-3.35 (m, 2H), 2.43-2.32 (m, IH), 2.00-1.80 (m, 3H) EXAMPLE 107 4-{2-[3,4-BIS(D-FLUOROMETHOXY)PHENYL]-2-{6-[l-(4- FLUOROPHENYL)CYCLOPENTYLAMINO]3-PYRIDYL}ETHYL}PYRIDINE-N- OXIDE Following the procedures described in Example 11 but substituting 1- (4-fluorophenyl)cyclopentylamιno] for cumylamine, the title compound was obtained (464 mg). iH NMR (500 MHz, Acetone-d6) δ 7.92 (d, 2H), 7.84 (d, IH), 7.50- 7 45 (m, 2H), 7.32-7.28 (m, 2H), 7.25-7.19 (m, 2H), 7.12 (d, 2H), 6.99 (t, 2H), 6.93 (t, IH), 6.90 (t, IH), 6.22 (d, IH), 6.09 (s, IH), 4.24 (t, IH), 3.40-3.27 (m, 2H), 2.37- 2.28 (m, 2H), 2.10-2.00 (m, 2H), 1.90-1.72 (m, 4H). EXAMPLE 108 4-{2-[3,4-BIS(DlFLUOROMETHOXY)PHENYL]-2-[6-(2-AMINOINDANE)3- PYR-DYLJETHYLJ PYRIDINE-N-OXIDE Step 1 4- { 2-13,4-Bιs(dιfluoromethoxy)phenyn-2-[6-(2-amιnoιndane)3-pyπdyl]ethyl Jpyndine Following the procedures descnbed in Example 1 but substituting (±)- 2-amιnoιndane at 160 °C for benzylamine at 100 ° C. 1.68 g (56%) of the pyridine were obtained as an oil. Step 2 4- , 2-[3,4-Bιs(dιfluoromethoxy)phenyll-2-{ 6-lN-(2-ιndanyl) tnfluoroacetamιdel3- pyridyl Jethyl Jpyndine The procedure for the protection of the amine described in Example 5, Step 1 was applied using the product of Step 1 above as starting matenal. The tnfluoroacetamide was obtained as an oil (235 mg, 100%). Step 3 4-{ 2-13,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-rN-(2-ιndanyl) tnfluoroacetamιdeJ3- pyndyl Jethyl Jpyndine-Ν-oxide The procedure for the oxidation of the pyndine descnbed in Example 5, Step 2 was applied using the product of Step 2 above as starting matenal. The N- oxide was obtained as a foam (226 mg, 93%). Step 4 4-{2-[3,4-Bιs(difluoromethoxy)phenyl]-2-[6-(2-amιnomdane)3- pyπdyllethyl Jpyndine-N-oxide The procedure for the deprotection of the amme descnbed in Example 5, Step 3 was applied using the product of Step 3 above as starting matenal. The title compound was obtained as a foam (195 mg, 100%). iH NMR (500 MHz, Acetone-d6) δ 7.99 (m, 3H), 7.42 (dd, IH), 7.36 (s, IH), 7.30 (dd, IH), 7.25 (d, IH), 7.20-7.15 (m, 4H), 7.13-7 08 (m, 2H), 6.96 (t, IH), 6.93 (t, IH), 6.46 (d, IH), 6.00 (d, IH), 4.70-4.60 (m, IH), 4.34 (t, IH), 3.40 (d, 2H), 3 29 (dd, 2H), 2.80 (dd, 2H). PREPARATION OF INTERMEDIATES INTERMEDIATE 1 [3,4-BIS(DIFLUOROMETHOXY)PHENYL]-(6-BROMO-3- PYRIDYL)METHANONE Step 1 J3,4-Bιs(dιfluoromethoxy)phenyl1-(6-bromo-3-pyndyl)methanol To a -78 ° C suspension of 2,5-dibromopyridine (1 1.4 g, 48.0 mmol) in 300 mL of Et2θ, was added 40.0 mL (48.0 mmol) of a 1.2 N solution of .j-butylhthium in hexane over 10 minutes. The orange mixture was stiπed (Mechanical stirrer) 10 minutes at -78 °C followed by the addition over 5 minutes of a precooled solution of bιs(dιfluoromethoxy)benzaldehyde (9 6 g, 40.0 mmol) in 60 mL of Et2θ This red solution was stirred 1 h at -78 °C and slowly poured into a saturated aqueous solution of NH4CI. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with bnne, dry over MgSO4 and concentrated under reduced pressure. The residue was punfied by chromatography on silica gel (Gradient 20% to 40% ethyl acetate/hexane) to afford 8.3 g (53%) of alcohol Step 2 13,4-Bιs(dιfluoromethoxy)phenyl1-(6-bromo-3-pyrιdyl)methanone To a solution of alcohol (3.96 g, 10.0 mmol) from Step 1 above in 60 mL of CH2CI2, was added 8.1 g (93.0 mmol) of Mnθ2- The resulting mixture was stiπed 20 h at room temperature and filtered on ce te. the volatile were removed under reduced pressure to afford 3.48 g (88%) of ketone. l H NMR (500 MHz, Acetone-d6) δ 8.72 (d, IH), 8.10 (dd, IH), 7.85- 7.78 (m, 3H), 7 55 (d, IH), 7.20 (t, IH), 7.12 (t, IH). INTERMEDIATE 2 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-(6-BROMO-3- PYRID YL)ETHYL J PYRIDINE Step 1 r3,4-Bιs(dιfluoromethoxy)phenvl]-(6-bromo-3-pyndyl)chloromethane To a solution [3,4-Bιs(dιfluoromethoxy)phenyl]-(6-bromo-3- pyπdyl)methanol (15.8 g,40.0 mmol) in 400 mL of CH2CI2, was added 3.8 mL (52.0 mmol) of SOCI2. The solution was stiπed 45 minutes at room temperature and poured into a saturated aqueous solution of NaHCO3 The aqueous layer was extracted with CH2CI2 and the combined organic layers were dry over MgSO4 and concentrated under reduced pressure. The crude chloπde was used directly for the next step without any punfication. Step 2 4-{ l-Carbethoxy-2-[3,4-bιs(dιfluoromethoxy)phenyl]-2-(6-bromo-3- pyndyl .ethyl Jpyndine To a 0 °C solution of ethyl 4-pyridyl acetate (19.8 g, 120 mmol) in 500 mL of THF, was added 21 0 mL (120 mmol) of HMPA and 240 mL (120 mmol) of a 0.5 M solution KHMDS in toluene. The resulting mixture was stirred 15 minutes at room temperature followed by the addition over 10 minutes of a solution of the crude chloπde from Step 1 above in 100 mL of THF. The reaction was stiπed 1 h at room temperature, poured into a saturated aqueous solution of NH4CI and the pH was adjusted to 7 with 1 N HCl. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with bnne, dry over MgSO4 and concentrated under reduced pressure. The residue was used directly for the next step without any purification Step 3 4-{ 2-[3,4-Bιs(dιfluoromethoxv)phenyl1-2-(6-bromo-3-pyπdyl)ethyl Jpyndine To a solution of crude ester from Step 2 above in a mixture of 540 mL of THF, 180 mL of MeOH and 180 mL of water, was added 180 mL of a 2 N solution of LiOH. The solution was stiπed 1.5 h at 65 °C, cooled down to room temperature and 360 mL of 1 N HCl solution were added. The mixture was rotovaped down, the residue was diluted in ethyl acetate and the organic phases was washed with brine, dry over MgSO4 and concentrated under reduced pressure to afford 18.2 g (97%, 3 steps) of pure bromopyndine. !H NMR (500 MHz. Acetone-d6) δ 8.40 (m, 3H), 7.78 (dd, IH), 7.50 (d, IH), 7.43 (s, IH), 7.36 (dd, IH), 7 28 (d, IH), 7.20 (m, 2H), 6.95 (t, IH), 6.94 (t, IH), 4.65 (t, IH), 3.58-3.48 (m, 2H) INTERMEDIATE 3 4-{2-[3,4-BIS(DIFLUOROMETHOXY)PHENYL]-2-(6-BROMO-3- P YRID YL)ETHYL } PYRIDINE To a solution of intermediate 2 (2.0 g, 4.2 mmol) in a mixture of 30 mL of CH2CI2 and 3 mL of MeOH was added 1.55 g (2.5 mmol) of 80% MMPP. The reaction was stirred at room temperature for 20 h and purified directly by chromatography on silica gel (Gradient 3% Et3N/ethyl acetate to 30% EtOH/ethyl acetate + 3% Et3N to 40% EtOH/ethyl acetate + 3% Et3N) to afford 1.91 g (93%) of desired pyπdine-N-oxide. !H NMR (500 MHz, Acetone-d6) δ 8.38 (d, IH), 7.95 (d, 2H), 7.77 (dd, IH), 7.51 (d, IH), 7.41 (s, IH), 7.35 (dd, IH), 7.29 (d, IH), 7.19 (d, 2H), 6.96 (t, IH), 6.94 (t, IH), 4.60 (t, IH), 3.57-3 47 (m, 2H).

Claims: WHAT IS CLAIMED IS : 1. A compound represented by formula I I or a pharmaceutically acceptable salt or hydrate thereof wherein Y represents N or N-oxide, R and R^ are independently selected from: H, Cι_6alkyl and haloCi-6 alkyl, R3 and R4 are independently selected from H and Ci-βalkyl, or R- and R^ attached to the same carbon atom are taken together and represent a carbonyl oxygen atom, or R3 and R4 attached to different carbon atoms considered in combination with the carbon atoms to which they are attached along with any intervening atoms and represent a saturated 5, 6 or 7 membered carbocychc ring, R5 IS present or absent; when present, R~ > represents a member selected from the group consisting of: H, Cι_6alkyl, C(O)Cι_6alkyl, C(O)Arl, CO 2 Ci-6alkyl, CO 2 Arl, or an oxide oxygen atom, the alkyl portions of which are optionally substituted with 1-3 halo, hydroxy, C1-.4 alkyl or with one aryl group selected from phenyl, thienyl, thiazolyl, pyπdyl and naphthyl; or R^ IS taken in combination with one R^ group that is present, and represents along with the R3 group and any inteivening atoms a 5-6 membered heterocyclic nng, or R5 IS taken with a substituent on Ar* and represents a 5-6 membered heterocyclic ring fused to Ar^ ; when R5 IS absent, the dotted line represents a bond and the carbon atom to which it is attached does not contain an R^ group, R6 and R7 are independently selected from the group consisting of. H, halo, Cι_6alkyl, haloCi-6alkyl and CN, n represents an integer of from 0-6; each Arl 1S independently selected from the group consisting of (a) thienyl, (b) thiazolyl, (c) pyridyl, (d) phenyl and (e) naphthyl, each Arl t> eιn g optionally substituted with 1-3 members selected from the group consisting of. (1) halo, (2) Ci-6alkoxy, (3) C 1-7 alkylthio, (4) CN, (5) Ci- 6 alkyl, (6) Ci-βhydroxyalkyl, (7) -CO H, -CO2Ci-6alkyl, (8) NH(SO2Me), N(SO2Me)2, (9) SO2Me, (10) NO2, (11) Cι_6alkenyl, (12) halo Ci-6 alkyl, and (13) NH 2 , and when Ar represents a phenyl or naphthyl group with two or three substituents, two such substituents may be considered in combination and represent a 5 or 6 membered fused lactone nng. 2 A compound in accordance with claim 1 wherein RI and R^ are C ι_6 alkyl or haloCi-βalkyl 3. A compound in accordance with claim 2 wherein R* and R^ are selected from the group consisting of CH3, CH2F, CHF2 and CF3. 4. A compound in accordance with claim 3 wherein RI and R^ are CHF2. 5. A compound in accordance with claim 1 wherein n is selected from 0, 1, 2 and 3. 6. A compound in accordance with claim 5 wherein n is selected from 0 and 1. 7. A compound in accordance with claim 1 wherein Ar^ is selected from phenyl and naphthyl. 8. A compound in accordance with claim 7 wherein Ar^ is phenyl. 9. A compound in accordance with claim 1 wherein R-> and R^ are H or methyl. 10. A compound in accordance with claim 9 wherein R^ and R^ are H. 11. A compound in accordance with claim 9 wherein n equals 1 and R 3 and R 4 are CH3. 12. A compound in accordance with claim 1 wherein RI and R^ are Ci-βalkyl or haloCi_6alkyl; Ar^ 1S phenyl or naphthyl, R3 and R 4 are H and methyl; R5 is present and represents a member selected from the group consisting of: H, Ci-6alkyl, C(O)Ci-6alkyl or CO2C1-.5 alkyl, the alkyl portions of which are optionally substituted with 1-3 halo, hydroxy, C1 -4 alkyl groups or with one phenyl, thienyl, thiazolyl, pyridyl or naphthyl group; R6 and R7 represent H or Cι_6alkyl; Y is in the 4 position relative to the point of attachment to the ethylene moiety; and the N shown in the pyndyl nng is in the 3 position relative to the point of attachment to the ethylene moiety. 13 A compound in accordance with claim 1 wherein R 1 and R 2 are CHF2, and n is 0, 1 or 2. 14. A compound in accordance with claim 13 wherein- R 1 and R 2 are CHF2; R 3 and R 4 are H and Arl ]S phenyl. 15 A compound selected from the group consisting of: 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(benzylammo)3- pyndyl]ethyl Jpyndme, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(5)-(l- phenylethylamιno)3-pyndyl]ethyl Jpyndme, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(E)-(l- phenylethylamιno)3-pyπdyl]ethyl Jpyπdine, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-(4- fluorophenyl)ethylamιno]3-pyπdyl Jethyl Jpyndine, 4- { 2- [3 ,4-Bιs(dιfluoromethoxy)phenyl] -2- { 6-[ 1 -(4- fluorophenyl)ethylamιno]3-pyπdyl Jethyl Jpyndme-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(benzylamιno)3- pyπdyl]ethyl Jpyndine-N-oxide, 4-{ 2-[3.4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(5)-(l- phenylethylammo)3-pyndyl]ethyl }pyπdιne-N-oxιde, 4-{ 2-[3.4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(R)-(l- phenylethylamιno)3-pyπdyl]ethyl}pyπdιne-N-oxιde, 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(2-phenylethylamιno)3- pyπdyl]ethyl Jpyπdine-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[2-(2- pyndyl)ethylammo]3-pyπdyl Jethyl Jpyndme-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(l-methyl-l- phenylethylammo)3-pyπdyl]ethyl}pyndιne-N-oxιde, (Enantiomer- 1)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(l- methyl-l-phenylethylammo)3-pyndyl]ethylJpyπdιne-N-oxιde, (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(l- methyl- l-phenylethylammo)3-pyπdyl]ethyl Jpyndme-N-oxide, (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(l- methyl-l-phenylethylamιno)3-pyndyl-N-oxιde]ethyl Jpyπdιne-N-oxιde, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[(2- pyndyl)methylammo]3-pyπdyl Jethyl Jpyndine-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[(2-pyπdyl-N- oxιde)methylamιno]3-pyndyl Jethyl Jpyndine-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(R)-(l- phenylpropylamιno)3-pyπdyl]ethylJpyndme-N-oxιde, (Enantιomer-l)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(l- methyl- l-phenylethylamιno.3-pyndyl]ethyl Jpyndine, (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(l- methyl-l-phenylethylammo)3-pyndyl]ethyl Jpyπdine, (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(l- methyl-l-phenylethylamιno)3-pyπdyl-N-oxιde]ethyl Jpyndine, (Enantiomer- 1)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{ 6-[ 1- methyl- 1 -(4-fluorophenyl )ethylammo]3-pyndyl Jethyl Jpyndine-N-oxide, (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l- methyl-l-(4-tolyl)ethylamιno]3-pyndyl Jethyl Jpyπdine-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(4- benzyloxyphenyl)ethylamιno]3-pyπdyl Jethyl Jpyndme-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{ 6-[l-methyl-l-(4- hydroxyphenyl)ethylammo]3-pyndyl Jethyl Jpyndme-N-oxide, (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l- methyl-l-(3-tolyl)ethylammo]3-pyπdyl Jethyl Jpyndme-N-oxide, (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l- methyl-l-(3-fluorophenyl)ethylamιno]3-pyπdyl Jethyl Jpyndme-N-oxide, (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l- methyl-l-(3-bromophenyl)ethylammo]3-pyndyl Jethyl Jpyndine-N-oxide, 4- { 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- { 6-[ 1 -methyl- 1-(2- pyπdyl)ethylammo]3-pyπdyl Jethyl Jpyndine-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(2-pyπdyl- N-oxιde)ethylamιno]3-pyndyl Jethyl Jpyndme-N-oxide, (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l- methyl- l-(4-chlorophenyl)ethylammo]3-pyπdyl Jethyl Jpyndine-N-oxide, (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l- methyl-l-(4-chlorophenyl)ethylammo]3-pyndyl Jethyl Jpyndine-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(2- tolyl)ethylamιno]3-pyπdyl Jethyl Jpyndme-N-oxide, (Enantιomer-l)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l- methyl-l-(4-methylsulfonylphenyl)ethylamιno]3-pyndyl Jethyl Jpyπdine-N-oxide, 4-{2-[3 . 4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(4- tnfluoromethylphenyl)ethylammo]3-pyπdyl Jethyl Jpyndme-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(3,4- dιfluorophenyl)ethylamιno]3-pyπdyl Jethyl Jpyndine-N-oxide, 4- { 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- { 6-[ 1 , 1 -dιmethyl-2-(4- fluorophenyl)ethylamιno]3-pyπdyl Jethyl Jpyπdine-N-oxide, 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[2-(4- fluorophenyl)ethylammo]3-pyndyl Jethyl Jpyndine-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(3,5- dιfluorophenyl)ethylamιno]3-pyπdyl Jethyl Jpyndine-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(2,4- dιfluorophenyl)ethylamιno]3-pyndyl Jethyl Jpyndine-N-oxide, (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(4- fluorobenzylamme)3-pyπdyl]ethyl Jpyndine-N-oxide, Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(4- fluorobenzylamme)3-pyπdyl]ethyl Jpyndme-N-oxide, (Enantiomer-l)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[l- methyl-l-(4-ethylphenyl)ethylamιno]3-pyndyl Jethyl Jpyπdme-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(2,4- dιfluorobenzylamme)3-pyπdyl]ethyl }pyndιne-N-oxιde, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[4-fluorophenylamιdo]3- pyndyl Jethyl Jpyπdine, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[4-fluorophenylamιdo]3- pyndyl Jethyl Jpyπdine-N-oxide, (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[4- fluorophenylamιdo]3-pyπdyl Jethyl Jpyndme-N-oxide, (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(l- methyl- l-thιazolylethylamιno)3-pyπdyl]ethyl Jpyndme-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[l-methyl-l-(4- dιfluoromethoxyphenyl)ethylammo]3-pyndyl Jethyl Jpyndine-N-oxide, (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(l- methyl-l-phenylethylamιno)3-pyrιdyl]ethyl }pyndιne-N-oxιde hydromethanesulfonate, 4- { 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- { 6-[ 1 -ethyl- 1-(4- fluorophenyl)propylamιno]3-pyndyl Jethyl Jpyndine-N-oxide, (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[4- methylphenylamιdo]3-pyndyl Jethyl Jpyndme-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[2-methyl-2-(4- fluorophenyl)propylamιno]3-pyndyl Jethyl Jpyndine-N-oxide, (Enantiomer- 1 )-4- { 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- { 6-[ 1 , 1 - dimethyl-2-(4-fluorophenyl)ethylammo]3-pyndyl Jethyl Jpyπdine-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-methyl-N- benzylamιno)3-pyπdyl]ethyl Jpyndine, 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N,N-dιbenzylammo)3- pyπdyl]ethyl Jpyndine, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-methyl-N- benzylammo)3-pyπdyl]ethyl}pyndme-N-oxιde, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-methyl-N- benzylamιno)3-pyπdyl]ethyl }pyπdιne-N-oxιde hydrochlonde, 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-methyl-N-2- phenylethylamιno)3-pyndyl]ethyl Jpyndme-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-ethyl-N- benzylamιno)3-pyndyl]ethyl }pyndιne-N-oxιde, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-.-propyl-N- benzylamιno)3-pyπdyl]ethyl}pyrιdιne-N-oxιde, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-tert-butyl-N- benzylammo)3-pyπdyl]ethyl Jpyndme-N-oxide, 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N-4- chlorobenzylamιno)3-pyndyl]ethyl }pyπdιne-N-oxιde, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N-3- methoxybenzylammo)3-pyndyl]ethyl }pyπdme-N-oxιde, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-[N-methyl-N-(3- pyndyl)methylamιno]3-pyπdyl Jethyl Jpyndine-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N-2- methylbenzylamιno)3-pyπdyl]ethyl }pyndιne-N-oxιde, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-[N-methyl-N-(2- naphthyl)methylammo]3-pyπdyl Jethyl Jpyndine-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-2-hydroxyethyl-N- benzylamιno)3-pyπdyl]ethyl Jpyπdιne-N-oxιde, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N-4- methoxyphenylammo)3-pyπdyl]ethyl Jpyndine, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N-4- methoxyphenylamιno)3-pyπdyl]ethyl Jpyndme-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N-(5)-l- phenylethylamιno)3-pyπdyl]ethyl Jpyndine, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N-(S)-l- phenylethylamιno)3-pyπdyl]ethyl }pyndιne-N-oxιde, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N-(R)-l- phenylethylamιno)3-pyndyl]ethyl Jpyndme-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-methyl-N- phenylamιno)3-pyπdyl]ethyl}pyπdιne-N-oxιde, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-hydroxyl-N- benzylamιno)3-pyndyl]ethyl Jpyndine-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-ethyl-N-(E)-l- phenylethylamιno)3-pyπdyl]ethyl Jpyπdιne-N-oxιde, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- 6-(N-ethyl-N-(S)-l- phenylethylamιno)3-pyπdyl]ethyl }pyndme-N-oxιde, 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-methyl-N-(3-pyndyl- N-oxιde)methylammo]3-pyndyl Jethyl Jpyndine-N-oxide, (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6- [methoxy(4-fluorophenyl)methanιmιne]3-pyπdyl Jethyl Jpyndine-N-oxide, (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N- methyl-4-fluorophenylamιdo)3-pyπdyl]ethyl }pyndme-N-oxιde, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-benzyl tπfluoroacetamιdo)3-pyπdyl]ethyl Jpyndme, 4-{2-r3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(N-benzyl acetamιdo)3- pyπdyflethyl Jpyπdine-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l-methyl-l- phenyl)ethyl-N-(tert-butyloxycarbonyl)amιno]3-pyπdyl Jethyl Jpyπdine-N-oxide, (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l- methyl-l-phenyl)ethyl-N-(tert-butyloxycarbonyl)ammo]3-pyndyl Jethyl Jpyπdine-N- oxide, (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l- methyl-l-phenyl)ethyl-N-(benzyloxycarbonyl)amιno]3-pyndyl Jethyl Jpyπdine, (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l- methyl-l-phenyl)ethyl-N-(benzyloxycarbonyl)amιno]3-pyndyl Jethyl Jpyndme, (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l- methyl-l-(4-methylphenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyndyl Jethyl Jpyπdine, (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l- methyl-l-(4-methylphenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyridyl Jethyl Jpyπdine, (Enantιomer-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l- methyl-l-(4-fluorophenyl))ethyl-N-(benzyloxycarbonyl)ammo]3- pyndyl Jethyl Jpyπdine, (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l- methyl-l-(4-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyndyl Jethyl Jpyndme, (Enantιomer-l)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l- methyl-l-(3-methylphenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyndyl Jethyl Jpyπdine, (Enantιomer-2)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l- methyl-l-(3-methylphenyl))ethyl-N-(benzyloxycarbonyl)ammo]3- pyndyl Jethyl Jpyπdine, (Enantιomer-l)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l- methyl-l-(3-bromophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyndyl Jethyl Jpyndine, (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l- methyl-l-(3-bromophenyl))ethyl-N-(benzyloxycarbonyl)ammo]3- pyπdyl Jethyl Jpyndme, (Enantιomeι-l)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l- methyl-l-(3-fluorophenyl))ethyl-N-(benzyloxycarbonyl)ammo]3- pyridyl Jethyl Jpyndme, (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-( l- methyl-l-(3-fluorophenyl))ethyl-N-(benzyloxycarbonyl)ammo]3- pyridyl Jethyl Jpyndine, (Enantiomer- 1 )-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- { 6-[N-( 1,1- dιmethyl-2-(4-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyndyl Jethyl Jpyndme-N-oxide, (Enantιomer-2)-4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l,l- dιmethyl-2-(4-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3- pyπdyl Jethyl Jpyπdine-N-oxide, 4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N-(l,l-dιmethyl-2-(4- fluorophenyl))ethyl-N-(benzyloxycarbonyl)amιno]3-pyπdyl-N-oxιde}ethyl}pyndme- N-oxide, (Enantιomer-2)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[N,N- dι(4-fluorobenzamιde)]3-pyndyl Jethyl Jpyndine-N-oxide, 4- { 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2- { 6-[ 1 ,2,3,4- tetrahydroιsoqumohne]3-pyndyl Jethyl Jpyndme-N-oxide, 4-{2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-[6-(l-amιnomdane)3- pyndyljethyl Jpyndme-N-oxide, (Dιastereomer-l)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[(R)-l- amιnomdane]3-pyπdyl Jethyl Jpyndine-N-oxide, (Dιastereomer-2)-4-{ 2-[3,4-Bιs(dιfluoromethoxy)phenyl]-2-{6-[(R)-l- amιnoιndane]3-pyndyl Jethyl Jpyndme-N-oxide, (Diastereomer-3)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[(S)-l- aminoindane]3-pyridyl Jethyl }pyridine-N-oxide, (Diastereomer-4)-4-{ 2-[3,4-Bis(difluoromethoxy)phenyl]-2-{ 6-[(S)-l- aminoindane]3-pyridyl Jethyl Jpyridine-N-oxide, 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(2-phenylpyrolidine)3- pyridyl]ethyl }pyridine-N-oxide, 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[l-(4- fluoropheny])cyclopentylamino]3-pyridyl Jethyl }pyridine-N-oxide, and 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(2-aminoindane)3- pyridyl]ethyl Jpyridine-N-oxide., 16. A pharmaceutical composition that is comprised of a compound in accordance with any one of claims 1 to 15 in combination with a pharmaceutically acceptable carrier. 17. A method of treating or preventing a disease or condition mediated by PDE 4, comprising administering to a mammalian patient in need thereof, a compound in accordance with claim 1 in an amount that is effective to treat or prevent said disease or condition. 18. A method in accordance with claim 17 wherein the disease or condition is selected from the group consisting of: asthma, inflammed lung associated with asthma, cystic fibrosis, inflammatory airway disease, chronic bronchitis, eosinophilic granuloma, psoriasis, other benign and malignant proliferative skin diseases, endotoxic shock, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium or brain, inflammatory arthritis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, tumour growth and cancerous invasion of normal tissues. 19. A method of treating or preventing asthma in a mammalian patient in need of such treatment or prevention, comprising administering to said patient a compound in accordance with claim 1 in an amount that is effective for treating or preventing asthma. 20. Use of a compound of formula (I) as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt or hydrate thereof, in the manufacture of a medicament for treatment or prevention of a disease or condition mediated by PDE 4. 21. Use of a compound of claim 15 in the manufacture of a medicament for treatment or prevention of asthma. 22. A compound of formula (I), as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment or prevention of a disease or condition mediated by PDE 4. 23. A compound of claim 15 for use in the treatment or prevention of a disease or condition mediated by PDE 4. 24. A phosphodiesterase IV inhibitor pharmaceutical composition comprising an acceptable PDE 4 inhibiting amount of a compound of formula (I), as defined in any one of claims 1 to 14, in association with a pharmaceutically acceptable caπier. 25. A phosphodiesterase IV inhibitor pharmaceutical composition comprising an acceptable PDE 4 inhibiting amount of a compound of claim 15, in association with a pharmaceutically acceptable carrier.

Inventors: BLOUIN MARC, COTE BERNARD, DUCHARME YVES, FRENETTE RICHARD, FRIESEN RICHARD, GIRARD MARIO, GIRARD YVES, GODBOUT CEDRICKX, GUAY DANIEL, HAMEL PIERRE, PRESCOTT SYLVIE, BLOUIN, MARC, COTE, BERNARD, DUCHARME, YVES, FRENETTE, RICHARD, FRIESEN, RICHARD, GIRARD, MARIO, GIRARD, YVES, GODBOUT, CEDRICKX, GUAY, DANIEL, HAMEL, PIERRE, PRESCOTT, SYLVIE
Applicants: BLOUIN MARC, COTE BERNARD, DUCHARME YVES, FRENETTE RICHARD, FRIESEN RICHARD, GIRARD MARIO, GIRARD YVES, GODBOUT CEDRICKX, GUAY DANIEL, HAMEL PIERRE, MERCK FROSST CANADA INC, PRESCOTT SYLVIE, BLOUIN, MARC, COTE, BERNARD, DUCHARME, YVES, FRENETTE, RICHARD, FRIESEN, RICHARD, GIRARD, MARIO, GIRARD, YVES, GODBOUT, CEDRICKX, GUAY, DANIEL, HAMEL, PIERRE, MERCK FROSST CANADA & CO., PRESCOTT, SYLVIE
Application year: 2000
Main classification: C07D213
IPC codes: A61K31, A61P1, A61P9, A61P11, A61P13, A61P17, A61P19, A61P25, A61P27, A61P29, A61P31, A61P35, A61P37, A61P43, C07D213, C07D401, C07D405, C07D409, C07D417