NICOTINAMIDE DERIVATIVES

Abstract: A compound of formula (I) wherein m, n, o, p, q, r, A, B, D, E, R<1>, R<2>,R<3>, R<4>, R<5>, R<6>, R<7> and R<8> are as defined in the description, useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS.

Description: NICOTINAMIDE DERIVATIVES Background of the Invention This invention relates to nicotinamide derivatives that are selective inhibitors of phosphodiesterase type 4 (PDE4) and the production of tumor necrosins factor (TNF), and as such are useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia, and AIDS This invention also relates to a method of using such compounds in the treatment of the foregoing diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds Since the recognition that cyclic adenosine tn-phosphate (cAMP) is an intracellular second messenger, inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes More recently, distinct classes of PDE have been recognized and their selective inhibition has led to improved drug therapy More particularly, it has been recognized that inhibition of PDE4 can lead to inhibition of inflammatory mediator release and airway smooth muscle relaxation Thus, compounds that inhibit PDE4, but which have poor activity against other PDE types, would inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects Recent molecular cloning has revealed a complexity and diversity of PDE4 enzymes It is now known that there are four distinct PDE4 isozymes (A, B, C and D), each encoded for by a separate gene Kinetic studies of human recombinant materials suggest that these four isozymes may differ in their Km's and Vmax's for hydrolysis of cAMP Analysis of tissue distribution of PDE4 mRNAs suggests that each isozyme may be localized in a cell-specific pattern For example, unlike human skeletal muscle human peripheral blood leukocytes do not express PDE4C message, and guinea pig eosmophils express predominantly PDE4D message The structural and distribution diversity of PDE4 isozymes offers an opportunity to discover an isozyme selective inhibitor that blocks the function of inflammatory cells only Using PDE4D isozyme selective inhibitors, we have demonstrated that the PDE4D isozyme plays a key role in regulating the activation and degranulation of human eosmophils In a primate model of asthma, PDE4D isozyme selective compounds inhibit antigen-induced pulmonary eosmophilia Therefore, by selectively blocking the D isozyme, PDE4D inhibitors exhibit reduced side effects and retain anti-asthmatic (anti-inflammatory) efficacy Summary of the Invention The present invention relates to a compound of the formula or the pharmaceutically acceptable salt thereof, wherein the broken line represents an optional double bond; m is 0 or 1 ; n is 0 or 1 ; o is O, 1, 2, 3 or 4; p is 0 or 1 ; q is O, 1, 2 or 3; 1 .8 0, 1 , 2, 3, 01- 4; t is 0 or 1 ; A is oxygen, >NH or sulfur; B is oxygen or NH; D is oxygen or NR 9 , wherein R 9 is hydrogen or (C r C 6 )alkyl; E is CH 2 , O, NH or S(0) a wherein a is 0, 1 or 2; R 1 is hydrogen, (C r C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkenyl, (C 6 -C 10 )aryl, bridged(C 7 -C 8 )bicycloalkyl or a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocyclic group; wherein said saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocyclic group contains from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above; wherein said R 1 cycloalkyl, cycloalkenyl, cycloalkanone, aryl, bicycloalkyl and heterocyclic groups are optionally substituted by one to three substituents independently selected from the substituents consisting of halo, cyano, carboxy, amino, nitro, hydroxy, (C r C 6 )alkyl, (C r C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, hydroxy(C r C 6 )alkyl, hydroxy(C r C 6 )alkylamino, (C r C 6 )alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C r C 6 )acylamino, (C r C 6 )acyloxy, (C r C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino, (C r C 6 )alkyl-NH-(C=0)-, ((C r C 6 )alkyl) 2 -N-(C=0)-, aminosulfonyl, (C r C 6 )alkylaminosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 ) heterocycle; wherein said saturated or unsaturated cyclic or bicyclic (C 3 - C 7 )heterocycle substituents on said R 1 cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups contain from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above, and wherein the heterocycles are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C C 6 )acyl, (C 6 -C 10 )aryl, (C r C 6 )acylamino, (C r C 6 )acyloxy, (C r C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino, (C r C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylaminosulfonyl, ((C r C 6 )alkyl) 2 aminosulfonyl or (C 2 -C 9 )heteroaryl; wherein said alkyl, alkoxy or cycloalkyl substituents on said R 1 cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups are optionally further independently substituted by one to three sub-substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6 )acyl, (C 6 - C 10 )aryl, (C r C 6 )acylamino, (C 1 -C 6 )acyloxy, (C r C 6 )alkylamino, ((C.,-C 6 )alkyl) 2 amino, (C C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylaminosulfonyl, ((C 1 -C 6 )alkyl) 2 aminosulfonyl or (C 2 - C 9 )heteroaryl; or said R cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups are additionally optionally independently substituted with from one to three substituents of the formula ,10 wherein R is hydrogen, (C r C 6 )alkyl, (C r C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 - C 7 )cycloalkenyl, (C 6 -C 10 )arylamino, (C 6 -C 10 )aryl, bridged(C 7 -C 9 )bicycloalkyl or a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocycle; wherein said R 10 saturated or unsaturated cyclic or bicyclic (C 3 - C 7 )heterocycle contains from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above; wherein said R 10 alkyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocycle groups are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C r C 6 )alkyl (C C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, hydroxy(C r C 6 )alkyl, hydroxy(C 1 -C 6 )alkylamino, (C r C 6 )alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C 1 -C 6 )acylamino, (C r C 6 )acyloxy, (C 1 -C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino, aminosulfonyl, (C r C 6 )alkylaminosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocycle; wherein said saturated or unsaturated cyclic or bicyclic (C 3 -C 7 ) heterocycle contains from one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above; wherein the heterocycle is optionally substituted by from one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6 )acyl, (C 6 -Cι 0 )aryl, (C C 6 )acylamino, (C r C 6 )acyloxy, (C r C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino, (C r C 6 )alkylsuifonyl, aminosulfonyl, (C-rC^alkylaminosulfonyl, ((C r C 6 )alkyl) 2 aminosulfonyl or (C 2 -C 9 )heteroaryl; wherein the alkyl, alkoxy or cycloalkyl substituents on said R 10 alkyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C 6 -C 10 )aryl, (C C 6 )acylamino, (C r C 6 )acyloxy, (C r C 6 )alkylamino, (C r C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylaminosulfonyl, ((C r C 6 )alkyl) 2 aminosulfonyl or (C 2 -C 9 )heteroaryl; or R 1 is a group of the formula wherein u is 0 or 1 ; and G, J, K and L are each independently oxygen, sulfur, nitrogen, NR 9 , wherein R 9 is as defined above, carbonyl or CHR 16 ; wherein the dashed lines represent optional double bonds and where it is understood that when a double bond exists between G and J, J and K or K and L that R 9 is absent, >CHR 16 is >CR 16 and G, J, K or L cannot be carbonyl; wherein R 16 is hydrogen, halo, cyano, carboxy, amino, nitro, hydroxy, (C.,-C 6 )alkyl (C r C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, hydroxy(C r C 6 )alkyl, hydroxy(C,-C 6 )alkylamino, (C C 6 )alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C r C 6 )acylamino, (C r C 6 )acyloxy, (C r C 6 )alkylamino, ((CrC^alkyl^annino, aminosulfonyl, (C CeJalkylaminosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 ) heterocycle containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above, wherein said heterocycle is optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6 )acyl, (C 6 -C 10 )aryl, (C C 6 )acylamino, (C r C 6 )acyloxy, ((C 1 -C 6 )alkyl) 2 amino, (C r C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylaminosulfonyl, ((C 1 -C 6 )alkyl) 2 aminosulfonyl or (C 2 -C 9 )heteroaryl; wherein said R 16 alkyl, alkoxy or cycloalkyl substituents are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C 6 -C 10 )aryl, (C r C 6 )acylamino, (CrC^acyloxy, (C r C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino, (C r C 6 )alkylsulfonyl, aminosulfonyl, (C^C^alkylaminosulfonyl, ((C r C 6 )alkyl) 2 aminosulfonyl or (C 2 -C 9 )heteroaryl; wherein each R 2 , R 3 and R 4 is independently hydrogen, hydroxy, halo, cyano, carboxy, nitro, amino, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, hydroxyamino, (C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, or a group of the formula wherein R 10 is as defined above; or R 2 and R 3 can be taken together with the carbon to which they are attached to form a carbonyl group or R 2 and R 3 taken together with the carbon to which they are attached form a (C 3 -C 7 )cycloalkyl ring; or when m is 1 , n is 1 , o is 1 and p is 0, A and R 2 can be taken together to form a group of the formula wherein the broken lines represent optional double bonds and q, A, B, R 1 , R 3 and R 4 are as defined above and when a double bond contains the carbon atom to which R 3 is attached then R 3 is absent; or when m is 1 , n is 1 , o is 1 and p is 0, A and R 2 are taken together and R 3 and -[R ] q -R 1 are taken together to form a group of the formula R 5 is a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocyclic group containing one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above; wherein the heterocyclic group is optionally substituted by one to three substitutents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C r C 6 )alkyl (C r C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, hydroxy(C r C 6 )alkyl, (C r C 6 )alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6 )acyl, (C r C 6 )acylamino, (C r C 6 )acyloxy, (C r C β )alkylamino, ((C r C 6 )alkyl) 2 amino, (C r C 6 )alkyl-NH-(C=0)-, ((C r C 6 )alkyl) 2 -N-(C=0)-, aminosulfonyl, (C 1 -C 6 )alkylaminosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C 3 - C 7 )heterocycle containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above; wherein the heterocycle substituent on said R 5 saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocyclic group is optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C 1 -C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C 1 -C 6 )alkoxy, (C r C 6 )alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C C 6 )acyl, (C 6 -C 10 )aryl, (C r C 6 )acylamino, (C r C 6 )acyloxy, (C r C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C r C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylaminosulfonyl, ((C 1 -C 6 )alkyl) 2 aminosulfonyl or (C 2 -C 9 )heteroaryl; wherein the alkyl, alkoxy or cycloalkyl substituents on said R 5 saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocyclic group, are optionally substituted by one to three sub-substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C r C 6 )alkoxy, (C 1 -C 6 )alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C 6 -C 10 )aryl, (C r C 6 )acylamino, (C r C 6 )acyloxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, (C r C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylaminosulfonyl, ((C r C 6 )alkyl) 2 aminosulfonyl or (C 2 -C 9 )heteroaryl; or said R 5 saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocyclic group is additionally optionally substituted by a group of the formula wherein R 10 is as defined above; or R 5 is a group of the formula wherein R 11 , R 12 , R 13 , R 14 and R 15 are each substituents independently selected from the group consisitng of hydrogen, halo, cyano, carboxy, amino, nitro, hydroxy, (C C 6 )alkyl (C C^alkoxy, (C 3 -C 7 )cycloalkyl, hydroxy (C r C 6 )alkyl, (C r C 6 )alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C C 6 )acyl, (C 6 -C 10 )alkyl- (C=0)-NH-(C=0)-, (C 6 -C 10 )aryl-(C=O)-NH-(C=O)-, (C r C 6 )acyloxy, (C r C 6 )alkylamino, ((C C 6 )alkyl) 2 amino, (C 1 -C 6 )alkyl-NH-(C=0)-, ((C r C 6 )alkyl) 2 -N-(C=0)-, aminosulfonyl, (C r C 6 )alkylaminosulfonyl, ((C r C 6 )alkyl) 2 aminosulfonyl or a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocycle containing one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above, and wherein said heterocycle is optionally substituted by one to three substituents independently selected from the group consisting of halo, cyano, carboxy, amino, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C C 6 )acyl, (C 6 -C 10 )aryl, (C r C 6 )acylamino, (C r C 6 )acyloxy, (C r C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino, (C 1 -C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylaminosulfonyl, ((C r C 6 )alkyl) 2 aminosulfonyl or (C 2 -C 9 )heteroaryl; or R 11 , R 12 , R 13 , R 14 and R 15 are optionally independently a group of the formula wherein R -10 is as defined above; wherein the alkyl, alkoxy or cycloalkyl groups of said R 11 , R 12 , R 13 , R 14 and R 15 groups are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C r C 6 )a\k y /\, hydroxy(C r C 6 )alkyl, (C C 6 )alkoxy, (C C 6 )alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6 )acyl, (C 6 -C 10 )aryl, (C r C 6 )acylamino, (C C 6 )acyloxy, (C r C 6 )alkyiamino, ((C r C 6 )alkyl) 2 amino, (^-C^alkylsulfonyl, aminosulfonyl, (C 1 -C 6 )alkylaminosulfonyl, ((C r C β )alkyl) 2 aminosulfonyl or (C 2 -C 9 )heteroaryl; or R 12 and R 3 can be taken together with the carbons to which they are attached to form a group of the formula wherein u, G, J, K and L are as defined above; R 6 , R 7 , and R 8 are each independently hydrogen, halo, cyano, carboxy, amino, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C 6 -C 10 )aryl, (C C 6 )acylamino, (C C 6 )acyloxy, (C r C 6 )alkylamino, ((CrC^alkyl^amino, (C r C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylaminosulfonyl, ((C r C 9 )alkyl) 2 aminosulfonyl or (C 2 -C 9 )heteroaryl; or R 7 and R 8 may be taken together with the carbons to which they are attached to form a fused bicyclic ring of the formula wherein the dashed lines represent optional double bonds; and M, P, Q and T are each independently oxygen, nitrogen or CR 17 wherein R 17 is hydrogen or (C r C 6 )alkyl; with the proviso that when m is 1; n is 1; o is 1; p is 0; q is 0; r is 0; A is oxygen, B is NH; R 2 and R 3 are hydrogen; R is phenyl substituted by methyl, methoxy, chloro or fluoro; E is oxygen and R 5 is phenyl optionally substituted by one or two fluoro or chloro; then R 1 must be at least di - substituted by substituents other than methyl, methoxy or halo; with the proviso that when t is one that the compound of formula I is a zwiterionic N- oxide, with the proviso that adjacent positions defined by G, J, K and L cannot both be defined by oxygen; and with the proviso that when the broken line of formula I represents a double bond, p is 0 and R 3 is absent. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. The term "alkoxy", as used herein, includes O-alkyl groups wherein "alkyl" is defined above The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C r C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy and (C r C 6 )alkyl The term "a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is as defined above", as used herein, unless otherwise indicated, includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, azindinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazo dinyl, 1 ,3-oxazolιdιn-3-yl, isothiazo dinyl, 1 ,3-thιazolιdιn-3-yl, 1 ,2-pyrazolιdιn-2-yl, 1 ,3-pyrazolιdιn-1-yl, pipeπdinyl, thiomorpho nyl, 1 ,2-tetrahydrothιazιn-2-yl, 1 ,3-tetrahydrothιazιn-3-yl, tetrahydrothiadiazmyl, morpholinyl, 1,2-tetrahydrodιazιn-2-yl, 1 ,3-tetrahydrodιazιn-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, tnazolyl, tetrazolyl, imidazolyl, 1 ,3,5-oxadιazolyl, 1 ,2,4-oxadιazolyl, 1 ,2,3-oxadιazolyl, 1 ,3,5-thιadιazolyl, 1 ,2,3-thιadιazolyl, 1 ,2,4-thιadιazolyl, pyridyl, pyπmidyl, pyrazinyl, pyridazinyl, 1,2,4-trιazιnyl, 1 ,2,3- tnazinyl, 1 ,3,5-trιazιnyl, pyrazolo[3,4-b]pyrιdιnyl, cinnolinyl, pteridinyl, punnyl, 6,7-dιhydro-5H- [1]pyrιndιnyl, benzo[b]thιophenyl, 5, 6, 7, 8-tetrahydro-quιnolιn-3-yl, benzoxazolyl, benzothiazolyl, benzothiadiazole, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indo zinyl, indazolyl, isoquinolyl, qumolyl, phthalazinyl, quinoxa nyl, quinazo nyl and benzoxazinyl Preferably, heterocyclic refers to furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,3-thιadιazolyl, pyridyl, benzoxazolyl or indolyl The term "acyl", as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy and the terms "alkyl" or "aryl" are as defined above The term "acyloxy", as used herein, includes O-acyl groups wherein "acyl" is defined above The compound of formula I may have chiral centers and therefore exist in different enantiomeric forms This invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof Preferred compounds of formula I include those wherein m is 1 , n is 1, o is 1 , p is 0, q is 0, r is 0, A is oxygen or nitrogen, B is NH, R 2 is hydrogen or (C r C 6 )alkyl, R 3 is hydrogen, R 1 is (C 6 -C 10 )aryl, (C 3 -C 7 )cycloalkyl or a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C r C 6 )alkyl wherein the aryl, cycloalkyl and heterocyclic groups are optionally substituted by halo, (C r C 6 )alkyl, (C r C 6 )alkoxy, hydroxy(C r C 6 )alkyl, ammo, (C C 6 )alkylamιno, ((C 1 -C 6 )alkyl) 2 amιno or hydroxy(C r C 6 )alkylamιno, E is oxygen and R 5 is a group of the formula or R 5 is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C r C 6 )alkyl More preferred compounds of formula I are those wherein R 1 is optionally substituted (C 6 -C 10 )aryi wherein said substituents are hydroxy(C C 6 )alkyl or wherein at least one of R 11 , R 12 , R 13 , R 14 or R 15 is halo or wherein R 12 and R 13 are taken together to form a fused bicyclic ring wherein u is zero, G and L are oxygen and J is CH 2 Other preferred compounds of formula I include those wherein m is 0, n is 0, o is 3, p is 0, q is 0, r is 0, R 2 and R 3 are hydrogen, R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C r C 6 )aikyl, (C r C 6 )alkoxy, hydroxy(C r C 6 )alkyl, ammo, (C CeJalkylammo, ((C 1 -C 6 )alkyl) 2 amιno or hydroxy(C r C 6 )alkylamιno, E is oxygen and R 5 is a group of the formula or R 5 is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C r C 6 )alkyl Other preferred compounds of formula I include those wherein m is 1 , n is 0, o is 2, p is 0, q is 0, r is 0, A is oxygen, R 2 and R 3 are hydrogen, R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C r C 6 )alkyl, (C C^alkoxy, hydroxy(C r C 6 )alkyl, ammo, (Ci-CeJalkylammo, ((C r C 6 )alkyl) 2 amιno or hydroxy(C 1 -C 6 )alkylamιno, E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C r C 6 )alkyl. Other preferred compounds of formula I include those wherein m is 0; n is 0; 0 is 1 ; p is 1 ; q is 1 ; r is 0; R 2 and R 3 are hydrogen; D is oxygen; R 4 is hydrogen; R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C 1 -C 6 )alkyl, (C r C 6 )alkoxy, hydroxy(C r C 6 )alkyl, amino, (C r C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino or hydroxy(C r C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R 5 is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C 1 -C 6 )alkyl. Other preferred compounds of formula I include those wherein m is 0; n is 0; o is 3; p is 0; q is 0; r is 0; R 2 is hydrogen or hydroxy; R 3 is hydrogen; R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C 1 -C 6 )alkyl, (C r C 6 )alkoxy, hydroxy(C r C 6 )alkyl, amino, (C r C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino or hydroxy(C r C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R 5 is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C r C 6 )alkyl. Other preferred compounds of formula I include those wherein m is 1; n is 0; o is 1 ; p is 1 ; q is 0; r is 0; A is oxygen; R 2 and R 3 are hydrogen; D is oxygen; R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C 1 -C 6 )alkyl, (C r C 6 )alkoxy, hydroxy(C r C 6 )alkyl, amino, (C r C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino or hydroxy(C 1 -C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C CeJalkyl. Other preferred compounds of formula I include those wherein m is 1; n is 1 ; o is 1; p is 0; q is 0; r is 0; A is oxygen; B is oxygen; R 2 and R 3 are hydrogen ; R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C r C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C r C 6 )alkyl, amino, (C r C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino or hydroxy(C 1 -C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R 5 is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C r C 6 )alkyl. Other preferred compounds of formula I include those wherein m is 1; n is 1 ; o is 0; p is 1 ; q is 0; r is 0; A is oxygen; B is NH; D is NR 8 wherein R 8 is hydrogen or (C r C 6 )alkyl; R 1 is (C 6 - C 10 )aryl optionally substituted by halo, (CrC^alkyl, (C r C 6 )alkoxy, hydroxy(C r C 6 )alkyl, amino, (C r C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino or hydroxy(C 1 -C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C r C 6 )alkyl. Other preferred compounds of formula I include those wherein m is 0; n is 1 ; o is 1 ; p is 0; q is 1 ; r is 0; B is NH; R 2 and R 3 are taken together to form a carbonyl group; R 4 is hydrogen; R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C r C 6 )alkyl, (C r C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, amino, (C 1 -C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino or hydroxy(C 1 -C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C 1 -C 6 )alkyl. Other preferred compounds of formula I include those wherein m is 1; n is 1; o is 1; p is 0; q is 0; r is 0; A and R 2 are taken together to form a group of the formula wherein A is nitrogen; B is NH; R 1 is (C r C 6 )alkyl or (C 1 -C 10 )aryl wherein the aryl group is optionally substituted by halo, (C r C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C r C 6 )alkyl, amino, (C-rCeJalkylamino, ((C r C 6 )alkyl) 2 amino or hydroxy(C C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C 1 -C 6 )alkyl. Other preferred compounds of formula I include those wherein m is 0; n is 0; o is 1 ; p is 0; q is 2; r is 0; R 2 is hydrogen or hydroxy; R 3 is hydroen; R 4 is independently hydrogen or hydroxy; R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C r C 6 )alkyl, (C r C 6 )alkoxy, hydroxy(C r C 6 )alkyl, amino, (C r C 6 )alkylamino, ((C-rC^alkyl^amino or hydroxy(C r C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R 5 is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C r C 6 )alkyl. Other preferred compounds of formula I include those wherein m is 1 ; n is 1 ; o is 1 , 2, 3 or 4; p is 0; q is 1, 2 or 3; r is 0; A is oxygen; B is oxygen; R 2 , R 3 , R 4 and R 1 are hydrogen; E is oxygen and R 5 is a group of the formula or R 5 is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C r C 6 )alkyl. Other preferred compounds of formula I include those wherein m is 1 ; n is 1 ; o is 1 ; p is 0; q is 0; r is 0; A and R 2 are taken together ttoo form a group of the formula wherein A is nitrogen; B is oxygen; R 1 is (C r C 6 )alkyl or (C 6 -C 10 )aryl wherein the aryl group is optionally substituted by halo, (C 1 -C 6 )alkyl, (C C 6 )alkoxy, hydroxy(C r C 6 )alkyl, amino, (^-CeJalkylamino, ((C 1 -C 6 )alkyl) 2 amino or hydroxy(C 1 -C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C 1 -C 6 )alkyl. Other preferred compounds of formula I include those wherein m is 1 ; n is 1 ; o is 1 ; p is 0; q is 0; r is 0; A and R 2 are taken together to form a group of the formula wherein A is oxygen; B is oxygen; R 1 is (C r C 6 )alkyl or (C 6 -C 10 )aryl wherein the aryl group is optionally substituted by halo, (C r C 6 )alkyl, (C C 6 )alkoxy, hydroxy(C r C 6 )alkyl, amino, (C 1 -C 6 )alkylamino, ((C r C 6 )lkyl) 2 amino or hydroxy(C C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C 1 -C 6 )alkyl. Other preferred compounds of formula I include those wherein m is 1 ; n is 0; o is 0; p is 0; q is 0; r is 0; A is oxygen; R 1 is (C 6 -Cι 0 )aryl or a saturated or unsaturated, cyclic or bicyclic (C 3 - C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is a hydrogen or (C C 6 )alkyl wherein the aryl or heterocyclic groups are optionally substituted by halo, (C r C 6 )alkyl, (C r C 6 )alkoxy, hydroxy(C r C 6 )alkyl, amino, (C r C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino or hydroxy(C r C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C,-C 6 )alkyl. Other preferred compounds of formula I include those wherein m is 1 ; n is 1 ; o is 0; p is 0; q is 1; r is 0; A is oxygen; B is NH; R 4 is hydroxy (C 1 -C 6 )alkyl; R 1 is (C 1 -C 6 )alkyl; E is oxygen and R 5 is a group of the formula or R 5 is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is hydrogen or (C r C 6 )alkyl Specific preferred compounds of formula I include the following N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-2-(3-methyl-benzo(d)ιsoxazol-7-yloxy)- nicotmamide, N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-2-(3-oxo-ιndan-5-yloxy)-nιcotιnamιde, 2-(3-(1-Hydroxyιmιno-ethyl)-phenoxy)-N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)- nicotinamide, N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-2-(4-oxo-chroman-6-yloxy)-nιcotιnamιde, (±) 2-(3-Acetyl-phenoxy)-N-(1-hydroxy-ιndan-5-ylmethyl)-nιcotιnamιde, 2-(2,3-Dιhydro-benzo(1 ,4)dιoxιn-6-yloxy)-N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)- nicotmamide, N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-2-(3-(1-methoxyιmιno-ethyl)-phenoxy)- nicotmamide, N-(2-Chloro-benzyl)-2-(4-fluoro-phenoxy)-nιcotιnamιde, N-(5-Chloro-thιophen-2-ylmethyl)-2-(pyrιdιn-3-yloxy)-nιcotιnamιde, 2-(4-Fluoro-phenoxy)-N-[4-(3-hydroxy-azetιdιn-1-yl)-benzyl]-nιcotιnamιde, N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(3-nιtro-phenoxy)-nιcotιnamιde, 2-(4-Fluoro-phenoxy)-N-(2-oxo-2,3-dιhydro-1 H-ιndol-5-ylmethyl)-nιcotιnamιde, N-[2-(3-Acetyl-phenoxy)-pyrιdιn-3-yI]-2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]- acetamide, 3-{3-[4-(1-Hydroxy-1-methyl-ethyl)-benzylcarbamoyl]-pyrιdιn-2-yloxy}-benzoιc acid methyl ester, 2-(4-Fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nιcotιnamιde, 2-(4-Fluoro-phenoxy)-N-(1-thιophen-2-yl-ethyl)-nιcotιnamιde, N-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(3-cyano-phenoxy)-nιcotιnamιde, 2-(3-Cyano-4-fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nιcotιnamιde, N-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(3,4-dιfluoro-phenoxy)- nicotmamide, (+)-2-(Benzo[1 ,3]dιoxol-5-yloxy)-N-[4-(1 -hydroxy-ethyl)-cyclohexylmethyl]- nicotmamide, (-)-2-(3-Cyano-4-fluoro-phenoxy)-N-[4-(1-hydroxy-ethyl)- cyclohexylmethyl]- nicot amide, (+)-2-(3-Cyano-4-fluoro-phenoxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]- nicotmamide, (+)-2-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yloxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]- nicotinamide; (-)-2-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yloxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]- nicotinamide; 2-(Benzo[1 ,3]dioxol-5-yloxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide, 2-(Benzo[1 ,3]dioxol-5-yloxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]- nicotinamide; 2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-ethyl)- cyclohexylmethyl]-nicotinamide; and 2-(3-Cyano-4-fluoro-phenoxy)-N-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]- nicotinamide; N-[2-Chioro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(3-cyano-4-fluoro-phenoxy)- nicotinamide; 2-(3-Acetyl-phenoxy)-N-[2-chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide; 2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]-nicotinamide; 2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide; 2-(3,4-Difluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide; 2-(4-Fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]-nicotinamide; 2-(3-Cyano-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]- nicotinamide; N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(3-methoxy-phenoxy)-nicotinamide; 2-(3-Cyano-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide; N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(pyridin-3-yloxy)-nicotinamide; and 2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide. The present invention also relates to a pharmaceutical composition for the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS in a mammal, including a human, comprising an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in such preventions or treatment and a pharmaceutically acceptable carrier. The present invention also relates to a method for the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS in a mammal, including a human, comprising administering to said mammal an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in such treatment The present invention also relates to a pharmaceutical composition for selective inhibition of PDE4 D isozymes which regulate the activation and degranulation of human eosmophils useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS in a mammal, including a human, comprising administering to said mammal a PDE4 D isozyme inhibiting effective amount of a PDE4 D isozyme inhibiting compound or a pharmaceutically acceptable salt thereof, effective in such treatment and a pharmaceutically acceptable carrier The present invention also relates to a method for selective inhibition of PDE4 D isozymes which regulate the activation and degranulation of human eosmophils useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS in a mammal, including a human, comprising administering to said mammal a PDE4 D isozyme inhibiting effective amount of a PDE4 D isozyme inhibiting compound or a pharmaceutically acceptable salt thereof, effective in such treatment Detailed Description of the Invention The following reaction Schemes illustrate the preparation of compounds of the present invention SCHEME 1 IV SCHEME2 IV VI III V SCHEME 3 IV X VIII IX VII SCHEME4 XI SCHEME5 XIII SCHEME6 XVI XV SCHEME7 XVII XVI SCHEME 8 XIX XVIII SCHEME9 XXI XX SCHEME 10 XXIII XXII SCHEME11 XXVI XXV SCHEME 12 XXVIII XXVII SCHEME 13 XXX XXIX SCHEME 14 XXX XXXII SCHEME15 XXXV XXXIV SCHEME 16 XXXVII XXXVI SCHEME 17 XXXIX XXXVIII SCHEME 18 XLI XL SCHEME19 XLIII XLII SCHEME 20 XLIV SCHEME21 XLIX XLVI 11 SCHEME 22 Llll LIV Lll SCHEME 23 LVI LV SCHEME 24 LVI 11 LVI I SCHEME25 LX LIX SCHEME 26 LXII LXII I XLVI 11 SCHEME27 LXVI LXVI I SCHEME28 LXVI LXVI I In reaction 1 of Scheme 1, the 2-chloropyridine compound of formula IV is converted to the corresponding compound of formula III by reacting IV with a compound of the formula, R 5 (CH 2 ) r -OH, in the presence of sodium hydride and a polar aprotic solvent, such as dimethylformamide. The reaction is carried out at room temperature for a time period between about 3 hours to about 20 hours, preferably about 4 hours. In reaction 1 of Scheme 2, the 3-carboxylic acid compound of formula IV is converted to the corresponding ethyl ester pyridine compound of formula VI by reacting IV with ethanol in the presence of thienyl chloride. The reaction mixture is heated to reflux for a time period between about 1 hour to about 3 hours, preferably about 1.5 hours. In reaction 2 of Scheme 2, the 2-chloropyridine compound of formula VI is converted to the corresponding compound of formula V by reacting IV with a compound of the formula, R 5 (CH 2 ) r -OH, in the presence of cesium carbonate and a polar aprotic solvent, such as dimethylformamide. The reaction is carried out at a temperature between about 65°C to about 90°C, preferably about 65°C, for a time period between about 10 hours to about 18 hours, preferably about 10 hours. In reaction 3 of Scheme 2, the ethyl ester pyridine compound of formula V is converted to the corresponding 3-carboxylic acid compound of formula III by reacting V with ethanol in the presence of sodium hydroxide. The reaction mixture is heated to reflux for a time period between about 3 hours to about 5 hours, preferably about 4 hours. In reaction 1 of Scheme 3, the 3-carboxylic acid compound of formula IV is converted to the corresponding benzyl ester pyridine compound of formula X by reacting IV with benzyl bromide in the presence of potassium carbonate and a polar aprotic solvent, such as dimethylformamide. The reaction is carried out at room temperature for a time period between about 1 hour to about 24 hours, preferably about 10 hours. In reaction 2 of Scheme 3, the 2-chloropyridine compound of formula X is converted to the corresponding compound of formula IX by reacting X with 3-iodophenol in the presence of cesium carbonate and a polar aprotic solvent, such as dimethylformamide. The reaction is carried out at a temperature between about 70°C to about 80°C, preferably about 75°C, for a time period between about 1 hours to about 6 hours, preferably about 2 hours. In reaction 3 of Scheme 3, the (3-iodo-phenoxy) pyridine compound of formula IX is converted to the corresponding compound of formula VIII by reacting IX with carbon monoxide and methanol in the presence of palladium acetate, 1 ,1-bix(diphenylphosphino)-ferrocene, triethylamide and a polar aprotic solvent, such as dimethylformamide. The reaction mixture is heated to a temperature between about 50° to about 70°C, preferably about 60°C, for a time period between about 2 hours to about 4 hours, preferably about 4 hours. In reaction 4 or Scheme 3, the benzyl ester pyridine compound of formula VIII is converted to the corresponding compound of VIII by hydrogenatmg VIII in the presence of palladium on carbon, methanol and ethyl acetate The reaction is carried out at room temperature for a time period between about 1 hour to about 2 hours, preferably about 2 hours In reaction 1 of Scheme 4, the carboxylic acid pyridine compound of formula III is converted to the corresponding compound of formula XI by reacting III with a compound of the formula by one of four different synthetic methods In the first method, the compound of formula III is reacted with XII in the presence of 1-ethyl-3-(3-dιmethylamιnopropyl)carbodιιmιde, 1-hydroxybenzotrιazole hydrate and a polar aprotic solvent, such as dimethylformamide The reaction is carried out at room temperature for a time period between about 1 hour to about 24 hours, preferably about 10 hours In the second method, III is reacted a chloroformate such as isobutylchloroformate, in the presence of N-methylmorpoiine and a polar aprotic solvent, such as methylene chloride, at a temperature between about 0°C to about -20°C, preferably about -10°C, for a time period between about 15 minutes to about 1 hour, preferably about 30 minutes The reaction mixture is warmed to room temperature and the compound of formula XII is added The resulting reaction mixture is stirred for a time period between about 1 hour to about 24 hours, preferably about 10 hours In the third method, the compound of formula III is heated to reflux in the presence of thionyl chloride for a time period between about 1 hour to about 24 hours, preferably about 1 hours The resulting acid chloride is then reacted with the compound of formula XII in the presence of pyndine and a polar aprotic solvent, such as tetrahydrofuran The reaction is carried out at a temperature between about 0°C to about room temperature, preferably about 0°C In the fourth method, the compound of formula II is reacted with XII in the presence of BOP, dnsopropyl ethyl amine and a polar aprotic solvent.such as dimethylformamide The reaction is carried out at room temperature for a time period between about 3 hours to about 4 hours, preferably about 4 hours In reaction 1 of Scheme 5, the 3-carboxylic acid pyridine compound of formula III is converted to the corresponding compound of formula XIII by reacting III with a compound of the formula in the presence of 4-dimethylaminopyridine, 1-(3-dimethylaminopropyl)-3-ethylcarbo- diimide hydrochloride, pyridine and diethyl ether. The reaction is carried out at room temperature for a time period between about 1 hour to about 3 hours, preferably about 1 hours. In reaction 1 of Scheme 6, the compound of formula XVI is converted to the corresponding compound of formula XV by reacting XVI with acetonitrile in the presence of formaldehyde and sodium cyanoborohydride. The reaction is carried out at room temperature for a time period between about 14 hours to about 16 hours, preferably about 16 hours. In reaction 1 of Scheme 7, the compound of formula XVII is converted to the corresponding compound of formula XVI by first reacting XVII with phosphorus oxychloride in an aprotic solvent, such as toluene, then treating the compound so formed with sodium hydroxide in a polar protic solvent, such as methanol. The reaction is carried out at a temperature between about 0°C to room temperature, preferably about 22°C, for a time period between about 1 hour to about 24 hours, preferably about 12 hours. In reaction 1 of Scheme S, the compound of formula XIX is converted to the corresponding compound of formula XVIII by a method to that described in reaction 1 of Scheme 7. In reaction 1 of Scheme 9, the 3-aminopyridine compound of formula XXI is converted to the corresponding compound of formula XX by reacting XXI with a compound of the formula in the presence of 1-hydroxybenzotriazole hydrate and a polar aprotic solvent, such as dimethylformamide. The reaction is carried out at room temperature for a time period between about 1 hour to about 24 hours, preferably about 16 hours. In reaction 1 of Scheme 10, the compound of formula XXIII is converted to the corresponding compound of formula XXII by reacting XXIII with a compound of the formula in the presence of p-toluenesulfonic acid and an aprotic solvent, such as toluene. The reaction is mixture heated to reflux for a time period between about 1 hour to about 48 hours, prefereably about 24 hours. In reaction 1 of Scheme H, the compound of formula XXVI is converted to the corresponding compound of formula XXV by reacting XXVI with methyl lithium in an aprotic solvent, such as tetrahydrofuran. The reaction is carried out at a temperature between about - 75°C to about -85°C, preferably about -78°C, for a time period between about 1 hour to about 6 hours, preferably about 2 hours. In reaction 1 of Scheme 12, the compound of formula XXVII by reacting XXVIII with boron tribromide in a polar aprotic solvent, such as methylene chloride. The reaction is carried out at a temperature between about -78°C to room temperature, preferably about 0°C, for a time period between about 1 hour to about 24 hours, preferably about 16 hours. In reaction 1 of Scheme 13, the compound of formula XXX is converted to the corresponding compound of formula XXIX by reacting XXX with a compound of the formula XXXI in the presence of triethylamine and a polar aprotic solvent, such as methylene chloride. The reaction is carried out at a temperature between about 0°C to room temperature, preferably about 0°C, for a time period between about 30 minutes to about 2 hours, prefereably about 1 hours. In reaction 1 of Scheme 14, the compound of formula XXX is converted to the corresponding compound of formula XXXII by reacting XXX with methanesulfonic anhydride in the presence of triethylamine. The reaction is carried out at room temperature for a time period between about 30 minutes to about 24 hours, preferably about 12 hours. In reaction 1 of Scheme 15, the compound of formula XXXV is converted to the corresponding compound of formula XXXIV by reacting XXXV with sodium hydroxide ma polar aprotic solvent, such as ethanol The reaction is heated to reflux for a time period between about 1 hour to about 24 hours, preferably about 9 hours In reaction 1 of Scheme 16, the compound of formula XXXVII is converted to the corresponding compound of formula XXXVI by oxidizing XXXVII with tetrapropylammonium perruthenate and 4-methylmorpholιne N-oxide in a polar aprotic solvent, such as methylene chloride The reaction is carried out at room temperature for a time period between about 2 hours to about 6 hours, perferably about 4 hours In reaction 1 of Scheme 17, the 2-amιnopyrιdιne compound of formula XXXIX is converted to the corresponding compound of formula XXXVIII by reacting XXXIX with a compound of the formula, R 5 -N=C=0 The reaction is heated to reflux for a time period between about 1 hour to about 24 hours, preferably about 16 hours In reaction 1 of Scheme 18, the 2-nιtropyπdιne compound of formula XLI is converted to the correspond 2-amιnopyrιdιne compound of formula XL by reducing XLI with 10% platinum oxide on carbon, methanol and tetrahydrofuran The reaction is carried out at room temperature for a time period between about 1 hour to about 3 hours, preferably about 2 hours In reaction 1 of Scheme 19, the compound of formula XLIII is converted to the corresponding compound of formula XLII by reacting XLIII with MCPBA in a polar aprotic solvent, such as methylene chloride The reaction is carried out at room temperature for a time period between about 1 hour to about 4 hours, prefereably about 1 hours In reaction 1 of Scheme 20, the2-chloropyrιdιne compound of formula XLV is converted to the corresponding compound of formula XLVI by reacting XLV with a compound of the formula, R 5 (CH 2 ) r OH, in the presence of cesium carbonate and a polar aprotic solvent, such as dimethylformamide The reaction is carried out at a temperatue between about 65°C to about 90°C, preferably about 80°C, for a time period between about 10 hours to about 18 hours, preferably about 16 hours In reaction 2 of Scheme 22, the 3-cyanopyrιdιne compound of formula XLVI is converted to the corresponding compound of formula XLVII by reacting XLVI with hydrogen peroxide in the presence of potassium hydroxide and a polar protic solvent, such as ethanol The reaction is carried out at room temperature for a time period between about 1 hour to about 24 hours, preferably about 12 hours In reaction 3 of Scheme 20, the compound of formula XLVII is converted to the corresponding compound of formula XLIV by reacting XLVII with a compound of the formula XLVIII wherein X is chloro, bromo or iodo, in the presence of potassium hydroxide and a polar aprotic solvent, such as dimethyl sulfoxide. The reaction is carried at room temperature for a time period between about 1 hour to about 24 hours, preferably about 1 hours. In reaction 1 of Scheme 21, the compound of formula XLIX is converted to the corresponding compound of formula L by reacting XLIX with a compound of the formula in a polar aprotic solvent, such a tetrahydrofuran. The reaction is carried out at a temperature between about -85°C to about -75°C, preferably about 78°C, for a time period between about 0.5 hours to about 16 hours, preferably about 2 hours. In reaction 2 of Scheme 21, the compound of formula L is converted to the corresponding compound of formula XLVIII by reacting L with chromic acid, sulfuric acid and water in a polar aprotic solvent, such as acetone. The reaction is carried out at a temperature between about 0°C to about 25°C, preferably about 0°C, for a time period between about 0.5 hours to about 16 hours, preferably 2 hours. In reaction 1 of Scheme 22, the compound of formula Llll is converted to the corresponding compound of formula LIV by reacting Llll with a compound of the formula XLVIII in the presence of sodium hydride and a polar aprotic solvent, such as tetrahydrofuran. The reaction is carried out at a temperature between about 0°C to about 60°C, preferably about 0°C, for a time period between about 1 hours to about 16 hours, preferably about 4 hours In reaction 2 of Scheme 22, the compound of formula LIV is converted to the corresponding compound of formula Lll by reacting LIV with tπfluoroacetic acid neat for a time period between about 1 hours to about 16 hours, preferably about 4 hours In reaction 1 of Scheme 23, the compound of formula LVI is converted tot he corresponding compound of formula LV by reacting LVI with a compound of the formula, R 1 CHO, in the presence of lithium diisopropylamide and a polar aprotic solvent, such as tetrahydrofuran The reaction is carried out at a temperature between about -75°C to about - 85°C, preferably about -78°C, for a time period between about 1 hour to about 6 hours, preferably about 1 hours In reaction 1 of Scheme 24, the compound of formula LVIII is converted to the corresponding compound of formula LVII by reacting LVIII with sodium borohydride in the presence of a polar protic solvent, such as methanol The reaction is carried out at a temperature between about -10°C to about 10°C, preferably about 0°C, for a time period between about 0 5 hours to about 16 hours, preferably about 1 hours In reaction 1 of Scheme 25, the compound of formula LX is converted to the corresponding compound of formula LIX by reacting LX with a compound of the formula wherein X is chloro, bromo or lodo, in the presence of sodium hydride and a polar aprotic solvent, such as dimethylformamide In reaction 1 of Scheme 25, the 2-fluoropyrιdιne compound of formula LXII is converted to the corresponding compound of formula LXIII, by reacting LXII, with a compound of the formula in the presence of lithium diisopropylamide and a polar aprotic solvent, suh as tetrahydrofuran In reaction 2 of Scheme 26, the compound of formula LXIII is converted to the corresponding compound of formula XLVIII, by reacting LXIII with a compound of the formula, HE-(CH 2 ) r -R 5 , in the presence of sodium hydride and a polar aprotic solvent, such as dimethylformamide In reaction 1 of Scheme 2Z, the compound of formula LXV is converted to the corresponding compound of formula LXVI, by reacting LXV with the Burgess reagent, CH 3 OOCNS0 2 NCH 2 CH 3 , in the presence of benzene In reaction 2 of Scheme 27, the compound of formula LXVI is converted to the corresponding compound of formula LXIV, by reacting LXVI with osmmum tetroxide in the presence of tert-butanol, NMO and actone In reaction 1 of Scheme 28, the compound of formula LXVI is converted tot he corresponding compound of formula LXVII by hydrogenatmg LXVI in the presence of pallidium on carbon and ethanol The compounds of formula I that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids Although such salts must be pharmaceutically acceptable for administration to humans or animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol Upon evaporation of the solvent, the desired solid salt is readily obtained The desired acid addition salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid Pharmaceutically acceptable salts of ammo groups include hydrochlonde (preferred), hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts Cationic salts of the compounds of formula I are similarly prepared except through reaction of a carboxy group, such as where R 6 is carboxy, with an appropriate cationic salt reagent such as sodium, potassium, calcium, magnesium, ammonium, N,N'-dιbenzylethylenedιamιne, N-methylglucamine (meglumine), ethanolamine, tromethamme, or diethanolamine For administration to humans in the curative or prophylactic treatment of inflammatory diseases, oral dosages of a compound of formula I or a pharmaceutically acceptable salt thereof (the active compounds) are generally in the range of 0 1 to 1000 mg daily, in single or divided doses, for an average adult patient (70 kg) The active compounds can be administered in single or divided doses Individual tablets or capsules should generally contain from 0 1 to 100 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier Dosages for intravenous administration are typically within the range of 0 1 to 10 mg per single dose as required For mtranasal or inhaler administration, the dosage is generally formulated as a 0 1 to 1% (w/v) solution In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and all such dosages are within the scope of this invention For human use, the active compounds of the present invention can be administered alone, but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substance, for example, enough salts or glucose to make the solution isotonic Additionally, the active compounds may be administered topically when treating inflammatory conditions of the skin and this may be done by way of creams, jellies, gels, pastes, and ointments, in accordance with standard pharmaceutical practice The therapeutic compounds may also be administered to a mammal other than a human The dosage to be administered to a mammal will depend on the animal species and the disease or disorder being treated The therapeutic compounds may be administered to animals in the form of a capsule, bolus, tablet or liquid drench The therapeutic compounds may also be administered to animals by injection or as an implant Such formulations are prepared in a conventional manner in accordance with standard veterinary practice As an alternative the therapeutic compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed The ability of the compounds of formula I or the pharmaceutically acceptable salts thereof to inhibit PDE 4 may be determined by the following assay Inhibition of Eosmophil Degranulation and Activation in Human Whole Blood Human Blood Eosinophil Degranulation and Activation Measurement Blood collection and compound incubation One hundred ml blood is obtained from normal volunteers in Vacutamer tube #6480 (14 3 USP units sodium heparm/ml blood) Hepaπnized blood is pooled in 50 ml conical centrifuge tubes at 22°C On ml blood is placed in a 12X75 mm si conized glass tube containing 1 ul DMSO or 1 ul test compound in triplicate After mixing, tubes are placed in a shaking water bath at 37°C for 15 minutes One ul PGE1 in DMSO is added to all tubes to give a final concentration of 1 uM After mixing, 100 ul PBS (negative control) or Sephadex G- 15 beads in PBS (8 25-16 5 mg/ml final concentration) is added to tubes After mixing, all tubes are incubated in a shaking water bath at 37°C for 1-2 hours Preparation of plasma samples At the end of incubation, 20 ul of 15% EDTA in PBS is added to each assay tube After mixing, the samples are centrifuged at 2,000 rpm (Sorvall 6000B centrifuge) at 22°C for 5 minutes EDN (or EPX) and LTE4 measurements and the effect of compounds All plasma samples are tested for EDN (eosmophil derived neurotoxin) and LTE4 (leukotnene E4) levels Extensive studies suggest that Sephadex beads trigger cosmophil- mediated EDN and LTE4 release in human whole blood The levels of EDN and LTE4 are determined by a RIA (Kabi Pharmacia Diagnostics) and EIA (Cayman Chemical), respectively EDN and LTE4 levels are calculated by comparison to a standard curve using Microsoft Excel or other appropriate software Percent of control EDN or LTE4 release is calculated by % Control EDN = [EDN (compound) - EDN(blank)]/[EDN(total) - EDN(blank)] % Control LTE4 = [LTE4(compound) - LTE4(blank)]/[LTE4(total) - LTE4(blank)] where the blank is the level of EDN or LTE4 in the absence of Sephadex beads and the total is the level of EDN or LTE4 in the presence of Sephadex beads An IC 30 or IC 50 value is defined as the concentration of a compound that inhibits specific EDN or LTE4 release by 30 or 50%, respectively Inhibition of PDE4 isozyme and eosmophil activation by (+) and (-) enantiomers To assess pharmacologically which PDE4 ιsozyme(s) is responsible for eosmophil activation, we have prepared enantiomers of PDE4 inhibitors and compare the inhibitory effect of these enantiomers on PDE activity and eosmophil activation PDE4 activity is assessed by measuring hydrolysis of 1 uM cAMP by individual human recombinant PDE4 isozymes (PDE4A, 4B, 4C or 4D) Eosmophil activation is estimated by measuring Sephadex beads- induced release of eosmophil derived neurotoxin (EDN) and leukotnene E4 in human whole blood Table 1 illustrates comparison of one example of (-) and (+) enantiomers on the activity of individual PDE4 isozymes and on the release of END and LTE4 (+) Enantiomer ((S)-(-)2(4- Fluoro-phenoxy)-N-[1-(4-methoxy-phenyl)-ethyl]-nιctιnamιde) is 22 times more potent in inhibiting PDE4D than (-) enantiomer ((R)2-(4-Fluoro-phenoxy)-N-[1-(4-metoxy-phenyl)-ethyl]- nicotinamide); however, they are approximately equipotent in inhibiting the other 3 isozymes, i.e., PDE4A, 4B and 4C. Importantly, the (+) enantiomer is 20-37 fold more effective against the EDN and LTE4 response. These results indicate that the differential effect of (+) and (-) enantiomers on PDE4D isozyme inhibition is identical to their effects on eosinophil EDN/LTE4 release, demonstrating that the PDE4D isozyme plays a key role in regulating eosinophil. Table t (+) vs. (-) enantiomers on PDE4 Isozvmes and Eosinophil Responses Including the aforementioned enantiomer, a total of 8 pairs of (+) and (-) enantiomers has been prepared. As illustrated in Table 2, the enantioselective effect of these compounds on PDE4D isozyme inhibition correlates significantly with those on the EDN and LTE4 response. Table 2. Correlation of enantioselective effects on the PDE activity and EDN/LTE4 response by 8 compounds, each having (+) and (-) enantiomers. Inhibition of pulmonary eosinophilia To evaluate these compounds for pulmonary efficacy, we have used a well- characterized monkey model of asthma (Turner et al.. Am. J. Respir. Crit. Care Med. 149, 1153-1159, 1994). Exposure of atopic Macaca fascicularis monkeys to antigen causes a significant influx of inflammatory cells observed in the bronchoalveolar (BAL) fluid of these monkeys at 4-24 hours post antigen challenge. In this model, PDE4D isozyme selective compounds given subcutaneously significantly inhibit pulmonary eosinophil infiltration by 59- 76% at 24h post antigen challenge. These compounds, however, do not affect neutrophil or lymphocyte infiltration, demonstrating selective inhibition of the eosinophil response by these compounds. Inhibition of TNF Production in Isolated Human-Monocytes The ability of the compounds I or the pharmaceutically acceptable salts thereof to inhibit the production TNF and, consequently, demonstrate their effectiveness for treating disease involving the production of TNF is shown by the following in vitro assay: Peripheral blood (100 mis) from human volunteers is collected in ethylenediaminetetraacetic acid (EDTA). Mononuclear cells are isolated by FICOLL/Hypaque and washed three times in incomplete HBSS. Cells are resuspended in a final concentration of 1 x 10 6 cells per ml in pre-warmed RPMI (containing 5% FCS, glutamine, pen/step and nystatin). Monocytes are plated as 1 x 10 6 cells in 1.0 ml in 24-well plates. The cells are incubated at 37°C (5% carbon dioxide) and allowed to adhere to the plates for 2 hours, after which time non- adherent cells are removed by gentle washing. Test compounds (10ml) are then added to the cells at 3-4 concentrations each and incubated for 1 hour. LPS (10ml) is added to appropriate wells. Plates are incubated overnight (18 hrs) at 37°C. At the end of the incubation period TNF was analyzed by a sandwich ELISA (R&D Quantikine Kit). IC 50 determinations are made for each compound based on linear regression analysis. Mass spectra were determined by the GC-MS, AMPI, APCI or thermospray method. All 1 H NMR were taken on a 400 MHz instrument. PREPARATION 1 2-(4-Fluoro-phenoxy)-nicotinic acid To a stirred solution of 4-fluorophenol (5.0 grams, 44.6 mmole) in dimethylformamide (40 ml) at room temperature was added 60% sodium hydride (3.6 grams, 89.0 mmole) portionwise and stirred for 30 minutes. 2-Chloronicotinic acid (7.1 grams, 45.0 mmole) was added portionwise and the mixture was refluxed for 3 hours. The solution was poured into 300 ml water and washed with diethyl ether. The aqueous was poured into 400 ml ice/water and acidified to pH 3 with acetic acid. The resulting precipitate was isolated by filtration to give an off-white solid (5.2 g). M.P. 180-182°C; MW 233.21 ; MS (m/e) 234 (M + +1). The compounds of Preparation 2-5 were prepared according to the procedure of Preparation 1 substituting the corresponding alcohol for 4-fluorophenol. The duration of reaction was between 1 and 24 hours. PREPARATION 2 2-(3-Fluoro-phenoxy)-nicotinic acid MW 233.21 ; MS (m/e) 233 (M + ). PREPARATION 3 2-(2.4-difluoro-phenoxy)-nicotinic acid MW 251.19; MS (m/e) 252 (M + +1). PREPARATION 4 2-(3-chloro-phenoxy)-nicotinic acid MW 249.65; MS (m/e) 250 (M + +1). PREPARATION 5 2-(3-Methoxy -phenoxy)-nicotinic acid MW 245.23; MS (m/e) 261 (M + +18). PREPARATION 6 2-(pyridin-3-yloxy)-nicotinic acid A solution of 2-(Pyridin-3-yloxy)-nicotinic acid ethyl ester (0.419 grams, 1.71 mmole) in ethanol (10 ml) and 1 N sodium hydroxide (4 ml) was refluxed for 4 hours. The mixture was poured into 100 ml water, acidified to pH 4 with 1 N hydrochloric acid and concentrated to dryness to give a solid (0.643 g). MW 216.21 ; MS (m/e) 217 (M + +1). The compounds of Preparations 7-22 were prepared according to the procedure of Preparation 6 substituting the corresponding ester for 2-(Pyridin-3-yloxy)-nicotinic acid ethyl ester. The duration of reaction was between 1 and 24 hours. PREPARATION 7 2-(5-Chloro-pyridin-3-yloxy)-nicotinic acid MW 250.65; MS (m/e) 251 (M + +1 ). PREPARATION 8 2-(3-Nitro-phenoxy)-nicotinic acid M.P. 172-174°C; MW 260; MS (m/e) 261 (M + +1) Anal, calcd. for C 12 H 8 N 2 O s : C, 55.39; H, 3.10; N, 10.77. Found: C, 54.71 ; H, 3.15; N, 10.65. PREPARATION 9 2-(3-Cyano-phenoxy)-nicotinic acid M.P. 220-222°C; MW 240.22; MS (m/e) 240 (M + ). PREPARATION 10 2-(3-Dimethylamino-phenoxy)-nicotinic acid MW 258.27; MS (m/e) 259 (M + +1 ). PREPARATION 11 2-(3-Acetylamino-phenoxy)-nicotinic acid M.P. 273-275°C; MW 272.26; MS (m/e) 273 (M + +1). PREPARATION 12 2-(1 H-lndol-4-yloxy)-nicotinic acid MW 254; MS (m/e) 255 (M + +1 ). PREPARATION 13 2-(3-Trifluoromethyl-phenoxy)-nicotinic acid M.P. 148-150°C; MW 283.05; Anal, calcd. for C 13 H 8 N0 3 F 3 : C, 55.10; H, 2.85; N, 4.95. Found: C, 54.71 ; H, 2.51 ; N, 4.83. PREPARATION 14 2-(3-Tetrazol-1-yl-phenoxy)-nicotinic acid M.P. 185-188°C; MW 283.2; MS (m/e) 282 (M + -1). PREPARATION 15 2-(3-Methylsulfanyl-phenoxy)-nicotinic acid MW 261.302; MS (m/e) 262 (M + +1). PREPARATION 16 2-(3-Acetyl-phenoxy)-nicotinic acid MW 257.248; MS (m/e) 256 (M + -1 ). PREPARATION 17 2-(3-Trifluoromethoxy-phenoxy)-nicotinic acid MW 299.208; MS (m/e) 300 (M + +1). PREPARATION 18 2-(3.4-difluoro-phenoxy)-nicotinic acid MW 251.20; MS (m/e) 251 (M + ). PREPARATION 19 2-(3.5-difluoro-phenoxy)-nicotinic acid MW 251.20; MS (m/e) 252 (M + +1). PREPARATION 20 2-(3-Fluoro-phenoxy)-nicotinic acid M.P. 135-137°C; Anal, calcd. for C 12 H 8 N0 3 F: C, 61.79; H, 3.46; N, 6.01. Found: C, 61.51 ; H, 3.69; N, 5.78. PREPARATION 21 2-(Benzo[1.31dioxol-5-yloxy)-nicotinic acid M.P. 162-164°C; 1 H NMR (DMSO-d 6 ) d 6.0 (2H, s), 6.5-8.3 (6 H, m). PREPARATION 22 2-(3-Dimethylcarbamoyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]- nicotinic acid 1 H NMR (DMSO-d 6 ) d 2.88 (3H, s), 2.93 (3H, s), 7.08 (4H, m), 7.42 (1 H, m), 8.22 (2 H, m). PREPARATION 23 2-(pyridin-3-yloxy)-nicotinic acid ethyl ester A solution 2-ChIoro-nicotinic acid ethyl ester (0.53 grams, 2.85 mmole), cesium carbonate (2.326 grams, 6.73 mmole) and Pyridin-3-ol (0.271 grams, 2.85 mmole) in dimethylformamide (20 ml) was heated to 65°C for 10 hours. The mixture was diluted with 300 ml water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over Na 2 S0 4 , filtered, and concentrated to an oil (0.55 g). MW 244.25; MS (m/e) 244 (M + ). The compounds of Preparations 24-43 were prepared according to the procedure of Preparation 23 substituting the corresponding alcohol for Pyridin-3-ol. The duration of reaction was between 1 and 24 hours. PREPARATION 24 2-(5-Chloro-pyridin-3-yloxy)-nicotinic acid ethyl ester A solution of 2-Chloro-nicotinic acid ethyl ester (2.07 grams, 11.2 mmole), Cesium carbonate (7.27 grams, 22.3 mmole) and 5-chloro-3-pyridinol (1.45 grams, 11.2 mmole) in dry dimethylformamide (40 ml) was stirred at 90°C overnight. The suspension was cooled to room temperature, poured into water and extracted with diethyl ether. The combined organics were washed with water and brine, dried over MgS0 4 and concentrated to a tan solid. Recrystalization from hexane gave a yellow solid (1.0 g). M.P. 65-69°C; Anal, calcd. for CwHuCINzOg: C, 56.03; H, 3.98; N, 10.05. Found: C, 56.14; H, 4.04; N, 10.16. MW 278.72; MS (m/e) 279 (M + +1 ). PREPARATION 25 2-(3-Nitro-phenoxy)-nicotinic acid ethyl ester M.P. 70-72°C; MW 288.26; MS (m/e) 289 (M + +1). PREPARATION 26 2-(3-Cyano-phenoxy)-nicotinic acid ethyl ester MW 268; 1 H NMR (CDCI 3 ) d 1.4 (3H, t), 4.39 (2 H, q), 7.12-8.4 (7 H, m). PREPARATION 27 2-(3-Dimethylamino-phenoxy)-nicotinic acid ethyl ester MW 286.33; MS (m/e) 287 (M + +1). PREPARATION 28 2-(4-Cyano-phenoxy)-nicotinic acid ethyl ester MW 268; MS (m/e) 268 (M + ). PREPARATION 29 2-(3-Acetylamino-phenoxy)-nicotinic acid ethyl ester MW 300.32; MS (m/e) 301 (M + +1). PREPARATION 30 2-(3-chloro-phenoxy)-nicotinic acid ethyl ester MW 277.71 ; MS (m/e) 278 (M + +1 ). PREPARATION 31 2-(1H-lndol-4-yloxy)-nicotinic acid ethyl ester MW 282; 1 H NMR (DMSO-d 6 ) d 5.9 (1 H, s), 6.4-8.4 (7 H, m), 11.20 (1 H, bs). PREPARATION 32 2-(3-Trifluoromethyl-phenoxy)-nicotinic acid ethyl ester M.P. 46-48°C; MW 311; MS (m/e) 312 (M + +1). PREPARATION 33 2-(3-Tetrazol-1-yl-phenoxy)-nicotinic acid ethyl ester M.P. 100-102°C; MW 311.27; MS (m/e) 312 (M + +1). PREPARATION 34 2-(3-Methylsulfanyl-phenoxy)-nicotinic acid ethyl ester MW 289.356; MS (m/e) 290 (M + +1 ). PREPARATION 35 2-(3-Acetyl-phenoxy)-nicotinic acid ethyl ester MW 285.302; MS (m/e) 286 (M + +1). PREPARATION 36 2-(3-Trifluoromethoxy-phenoxy)-nicotinic acid ethyl ester MW 327.262; MS (m/e) 328 (M + +1). PREPARATION 37 2-(3.4-difluoro-phenoxy)-nicotinic acid ethyl ester MW 279.26; MS (m/e) 279 (M + ). PREPARATION 38 2-(3.5-difluoro-phenoxy)-nicotinic acid ethyl ester MW 279.26; MS (m/e) 279 (M + ). PREPARATION 39 2-(3-Fluoro-phenoxy)-nicotinic acid ethyl ester MW 261.26 MS (m/e) 262 (M + ). PREPARATION 40 2-(3-Cyano-4-fluoro-phenoxy)-nicotinic acid ethyl ester MW 286.28 MS (m/e) 286 (M + ). PREPARATION 41 2-(Benzo[1.3]dioxol-5-yloxy)-nicotinic acid ethyl ester MW 287, 1 H NMR (DMSO-d 6 ) d 1.2 (3H, t), 4.30 (2 H, q), 6.0 (2 H, s), 6.5-8.4 (6 H, m). PREPARATION 42 2-(3-Dimethylcarbamoyl-phenoxy)-nicotinic acid ethyl ester 1 H NMR (CDCL 3 ) d 1.36 (3H, t), 3.00 (3H, s), 3.07 (3H, s), 4.38 (2H, q), 7.06 (1 H, m), 7.19 (1H, m), 7.24 (2 H, m), 7.42 (1 H, m), 8.24 (2 H, dd). PREPARATION 43 2-(3-Formyl-phenoxy)-nicotinic acid ethyl ester MW 271.29 MS (m/e) 271 (M + ). PREPARATION 44 2-Chloro-nicotinic acid ethyl ester To a solution 2-Chloro-nicotinic acid (12.5 g) in Ethanol (250 ml) was added thionyl chloride (5.77 ml) dropwise and refluxed for 1.5 hours. The mixture was concentrated to remove ethanol and diluted with 300 ml water. Solid sodium bicarbonate was added to adjust the solution to pH 8.0. This was extracted with ethyl acetate, wahed with water, saturated bicarbonate solution, water and brine, dried over Na 2 S0 4 , filtered and concentrated to a yellow liquid (10.0 g). MW 185.61 ; MS (m/e) 185 (M + ). PREPARATION 45 2-(4-Cyano-phenoxy)-nicotinic acid A solution of 2-(4-Cyano-phenoxy)-nicotinic acid methyl ester (0.200 grams, 0.787 mmole) in tetrahydrofuran (3 ml) and 1 M LiOH»H 2 0 (1.97 ml) was stirred over night. The mixture was diluted with 25 ml water, acidified to pH 1with 2 N hydrochloric acid and filtered to give a white solid (0.144 g). MW 240; 1 H NMR (DMSO-d 6 ) d 7.2 (3H, m), 7.90 (2 H, m), 8.35 (2 H, m), 13.5 (1 H, bs). The compounds of Preparations 46 was prepared according to the procedure of Preparation 45 substituting the corresponding ester for 2-(4-Cyano-phenoxy)-nicotinic acid methyl ester. The duration of reaction was between 1 and 24 hours. PREPARATION 46 2-(3-Cyano-4-fluoro-phenoxy)-nicotinic acid MW 258 22 MS (m/e) 258, 257 (M + ) Preparation 47 2-(4-aminomethyl-phenyl)-propan-2-ol To a stirred solution of 4-(1-hydroxy-1-methyl-ethyl)-benzonιtrιle (20 9 g, 0 13 mol ) in dry tetrahydrofuran (300 mL) at 0°C was added slowly dropwise 1 OM lithium aluminium hydride in tetrahydrofuran (388 mL, 0 39 mol ) The mixture was refluxed for 30 mm then cooled to 0°C and quenched with methanol (50 mL) added slowly dropwise The mixture was concentrated in vacuo to half volume and diluted with chloroform (1200 mL) then washed with water (300 mL) The resulting suspension was filtered through Celite and the filtrate layers seperated The organic extract was dried (MgS0 4 ) and concentrated to give 16 2g as a light yellow solid mp 64-6°C NMR (CDCI 3 ) 7 45 (d, 2H), 7 26 (d, 2H), 3 83 (s, 2H), 1 57 (s, 6H) GC-MS (m/e, %) 164 (M + , 15), 150 (80), 132 (75), 106 (100) PREPARATION 48 2-(4-Cyano-phenoxy)-nicotinic acid methyl ester A solution of 2-(4-Cyano-phenoxy)-nιcotιnιc acid ethyl ester (0 90 grams, 2 44 mmole) in methanol (10 ml) and potassium carbonate (1 01 grams, 7 33 mmole) was refluxed for 20 minutes The mixture was diluted with 100 ml water, acidified to pH 1 and filtered to give a solid (0 200 g) MW 254, MS (m/e) 254 (M + ) PREPARATION 49 2-(3-Chloro-phenoxy)-nicotinamide A solution of 2-(3-Chloro-phenoxy)-nιcotιnonιtrιle (7 81 grams, 33 9 mmole), 3% hydrogen peroxide (190 ml, 169 mmole) and 50 % potassium hydroxide (380 ml, 3 39 mmole) in ethanol (100 ml) was stirred at 70° C over night The mixture was concentrated to 250 ml and cooled to 0°C A solid was isolated by filtration, dissolved in ethyl acetate, dired over magnesium sulfate and concentrated to a white solid (6 51 g) M P 225-228°C, MW 248 67, MS (m/e) 250 (M + +1) PREPARATION 50 2-(3-Chloro-phenoxy)-nicotinonitrile A solution 2-Chloro-nιcotιnonιtrιle (5 0 grams, 36 1 mmole), cesium carbonate (23 5 grams, 72 2 mmole) and 3-chlorophenol (4 65 grams, 36 1 mmole) in dimethylformamide (100 ml) was heated to 80°C over night The mixture was cooled and poured into 500 ml water and extracted with diethyl ether The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to a white solid (8 21 g) M P 88-90°C, Anal calcd for C 12 H 7 N 2 0CI C, 62 49, H, 3 06, N, 12 15 Found C, 62 43, H, 3 00, N, 12 13 PREPARATION 51 2-(4-Fluoro-phenoxy)-pyridin-3-ylamine To a solution 2-(4-Fluoro-phenoxy)-3-nitro-pyridine (3.00 grams, 12.81 mmole) in ethyl acetate (100 ml) was added 10% palladium on carbon ( 0.600 g). This was shaken under 50 psi hydrogen for 1 hour. The catalyst was removed by filtration, and the solution was concentrated to give a white solid (2.49 g). M.P. 92-94°C; MW 204.20; MS (m/e) 204 (M + ). The compound of Preparation 10a was prepared according to the procedure of Preparation 10 substituting the corresponding nitro for 2-(4-Fluoro-phenoxy)-3-nitro-pyridine. The duration of reaction was between 1 and 24 hours. PREPARATION 52 2-(Pyridin-3-yloxy)-pyridin-3-ylamine MW 187; MS (m/e) 188 (M + +1). PREPARATION 53 2-(4-Fluoro-phenoxy)-3-nitro-pyridine A solution 2-Chloro-3-nitro-pyridine (5.0 grams, 31.54 mmole), cesium carbonate (25.7 grams, 78.85 mmole) and 4-fluorophenol (3.6 grams, 34.69 mmole) in dimethylformamide (85 ml) was stirred for 2 hours at room temperature. The mixture was diluted with 250 ml water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over Na 2 S0 4 , filtered, and concentrated to a yellow solid (7.16 g). M.P. 87-89°C; MW 234.1 ; MS (m/e) 234 (M + ). The compound of Preparation 54 was prepared according to the procedure of Preparation 53 substituting the corresponding alcohol for 4-fluorophenol. The duration of reaction was between 1 and 24 hours. PREPARATION 54 2-(Pyridin-3-yloxy)-3-nitro-pyridine MW 217.186; MS (m/e) 218 (M + +1). PREPARATION 55 2-(3-Chloro-phenoxy)-pyridine-3-carbaldehyde To a solution of methyl sulfoxide (0.23 ml, 3.3 mmole) and methylene chloride (10 ml) at -70°C was added oxalyl chloride (0.20 ml, 2.3 mmole) dropwise over 5 minutes and stirred for 1 hour. A solution of [2-(3-Chloro-phenoxy)-pyridin-3-yl]-methano! (0.39 grams, 1.7 mmole) in methylene chloride (10 ml) was added to the stirring mixture dropwise and stirred at - 70°C for 1 hour. It was warmed to - 35°C for 15 minutes and cooled down to - 70°C at which time triethylamine (1.15 ml, 8.3 mmole) was added and the mixture was warmed to 0°C. The mixture was diluted with 20 ml methylene chloride and washed with saturated sodium hydrogencarbonate and brine, dried over Na 2 S0 4 , filtered, and concentrated to an orange oil which was which was purified by chromatography on silica gel eluting with 1/3 ethyl acetate/ hexane to give a yellow oil (0.180 g). MW 233.65; MS (m/e) 234 (M + +1). The compound of Preparation 56 was prepared according to the procedure of Preparation 55 substituting the corresponding alcohol for [2-(3-Chloro-phenoxy)-pyridin-3-yl]- methanol. The duration of reaction was between 1 and 24 hours. PREPARATION 56 2-(Pyridin-3-yloxy)-pyridine-3-carbaldehyde MW 200.20; MS (m/e) 201 (M + +1). PREPARATION 57 [2-(3-Chloro-phenoxy)-pyridin-3-yl]-methanol To a solution of 2-(3-Chloro-phenoxy)-nicotinic acid ethyl ester (0.5 g) and tetrahydrofuran (10 ml) at 0°C was added lithium aluminum hydride (0.4 g) in two portions and stirred for 30 minutes. The solution was allowed to warm to room temperature and stirred over night. The mixture was quenched with 1 N sodium hydroxide (0.5 ml) and diluted with water. The mixture was filtered through celite which was washed with ethyl acetate to extract the product. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to an oil (0.39 g). MW 235.67; MS (m/e) 236 (M + +1 ). The compound of Preparation 58 was prepared according to the procedure of Preparation 57 substituting the corresponding ester for 2-(3-Chloro-phenoxy)-nicotinic acid ethyl ester. The duration of reaction was between 1 and 24 hours. PREPARATION 58 [2-(Pyridin-3-yloxy)-pyridin-3-yl]-methanol MW 202.21 ; MS (m/e) 203 (M + +1 ). PREPARATION 59 3-Tetrazol-1-yl-phenol To a solution 1-(3-Benzyloxy-phenyl)-1 H-tetrazole (0.640 grams, 2.54 mmole) in ethanol (15 ml) was added 10% palladium on carbon ( -0.100 g). This was stirred under hydrogen balloon over night. The catalyst was removed by filtration, and the solution was concentrated to give a white solid (0.364 g). M.P. 171-172°C; MW 162.12; MS (m/e) 163 (M + +1 ). PREPARATION 60 1 -(3-Benzyloxy-phenyl)-1 H-tetrazole To a solution of 3-Benzyloxy-phenylamine (1.50 grams, 7.53 mmole) and acetic acid (15 ml) at 70°C was added a solution of ethyl orthoformate (1.116g, 7.53 mmole) in acetic acid (4 ml) and stirred for 4 hours. To the solution was added sodium azide (1.468g, 22.6 mmole) in two portions and stirred for 20 hours at 70 °C. The mixture was extracted with ethyl acetate The combined extracts were washed with saturated sodium hydrogencarbonate and brine, dried over Na 2 S0 4 , filtered, and concentrated The product was purified via flash chromatography on silica using 3/1 hexane/ ethyl acetate as eluent to give white crystals (0 650 g) M P 85-86°C, MW 252 25, MS (m/e) 252 8 (M + ) PREPARATION 61 3-Methylsulfanyl-phenol To a solution of acetic acid (200 ml) was cooled to - 50°C was bubbled in HBr gas (20 g) m-Methoxyphenylmethylsulfide (20 grams, 130 mmole) and 48% aqueous HBr (10 ml) was added and the mixture was refluxed for 3 hours The acetic acid was removed, and the oil was poured into 150 ml ice water It was extracted with diethyl ether The combined extracts were washed with 15% KOH, and the agueous was acidified with concentrated hydrochloric acid and extracted with diethyl ether The combined extracts weredned over Na 2 S0 4 , filtered, and concentrated to an oil (11 5 g) MW 140 205, MS (m/e) 141 (M + +1) PREPARATION 62 1 -Methoxy -3-methylsulfanyl-benzene To a suspension of magnesium (7 2 grams, 296 mmole) and iodine (100 ml) in diethyl ether (250 ml) m-Bromoanisole (47 0 grams, 250 mmole) was added slowly with spontaneous refluxing Methyl disulfide (16 0 grams, 160 mmole) was added and stirred for 1 hour A solution of water (100 ml) and concentrated hydrochloric acid ( 30 ml) was added as the mixture was being cooled The layers were separated and the aqueous was extracted with diethyl ether The combined extracts were dried over MgS0 4 , filtered and concentrated to an oil which was purified by distilation (20 mm Hg) at 130-135°C (23 5 g) PREPARATION 63 2-(Pyridin-3-ylmethoxy)-nicotinic acid ethyl ester To a solution of Pyrιdιn-3-yl-methanol (0 59 grams, 5 4 mmole) in dimethylformamide (20 ml) sodium hydride (0 259 grams, 6 5 mmole) was added and stirred for 30 minutes 2- Chloro-nicotmic acid ethyl ester (1 0 grams, 54 mmole) was added via syringe and stirred at room temperature over night The mixture was diluted with water (150 ml) and extracted by diethyl ether and ethyl acetate The combined extracts were washed with 1 N NaOH, water and brine, dried over Na 2 S0 4 , filtered, and concentrated to an oil (1 3 g) MW 258 28, MS (m/e) 259 (M + +1) PREPARATION 64 2-(3-Methoxycarbonyl-phenoxy)-nicotinic acid To a solution 2-(3-Methoxycarbonyl-phenoxy)-nιcotιnιc acid benzyl ester (1 1 g) in methanol (15 ml) and ethyl acetate (15 ml) was added 10% palladium on carbon ( 0 2 g) This was shaken under 30 psi hydrogen for 2 hours The catalyst was removed by filtration, and the solution was concentrated to give a solid which was triturated in methylene chloride/ hexane to give a white solid (0.630 g). MW 273.26; MS (m/e) 274 (M + +1). PREPARATION 65 2-(3-Methoxycarbonyl-phenoxy)-nicotinic acid benzyl ester Into a solution of 2-(3-lodo-phenoxy)-nicotinic acid benzyl ester (1.7 grams, 3.94 mmole), dppf (0.131 grams, 0.24 mmole), Pd(OAc) 2 (0.027 grams, 0.12 mmole) and triethylamine (0.797 grams, 7.9 mmole) in methanol (10 ml) was bubbled in carbon monoxide gas for 5 minutes. The mixture was heated to 60°C for 4 hours, poured into 200 ml water, and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to an oil which was purified via flash chromatography on silica using 25% ethyl acetate/ hexane as eluent (1.2 g). MW 363.39; MS (m/e) 364 (M + +1). PREPARATION 66 2-(3-lodo-phenoxy)-nicotinic acid benzyl ester A solution 2-Chloro-nicotinic acid benzyl ester (1.7 grams, 6.86 mmole), cesium carbonate (4.5 grams, 13.7 mmole) and 3-iodophenol (1.7 grams, 7.54 mmole) in dimethylformamide (20 ml) was stirred for 2 hours at 70-80°C. The mixture was poured into 150 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to an oil which was purified via flash chromatography on silica using 30% ethyl acetate/ hexane as eluent (2.32 g). MW 431.24; MS (m/e) 432 (M + +1 ). PREPARATION 67 2-Chloro-nicotinic acid benzyl ester A solution 2-Chloro-nicotinic acid (3.0 grams, 19.0 mmole), potassium carbonate (6.5 grams, 48.0 mmole) and benzyl bromide (2.8 ml, 24.0 mmole) in dimethylformamide (20 ml) was stirred at room temperature over night. The mixture was poured into 200 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to an oil which was purified via flash chromatography on silica using 10% ethyl acetate/ hexane as eluent (2.8 g). MW 247.69; MS (m/e) 247 (M + ). PREPARATION 68 C-(5-Chloro-furan-2-yl)-methylamine To a solution of 5-Chloro-furan-2-carbaldehyde oxime (1.38 grams, 9.5 mmole) in tetrahydrofuran (30 ml) was added dropwise 1.0 M lithium aluminum hydride (21 ml, 21 mmole) and refluxed for 30 minutes. The mixture was cooled to 0°C and quenched with 5 ml methanol and 5 ml saturated NH 4 CI. The mixture was poured into 150 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to an oil (0.403 g). MW 131.57; MS (m/e) 130/131 (M + ). The compounds of Preparations 69-71 were prepared according to the procedure of Preparation 68 substituting the corresponding oxime for 5-Chloro-furan-2-carbaldehyde oxime. The duration of reaction was between 30 minutes and 24 hours. PREPARATION 69 C-(5-Methyl-furan-2-yl)-methylamine MW 111.16; MS (m/e) 111 (M + ). PREPARATION 70 C-(4-Chloro-thiophen-2-yl)-methylamine MW 147.64. PREPARATION 71 C-Thiazol-2-yl-methylamine MW 114.19. PREPARATION 72 5-Chloro-furan-2-carbaldehyde oxime To a solution 5-Chloro-furan-2-carbaldehyde (1.3 grams, 9.96 mmole) and NaOAc (1.8 grams, 21.9 mmole) in methylene chloride (30 ml) and water (30 ml) was added NH 2 OH»HCI (0.761 grams, 10.96 mmole) and stirred at room temperature over night. The mixture was poured into 150 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to a solid (1.38 g). MW 145.55; MS (m/e) 145/147 (M + ). The compounds of Preparations 73-75 were prepared according to the procedure of Preparation 72 substituting the corresponding aldehyde for 5-Chloro-furan-2-carbaldehyde. The duration of reaction was between 1 and 24 hours. PREPARATION 73 5-Methyl-furan-2-carbaldehyde oxime Mixture of E/Z isomers; MW 125.11 ; H NMR (CDCI 3 ) d 2.32 (3H, s), 6.03 (1 H, d), 6.12 (1 H, d), 6.0 (2 H, s), 6.48 (1 H, d), 7.22 (1 H, d), 7.42 (1 H, s), 7.91 (1 H, s). PREPARATION 74 4-Chloro-thiophene-2-carbaldehyde oxime MW 161.62. PREPARATION 75 Thiazole-2-carbaldehyde oxime MW 128.17. PREPARATION 76 5-Chloro-furan-2-carbaldehyde A solution of 5-Nιtro-furan-2-carbaldehyde (14 1 g,) in concentrated hydrochloric acid (60 ml) was steam distilled until ~150 ml liquid was collected The mixture was poured into 150 ml water and extracted with diethyl ether The combined extracts were washed with saturated NaHC0 3 , water and brine, dried over MgS0 4 , filtered, and concentrated to an oil which was purified via flash chromatography on silica using 20% ethyl acetate/ hexane as eluent to give a white solid (1 3 g) MW 130 53, MS (m/e) 129/131 (M + +1 ) PREPARATION 77 2.4.6-Trifluoro-benzylamine A solution of 2-Bromomethyl-1 ,3,5-trιfluoro-benzene (2 0 g,8 9 mmole) and HMTA (3 1 grams, 22 2 mmole) in chloroform (35 ml) was refluxed for 18 hours A resulting precipitate was isolated by filtration and taken up into methanol (10 ml), water (5 ml) and concentrated hydrochloric acid (5 ml) and refluxed for 4 hours The mixture was poured into 200 ml water and washed with diethyl ether The aqueous was basified with 5 N sodium hydroxide and extracted with diethyl ether The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to an oil which solidified on standing (1 32 g) MW 161 14, MS (m/e) 145 (M + -NH 2 ) The compounds of Preparation 78-79 were prepared according to the procedure of Preparation 77 substituting the corresponding halide for 2-Bromomethyl-1 ,3,5-trιfluoro- benzene The duration of reaction was between 1 and 24 hours PREPARATION 78 C-(5-Chloro-thiophen-2-yl)-methylamine MW 147 64, MS (m/e) 147 (M + ) PREPARATION 79 C-(3.5-Dichloro-thiophen-2-yl)-methylamine MW 182 08, MS (m/e) 181-186 (M + ) PREPARATION 80 C-(3.4-Dichloro-thiophen-2-yl)-methylamine To a solution 3,4-Dιchloro-thιophene-2-carboxylιc acid amide (0 640 grams, 3 3 mmole) in tetrahydrofuran (20 ml) was added dropwise 1 0 M lithium aluminum hydride (7 ml, 7 mmole) and stirred at room temperature for 30 minutes The mixture was cooled to 0°C and quenched with 3 ml methanol and 5 ml saturated NH 4 CI added dropwise The mixture was poured into 100 ml water and extracted with diethyl ether This was then filtered through celite The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to an oil which was purified via flash chromatography on silica using 5% methanol/ methylene chloride as eluent to give an oil (0.335 g). MW 182.08; 1 H NMR (CDCI 3 ) d 4.01 (2H, s), 7.09 (1 H, s). The compounds of Preparations 81-88 were prepared according to the procedure of Preparation 80 substituting the corresponding amide for 3,4-Dichloro-thiophene-2-carboxylic acid amide. The duration of reaction was between 30 minutes and 24 hours. PREPARATION 81 C-(3-Chloro-thiophen-2-yl)-methylamine MW 147.64; 1 H NMR (CDCI 3 ) d 3.99 (2H, s), 6.86 (1 H, d), 7.16 (1 H, d). PREPARATION 82 C-Benzo[b]thiophen-2-yl-methylamine MW 163.26; MS (m/e) 163 (M + ). PREPARATION 83 C-(5-Trifluoromethyl-thiophen-2-yl)-methylamine MW 181.20; MS (m/e) 181 (M + ). PREPARATION 84 2-(5-Aminomethyl-thiophen-2-yl)-propan-2-ol MW 171.29. PREPARATION 85 2-(5-Aminomethyl-3-chloro-thiophen-2-yl)-propan-2-ol MW 205.73; 1 H NMR (CDCI 3 ) d 1.69 (6H, s), 3.92 (2 H, s), 6.69 (1 H, s). PREPARATION 86 2-(5-Aminomethyl-furan-2-yl)-propan-2-ol MW 155.22; 1 H NMR (CDCI 3 ) d 1.56 (6H, s), 3.77 (2H, s), 6.02 (1 H, d), 6.06 (1 H, d). PREPARATION 87 3-(5-Aminomethyl-thiophen-2-yl)-pentan-3-ol MW 199.35; 1 H NMR (CDCI 3 ) d 0.85 (6H, t), 1.82 (4H, q), 3.97 (2H, s), 6.67 (1 H, d), 6.73 (1 H, d). PREPARATION 88 2-(5-Aminomethyl-4-chloro-thiophen-2-yl)-propan-2-ol MW 205.73; 1 H NMR (CDCI 3 ) d 1.60 (6H, s), 3.92 (2H, s), 6.71 (1 H, s). PREPARATION 89 3.4-Dichloro-thiophene-2-carboxylic acid amide To a stirred suspension of 3,4-Dichloro-thiophene-2-carboxylic acid (1.0 grams, 5.08 mmole) in methylene chlroride (20 ml) and dimethylformamide (0.2 ml) was added thionyl chloride (1.9 ml, 25.3 mmole) and refluxed for 3 hours. The mixture was concentrated to give an oil. The oil was taken up in methylene chloride (15 ml), cooled to 0°C and NH 3 gas was bubbled in for 5 minutes and stirred for 20 minutes. The mixture was diluted with methylene chloride (150 ml) washed with water and brine, dried over MgS0 4 , filtered, and concentrated to a solid which was purified via flash chromatography on silica using 2.5 % methanol/ methylene chloride as eluent to give a solid which was triturated in methylene chloride to give a white solid (0.475 g). MW 196.06; MS (m/e) 195/197 (M + ). The compounds of Preparations 90-92 were prepared according to the procedure of Preparation 89 substituting the corresponding acid for 3,4-Dichloro-thiophene-2-carboxylic acid. The duration of reaction was between 1 and 24 hours. PREPARATION 90 3-Chloro-thiophene-2-carboxylic acid amide MW 161 ; MS (m/e) 161/163 (M + ). PREPARATION 91 5-Trifluoromethyl-thiophene-2-carboxylic acid amide MW 195.18; MS (m/e) 196 (M + +1). PREPARATION 92 5-(1-Hydroxy-1-methyl-ethyl)-furan-2-carboxylic acid amide MW 169.18; 1 H NMR (DMSO-d 6 ) d 1.40 (6H, s), 5.20 (1 H, d), 6.26 (1 H, d), 6.93 (1 H, d), 7.24 (1 H, bs), 7.58 (1 H, bs). PREPARATION 93 4-(2.2.2-Trifluoro-ethoxy)-benzylamine To a solution 4-(2,2,2-Trifluoro-ethoxy)-benzonitrile (0.5 grams, 2.48 mmole) in tetrahydrofuran (10 ml) was added 1.0 M lithium aluminum hydride (6.2 ml, 6.2 mmole) and refluxed for 40 minutes. The mixture was cooled to 0°C and quenched with 5 ml methanol added dropwise and diluted with saturated NH 4 CI (50 ml). The mixture was extracted with diethyl ether. The combined extracts were washed with brine, dried over Na 2 S0 4 , filtered, and concentrated to an oil which was purified via flash chromatography on silica using 5% methanol/ methylene chloride as eluent to give an oil (0.230 g). MW 205.18; MS (m/e) 206(M + +1). The compounds of Preparations 94-106 were prepared according to the procedure of Preparation 93 substituting the corresponding nitrile for 4-(2,2,2-Trifluoro-ethoxy)- benzonithle. The duration of reaction was between 30 minutes and 24 hours. PREPARATION 94 4-Difluoromethoxy-benzylamine MW 173.18; 1 H NMR (CDCI 3 ) d 3.85 (2H, s), 6.48 (1 H, t), 7.09 (2H, m), 7.30 (2 H, m). PREPARATION 95 C-(1 H-lndol-5-yl)-methylamine MW 146.21 ; MS (m/e) 146 (M + ). PREPARATION 96 5-Fluoro-thiophene-2-(2-methylamine) 1 H-NMR (CDCI 3 ): d 6.47 (m, 1 H), 6.26 (m, 1 H), 3.91 (m, 2H). GC-MS (m/e, %) 131 (M + , 100). PREPARATION 97 4-Aminomethyl-2.6-di-tert-butyl-phenol MW 235; MS (m/e) 235 (M + ). PREPARATION 98 2.3-Difluoro-benzylamine MW 143.14. PREPARATION 99 2-(4-Aminomethyl-2-chloro-phenyl)-propan-2-ol MW 199.70; MS (m/e) 199/201 (M + ). PREPARATION 100 2-(4-Aminomethyl-3-chloro-phenyl)-propan-2-ol MW 199.70; MS (m/e) 198/200 (M + +1). 1 H NMR (CDCI 3 ) d 1.54 (6H, s), 3.89 (2H, s), 7.31 (2H, m), 7.48 (1 H, d). PREPARATION 101 1-(4-Aminomethyl-phenyl)-cyclobutanol MW 177.27; MS (m/e, %) 177 (M + , 3), 160 (45), 148 (100). PREPARATION 102 1 -(4-Aminomethyl-phenyl)-prop-2-yn-1 -ol MW 161.22; MS (m/e, %) 160(M + , 15), 115 (20), 106 (100). PREPARATION 103 4-(2-Methyl-[1.3]dioxolan-2-yl)-benzylamine MW 193.248; MS (m/e) 178 (M + -NH 3 ). PREPARATION 104 C-(1.4-Dioxa-spiro[4.5]dec-8-yl)-methylamine MW 171.241 ; MS (m/e) 172 (M + +1). PREPARATION 105 1-(4-Aminomethyl-phenyl)-ethanol MW 151.21 ; MS (m/e) 152 (M + +1). PREPARATION 106 2-(4-Aminomethyl-3-fluoro-phenyl)-propan-2-ol 1 H NMR (CDCI 3 ) d 1.54 (6H, s), 3.89 (2H, s), 7.30 (2H, m), 7.48 (1 H, s). Preparation 107 4-(1-hydroxy-1-methyl-ethyl)-benzonitrile. To a stirred solution of 4-cyanoacetophenone (49.5 g, 0.34 mol.) in dry tetrahydrofuran (400 mL) at -78°C was added dropwise 3.0M methylmagnesium chloride (150 mL, 0.45 mol.). The mixture was allowed to slowly warm to 0°C over 3.5h then quenched with methanol (80 mL) added dropwise. The mixture was poured into water (1000 mL) and acidified to pH~3 with oxalic acid then extracted with ethyl acetate (2 X 500mL). The organic extracts were combined and washed with water (2 X 100 mL), brine (100 mL), dried (MgS0 4 ) then concentrated to give a white residue. Flash Chromatography on Silica Gel eluting with 20% ethyl acetate/ hexanes yielded 13.5g clear oil which solidified upon standing mp 45-7°C. PREPARATION 108 4-(2.2.2-Trifluoro-ethoxy)-benzonitrile To a solution 4-cyanophenol (5.0 grams, 42.0 mmole) in HMPT (40 ml) was added sodium hydride (1.68 grams, 42.0 mmole) and stirred for 15 minutes at room temperature. Via syringe 2,2,2-trifluoroethyl methane sulphonate (8.98 grams, 50.4 mmole) was added and the mixture was stirred at 140°C over night. The mixture was cooled to room temperature, diluted with 300 ml ice water and 50 ml 2 N hydrochloric acid and extracted with diethyl ether. The combined extracts were washed with water, 1N sodium hydroxide and brine, dried over Na 2 S0 4 , filtered, and concentrated to an oil which was purified via flash chromatography on silica using 25% diethyl ether/ hexane as eluent to give an oil (2.68 g). Synthesis 727 (1980). PREPARATION 109 1-(5-Chloro-thiophen-2-yl)-ethylamine A solution of 1-(5-Chloro-thiophen-2-yl)-ethanone (5.0 grams, 31.0 mmole) in formamide (6 ml, 150.0 mmole) was stirred at 160°C for 18 hours. The mixture was poured into 200 ml and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to an oil which was purified via flash chromatography on silica using 20% ethyl acetate/ hexane as eluent to give an oil. The oil was taken up in 26 ml 6 NaOH, 20 ml methanol and 5 ml tetrahydrofuran and refluxed for three hours. The mixture was poured into 200 ml and extracted with diethyl ether. The combined extracts were concentrated to give a dark oil (2.3 g). MW 161.67; MS (m/e) 161 (M + ). The compounds of Preparation 110-111 were prepared according to the procedure of Preparation 109 substituting the corresponding aldehyde or ketone for 1-(5-Chloro-thiophen- 2-yl)-ethanone. The duration of reaction was between 30 minutes and 24 hours. PREPARATION 110 C-(5-Methyl-thiophen-2-yl)-methylamine MW 127.23; MS (m/e) 127 (M + ). PREPARATION 111 C-(3-Methyl-thiophen-2-yl)-methylamine MW 127.23; MS (m/e) 127 (M + ). PREPARATION 112 5-Aminomethyl-1.3-dihydro-indol-2-one To a solution of 2-Oxo-2,3-dihydro-1 H-indole-5-carbonitrile ( 1.3 g) in methanol (30 ml) was added 10% Pt0 2 ( 0.200 g). This was shaken under 44 psi hydrogen over night. The catalyst was removed by filtration, and the mixture was dried over Na 2 S0 4 . The solution was concentrated to give a yellow solid. (1.1 g). MW 162; MS (m/e) 162 (M + ). PREPARATION 113 2-Oxo-2.3-dihydro-1H-indole-5-carbonitrile A solution of 3,3-Dibromo-2-oxo-2,3-dihydro-1 H-indole-5-carbonitrile (10.5 grams, 33.3 mmole) and Zn dust (22.0 grams, 338.5 mmole) in acetic acid (250 ml) was stirred at room temperature for 45 minutes. The mixture was filtered through celite and concentrated to dryness. The resulting oil was diluted with 300 ml water and extracted with ethyl acetate. The combined extracts were washed with 1 N sodium hydroxide and brine, dried over MgS0 4 , filtered, and concentrated to give a white solid (1.9 g). MW 158. PREPARATION 114 3.3-Dibromo-2-oxo-2.3-dihydro-1H-indole-5-carbonitrile To a solution of 1 H-lndole-5-carbonitrile (5.0 grams, 35.2 mmole) in t-Butanol (300 ml) was added pyridinium bromide perbromide (37.5 grams, 105.6 mmole) over 10 minutes and stirred at room temperature for 2 hours. The mixture was concentrated to an orange oil. The resulting oil was diluted with 500 ml water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over Na 2 S0 4 , filtered, and concentrated to give a yellow solid (10.37 g). MW 315.95; MS (m/e) 316 (M + +1 ). PREPARATION 115 6-Amino-3H-benzooxazol-2-one A solution of 6-Nitro-3H-benzooxazol-2-one (8.4 grams, 46.0 mmole) and Tin (16.0 g) in concentrated hydrochloric acid (100 ml) was stirred at 60°C for 2 hours. The mixture was diluted with water, basified to pH 12 and extracted with ethyl acetate. The combined extracts were dried over Na 2 S0 4 , filtered, and concentrated to give an orange solid (2.45 g). MW 150; MS (m/e) 151 (M + +1). PREPARATION 116 6-Nitro-3H-benzooxazol-2-one A solution of 3H-Benzooxazol-2-one (10.0 g) in concentrated HN0 3 (100 ml) was stirred at 40°C. A precipitate formed and the reaction temperature rose. It was cooled below 50 °C in an ice bath. The mixture was diluted with ice water, and the precipitate was isolated by filtration. The product was washed with water to give a white solid. (8.4 g). M.P. 239-241. PREPARATION 117 5-Aminomethyl-1H-indole-2-carboxylic acid ethyl ester A solution of 5-Cyano-1 H-indoie-2 -carboxylic acid ethyl ester (1.8 grams, 8.4 mmole) and Bu 4 N + BH 3 " in methylene chloride (80 ml) was refluxed for 4 hours. The mixture was concentrated to a brown oil which was dissolved in 10% hydrochloric acid (50 ml) and refluxed for 1 hour. The mixture was extracted with ethyl acetate (discarded) and the pH was neutralized. The aqueous was extracted with ethyl acetate. The combined extracts were dried over Na 2 S0 4 , filtered, and concentrated to give a solid. (0.920 g). MW 218.258; MS (m/e) 218 (M + ). PREPARATION 118 3.5-Di-tert-butyl-4-hydroxy-benzonitrile A solution of 3,5-Di-tert-butyl-4-hydroxy-benzaldehyde oxime (3.0 grams, 8.4 mmole) in acetic anhydride (6 ml) was was refluxed for 2 hours. The mixture was cooled to 0°C and saturated sodium hydrogencarbonate was added. The mixture was extracted with methylene chloride. The combined extracts were washed with saturated NaHC0 3ι dried over Na 2 S0 4 , filtered, and concentrated to give a solid. This was dissolved in diethyl ether and extracted with 1 N sodium hydroxide which was then acidified to pH 1 and extracted with ethyl acetate. The extract was dried and concentrated to a yellow solid which was recrystalized from ethyl acetate/ hexane to give white crystals (1.05 g). MW 231; MS (m/e) 249 (M + +NH4 + ). PREPARATION 119 3.5-Di-tert-butyl-4-hydroxy-benzaldehyde oxime A solution of 3,5-Di-tert-butyl-4-hydroxy-benzaldehyde (10.0 grams, 42.67 mmole), NH 2 OH»HCI (14.83 grams, 213.3 mmole) and 40% KOH (80 ml) in methanol (100 ml) was stirred at room temperature over the weekend. The mixture was concentrated to remove methanol. The aqueous phase was acidified and extracted with ethyl acetate. The combined extracts were washed with water and brine , dried over Na 2 S0 4 , filtered, and concentrated to give a yellow solid. (8.9 g). M.P. 122-124°C; MW 249; MS (m/e) 249 (M + ). The compound of Preparation 120 was prepared according to the procedure of Preparation 119 substituting the corresponding aldehyde for 3,5-Di-tert-butyl-4-hydroxy- benzaldehyde. The duration of reaction was between 1 and 48 hours. PREPARATION 120 4-Hydroxy-3.5-dimethyl-benzaldehvde oxime MW 165; MS (m/e) 166 (M + +1). PREPARATION 121 4-Aminomethyl-2.6-dimethyl-phenol A solution of 4-Hydroxy-3,5-dimethyl-benzaldehyde oxime (1.0 grams, 6.06 mmole) in acetic acid (30 ml) and Zn dust (4.0 grams, 61.2 mmole) was stirred at ~60°C for 2 hours. The mixture was filtered through celite, basified by aqueous ammonium hydroxide and extracted with chloroform. The combined extracts were dried over MgS0 4 , filtered, and concentrated to give a foam (0.90 g). MW 151 ; MS (m/e) 151 (M + ). PREPARATION 122 1-(2-Chloro-phenyl)-ethane-1.2-diol To a vigrouosly stirred mixture of AD-mix (1.4g) in water (5 ml) and t-butanol (5 ml) at 0°C was added 1-Chloro-2-vinyl-benzene (0.140 grams, 1.0 mmole) and stirred at 0°C for 2 hours. To the mixture sodium sulfite (1.5 g) was added and allowed to warm to room temperature for 1 hour. The mixture was extracted with methylene chloride. The combined extracts were washed with brine, dried over Na 2 S0 4 , filtered, and concentrated to give a colorless oil (0.190 g). MW 172.61 ; MS (m/e) 190 (M + +18). PREPARATION 123 4-Chloro-5-(1-hydroxy-1-methyl-ethyl)-thiophene-2-carboxylic acid amide A solution of 4-Chloro-5-(1-hydroxy-1-methyl-ethyl)-thiophene-2-carboxylic acid methyl ester (2.4 g) in condensed NH 3 (20 ml) and methanol (10 ml) was stirred at room temperature in a sealed tube for 3 days. The solvent was evaporated to give a solid which was purified via flash chromatography on silica using 5% methanol/ methylene chloride as eluent to give a tan solid. This was triturated in diethyl ether to give a white solid (1.6 g). MW 219.71 ; MS (m/e) 237 (M + +18) 220 (M + +1) . The compounds of Preparations 124-125 were prepared according to the procedure of Preparation 123 substituting the corresponding ester for 4-Chloro-5-(1-hydroxy-1 -methyl- ethyl)-thiophene-2-carboxylic acid methyl ester. The duration of reaction was between 1 and 72 hours. PREPARATION 124 5-(1-Ethyl-1-hydroxy-propyl)-thiophene-2-carboxylic acid amide MW 213.33; MS (m/e) 213 (M + ). PREPARATION 125 3-Chloro-5-(1-hydroxy-1-methyl-ethyl)-thiophene-2-carboxylic acid amide MW 186.63; 1 H NMR (CDCI 3 ) d 1.63 (6H, s), 6.85 (1 H, s). PREPARATION 126 4-Chloro-5-(1-hydroxy-1-methyl-ethyl)-thiophene-2-carboxylic acid methyl ester To a solution of diisopropyl amine (6 ml, 38.9 mmole) in tetrahydrofuran (15 ml) at 0°C was added dropwise 2.5 M nBuLi (16 ml) and stirrred at 0°C for 10 minutes. The mixture was cooled to -78°C and 4-Chloro-thiophene-2-carboxylic acid (3.0 grams, 18.5 mmole) in tetrahydrofuran (15 ml) was added dropwise and stirred for 20 minutes then acetone (1.6 mL, 22.2 mmol.) was added and the mixture was allowed to warm to room temperature over 1 hour. The mixture was poured into 200 ml water and extracted with diethyl ether. The aqueous was acidified to pH 4 with oxalic acid and extracted with methylene chloride. The combined extracts were washed with water dried over MgS0 4 , filtered, and concentrated to a solid. This was taken up in diethyl ether (100 ml) and treated with CH 2 N 2 at 0°C. The reaction was quenched with acetic acid, diluted with diethyl ether (300 ml) and washed with saturated NaHC0 3ι water, and brine , dried over MgS0 4 , filtered, and concentrated to give an oil which was purified via flash chromatography on silica using 20% ethyl acetate/ hexane as eluent to give a solid (2.42 g). MW 234.72; MS (m/e) 234/236 (M + +1). The compounds of Preparations 127-129 were prepared according to the procedure of Preparation 126 substituting the corresponding acid for 4-Chloro-thiophene-2-carboxylic acid. The duration of reaction was between 1 and 24 hours. PREPARATION 127 5-(1-Hydroxy-1-methyl-ethyl)-furan-2-carboxylic acid amide MW 184.21 ; MS (m/e) 184 (M + ). PREPARATION 128 5-(1-Ethyl-1-hydroxy-propyl)-thiophene-2 -carboxy lie acid methyl ester MW 228.34; MS (m/e) 228 (M + ). PREPARATION 129 3-Chloro-5-(1-hydroxy-1-methyl-ethyl)-thiophene-2-carboxylic acid methyl ester MW 234.70; 1 H NMR (CDCI 3 ) d 1.62 (6H, s), 3.85 (3H, s), 6.84 (1 H, s). PREPARATION 130 5-Amino-pentanoic acid ethyl ester A solution of 5-Amino-pentanoic acid (1.06 grams, 9.0 mmole) and thionyl chloride (20.0 ml) was stirred at room temperature for 2 hours. The solvent was evaporated and ethanol (26.5 ml) was added and gently warmed. After 2 hours the solution was concentrated to give a yellow solid ( 0.580 g). MW 145.22; MS (m/e) 146 (M + +1 ). The compound of Preparations 131 was prepared according to the procedure of Preparation 130 substituting the corresponding acid for 5-Amino-pentanoic acid. The duration of reaction was between 1 and 24 hours. PREPARATION 131 trans-4-Aminomethyl-cyclohexanecarboxylic acid ethyl ester MW 185.28; MS (m/e) 186 (M + +1). PREPARATION 132 5-(1-Hydroxy-1-methyl-ethyl)-furan-2-carboxylic acid methyl ester To a solution of diisopropylamine ( 7.6 ml, 54.0 mmole) in tetrahydrofuran (20 ml) at 0°C was added 2.5 IVLnButyl lithium ( 22 ml, 54.0 mmole). The mixture was cooled to -78°C and a solution of Furan-2-carboxylic acid (3.0 grams, 27.0 mmole) in tetrahydrofuran (20 ml) was added dropwise and stirred for 20 minutes and acetone (2.4 ml, 32.0 mmole) was added. The mixture was stirred at -78°C for 10 minutes and allowed to warm to room temperature over 1 hour. The mixture was poured into 200 ml water, acidified with oxalic acid to pH 2 and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to give a solid. ( 0.580 g). MW 145.22; MS (m/e) 146 (M + +1). PREPARATION 133 3-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzonitrile To a solution of 3-Chloro-4-cyano-benzoic acid methyl ester ( 2.0 grams, 10.0 mmole) in tetrahydrofuran (30 ml) at -40°C was added 3.0 M CH 3 MgCI (8 ml, 22.0 mmole) dropwise. The mixture was allowed to warm to room temperature over one hour. The reaction was quenched with 10 ml methanol added dropwise, poured into 200 ml water, acidified with oxalic acid and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to give an oil. (2.1 g). MW 195.60; MS (m/e) 195/197 (M + ). The compound of Preparation 134 was prepared according to the procedure of Preparation 133 substituting the corresponding ester for 3-Chloro-4-cyano-benzoic acid methyl ester. The duration of reaction was between 1 and 24 hours. PREPARATION 134 2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzonitrile MW 195.60; MS (m/e) 195/197 (M + ). PREPARATION 135 2-Chloro-4-cyano-benzoic acid methyl ester A solution of 4-Bromo-2-chloro-benzoic acid methyl ester ( 3.1 grams, 12.0 mmole), Zn(CN) 2 0.875 grams, 7.0 mmole) and Pd(PPh 3 ) 4 (0.555 grams, 48.0 mmole) in dimethylformamide (30 ml) was heated to 90°C over night . The reaction was poured into 200 ml saturated sodium hydrogencarbonate and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to give an oil which was purified via flash chromatography on silica using 20% ethyl acetate/ hexane as eluent to give a white solid. (2.1 g). MW 195.61 ; MS (m/e) 195/197 (M + ). The compounds of Preparation 136 was prepared according to the procedure of Preparation 135 substituting 3-chloro-4-trifluoromethane sulfonyloxy-benzoic acid methyl ester for 4-Bromo-2-chioro-benzoic acid methyl ester. The duration of reaction was between 1 and 24 hours. PREPARATION 136 4-Trifluoroacetyl-benzonitrile MW 199.13; MS (m/e) 199 (M + ). Preparation 137 (S)-(+)-frans-1-(4-Aminomethyl-cyclohexyl)-ethanol. Prepared in an analogous manner to that of Preparation 253 from (S)-(+)-(frans-4-(1- Hydroxy-ethyl-)cyclohexylmethyl)carbamic acid benzyl ester which was obtained from (trans- 4-Acetyl-cyclohexylmethyl)-carbamic acid benzyl ester using (R)-2-Methyl-CBS- oxazaborolidine monohydrate in an analogous fashion as that of Preparation 254. PREPARATION 138 1-(4-Aminomethyl-phenyl)-2.2.2-trifluoro-ethanol To a solution of 4-Trifluoroacetyl-benzonitrile ( 0.840 grams, 4.49 mmole) in tetrahydrofuran (20 ml) was added 1.0 M lithium aluminum hydride (15 ml, 14.8 mmole) dropwise, stirred at 0°C for 10 minutes and refluxed for 30 minutes. The mixture was cooled to 0°C, quenched with 10 ml methanol added dropwise and diluted with chlroform (300 ml). The mixture was washed with water, dried over MgS0 4 , filtered, and concentrated to an oil which was purified via flash chromatography on silica using 5% methanol/ methylene chloride as eluent to give a solid (0.350 g). MW 205.20; MS (m/e) 205(M + ). The compound of Preparation 139 was prepared according to the procedure of Preparation 138 substituting the corresponding nitrile for 4-Trifluoroacetyl-benzonitrile. The duration of reaction was between 30 minutes and 24 hours. PREPARATION 139 7-Aminomethyl-chroman-4-ol MW 179.24; MS (m/e) 179 (M + ). PREPARATION 140 4-Oxo-chroman-7-carbonitrile A solution of Trifluoro-methanesulfonic acid 4-oxo-chroman-7-yl ester ( 2.0 grams, 6.80 mmole), Zn(CN) 2 (0.476 grams, 4.1 mmole) and Pd(PPh 3 ) 4 (0.314 grams, 0.27 mmole) in dimethylformamide (20 ml) was heated to 80°C over night . The reaction was poured into 200 ml 1/1 saturated NaHC0 3 / water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to give an oil which was purified via flash chromatography on silica using 30% ethyl acetate/ hexane as eluent to give a solid. (1.02 g). MW 173.20; MS (m/e) 173 (M + ). The compound of Preparation 141 was prepared according to the procedure of Preparation 140 substituting the corresponding triflate for Trifluoro-methanesulfonic acid 4- oxo-chroman-7-yl ester. The duration of reaction was between 30 minutes and 24 hours. PREPARATION 141 3-Chloro-4-cyano-benzoic acid methyl ester MW 195.61 MS (m/e, %) 195(M + , 25), 164 (100). PREPARATION 142 4-(1-Hydroxy-cyclobutyl)-benzonitrile To a solution of 4-Bromo-benzonitrile (2.0 grams, 10.99 mmole) in tetrahydrofuran (30 ml) at -100°C was added dropwise 2.5 M nBuLi (4.8 ml) and stirrred at -100°C for 15 minutes. Cyclobutanone (0.965 grams, 13.19 mmole) was added dropwise and stirred for 10 minutes and allowed to warm to room temperature over 1 hour. The mixture was poured into 200 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to an oil which was purified via flash chromatography on silica using 40% ethyl acetate/ hexane as eluent to give a clear oil (1.5 g). MW 173.23; MS (m/e) 173 (M + ). PREPARATION 143 4-(1-Hydroxy-prop-2-ynyl)-benzonitrile To a solution of 4-Formyl-benzonitrile ( 1.5 grams, 10.0 mmole) in tetrahydrofuran (20 ml) at -78°C was added 0.5 M ethynyl magnesium bromide (26 ml, 13.0 mmole) dropwise. The mixture was stirred at - 78°C for 30 minutes and allowed to warm to room temperature over one hour The reaction was cooled to 0°C, quenched with 10 ml methanol, poured into 200 ml water, acidified with oxalic acid and extracted with diethyl ether The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to give an oil which was purified via flash chromatography on silica using 30% ethyl acetate/ hexane as eluent to give a solid (1 6 g) MW 157 18, MS (m/e) 157 (M + ) PREPARATION 144 3-Chloro-4-trifluoromethanesulfonyloxy-benzoic acid methyl ester To a solution of 3-Chloro-4-hydroxy-benzoιc acid methyl ester ( 15 0 grams, 80 0 mmole), triethylamine (20 2 grams, 200 mmole) and DMAP (1 0 grams, 8 0 mmole) in methylene chloride (200 ml) at 0°C was added triflic anhydride (17 ml, 100 0 mmole) dropwise The mixture was allowed to warm to room temperature and stirred for four hours It was diluted with methylene chloride (600 ml), washed with water, dried over MgS0 4> filtered, and concentrated to give an oil which was purified via flash chromatography on silica using 20% ethyl acetate/ hexane as eluent to give an oil (20 9 g) MW 322 05, MS (m/e) 322 (M + ) PREPARATION 145 4-(1 -Azetedinyl)-benzonitrile A mixture of 6 34 g (52 5 mmol) of 4-fluorobenzonιtrιle, 3 00 g (52 5 mmol) of azetidine, 7 26 g (52 5 mmol) of K 2 C0 3 , and 50 mL of methyl sulfoxide was heated to 60 °C for 16 h The cooled mixture was diluted with 200 mL of water and extracted with EtOAc (2 x 150 mL) The combined organic extracts were washed with water (1 x 150 mL), brine (1 x 150 mL), dried (Na 2 S0 4 ), and evaporated to 5 65 g of a white solid Trituration in hexane gave 3 85 g (56% yield) of the title compound as a white solid, mp 98-99°C 1 H NMR (CDCI 3 ) d 2 39-2 45 (2 H, m), 3 96 (4 H, t, J = 7 Hz), 6 32 (2 H, d, J = 9 Hz), 7 41 (2 H, d, J = 9 Hz), AMPI MS (m/e) 159 (M + +1) The compounds of Preparations 146-151 were prepared according to the procedure of Preparation 145 substituting the corresponding amine for azetidine Temperatures ranged from 90-115 °C For preparations of the amines used in Preparations 54a and 54f, see Rosenberg, S H et al J Med Chem , 1993, 36, 460 and Goldberg, S D , J Am Chem Soc , 1939, 61, 3526, respectively Temperatures ranged from 90-115 °C Mass spectra were determined by the AMPI method PREPARATION 146 4-(3-Hydroxy-azetidin-1-yl)-benzonitrile M.P. 75-78°C; 1 H NMR (CDCI 3 ) d 2.37 (1 H. d, J = 7 Hz), 4.04 (4 H, ABX pattern, J AB = 8 Hz, J AX = 7 Hz, J B χ = 4 Hz), 4.77-4.88 (1 H, m), 6.36 (2 H, d, J = 8 Hz), 7.41 (2 H, d, J = 8 Hz); MS (m/e) 175 (M + +1 ). PREPARATION 147 4-Pyrrolidin-1-yl-benzonitrile M.P. 75-76°C; 1 H NMR (CDCI 3 ) d 2.01-2.04 (4 H, m), 3.29-3.33 (4 H, m), 6.49 (2 H, d, J = 8 Hz), 7.43 (2 H, d, J = 8 Hz); MS (m/e) 173 (M + +1). PREPARATION 148 4-Piperidin-1-yl-benzonitrile 1 H NMR (CDCI 3 ) d 1.63-1.69 (6 H, m), 3.29-3.33 (4 H, m), 6.83 (2 H, d, J = 9 Hz), 7.44 (2 H, d, J = 9 Hz). PREPARATION 149 4-Morpholin-4-yl-benzonitrile M.P. 81-82°C; 1 H NMR (CDCI 3 ) d 3.25-3.27 (4 H, m), 3.82-3.85 (4 H, m), 6.85 (2 H, d, J = 9 Hz), 7.49 (2 H, d, J = 9 Hz); MS (m/e) 189 (M + +1). PREPARATION 150 4-(1.4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzonitrile M.P.133-134°C; Anal. Calcd for C 14 H 16 N 2 0 2 : C, 68.83; H, 6.60; N, 11.47. Found: C, 69.21 ; H, 6.64; N, 11.61. PREPARATION 151 4-[(2-Hydroxy-2-methyl-propyl)-methyl-amino1-benzonitrile 1 H NMR (CDCI 3 ) d 1.27 (6 H, s), 1.56 (1 H, s), 3.09 (3 H, s), 3.39 (2 H, s),6.79 (2 H, d, J = 9 Hz), 7.44 (2 H, d, J = 9 Hz); MS (m/e) 205 (M + +1). PREPARATION 152 1-[4-(Aminomethyl)phenyl]-azetidine To a solution of 2.00 g (12.6 mmol) of the compond of Preparation 145 in 50 mL of tetrahydrofuran was added portionwise 479 mg (12.6 mmol) of lithium aluminum hydride. When the addition was complete, the mixture was stirred for 4 h at rt. The mixture was quenched by the sequential addition of 2 mL of water, 2 mL of aqueous 15% sodium hydroxide solution, and 6 mL of water. The precipitate was removed by filtration washing well with THF. The filtrate was dried (Na 2 S0 4 ) and evaporated to a yellow solid, which was purified by flash chromatography using EtOAc followed by 76:20:4 CHCI 3 :MeOH: cone. NH 3 (aq.) as eluants to give 1.22 g of a semisolid. Trituration in hexane afforded 815 mg (40% yield) of the title comound as a yellow solid, mp 58-60°C. 1 H NMR (CDCI 3 ) d 1.60 (2 H, s), 2 29-2 37 (2 H, m), 3 73 (2 H, s), 3 83 (4 H, t, J = 7 Hz), 6 42 (2 H, ό, J = 8 Hz), 7 13 (2 H, d, J = 8 Hz) The compounds of Preparations 153-158 were prepared according to the procedure of Preparation 55 substituting the appropriate substrate for the compound of Preparation 145 Mass spectra were determined by the AMPI method PREPARATION 153 1-(4-Aminomethyl-phenyl)-azetidin-3-ol 1 H NMR (CDCI 3 ) d 2 65 (3 H, br s), 3 54-3 61 (2 H, m), 3 70 (2 H, s), 4 08-4 12 (2 H, m), 4 68-4 79 (1 H, m), 6 40 (2 H, d, J = 8 Hz), 7 09 (2 H, d, J = 8 Hz), MS (m/e) 162 (M + +2-18 (H 2 0)) PREPARATION 154 1-(4-Aminomethyl-phenyl)-azetidin-3-ol M P 108-110°C, 1 H NMR (CDCI 3 ) d 1 87 (2 H, s), 1 96-1 99 (4 H, m), 3 25 (4 H, \, J = 7 Hz), 3 73 (2 H, s), 6 52 (2 H, d, J = 8 Hz), 7 15 (2 H, d, J = 8 Hz), MS (m/e) 160 (M + +2-18) PREPARATION 155 4-Piperidin-1-yl-benzylamine M P 108-110°C, 1 H NMR (CDCI 3 ) d 1 52-1 58 (2 H, m), 1 68-1 72 (4 H, m), 1 80 (2 H, s), 3 08-3 12 (4 H, m), 3 76 (2 H, s), 6 89 (2 H, d, J = 9 Hz), 7 17 (2 H, d, J = 9 Hz) PREPARATION 156 4-Morpholin-4-yl-benzylamine M P 53-54°C, 1 H NMR (CDCI 3 ) d 1 51 (2 H, s), 3 11-3 14 (4 H, m), 3 78 (2 H, s), 3 83- 3 86 (4 H, m), 6 88 (2 H, ά, J = 8 Hz), 7 22 (2 H, d, J = 8 Hz) PREPARATION 157 4-(1.4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylamine M P 107-110°C, 1 H NMR (CDCI 3 ) d 1 81 (4 H, t, J = 6 Hz), 3 07 (2 H, br s), 3 29 (4 H, t, J = 6 Hz), 3 80 (2 H, s), 3 98 (4 H, s), 6 89 (2 H, d, J = 8 Hz), 7 22 (2 H, d, J = 8 Hz) PREPARATION 158 1-[(4-Aminomethyl-phenyl)-methyl-amino]-2-methyl-propan-2-ol 1 H NMR (CDCI 3 ) d 1 26 (6 H, s), 1 97 (3 H, br s), 2 97 (3 H, s), 3 25 (2 H, s), 3 78 (2 H, s), 6 80 (2 H, d, J = 9 Hz), 7 20 (2 H, d, J = 9 Hz) PREPARATION 159 2-(4-Fluorophenoxy)-3-pyridinecarboxylic Acid Methyl Ester A mixture of 20 0 g (89 6 mmol) of 2-(4-fluorophenoxy)-3-pyrιdιnecarboxylιc acid (for preparation, see Villani, F J et al J Med Chem , 1975, 18,3), 300 mL of methanol, and 5 5 mL of concentrated sulfunc acid was heated to reflux for 2 h The cooled mixture was poured onto 500 mL of ice cold saturated aqueous sodium hydrogencarbonate solution, and the resulting precipitate was filtered, washed with water, and dreid under vacuum to give 12 9 g (64% yield) of the title compound as a white solid, mp 97-99°C Anal Calcd for C 13 H 10 NO 3 F C, 63 16, H, 4 08, N, 5 67 Found C, 62 80, H, 4 08, N, 5 50 PREPARATION 160 2-(4-Fluorophenoxy.-3-pyridinemethanol A solution of 10 00 g (40 45 mmol) of the compound of Preparation 56 in 200 mL of anhydrous toluene was cooled to -78 °C and treated dropwise with 84 95 mL (84 95 mmol) of a 1 M solution of diisobutylaluminum hydride in CH 2 CI 2 When the addition was complete, 200 mL of water was added followed by 200 mL of EtOAc , and the mixture was allowed to warm to rt Following adjustment of the aqueous layer to pH 4 with aqueousI N hydrochloric acid solution, the organic layer was separated and combined with a 200 mL backwash of the aqueous layer The organic extracts were washed with saturated aqueous sodium hydrogencarbonate solution, brine, dried (Na 2 S0 4 ), and evaporated to give 9 00 g (90% yield) of the title compound as an off-white solid, mp 70-72 °C 1 H NMR (CDCI 3 ) d 1 59 (1 H, s), 4 84 (2 H, d, J = 6 Hz), 6 99-7 13 (5 H, m), 7 76-7 80 (1 H, m), 8 07 (1 H, dd, J = 2, 5 Hz) PREPARATION 161 2-(4-Fluorophenoxy)-3-pyridinecarboxaldehyde A mixture of 932 mg (4 25 mmol) of the compound of Preparation 57, 2 00 g ( 23 0 mmol) of manganese dioxide, and 30 mL of benzene was heated to reflux for 3 h with water separation The cooled mixture was filtered, evaporated to a white solid, and purified by flash chromatography using 15% EtOAc-hexane as eluant to provide 735 mg (80% yield) of the title compound as a white solid, mp 61-62 °C 1 H NMR (CDCI 3 ) d 7 08-7 21 (5 H, m), 8 19-8 32 (2 H, m), 10 55 (1 H, s) PREPARATION 162 3-[2-(4-Fluorophenoxy)-3-pyridinyl]-3-hydroxypropenoic Acid f-Butyl Ester At -78 °C, 115 3 mL (115 3 mmol) of a solution of 1 M lithium bιs(trιmethylsιlyl)amιde in tetrahydrofuran was treated dropwise with 15 43 mL (13 39 grams, 115 3 mmol) of .-butyl acetate When the addition was complete, the mixture was stirred for 15 mm and then treated with a solution of 9 500 g (38 43 mmol) of the compound of Preparation 56 in 50 mL of THF When the addition was complete, the mixture was stirred for 15 mm and then quenched by the additon of 230 mL of aqueous 1 N hydrochloric acid solution After warming to rt, the organic layer was extracted with ether (2 x 500 mL) and the combined organic layers were washed with saturated aqueous sodium hydrogencarbonate solution (1 x 100 mL), brine (1 x 200 mL), dried (Na 2 S0 4 ), and evaporated to 13 8 g of a pale yellow oil Purification by flash chromatography using 15 to 85% ether-hexane as eluant gave 11 7 g of a semi-solid, which was tnurated with hexane to give 6 124 g (48% yield) of the title compound as a white solid mp 87-89°C 1 H NMR (CDCI 3 ) d 1 54 (9 H, s), 6 12 (1 H, s), 7 01-7 16 (5 H, m), 8 14 (1 H, dd, J = 2, 5 Hz), 8 30 (1 H, dd, J = 2, 8 Hz), 12 99 (1 H, s) The NMR also showed the presence of <10% of the keto tautomer After standing for 12 days, the concentrated mother liquor crystallized and was triturated in hexane to give an additional 2 21 g (17% yield) of the title compound PREPARATION 163 a-[(2-Chlorophenyhmethyl]-2-(4-fluorophenoxy.- β -oxo-3-pyridinepropanoic Acid t-Butyl Ester The sodium hydride obtained after washing 28 9 mg (0 604 mmol) of 50% sodium hydride dispersion in mineral oil with pentane (3 x 5 mL) was suspended in 5 mL of THF, cooled to 0 °C, and treated dropwise with a solution of 200 mg (0 604 mmol) of the compound of preparation 59 in 5 mL of THF After stirring for 15 mm, 0 078 mL (124 mg, 0 604 mmol) of 2-chlorobenzyl bromide was added, and the mixture was allowed to warm to rt, stirred for 4 h, and then heated to reflux for 16 h The cooled mixture was partitioned between 100 mL of saturated aqueous NH 4 CI solution and 200 mL of EtOAc The separated organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (100 mL), brine (100 mL), dried (Na 2 S0 4 ), and evaporated to an oil Punfiaction by flash chromatography using 60% CH 2 CI 2 -hexane as eluant gave 226 mg (82% yield) of the title compound as an oil 1 H NMR (CDCI 3 ) d 1 54 (9 H, s), 3 32-3 52 (2 H, m), 5 09 (1 H, dd, J = 7, 8 Hz), 7 02-7 30 (9 H, m), 8 05 (1 H, dd, J = 2, 8 Hz), 8 22 (1 H, dd, J = 2, 5 Hz) The NMR also showed the presence of <10% of the enol tautomer The compounds of Preparations 164-168 were prepared according to the procedure of Preparation 163 substituting the indicated benzyl ha de for 2-chlorobenzyl bromide In the cases of Preparations 165-168 one equivalent of Kl was added immediately after the addition of the benzyl ha de All compounds were oils Mass spectra were determined by the thermospray method PREPARATION 164 2-(4-Fluoro-benzyl)-3-[2-(4-fluoro-phenoxy)-pyridin-3-yl]-3-oxo-propionic acid tert-butyl ester MS (m/e) 440 (M + +1), 1 H NMR (CDCI 3 ) d 1 27 (9 H, s), 3 17-3 44 (2 H, m), 4 80 (1 H, dd, J = 7, 8 Hz), 6 85-7 30 (9 H, m), 8 08 (1 H, dd, J = 2, 8 Hz), 8 23-8 25 (1 H, m) PREPARATION 165 3-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-3-oxo-2-(4-trifluoromethyl-benzyl)-propionic acid tert butyl ester MS (m/e) 490 (M + +1); 1 H NMR (CDCI 3 ) d 1.24 (9 H, s), 3.36 (2 H, ABX pattern, J AB = 14 Hz, J AX = 7 Hz, J BX = 8 Hz), 4.83 (1 H, dd, J = 7, 8 Hz), 6.99-7.50 (9 H, m), 8.02-8.22 (2 H, m). PREPARATION 166 3-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-3-oxo-2-(4-trifluoromethoxy-benzyl)-propionic acid tert-butyl ester MS (m/e) 506 (M + +1); 1 H NMR (CDCi 3 ) d 1.25 (9 H, s), 3.32-3.46 (2 H, m), 4.82 (1 H, t, J = 7), 7.03-7.28 (9 H, m), 8.09 (1 H, dd, J = 2,8 Hz), 8.24 (1 H, dd, J = 2,5 Hz). PREPARATION 167 2-(3 T 5-Difluoro-benzyl)-3-[2-(4-fluoro-phenoxy)-pyridin-3-yl]-3-oxo-propionic acid tert-butyl ester MS (m/e) 458(M + +1); 1 H NMR (CDCI 3 ) d 1.25 (9 H, s), 3.28 (2 H, ABX pattern, J AB = 14 Hz, J AX = 7 Hz, J BX = 8 Hz), 4.79 (1 H, dd, J = 7,8 Hz), 6.55-7.18 (8 H, m), 8.09 (1 H, dd, J = 2, 8 Hz), 8.23 (1 H, dd, J = 2, 4 Hz). PREPARATION 168 3-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-3-oxo-2-(2.4.6-trifluoro-benzyl)-propionic acid tert-butyl ester MS (m/e) 476(M + +1); 1 H NMR (CDCI 3 ) d 1.22 (9 H, s), 3.22-3.35 (2 H, m), 4.82 (1 H, J = 8 Hz), 6.56 (2 H, t, J = 8 Hz), 7.02-7.12 (5 H, m), 8.11 (1 H, dd, J = 2, 8 Hz), 8.22 (1 H, dd, J = 2, 5 Hz). PREPARATION 169 4-(1-Hydroxy-1-methylethyl)-benzeneproanoic Acid A mixture of 12.61 g (224.7 mmol) of KOH, 73 mL of water, and 425 mL of ethanol was combined with 15.00 g (68.10 mmol) of 3-[4-(1-oxoethyl)phenyl]propionic acid ethyl ester (for preparation, see: Marechal, E.; Quere, J.-P. Bull. Chem. Soc. Fr., 1971, 2227), and the resulting mixture was stiired at rt for 2 h. The mixture was concentrated, and the residue was dissolved in 100 mL of water, cooled to 0 °C, and acidified with concentrated aqueous hydrochloric acid solution. The precipitate was filtered and recrystallized from methanol-water to give 10.11 g (77% yield) of 3-[4-(1-oxoethyl)phenyl]propionic acid as awhite solid, mp 118- 119°C. Anal. Calcd for CnH^Oa: C, 68.52; H, 6.06. Found: C, 68.74; H, 6.29. A solution of 5.000 g (26.01 mmol) of the above acid in 500 mL of tetrahydrofuran was cooled to -17 °C and treated dropwise with 21.67 mL (65.03 mmol) of a 3 M solution of methylmagnesium iodide in ether. Additional Griganrd reagent solution was added in three portions, 5, 5, and 10 mL, respectively, over several hours, as the course of the reaction was monitored by NMR. The mixture was cooled to -30 °C, quenched by the addition of 200 mL of saturated aqueous NH 4 CI solution, and allowed to warm to rt. The aqueous layer was adjusted to pH 1 with aqueous 1 N hydrochloric acid solution, and the organic layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (3 x 500 mL), dried (Na 2 S0 4 ), and evaporated to 5.62 g of a yellow solid. Recrystallization from hexane-EtOAc gave 2.20 g (40% yield) of the title compound as a pale yelllow solid, mp 92- 94°C. 1 H NMR (DMSO-d 6 ) d 1.36 (6 H, s), 2.47 (2 H, t, J = 7 Hz), 2.74 (2 H, t, J = 7 Hz), 4.90 (1 H, s), 7.21 (4 H, AB quartet, J = 7 Hz), 12.09 (1 H, s). PREPARATION 170 N-Methoxy-N-methyl-4-fluoro-benzenepropanamide A suspension of 10.00 g (59.46 mmol) of 3-(4-fluorophenyl)propionic acid, 12.54 g (65.41 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 6.381 g (65.41 mmol) of N,0-dimethylhydroxylamine hydrochloride in 300 mL of CH 2 CI 2 was cooled to 0°C and treated with 18.23 mL (13.23 grams, 130.8 mmol) of triethylamine. The mixture was stirred for 16 h with slow warming to rt. The mixture was concentrated, and the residue was partitioned between 300 mL of EtOAc and 200 mL of aqueous 1 N hydrochloric acid solution. The separated organic layer was washed with aqueous 1 N hydrochloric acid solution (1 x 100 mL), saturated aqueous sodium hydrogencarbonate soution (2 x 200 mL), brine (1 x 100 mL), dried (Na 2 S0 ), and evaporated to give 9.56 g (76% yield) of the title compound as an oil. 1 H NMR (CDCI 3 ) d 2.70 (2 H, t, J = 8 Hz), 2.91 (2 H, t, J = 8 Hz), 3.15 (3 H, s), 3.59 (3 H, s), 6.92- 6.97 (2 H, m), 7.15-7.19 (2 H, m). APCI MS (m/e) 212 (M + +1). The compounds of Preparations 171-180 were prepared according to the procedure of Preparation 170 substituting the corresponding carboxylic acid for 3-(4- fluorophenyl)propionic acid. The carboxylic acid used in Preparation 174 was the compound of Preparation 163, whereas all other carboxylic acids were commercially available. Mass spectra were determined by the APCI method. PREPARATION 171 N-Methoxy-N-methyl-3-phenyl-propionamide Anal. Calcd for CnH^NO^ C, 68.37; H, 7.82; N, 7.25. Found: C, 68.65; H, 8.11 ; N, 7.18. PREPARATION 172 N-Methoxy-2.N-dimethyl-3-phenyl-propionamide 1 H NMR (CDCI 3 ) d 1.16 (3 H, d, J = 7 Hz), 2.83-3.28 (2 H, ABX pattern, J AB = 13 Hz, J A X = 7 Hz, J BX = 8 Hz), 3.08-3.18 (1 H, m), 3.14 (3 H, s), 3.48 (3 H, s), 7.15-7.32 (5 H, m); MS (m/e) 208 (M + +1 ). PREPARATION 173 N-Methoxy-N-methyl-3-phenyl-butyramide 1 H NMR (CDCI 3 ) d 1.31 (3 H, d, J = 7 Hz), 2.59-2.78 (2 H, m), 3.14 (3 H, s), 3.32-3.44 (1 H, m), 3.58 (3 H, s), 7.14-7.32 (5 H, m); MS (m/e) 208 (M + +1 ). PREPARATION 174 3-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-N-methoxy-N-methyl-propionamide 1 H NMR (CDCI 3 ) d 1.56 (6 H, s), 1.71 (1 H, s), 2.72 (2 H, t, J = 8 Hz), 2.93 (2 H, t, J = 8 Hz), 3.17 (3 H, s), 3.60 (3 H, s), 7.30 (4 H, AB quartet, J = 8 Hz); MS (m/e) 234(M + +1 -18 (H 2 0)). PREPARATION 175 N-Methoxy-N-methyl-2-phenyl-acetamide 1 H NMR (CDCi 3 ) d 3.18 (3 H, s), 3.54 (3 H, s), 3.78 (2 H, s), 7.20-7.34 (5 H, m); MS (m/e) 180 (M + +1 ). PREPARATION 176 N-Methoxy-N-methyl-2-phenoxy-acetamide 1 H NMR (CDCI 3 ) d 3.22 (3 H, s), 3.74 (3 H, s), 4.79 (2 H, s), 6.92-6.97 (3 H, m), 7.24- 7.29 (2 H, m); MS (m/e) 196 (M + +1). PREPARATION 177 N-Methoxy-N-methyl-3-phenyl-acrylamide M.P. 40-42°C; H NMR (CDCI 3 ) d 3.30 (3 H, s), 3.76 (3 H, s), 7.02 (1 H, ύ, J = 16 Hz), 7.34-7.39 (3 H, m), 7.55-7.57 (2 H, m), 7.72 (1 H, d, J = 16 Hz); MS (m/e) 192 (M + +1). PREPARATION 178 Benzofuran-3-carboxylic acid methoxy-methyl-amide 1 H NMR (CDCI 3 ) d 3.41 (3 H, s), 3.82 (3 H, s), 7.24-7.43 (2 H, m), 7.50 (1 H, s), 7.59 (1 H, dd, J = 1 , 8 Hz), 7.66 (1 H, dd, J = 1 , 8 Hz); MS (m/e) 206 (M + +1). PREPARATION 179 1H-lndole-3-carboxylic acid methoxy-methyl-amide M.P. 136-137°C; Anal. Calcd for C^H^NA,: C, 64.69; H, 5.94; N, 13.72. Found: C, 64.97; H, 5.81 ; N, 13.65. PREPARATION 180 2-(2-Chloro-phenoxy)-N-methoxy-N-methyl-acetamide 1 H NMR (CDCI 3 ) d 3 21 (3 H, s), 3 74 (3 H, s), 4 88 (2 H, s), 6 89-6 93 (2 H, m), 7 15- 7 19 (1 H, m), 7 34-7 36 (1 H, m) PREPARATION 181 1 -[2-Fluoro-3-pyridinyl1-3-(4-f luoropheny l)-1 -propanone A solution of 5 90 mL (4 56 grams, 45 0 mmol) of diisopropylamine in 20 mL of tetrahydrofuran was cooled to -78 °C and treated dropwise with 18 0 mL (45 0 mmol) of a solution of 2 5 M /7-butyllιthιum in hexane When the addition was complete, the mixture was stirred for 0 5 h at -78 °C and treated dropwise with 3 88 mL (4 37 grams, 45 0 mmol) of freshly distilled 2-fluoropyrιdιne After the addition was complete, the resulting yellow suspension was stirred for 0 5 h at -78 °C To the suspension was added dropwise a solution of 9 51 g ( 45 0 mmol) of the compound of Preparation 62 in 200 mL of tetrahydrofuran dropwise The mixture was stirred for 16 h with slowing warming to rt as the dry ice/acetone bath melted The mixture was quenched by the addition of 50 mL of aqueous 1 N hydrochloric acid solution, and theTHF was removed by partial evaporation The residue was partitioned between EtOAc (300 mL) and aqueous 1 N hydrochloric acid solution (100 mL) The separated organic layer was washed with aqueous 1 N hydrochloric acid solution (100 mL), saturated aqueous sodium hydrogencarbonate solution (100 mL), brine (100 mL), dried (Na 2 S0 4 ), and evaporated to 12 6 g of a yellow oil Purification by flash chromatography using 25% EtOAc-hexane as eluant gave 7 11 g of a yellow which solidified on standing Trituration in hexane gave 6 87 g (62% yield) of the title compound as a light yellow solid, mp 73-74°C 1 H NMR (CDCI 3 ) d 3 02 (2 H, t, J = 7 Hz), 3 29- 3 36 (2 H, m), 6 91-6 99 (2 H, m), 7 17-7 33 (3 H, m), 8 29-8 38 (2 H, m), APCI MS (m/e) 248 (M + +1 ) The compounds of Preparations 182-190 were prepared according to the procedure of Preparation 191 substituting the corresponding N-methoxy-N-methylamide or ester substrate for the compound of Preparation 170 In the case of Preparations 185 and 191 , an additional equivalent of in s/fø-prepared 2-fluoro-3-lιthιopyrιdιne was utilized Products were purified by direct trituration and/or flash chromatography Mass spectra were determined by the APCI method PREPARATION 182 1-(2-Fluoro-pyridin-3-yl)-3-phenyl-propan-1-one 1 H NMR (CDCI 3 ) d 3 05 (2 H, \, J = 7 Hz), 3 32-3 64 (2 H, m), 7 17-7 33 (6 H, m), 8 29-8 38 (2 H, m) PREPARATION 183 1 -(2-Fluoro-pyridin-3-yl)-2-methy l-3-pheny l-propan-1 -one 1 H NMR (CDCIg) d 1.18 (3 H, d, = 7 Hz), 2.88 (2 H, ABX pattern, J AB = 14 Hz, J AX = 6 Hz, J BX = 8 Hz), 3.63-3.72 (1 H, m), 7.14-7.29 (6 H, m), 8.14-8.19 (1 H, m), 8.33-8.35 (1 H, m); MS (m/e) 244 (M + +1 ). PREPARATION 184 1 -(2-Fluoro-pyridin-3-y l)-3-phenyl-butan-1 -one M.P. 51-53°C; Anal. Calcd for C 15 H 14 FNO: C, 74.06; H, 6.00; N, 5.76. Found: C, 73.82; H, 5.83; N, 5.90. PREPARATION 185 1-(2-Fluoro-pyridin-3-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-propan-1-one 1 H NMR (CDCI 3 ) d 1.56 (6 H, s), 3.03 (2 H, t, J = 7 Hz), 3.31-3.36 (2 H, m), 7.20-7.25 (2 H, m), 7.30-7.34 (1 H, m), 7.40-7.42 (2 H, m), 8.30-8.38 (2 H, m); MS (m/e) 270 (M + +1-18 (H 2 0)). PREPARATION 186 1-(2-Fluoro-pyridin-3-yl)-2-phenyl-ethanone 1 H NMR (CDCI 3 ) d 4.31 (2 H, s), 7.19-7.34 (6 H, m), 8.27-8.37 (2 H, m); MS (m/e) 216 (M + +1). PREPARATION 187 1-(2-Fluoro-pyridin-3-yl)-2 -phenoxy -ethanone M.P. 82-83°C; 1 H NMR (CDCI 3 ) d 5.21 (2 H, d, J = 3 Hz), 6.91-7.01 (3 H, m), 7.27- 7.31 (2 H, m), 7.37-7.40 (1 H, m), 8.41-8.45 (2 H, m); MS (m/e) 232 (M + +1). PREPARATION 188 2-(2-Chloro-phenoxy)-1-(2-fluoro-pyridin-3-yl)-ethanone M.P. 84-86°C; 1 H NMR (CDCI 3 ) d 5.34 (2 H, , J = 3 Hz), 6.85-7.45 (5 H, m), 8.42- 8.50 (2 H, m); MS (m/e) 266, 268 (M + +1). PREPARATION 189 1-(2-Fluoro-pyridin-3-yl)-3-phenyl-propenone M.P. 83-84°C; 1 H NMR (CDCI 3 ) d 7.34-7.37 (1 H, m), 7.41-7.47 (4 H, m), 7.62-7.65 (2 H, m), 7.90 (1 H, d, J = 15 Hz), 8.29-8.31 (1 H, m), 8.38-8.41 (1 H, m). PREPARATION 190 Benzofuran-3-yl-(2-fluoro-pyridin-3-yl)-methanone M.P. 110-111°C; Anal. Calcd for C 14 H 8 FN0 2 : C, 69.71 ; H, 3.34; N, 5.81. Found: C, 69.64; H, 3.36; N, 6.12. PREPARATION 191 (2-Fluoro-pyridin-3-yl)-(1H-indol-3-yl)-methanone M.P. 195-198°C; Anal. Calcd for C 14 H 9 FN 2 0 2 : C, 70.00; H, 3.78; N, 11.66. Found: C, 69.69; H, 3.60; N, 11.59. PREPARATION 192 1-(2-Fluoro-pyridin-3-yl)-ethanone 1 H NMR (CDCI 3 ) d 2.67 (3 H, d, J = 0.5 Hz), ), 7.30-7.33 (1 H, m), 8.30-8.38 (2 H, m). PREPARATION 193 1-(2-Fluoro-pyridin-3-yl)-2-(methyl-phenyl-amino)-ethanone 1 H NMR (CDCI 3 ) d 3.10 (3 H, s), 4.72 (2 H, d, J = 3 Hz), 6.63-6.74 (3 H, m), 7.18-7.24 (2 H, m), 7.32-7.36 (1 H, m), 8.30-8.42 (2 H, m); MS (m/e) 245 (M + +1 ). PREPARATION 194 1-[2-(4-Fluorophenoxy)-3-pyridinyl]-ethanone 1 H NMR (CDCI 3 ) d 2.75 (3 H, s), 7.07-7.12 (5 H, m), 8.20 (1 H, dd, J = 2, 7 Hz), 8.24 (1 H, dd, J = 2, 5 Hz). PREPARATION 195 1-[2-(3-Pyridinyloxy)-3-pyridinyl]-ethanone 1 H NMR (CDCI 3 ) d 2.76 (3 H, s), 7.13-7.15 (1 H, m), 7.39 (1 H, dd, J = 5, 9 Hz), 7.53- 7.56 (1 H, m), 8.22-8.24 (2 H, m), 8.50-8.53 (2 H, m). PREPARATION 196 2-Fluoro-a-phenyl-3-pyridinemethanol 1 H NMR (CDCI 3 ) d 2.61 (1 H, br s), 6.03 (1 H, s), 7.14-7.38 (6 H, m), 7.97-8.08 (2 H, m). PREPARATION 197 (2-Fluoro-3-pyridinyl)phenyl-methanone 1 H NMR (CDCI 3 ) d 7.32-7.38 (1 H, m), 7.47-7.50 (2 H, m), 7.61-7.67 (1 H, m), 7.78- 7.82 (2 H, m), 7.98-8.07 (1 H, m), 8.38-8.42 (1 H, m). PREPARATION 198 4-(1-hydroxy-1-methyl-ethyl)-benzonitrile To a stirred suspension of anhydrous cerium (III) chloride (3.8g, 16 mmol) in 20 mL dry tetrahydrofuran at 0°C was added slowly dropwise a solution of 3.0M methyl magnesium chloride in tetrahydrofuran ( 10 mL, 31 mmol). The mixture was stirred at 0°C for 30 min. then a solution of Methyl 4-cyanobenzoate (2.0g, 12.4 mmol) in 20 mL dry tetrahydrofuran slowly dropwise. The mixture was stirred for an additional 30 min. at 0°C then quenched with 2.0 M acetic acid (-10 mL) added slowly dropwise. The mixture was poured into 200 mL water and extracted with ethyl acetate (2 X 200 mL). The organic extracts were combined, washed with sodium bicarbonate solution (1 X 40 mL), water (2 X 40 mL), brine (1 X 40 mL), dried (MgS0 4 ) and concentrated in vacuo to give an oil. The oil was absorbed onto Silica Gel (10g) and washed with ethyl acetate/hexane (1 :2, 1500mL). Concentration of the washings in vacuo afforded 1.75g (88%) 4-(1-hydroxy-1-methyl-ethyl)-benzonitrile as a clear oil. 1 H-NMR (CDCI 3 ): δ 7.60 (m, 4H), 1.58 (m, 6H). GC-MS (m/e, %): 161 (M + , 2), 146 (100). PREPARATION 199 2-Fluoro-5-hydroxy-benzonitrile To a solution of 2-Fluoro-5-methoxy-benzonitrile ( 4.0 grams, 26.5 mmole) in CH 2 CI 2 (100 ml) at 0°C was added 1.0 M BBr 3 (29 ml, 29 mmole) dropwise, warmed to room temperature and stirred over night. The mixture was poured into 300 ml ice water and stirred for 10 minutes. This was poured into 100 ml methylene chloride, and the layers were separated. The mixture was washed with water, dried over MgS0 4 , filtered, and concentrated to a solid (2.8 g). MW 137.12; MS (m/e) 137(M + ). The compound of Preparation 200 was prepared according to the procedure of Preparation 199 substituting the corresponding ether for 2-Fluoro-5-methoxy-benzonitrile. The duration of reaction was between 1 and 24 hours. PREPARATION 200 3-Hydroxy-N.N-dimethyl-benzamide MW 165.21 MS (m/e, %) 165(M + , 30), 121 (100). PREPARATION 201 2-Fluoro-5-methoxy-benzonitrile A solution of 2-Chloro-1-fluoro-4-methoxy-benzene ( 10.4 grams, 65.0 mmole), CuCN (6.4 grams, 71.0 mmole) and N-methylpyrrolidinone (100 ml) was refluxed for 18 hours. An additional 2.3 g CuCN was added, and the mixture was refluxed for 40 hours. The mixture was poured into 300 ml ice water and stirred for 10 minutes. This was poured into 100 ml methylene chloride, and the layers were separated. The mixture was washed with water, dried over MgS0 4 , filtered, and concentrated to a solid (2.8 g). MW 137.12; MS (m/e) 137(M + ). PREPARATION 202 1.4-Dioxa-spiro[4.5]decane-8-carbonitrile To a solution of 1 ,4-Dioxa-spiro[4.5]decan-8-one (2.0 grams, 12.8 mmole) and tosyl- methyl isocyanate (5.0 grams, 25.6 mmole) in dimethylformamide (25 ml) at 0°C was added 1.0 M tBuOK in tButanol (25.6 ml) and stirrred at 0°C for 1 hour and room temperature over night. The mixture was diluted with water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to a solid which was purified via flash chromatography on silica using 30% ethyl acetate/ hexane as eluent to give a solid (1.45 g). MW 167.209; MS (m/e) 168 (M + +1). PREPARATION 203 C-(4.5-Pichloro-thiophen-2-yl)-methylamine To a stirred suspension of 2-(4,5-Dichloro-thiophen-2-ylmethyl)-isoindole-1 ,3-dione (0.770 grams, 2.47 mmole) in methanol (30 ml) and tetrahydrofuran (10 ml) at room temperature was added hydrazine hydrate (0.395 grams, 12.3 mmole) and stirrred at room temperature over night. A precipitate formed, and the mixture was concentrated to about 15 ml and filtered. The filtrate was poured into 100 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to an oil which was purified via flash chromatography on silica using 5% methanol/ methylene chloride as eluent to give an oil (0.341 g). MW 182.08; MS (m/e) 183 (M + +1). PREPARATION 204 2-(4.5-Dichloro-thiophen-2-ylmethyl)-isoindole-1.3-dione To a stirred solution of (4,5-Dichloro-thiophen-2-yl)-methanol (0.660 grams, 3.60 mmole), Phthalimide (0.636 grams, 4.32 mmole), and triphenyl phosphene (1.1 grams, 4.32 mmole) in tetrahydrofuran (20 ml) at room temperature was added diethyl azodicarboxylate (0.395 grams, 12.3 mmole) and stirrred at room temperature over night. The mixture was poured into 100 ml water and extracted with diethyl ether. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgS0 , filtered, and concentrated to an oil from which triphenylphosphine was crystalized out using diethyl ether/hexane. The mother liquor was concentrated to give a solid which was purified via flash chromatography on silica using 30% ethyl acetate/ hexane as eluent to give a yellow solid. This was triturated in hexane to give a white solid (0.772 g). MW 312.18; MS (m/e) 313 (M + +1). PREPARATION 205 (4.5-Dichloro-thiophen-2-yl)-methanol To a solution of 4,5-Dichloro-thiophene-2-carboxylic acid (0.500 grams, 2.53 mmole) and thionyl chloride (1.0 ml) in methylene chloride (10 ml) was refluxed for 3 hours. The mixture was concentrated to remove solvent and diluted with 15 ml dioxane and sodium borohydride (0.143 grams, 3.8 mmole) and refluxed for 3 hours. The mixture was cooled to 0 °C and 3 ml water was added dropwise. The mixture was poured into 100 ml water. This was extracted with diethyl ether, washed with 1 N NaOH, water, and brine, dried over MgS0 4 , filtered and concentrated to an oil which was purified via flash chromatography on silica using 30% ethyl acetate/ hexane as eluent to give an oil (0.671 g). MW 183.06; MS (m/e) 184 (M + +1). PREPARATION 206 4.5-Dichloro-thiophene-2-carboxylic acid Into a solution of sodium hydroxide (19.2 grams, 48.0 mmole) in water (30 ml) and ice (120 g) at -10°C was bubbled Cl 2 gas until 14.4 g was obtained. The solution was warmed to 50°C and 1-(4,5-Dichloro-thiophen-2-yl)-ethanone (8.5 0 grams, 40.0 mmole) in dioxane (40 ml) was added dropwise as the temperature rose to 80-90°C. This temperature was maintained for 30 minutes. The mixture was poured into 500 ml water. This was extracted with diethyl ether, and the aqueous was treated with NaHS0 3 , then acidified to pH 1 with concentrated HCl. The resultant precipitate was filtered, and dried to give a white solid. (5.7 g). MW 197.04; 1 H NMR (DMSO-d 6 ) d 7.731 (1 H, s). PREPARATION 207 1-(4.5-Dichloro-thiophen-2-yl)-ethanone To a solution of 1-Thiophen-2-yl-ethanone (5.0 grams, 40.0 mmole) in chloroform (50 ml) at 20°C was added portionwise aluminum chloride (15.9 grams, 119.0 mmole). The mixture was stirred at 20 °C for 10 minutes and 1 M Cl 2 in carbon tetrachloride (120 ml) was added dropwise. The mixture was stirred at room temperature for 30 minutes and diluted with methylene chloride (300 ml) and washed with 1 N sodium hydroxide and water and dried over magnesium sulfate and concentrated to give a solid (8.5 g). MW 195.07; MS (m/e) 196 (M + +1). PREPARATION 208 2-Bromomethyl-3.5-dichloro-thiophene A solution of 3,5-Dichloro-2-methyl-thiophene (1.3 grams, 7.8 mmole), NBS (1.4 grams, 7.8 mmole) and benzoyl peroxide (0.065 g) in carbon tetrachloride (40 ml) was refluxed for 18 hours. The mixture was cooled to 0 °C, diluted with 40 ml hexane and filtered. The filtrate was concentrated to an oil which was purified via flash chromatography on silica using hexane as eluent to give an oil (1.06 g). MW 245.95; MS (m/e) 246 (M + +1 ). PREPARATION 209 3.5-Dichloro-2-methyl-thiophene To a solution of 2-methylthiophene (7.0 grams, 70.0 mmole), in methylene chloride (50 ml) at room temperature was added S0 2 CI 2 dropwise. The mixture was stirred at room temperature over night, diluted with hexane (300 ml), washed with 1 N NaOH, water and brine, dried over MgS0 4 , filtered and concentrated to an oil which was purified via vacuum distillation to give an oil. This was further purified via chromatography on silica using hexane as eluent to give an oil (1.32 g). MW 167.06; MS (m/e) 166 (M + -1). PREPARATION 210 2-(3-Carbamoyl-phenoxy)-N-(2-chloro-benzyl)-nicotinic acid A solution of 2-(3-Carbamoyl-phenoxy)-N-(2-chloro-benzyl)-nιcotιnιc acid ethyl ester (4 31 grams, 16 08 mmole) in ethanol (100 ml) and 1 \_ sodium hydroxide (40 21 ml) was refluxed for 4 hours The mixture was concentrated to 1/3 volume, diluted to 300 ml with water, acidified to pH 3 with 1 N hydrochloric acid and filtered to isolate a white solid which was recrystalized from ethyl acetate/ hexane (3 8 g) M P 220-224°C, Anal calcd for C 13 H 10 N 2 O 4 C, 60 45, H, 3 91 , N, 10 85 Found C, 61 70, H, 3 61 , N, 10 69 PREPARATION 211 3-Methoxy-N.N-dimethyl-benzamide Into a solution of 3-Methoxy-benzoyl chloride (5 0 g) in methylene chloride (50 ml) at 0 °C was bubbled in dimethylamine gas for 5 minutes The mixture was stirred at 0 °C for 30 minutes, diluted with 300 ml methylene chloride, washed with water, dried over MgS0 4 , filtered and concentrated to give an oil (4 8 g) MW 179 24, MS (m/e) 179 (M + ) PREPARATION 212 2-[3-(2.2 t 2-Trifluoro-1-hydroxy-ethyl)-phenoxy]-nicotinic acid ethyl ester To a solution of 2-(3-Formyl-phenoxy)-nιcotιnιc acid ethyl ester (2 0 grams, 7 4 mmole) in 0 5 J\/Ltrιmethyl(trιfluoromethyl)sιlane (18 ml) in tetrahydrofuran (20 ml) at 0 °C was added tetrabutyl ammonium fluoride (0 050 g) The mixture was stirred at 0 °C for 1 hour To the mixture was added 1 0 M hydrochloric acid (10 ml) and stirred at room temperature for 30 minutes The mixture was poured into 200 ml water and extracted with diethyl ether The combined extracts were washed with saturated NaHC0 3 , and water, dried over magnesium sulfate and concentrated to give an oil which was purified via flash chromatography on silica using 60 % ethyl acetate/ hexane as eluent to give an oil (1 97 g) MW 341 31 , MS (m/e) 341 (M + ) PREPARATION 213 2-Fluoro-4-(1 -hydroxy-1 -methyl-ethy l)-benzonitrile To a stirred suspension of CeCI 3 (4 7 grams, 19 0 mmole) in tetrahydrofuran (30 ml) at 0 °C was added dropwise 3 0 M methyl magnesium chloride (6 0 ml, 19 0 mmole) The mixture was stirred at 0 °C for 45 minutes and 4-Acetyl-2-fluoro-benzonιtrιle (2 5 grams, 15 0 mmole) in tetrahydrofuran (20 ml) was added dropwise The mixture was stirred at 0°C for 1 hour and quenched with 5 ml 2 N acetic acid added dropwise The mixture was poured into 200 ml water, acidified to pH 2 with 2 N acetic acid and extracted with ethyl acetate The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated to give an oil which was purified via flash chromatography on silica using 50 % ethyl acetate/ hexane as eluent to give an oil (1 95 g) MW 179 21 , MS (m/e) 179 (M + ) PREPARATION 214 4-Acetyl-2-fluoro-benzonitrile A mixture of 4-Bromo-2-fluoro-benzonitrile (5.0 grams, 20.0 mmole), butyl vinyl ether (12.5 grams, 124.0 mmole), triethylamine (4.0 grams, 40.0 mmole), dppp (0.453 grams, 1.1 mmole), Thallium acetate (5.8 grams, 22.0 mmole) and Pd(OAc) 2 (0.224 grams, 1.0 mmole) in dimethylformamide (50 ml) under N2 was heated to 90 °C for 3 hours. An additional 0.453 g dpp and 0.244 g Pd(OAc) 2 was added and the mixture was heated to 90 °C for 4 hours. The mixture was cooled to room temperature, 25 ml 2 N hydrochloric acid was added and the mixture was stirred at room temperature for 30 hours. The mixture was poured into 300 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated to give an oil which was purified via flash chromatography on silica using 30 % ethyl acetate/ hexane as eluent to give an oil (2.5 g). 1 H-NMR (CDCI 3 ): δ 2.63 (s, 3H), 7.73 (m, 2H), 7.81 (m, 1 H). PREPARATION 215 4-Oxo-cyclohexanecarbonitrile A solution of 1 ,4-Dioxa-spiro[4.5]decane-8-carbonitrile (2.0 grams, 12.8 mmole) and 2 \_ hydrochloric acid (21.0 grams, 42.0 mmole) in tetrahydrofuran (30 ml) at room temperature was stirred over night. The mixture was diluted with ethyl acetate, washed with water and brine, dried over MgS0 4 , filtered, and concentrated to an oil which was purified via flash chromatography on silica using 10% ethyl acetate/ hexane as eluent to give an oil (0.800 g). MW 123.15. PREPARATION 216 2-[4-(1-Hydroxy-1-methyl-ethyl)-cyclohex-1-enylmethyl1-isoindole-1.3-dione To a stirred solution of 2-(4-Hydroxymethyl-cyclohex-3-enyl)-propan-2-ol (5.765 grams, 34.270 mmole), Phthalimide (6.50 grams, 44.208 mmole), and triphenyl phosphene (11.60 grams, 44.208 mmole) in tetrahydrofuran (200 ml) at room temperature was added DIAD (9.010 grams, 44.552 mmole) dropwise, and the peach mixture was stirrred at room temperature over night. The mixture was quenched with 150 ml water and extracted with 2 X 100 ml ethyl acetate. It was then concentrated to a yellow residue. This was taken up in diethyl ether, diluted with hexane, chilled and filtered. The crude product was purified via flash chromatography on silica using 50% ethyl acetate/ hexane as eluent to give a yellow gum (5.73 g). MW 299.373; MS (m/e) 279 (M + -18). PREPARATION 217 2-(Benzo[1.3]dioxol-5-yloxy)-nicotinic acid ethyl ester A solution 2-Chloro-nicotinic acid ethyl ester (5.0 grams, 27.0 mmole), cesium carbonate (2.96 grams, 67.5 mmole) and Benzo[1 ,3]dioxol-5-ol (4.19 grams, 29.7 mmole) in dimethylformamide (80 ml) was heated to 65°C for 10 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to a solid (7.0 g). MW 287.275. PREPARATION 218 2-[4-(1-Hydroxy-1-methyl-ethyl)-cyclohex-1-enylmethyl1-isoindole-1.3-dione To a stirred solution of 2-(4-Hydroxymethyl-cyclohex-3-enyl)-propan-2-ol (5.765 grams, 34.270 mmole), Phthalimide (6.50 grams, 44.208 mmole), and triphenyl phosphene (11.60 grams, 44.208 mmole) in tetrahydrofuran (200 ml) at room temperature was added DIAD (9.010 grams, 44.552 mmole) dropwise, and the peach mixture was stirrred at room temperature over night. The mixture was quenched with 150 ml water and extracted with 2 X 100 ml ethyl acetate. It was then concentrated to a yellow residue. This was taken up in diethyl ether, diluted with hexane, chilled and filtered. The crude product was purified via flash chromatography on silica using 50% ethyl acetate/ hexane as eluent to give a yellow gum (5.73 g). MW 299.373; MS (m/e) 279 (M + -18). PREPARATION 219 2-(4-Aminomethyl-cyclohex-3-enyl)-propan-2-ol A solutoin of 0.3 M methanolic hydrazine hydrate was prepared by adding hydrazine hydrate (1.96 g) to 204 ml methanol. This was added to 2-[4-(1-Hydroxy-1-methyl-ethyl)- cyclohex-1-enylmethyl]-isoindole-1 ,3-dione (5.73g, 19.140 mmole) and stirred at room temperature over night. 5% hydrochloric acid was added and a precipitate was formed over two hours, which was filtered through celite and washed with water. The filtrate was poured into water and extracted with diethyl ether. The aqueous layer was basified to pH= 9 with sodium hydroxide and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgS0 4 , filtered, and concentrated to an oil which solidified on standing (0.188 g). M.P. 95-97 °C; MW 169.269. The compounds in Preparations 220-228 were synthesized in a manner analogous to that of Preparation 23 substituting the indicated phenol. Preparation 220 2-(3-Oxo-indan-5-yloxy)-nicotinic acid ethyl ester. Prepared using 6-hydroxy-indan-1-one ( Phialas et. al. J. Chem. Soc. Perkin Trans. 1 , 4, 1984, 687-695). MS (m/e): 297 (M + ). Preparation 221 2-(2-Methyl-benzothiazol-5-yloxy)-nicotinic acid ethyl ester. Prepared using 2-methyl-5-benzothiazolol. MS (m/e): 314 (M + ) Preparation 222 2-(2-Methyl-benzothiazol-6-yloxy)-nicotinic acid ethyl ester. Prepared using 2-methyl-6-benzothιazolol (Tardieu et al Helv Chim Acta, 75, 4, 1992, 1185-1197) MS (m/e) 314 (M + ) Preparation 223 2-(Benzothiazol-6-yloxy)-nicotinic acid ethyl ester. Prepared using benzothιazol-6-ol (El'tsov et al J Gen Chem USSR 51 , 1981 , 1822- 1831) MS (m/e) 301 (M + +1 , 100) Preparation 224 2-(Benzooxazol-6-yloxy)-nicotinic acid ethyl ester. Prepared using benzoxazol-6-ol (Cole et al Aust J Chem 39, 2, 1986, 295-301 ) MS (m/e) 284 (M + ) Preparation 225 2-(3-Acetyl-4-chloro-phenoxy)-nicotinic acid ethyl ester. Prepared using 3-acetyl-4-chlorophenol MS (m/e) 319 (M + ) Preparation 226 2-(3-Acetyl-5-chloro-phenoxy)-nicotinic acid ethyl ester. Prepared using 1-(3-chloro-5-hydroxy-phenyl)-ethanone MS (m/e) 319 (M + ) Preparation 227 2-(3-Methyl-benzo-(d)isoxazol-5-yloxy)-nicotinic acid ethyl ester. Prepared from 5-hydroxy-3-methyl-benzo(d)ιsoxazole MS (m/e) 299 (M + +1 , 100) Preparation 228 2-(3-Methyl-benzo-(d)isoxazol-7-yloxy)-nicotinic acid ethyl ester Prepared from 7-hydroxy-3-methyl-benz(d)ιsoxazole MS (m/e) 298 (M + ) Preparation 229 2-(2.3-Dihydro-benzo[1.41dioxin-6-yloxy)-nicotinic acid ethyl ester Prepared from 2,3-Dιhydro-benzo[1 ,4]dιoxιn-6-ol (BIOSCI Biotech Biochem , 56(4), 1992, 630-635) MS m/e 302 (M + +1 ) Preparation 230 3-acetyl-4-chlorophenol A mixture of 3-acetyl-4-chloroanιsole (6 3 g, 0 03 mol ), (Atkinson et al J Med Chem 26, 10, 1983, 1353-1360) and pyridine hydrochloride (19 4 g, 0 17 mol ) was heated at 220°C for 2 hrs The mixture was poured into water (200mL) and extracted with ethyl acetate (2X200mL) The organic extracts were combined, washed with water (40mL), brine (40mL), dried (MgS0 4 ) and concentrated to give an oil Chromatography on Silica Gel eluting with ethyl acetate/hexanes (1 1) gave 5 1 g oil MS (m/e) 172/170 (M + , 100) Preparation 231 7-hydroxy-3-methyl-benz.d.isoxazole A mixture of 7-methoxy-3-methyl-benz(d)ιsoxazole (2 9 g, 0 017 mmol ) (Borsche et al Justus Liebigs Ann Chem 570, 1950, 155, 163) in glacial acetic acid (15 mL) and 48% hydrobromic acid (15 mL) was refluxed for 6 hrs The mixture was concentrated to give 4 0 g solid MS (m/e) 227/229 (M + +HBr), 149(M + ) Preparation 232 1-(3-chloro-5-hydroxy-phenyl.-ethanone A mixture of 1-(3-chloro-5-methoxy-phenyl)-ethanone (14 3 g, 0 08 mol ) and pyndine hydrochloride (44 8 g, 0 39 mol ) was heated at 220°C for 2 hrs The mixture was poured into water (200 mL) and extracted with ethyl acetate (2X200 mL) The organic extracts were combined, washed with water (40 mL), brine (40 mL) and concentrated to give an oil Flash Chromatography on Silica Gel eluting with ethyl acetate/hexanes (1 1 ) gave 6 6g solid MS (m/e) 170/172 (M + ) Preparation 233 1-(3-chloro-5-methoxy-phenyl)-ethanone A mixture of trifluoromethanesulfonic acid 3-chloro-5-methoxy -phenyl ester (26 5 g, 0 091 mol ), butyl vinyl ether (59 mL, 0 46 mol ), 1 ,3-Bιs(dιphenyl-phosphιnopropane) (1 1 g, 0 003 mol ), palladium acetate (0 51 g, 0 002 mol ) and triethylamine (28 mL, 0 20 mol ) in dimethylforamide (90 mL) was heated at 80°C for 4 hrs The mixture was poured into water (400 mL) and extracted with diethyl ether (2X400 mL) The organic extracts were combined, washed with 1 N hydrochloric acid (80 mL), 1 N sodium hydroxide (80 mL), water (80 mL), brine (80 mL), dried (MgS0 4 ) and concentrated to give an oil Flash Chromatography on Silica Gel eluting with ethyl acetate/hexanes (1 9) gave 14 3 g solid MS (m/e) 184/186 (M + ) Preparation 234 Trifluoromethanesulfonic acid 3-chloro-5-methoxy -phenyl ester To a stirred solution of 3-chloro-5-methoxyphenol (15g, 0 09 mol ), triethylamine (31 mL, 0 23 mol ) and 4-dιmethylamιnιpyrιdιne (1 1g, 0 009 mol ) in methylene chloride (200mL) at -78°C was added dropwise, trifluoromethanesulfonic anhydride (20 mL, 0 118 mol ) The mixture was allowed to slowly warm to room temperature over 2 hrs , then diluted with methylene chloride (400 mL) and washed with water (100 mL), dried (MgS0 4 ) and concentrated to give an oil Flash Chromatography on Silica Gel eluting with ethyl acetate/hexanes (1 9) gave 26 6 g oil MS (m/e) 290 (M + ) Preparation 235 5-hydroxy-3-methyl-benzo(d)isoxazole A mixture of 5-Methoxy-3-methyl-benzo(d)ιsoxazole (4 9g, 0 03 mol ) in 48% hydrobromic acid (20 mL) and acetic acid (20 mL) was refluxed for 4 hrs The mixture was concentrated to give 6 2g solid MS (m/e) 149 (M + ) Preparation 236 5-Methoxy-3-methyl-benzo(d)isoxazole A mixture of 1-(2-Hydroxy-5-methoxy-phenyl)-ethanone-0-acetyl oxime (15 3g, 0 069 mol ) in pyndine (50 mL) was refluxed for 4 hrs The mixture was poured into water (800 mL), acidified with concentrated hydrochloric acid to pH 1 , then extracted with ethyl acetate (2X800 mL) The organic extracts were combined, washed with 1 N hydrochloric acid (100 mL), 1 N sodium hydroxide (100 mL), water (100 mL), brine (100 mL), dried (MgS0 4 ) and concentrated to give an oil Flash Chromatography on Silica Gel eluting with ethyl acetate/hexanes (1 2) gave 5 9 g solid MS (m/e) 163 (M + ) Preparation 237 1-(2-Hydroxy-5-methoxy-phenyl)-ethanone-Q-acetyl oxime A mixture of 1-(2-Hydroxy-5-methoxy-phenyl)-ethanone oxime (13 7g, 0 076 mol ) and acetic anhydride (50 mL) was heated at 50°C for 10 mm The mixture was cooled to 0°C, filtered, and the filtrant washed with water (50 mL) and dried to give 15 5g solid MS (m/e) 224 (M + +1), 164 (100) Preparation 238 1-(2-Hydroxy-5-methoxy-phenyl)-ethanone oxime A mixture of 2-Hydroxy-5-methoxyacetophenone (15 Og, 0 09 mol ), potassium hydroxide (23 6g, 0 36 mol ) and hydroxylamine hydrochlonde (9 4g, 0 14 mol ) in water (300 mL) was refluxed for 2 hrs The mixture was poured into ice and acidified with 1 N hydrochloric acid to pH 1 The resulting precipitate was filtered and dried to give 13 7g solid MS (m/e) 182 (M + +1 , 100) The compounds in Preparations 238-247 were synthesized in a manner analogous to that of Preparation 45 Preparation 239 2-(3-Oxo-indan-5-yloxy)-nicotinic acid MS (m/e) 269 (M + ) Preparation 240 2-(2-Methyl-benzothiazol-5-yloxy)-nicotinic acid MS (m/e) 287 (M + +1, 100) Preparation 241 2-(2-Methyl-benzothiazol-6-yloxy)-nicotinic acid MS (m/e) 287 (M + +1 , 100) Preparation 242 2-(Benzothiazol-6-yloxy)-nicotinic acid MS (m/e) 273 (M + +1) Preparation 243 2-(Benzooxazol-6-yloxy)-nicotinic acid MS (m/e) 256 (M + ), 211 (100) Preparation 244 2-(3-Acetyl-4-chloro-phenoxy)-nicotinic acid MS (m/e) 292/290 (M + , 100) Preparation 245 2-(3-Acetyl-5-chloro-phenoxy)-nicotinic acid MS (m/e) 292/290 (M + , 100) Preparation 246 2-(3-Methyl-benzo-(d)isoxazol-5-yloxy)-nicotinic acid MS (m/e) 270 (M + +1 , 100) Preparation 247 2-(3-Methyl-benzo-(d)isoxazol-7-yloxy)-nicotinic acid MS (m/e) 270 (M + +1 , 100) Preparation 248 2-(2.3-Dihydro-benzo[1.4]dioxin-6-yloxy)-nicotinic acid MS m/e 274 (M + +1 ) Preparation 249 (SH-)-1-(4-Aminomethyl-phenyl)-ethanol. To a stirred solution of (S)-(-)-4-(1-Hydroxy-ethyl)-benzonιtrιle (2 2 g, 0 015 mol ) in tetrahydrofuran (20 mL) at 0°C was added dropwise a 1 0M solution of lithium aluminium hydride in tetrahydrofuran (45 mL, 0 045 mol ) The mixture was refluxed for 30 mm then cooled to 0°C then quenched with methanol (5 mL) added dropwise The mixture was diluted with chloroform (300mL) and washed with water (40 mL) The resulting suspension was filtered through Celite and the organic extract of the filtrate separated, dried (MgS0 4 ) and concentrated to give 2 0 g solid α D (CHCI 3 ) - 40 3° Preparation 250 (S)-(-)-4-(1-Hydroxy-ethyl)-benzonitrile To a stirred solution of 4-acetylbenzonιtrιle (3 Og, 0 021 mol ) and a solution of 1 0 M (R)-2-Methyl-CBS-oxazaborolιdιne in toluene (1 0 mL, 0 001 mol ) in tetrahydrofuran (50 mL) at room temperature was added dropwise a solution of 2 0M Borane-Dimethylsulfide complex in tetrahydrofuran (9 0 mL, 0 017 mol ) over 30 mm The mixture was stirred at room temperature for 1 hr , cooled to 0°C, then quenched with methanol (10 mL) added dropwise The volume was reduced by half, diluted with diethyl ether (300 mL) and washed with pH 4 buffer (40 mL), water (40 mL), brine (40 mL), dried (MgS0 4 ) then concentrated to give an oil Flash Chromatography on Silica Gel eluting with ethyl acetate/hexane (2 3) to give 2 2 g clear oil α D (CHCI 3 ) - 40 0° Preparation 251 (R)-(+)-1-(4-Aminomethyl-phenyl)-ethanol. Prepared in an analogous manner to that of Preparation 247 starting with (R)-(+)-4-(1- Hydroxy-ethyl)-benzonιtrιle which is obtained from 4-acetylbenzonιtrιle using 1 0 M (S)-2- Methyl-CBS-oxazaborolidme in toluene in an analogous fashion as in Preparation 248 Preparation 252 fra/7s-2-(Aminomethyl-cyclohexyl)-propan-2-ol. A mixture of .rans-(4-(1-Hydroxy-1-methyl-ethyl)-cyclohexylmethyl)-carbamιc acid benzyl ester (8 3 g, 0 027 mole) and Pearlman's catalyst (400 mg) in ethyl acetate (100 mL) and methanol (25 mL) was shaken in a Parr Apparatus under 40 psi hydrogen at room temperature for 1 hr The mixture was filtered through Celite and the filtrate concentrated to give 5 1 g white solid MS (m/e) 171 (M\ 100) Preparation 253 trans-(4-(1-Hydroxy-1-methyl-ethyl)-cyclohexylmethyl)-carbamic acid benzyl ester. A mechanically stirred suspension of anhydrous cerium (III) chloride (29 8 g, 0 12 mol ) in tetrahydrofuran was refluxed for 10 mm , cooled to 0°C, and a solution of trans-4- (Benzyloxycarbonylamιno-methyl)-cyclohexanecarboxylιc acid ethyl ester (35 8 g, 0 11 mol ) in tetrahydrofuran (200 mL) was added dropwise follwed by a solution of 3 0 M methylmagnesium chloride (121 mL, 0 363 mol ) in tetrahydrofuran added dropwise The mixture was stirred at 0°C for 1 hr , then quenched with 2N acetic acid added dropwise The mixture volume was reduced by half, poured into water (800 mL) and acidified with 2N acetic acid to pH 3 then extracted with ethyl acetate (2 X 800 mL) The organic extracts were combined, washed with sodium bicarbonate (100 mL), water (100mL), brine (100 mL), dried (MgS0 4 ), and concentrated to give an oil Flash Chromatography on Silica Gel eluting with ethyl acetate/hexanes (2 3) gave 8 34 g solid MS (m/e) 323 (M + +NH 3 , 100) Preparation 254 fra/.s-4-(Benzyloxycarbonylamino-methyl)-cyclohexanecarboxylic acid ethyl ester. To a stirred solution of fra/ιs-4-Amιnomethyl-cyclohexanecarboxylιc acid ethyl ester (23 8 g, 0 11 mol ) and triethylamine (34 mL, 0 24 mol ) in dioxane (100 mL) at room temperature was added N-(Benzyloxycarbonyloxy)succιnιmιde (26 7 g, 0 11 mol ) The mixture was stirred at room temperature for 18 hr , poured into water (800 mL) and extracted with ethyl acetate (2 X800 mL) The organic extracts were combined, washed with 0 5 N sodium hydroxide (100 mL) 0 5 N hydrochloric acid (100 mL), water (100 mL), brine (100 mL), dried (MgS0 4 ), and concentrated to give 36 0 g solid MS (m/e) 337 (M + +NH 3 , 100) Preparation 255 (R)-(-)-frans-1-(4-Aminomethyl-cyclohexyl)-ethanol. A mixture of (R)-(-)-(trans-4-(1-Hydroxy-ethyl-)cyclohexylmethyl)carbamιc acid benzyl ester (870 mg, 2 98 mmol ) and Pearlman's Catalyst (100 mg) in ethyl acetate (100 mL) and methanol (25 mL) was shaken in a Parr Apparatus under 40 psi hydrogen at room temperature for 1 hr The mixture was filtered through Celite and the filtrate concentrated to give 484 mg oil α D (CHCI 3 ) - 1 6° Preparation 256 (R)-(-)-(fra/7s-4-(1-Hydroxy-ethyl-)cyclohexylmethyl)carbamic acid benzyl ester. To a stirred solution of (frans-4-Acetyl-cyclohexylmethyl)-carbamιc acid benzyl ester (1 0 g, 3 46 mmol ) and (S)-2-Methyl-CBS-oxazaborolιdιne monohydrate (102 mg, 0 34 mmol ) in tetrahydrofuran (15 mL) at 0°C was added dropwise a 2 0 M solution of Borane- Dimethylsulfide complex (1 4 mL, 2 77 mmol ) in tetrahydrofuran over 20 mm The mixture was stirred at 0°C for 30 mm , then quenched with methanol (10 mL) the mixture volume was reduced by half, poured into water (200 mL) and extracted with ethyl acetate (2 X 200 mL) The organic extracts were combined, washed with pH 4 buffer (40 mL), water (40 mL), brine (40 mL), dried (MgS0 4 ) and concentrated to give an oil Flash Chromatography on Silica Gel eluting with ethyl acetate/hexanes (1 1) gave 870 mg solid α D (CHCI 3 ) - 0 8° Preparation 257 (fra/.s-4-Acetyl-cyclohexylmethyl)-carbamic acid benzyl ester To a stirred solution of (frans-4-(Methoxy-methyl-carbamoyl)-cyclohexylmethyl)- carbamic acid benzyl ester (5 8 g, 0 017 mol ) in tetrahydrofuran (100 mL) at 0°C, was added dropwise a solution of 3 0M Methylmagnesium chloride in tetrahydrofuran (13 mL, 0 038 mol ) The mixture was stirred at 0°C for 1 hr , then quenched with 2 N acetic acid added dropwise The mixture was poured into water (300 mL) and extracted with ethyl acetate (2 x 300 mL) The organic extracts were combined, washed with 0 5 N hydrochloric acid (80 mL), water (80 mL), brine (80 mL), dried (MgS0 4 ) and concentrated to give an oil Flash Chromatography on Silica Gel eluting with ethyl acetate/hexanes (2 3) gave 2 0 g solid MS (m/e) 307 (M + +NH 3 , 100) Preparation 258 ( ans-4-(Methoxy-methyl-carbamoyl)-cyclohexylmethyl)-carbamic acid benzyl ester. To a stirred solution of fraA7S-4-(Benzyloxycarbonylamιno-methyl)-cyclohexane carboxylic acid (16 7 g, 0 057 mol ), N,0-dιmethylhydroxylamιne hydrochloride (6 2 g, 0 063 mol ), triethylamine (9 mL, 0 063 mol ) and 1-hydroxy-benzotrιazole hydrate (8 5 g, 0 063 mol ) in dimethylformamide (200 mL) at room temperature was added 1-(3-(dιmethylamιno)-propyl)- 3-ethylcarbodιιmιde hydrochloride (13 1 g, 0 068 mol ) The mixture was stirred at room temperature for 72 hrs , poured into water (800 mL) and extracted with ethyl acetate (2 X 800 mL) The organic extracts were combined, washed with 1 N sodium hydroxide (80 mL), 1 N hydrochloric acid (80 mL), water (80 mL), brine (80 mL), dried (MgS0 4 ) and concentrated to give an oil Flash Chromatography on Silica Gel eluting with ethyl acetate/hexanes (3 2) gave 5 8 g oil MS (m/e) 352 (M + +NH 3 , 100) Preparation 259 frans-4-(Benzyloxycarbonylamino-methyl)-cyclohexane carboxylic acid. To a stirred solution of frans-4-(Amιnomethyl)-cyclohexane carboxylic acid (10 0 g, 0 063 mol ) and potassium carbonate (30 5 g, 0 22 mol ) in dioxane (200 mL) and water (200 mL) at room temperature was added benzyl chloroformate (11 mL, 0 08 mol ) The mixture was stirred at room temperature for 18 hrs , poured into water (800 mL) and washed with diethyl ether (800 mL) The aqueous extract was acidified and the resulting precipitate filtered and dried to give 16 7 g white solid MS (m/e) 309 (M + +NH 3 , 100) Mass spectra were determined by the GC-MS, AMPI, APCI or thermospray method All 1 H NMR were taken on 400 MHz instruments EXAMPLE 1 2-(4-Fluoro-phenoxy)-N-thiophen-2-ylmethyl-nicotinamide To a stirred solution of 2-(4-Fluoro-phenoxy)-nιcotιnιc acid (0 300 grams, 1 29 mmole) and NMM (0 137 grams, 1 35 mmole) in dry methylene chloride (15 ml) at -10°C was added isobutyl chloroformate (0 164 grams, 1 35 mmole) After 30 minutes at -10°C 2- aminomethylthiophene (0 152 grams, 1 35 mmole) was added and the mixture was allowed to warm to room temperature over night The mixture was poured into water and extracted with ethyl acetate The combined organics were washed with 1 \_ sodium hydroxide and water, dried over MgS0 4 , filtered, and concentrated to give a clear oil that was purified by chromatography on silica gel eluting with 30% ethyl acetate/ hexane to give a solid Recrystalization from ethyl acetate/ hexane gave white crystals (0 326 g) M P 89-91 °C, MS (m/e) 329 (M + +1) The compounds of Examples 2-9 were prepared according to the procedure of Example 1 substituting the corresponding amine for 2-amιnomethylthιophene The duration of reaction was between 1 and 24 hours EXAMPLE 2 2-(4-Fluoro-phenoxy)-N-furan-2-ylmethyl-nicotinamide M P 71-73°C, Anal calcd for C 17 H 13 N 2 0 3 F C, 65 38, H, 4 20, N, 6 97 Found C, 65 53, H, 4 34, N, 9 31 EXAMPLE 3 (R)(-)2-(4-Fluoro-phenoxy)-N-[1-(4-methoxy-phenyl)-ethyl]-nicotinamide M P 101-103°C, Anal calcd for C 12 H 19 N 2 0 3 F C, 68 84, H, 5 23, N, 7 65 Found 068 46, H, 5 20, N, 7 62 EXAMPLE 4 (S)-(+) 2-(4-Fluoro-phenoxy)-N-[1-(4-methoxy-phenyl)-ethyπ-nicotinamide M P 97-99°C, Anal calcd for C 21 H 19 N 2 0 3 F C, 68 84, H, 5 23, N, 7 65 Found C,68 84, H, 5 17, N, 7 71 α D = +54 2° (C=0 2, chloroform) EXAMPLE 5 N-(2-Chloro-6-fluoro-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide M P 115-118°C, Anal calcd for C 19 H 13 N 2 0 2 F 2 CI C, 60 89, H, 3 50, N, 7 47 Found C, 60 63, H, 3 45, N, 7 38 EXAMPLE 6 (S)(-)2-(4-Fluoro-phenoxy)-N-(1-thiophen-2-yl-ethyl)-nicotinamide M P 59-61°C, Anal calcd for C 18 H 15 N 2 S0 2 F C, 63 14, H, 442, N, 8 18 Found C, 63 21 , H, 4 34, N, 8 16 D = -26 5° (C=0 3, chloroform) EXAMPLE 7 (R)(+)2-(4-Fluoro-phenoxy)-N-(1-thiophen-2-yl-ethyl)-nicotinamide M P 60-62°C, Anal calcd for C 18 H 15 N 2 S0 2 F C, 63 14, H, 4 42, N, 8 18 Found C, 62 75, H, 4 27, N, 8 06 α D = +26 2° (C=0 4, chloroform) EXAMPLE 8 N-[1-(5-Chloro-thiophen-2-yl)-ethyl]-2-(4-fluoro-phenoxy)-nicotinamide M P 87-89°C, Anal calcd for C 18 H 14 N 2 S0 2 CIF C, 57 37, H, 3 74, N, 7 43 Found C, 57 51 , H, 3 68, N, 7 48 EXAMPLE 9 N-(2-Chloro-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide M P 118-120°C, Anal calcd for C 19 H 14 N 2 0 2 CIF C, 63 96, H, 3 95, N, 7 85 Found C, 63 54, H, 3 96, N, 7 72 EXAMPLE 10 N-(2-Chloro-benzyl)-2-(2.4-difluoro-phenoxy)-nicotinamide To a stirred solution of 2-(2,4-dιfluoro-phenoxy)-nιcotιnιc acid (0 300 grams, 1 19 mmole) and NMM (0 133 grams, 1 31 mmole) in dry methylene chloride (15 ml) at -10°C was added isobutyl chloroformate (0 202 grams, 1 31 mmole) After 20 minutes at -10°C 2- chlorobenzylamine (0 202 grams, 1 43 mmole) was added and the mixture was allowed to warm to room temperature over night The mixture was poured into water and extracted with ethyl acetate The combined organics were washed with 1 N NaOH, water and brine, dried over MgS0 4 , filtered and concentrated to give a clear oil that was purified by chromatography on silica gel eluting with 30% ethyl acetate/ hexane to give a solid Recrystalization from ethyl acetate/ hexane gave a solid (0 295 g) M P 122-124°C, Anal calcd for C 19 H 13 N 2 0 2 F 2 CI C, 60 89, H, 3 50, N, 7 47 Found C, 60 77, H, 3 44, N, 7 38 EXAMPLE 11 N-(2-Chloro-benzyl)-2-(3-fluoro-phenoxy)-nicotinamide To a stirred solution of 2-(3-Fluoro-phenoxy)-nιcotιnιc acid (0 300 grams, 1 29 mmole) and NMM (0 144 grams, 1 41 mmole) in dry methylene chloride (15 ml) at -10°C was added isobutyl chloroformate (0 193 grams, 1 41 mmole) After 20 minutes at -10°C 2- chlorobenzylamme (0 219 grams, 1 55 mmole) was added and the mixture was allowed to warm to room temperature over night The mixture was poured into water and extracted with ethyl acetate The combined organics were washed with 1 N NaOH, water and brine, dried over MgS0 4 , filtered and concentrated to give a solid that was purified by chromatography on silica gel eluting with 30% ethyl acetate/ hexane to give a white solid Recrystalization from ethyl acetate/ hexane gave a solid (0 328 g) M P 115-117°C, Anal calcd for C 19 H 14 N 2 0 2 CIF C, 63 96, H, 3 95, N, 7 85 Found C, 64 04, H, 3 92, N, 7 85 EXAMPLE 12 N-(2-Chloro-benzyl)-2-(pyridin-3-yloxy)-nicotinamide To a stirred solution of 2-(pyrιdιn-3-yloxy)-nιcotιnιc acid (0 300 grams, 1 39 mmole), o- chlorobenzylamme (0 216 grams, 1 53 mmole), and 1 -hydroxy benzotriazole hydrate (0 207 grams, 1 53 mmole) in dry dimethylformamide (15 ml) was added (3-(dιmethylamιno)-propyl)- 3-ethylcarbodιmιde hydrochloride (0 319 grams, 1 67 mmole) and stirred over night The mixture was diluted with 200 ml ethyl acetate washed with 1 NaOH, water and brine, dried over MgS04, filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 5% methanol/methylene chloride Recrystalization from ethyl acetate/ hexane gave a white solid (0 275 g) M P 123-125°C, Anal calcd for C 18 H 14 N 3 0 2 CI C, 63 63, H, 4 15, N, 12 37 Found C, 63 19, H, 3 85, N, 11 67 The compounds of Examples 13-44 were prepared according to the procedure of Example 12 substituting the corresponding amine for o-chlorobenzylamine The duration of reaction was between 1 and 24 hours EXAMPLE 13 N-(4-Methyl-benzyl)-2-(pyridin-3-yloxy)-nicotinamide M P 91-93°C, Anal calcd for C 19 H 17 N 3 0 2 C, 71 46, H, 5 37, N, 13 16 Found C, 71 51 , H, 5 40, N, 13 26 EXAMPLE 14 N-[1-(5-Chloro-thiophen-2-yl)-ethyl]-2-(pyridin-3-yloxy)-nicotinamide M P 74-76°C, Anal calcd for C 17 H 14 N 3 S0 2 CI C, 56 75, H, 3 92, N, 11 68 Found C, 56 54, H, 4 06, N, 11 80 EXAMPLE 15 N-Furan-2-ylmethyl-2-(pyridin-3-yloxy)-nicotinamide M P 84-86°C, Anal calcd for C 16 H 13 N 3 0 3 C, 65 08, H, 4 44, N, 14 23 Found C, 65 04, H. 4 50, N, 14 55 EXAMPLE 16 N-(5-Chloro-thiophen-2-ylmethyl)-2-(pyridin-3-yloxy)-nicotinamide M P 110-112°C, Anal calcd for C 16 H 12 N 3 S0 2 CI C, 55 57, H, 3 50, N, 12 15 Found C, 55 23, H, 3 57, N, 12 45 EXAMPLE 17 N-[1-(5-Methyl-thiophen-2-yl)-ethyl]-2-(pyridin-3-yloxy)-nicotinamide M P 162-164°C, MS (m/e) 340 (M + +1 ) EXAMPLE 18 N-(5-Methyl-thiophen-2-ylmethyl)-2-(pyridin-3-yloxy)-nicotinamide M P 111-113°C, Anal calcd for C 17 H 15 N 3 S0 2 C, 62 75, H, 4 65, N, 12 91 Found C, 62 77, H, 4 67, N, 12 50 EXAMPLE 19 N-(5-Methyl-furan-2-ylmethyl)-2-(pyridin-3-yloxy)-nicotinamide M P 65-67°C, Anal calcd for C 17 H 15 N 3 0 3 C, 66 01 , H, 4 89, N, 13 58 Found C, 65 77, H. 4 90, N, 13 28 EXAMPLE 20 N-(3-Methyl-thiophen-2-ylmethyl)-2-(pyridin-3-yloxy)-nicotinamide M P 89-91°C, Anal calcd for C 17 H 15 N 3 S0 2 C, 62 75, H, 4 65, N, 12 91 Found C, 62 71 , H, 4 64, N, 12 80 EXAMPLE 21 N-(4-Chloro-thiophen-2-ylmethyl)-2-(pyridin-3-yloxy)-nicotinamide M P 118-120°C, Anal calcd for C 16 H 12 N 3 S0 2 CI C, 55 57, H, 3 50, N, 12 15 Found C, 55 50, H, 3 89, N, 11 37 EXAMPLE 22 N-Benzo[b1-hiophen-2-ylmethyl-2-(pyridin-3-yloxy)-nicotinamide M P 93-95°C, Anal calcd for C 20 H 15 N 3 SO 2 C, 6647, H, 4 18, N, 11 63 Found C, 66 00, H, 4 19, N, 11 66 EXAMPLE 23 N-(5-Chloro-furan-2-ylmethyl)-2-(pyridin-3-yloxy)-nicotinamide M P 80-82°C, Anal calcd for C 16 H 12 N 3 0 3 CI C, 58 28, H, 3 67, N, 12 74 Found C, 58 52, H, 3 73, N, 12 80 EXAMPLE 24 2-(Pyridin-3-yloxy)-N-thiazol-2-ylmethyl-nicotinamide M P 94-96°C, MS (m/e) 313 (M + +1) EXAMPLE 25 2-(Pyridin-3-yloxy)-N-[4-(2.2.2-trifluoro-ethoxy)-benzyl]-nicotinamide M P 98-100°C, Anal calcd for C 2 oH 16 N 3 0 3 F 3 C, 59 55, H, 4 00, N, 10 42 Found C, 59 74, H, 3 92, N, 10 53 EXAMPLE 26 N-(2-Fluoro-benzyl)-2-(pyridin-3-yloxy)-nicotinamide M P 90-92°C, Anal calcd for C 18 H 14 N 3 0 2 F C, 66 87, H, 4 36, N, 13 00 Found C, 67 08, H, 4 23, N, 13 07 EXAMPLE 27 N-(4-Difluoromethoxy-benzyl)-2-(pyridin-3-yloxy)-nicotinamide M P 91-93°C, Anal calcd for C 19 H 15 N 3 0 3 F 2 C, 61 46, H, 4 07, N, 11 32 Found C, 61 47, H, 3 84, N, 11 24 EXAMPLE 28 N-(4-Fluoro-benzyl)-2-(pyridin-3-yloxy)-nicotinamide M P 129-131°C, Anal calcd for C 18 H 14 N 3 0 2 F C, 66 87, H, 4 36, N, 13 00 Found C, 66 63, H. 4 42, N, 13 04 EXAMPLE 29 N-(4-Methoxy-benzyl)-2-(pyridin-3-yloxy)-nicotinamide M P 62-64°C, Anal calcd for C 19 H 17 N 3 0 3 C, 68 05, H, 5 11 , N, 12 53 Found C, 68 20, H, 4 96, N, 12 58 EXAMPLE 30 2-(Pyridin-3-yloxy)-N-(5-trifluoromethyl-thiophen-2-ylmethyl)-nicotinamide M P 122-124°C, Anal calcd for C 17 H 12 N 3 0 2 SF 3 C, 53 82, H, 3 19, N, 11 08 Found C, 54 44, H, 3 22, N, 11 10 EXAMPLE 31 N-(2-Chloro-benzyl)-2-(pyridin-3-yloxy)-nicotinamide M P 174-176°C, Anal calcd for C 18 H 14 N 3 0 2 CI«HCI, C, 57 46, H, 4 02, N, 11 17 Found C, 57 16, H, 4 11 , N, 11 09 EXAMPLE 32 N-(5-Fluoro-thiophen-2-ylmethyl)-2-(pyridin-3-yloxy)-nicotinamide M P 99-101°C, Anal calcd for C 16 H 12 N 3 0 2 SF C, 58 35, H, 3 67, N, 12 76 Found C, 58 35, H, 3 55, N, 12 71 EXAMPLE 33 N-(2-Oxo-2.3-dihydro-1H-indol-5-ylmethyl)-2-(pyridin-3-yloxy)-nicotinamide M P 109-111°C, Anal calcd for C 20 H 16 N 4 O 3 C, 66 66, H, 4 47, N, 15 55 Found C, 65 92, H. 4 56, N, 14 84 EXAMPLE 34 N-(3 T 5-Di-tert-butyl-4-hydroxy-benzyl)-2-(pyridin-3-yloxy)-nicotinamide M P 42-44°C, Anal calcd for C 26 H 31 N 3 0 3 C, 72 03, H, 7 21 , N, 9 69 Found C, 71 19, H, 7 22, N, 9 79 EXAMPLE 35 N-[5-(1-Hydroxy-1-methyl-ethyl)-thiophen-2-ylmethyl]-2-(pyridin-3-yloxy)- nicotinamide M P 110-112°C, Anal calcd for C 19 H 19 N 3 S0 3 C, 61 77, H, 5 18, N, 11 37 Found C, 61 63, H, 5 40, N, 10 60 EXAMPLE 36 N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(pyridin-3-yloxy)-nicotinamide M P 79-81°C, Anal calcd for C 21 H 21 N 3 0 3 C, 69 41 , H, 5 82, N, 11 56 Found C, 69 19, H, 5 85, N, 11 58 EXAMPLE 37 4-({[2-(Pyridin-3-yloxy)-pyridine-3-carbonyl]-amino>-methyl)-benzoicacid methyl ester M P 125-127°C, Anal calcd for C 20 H 17 N 3 O 4 C, 66 11 , H, 4 72, N, 11 56 Found C, 65 83, H. 4 52, N, 11 39 EXAMPLE 38 N-[3-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(pyridin-3-yloxy)- nicotinamide M P 139-141°C, Anal calcd for C 21 H 20 N 3 O 3 CI C, 63 40, H, 5 07, N, 10 56 Found C, 63 24, H, 4 85, N, 10 21 EXAMPLE 39 N-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(pyridin-3-yloxy)- nicotinamide MS (m/e) 400/398 (M + +1), 1 H NMR (400mhz, CDCI 3 ) d 1 54 (s, 6H), 4 73 (d, 2H), 7 16-7 56 (m, 6H), 8 16 (d, 1 H), 8 34 (m , 1 H), 8 49 (dd, 2H), 8 61 (d , 1 H) EXAMPLE 40 2-(Pyridin-3-yloxy)-N-[4-(2.2.2-trifluoro-1-hydroxy-ethyl)-benzyl]-nicotinamide MS (m/e) 404 (M + +1 ), 1 H NMR (400mhz, CDCI 3 ) d 4 70 (dd, 2H), 4 98 (dd, 1 H), 7 16- 7 56 (m, 7H), 8 00 (m, 1 H), 8 18 (dd , 1 H), 8 28 (d, 1 H), 8 43 (m, 1 H), 8 60 (dd, 1 H) EXAMPLE 41 N-(4-Hydroxy-chroman-7-ylmethyl)-2-(pyridin-3-yloxy)-nicotinamide M P 134-136°C, Anal calcd for C 21 H 19 N 3 0 4 C, 66 83, H, 5 07, N, 11 13 Found C, 66 50, H, 4 90, N, 11 60 EXAMPLE 42 N-[4-(1-Hydroxy-cyclobutyl)-benzyl]-2-(pyridin-3-yloxy)-nicotinamide M P 116-118°C, Anal calcd for C 22 H 21 N 3 0 3 C, 70 83, H, 5 64, N, 11 19 Found C, 70 41 , H, 5 67, N, 10 97 EXAMPLE 43 N-[4-(1-Hydroxy-prop-2-ynyl)-benzyl]-2-(pyridin-3-yloxy)-nicotinamide MS (m/e) 360/344 (M + +1), 1 H NMR (400mhz, CDCI 3 ) d 4 69 (d, 2H), 5 19 (m, 1 H), 7 15-7 53 (m, 8H), 7 99 (m, 1 H), 8 18 (dd , 1 H), 8 35 (dd, 1 H), 8 49 (d, 1 H), 8 63 (dd, 1 H) EXAMPLE 44 N-[3-Chloro-5-(1-hydroxy-1-methyl-ethyl)-thiophen-2-ylmethyl1-2-(pyridin-3- yloxy)-nicotinamide M P 74-76°C, Anal calcd for C 19 H 18 N 3 0 3 SCI C, 56 50, H, 4 49, N, 10 40 Found C, 56 79, H, 4 68, N, 9 64 EXAMPLE 45 2-(Pyridin-3-yloxy)-N-(1-thiophen-2-yl-ethyl)-nicotinamide To a stirred suspension of 2-(pyrιdιn-3-yloxy)-nιcotιnιc acid (0 300 grams, 1 39 mmole) and NMM (0 155 grams, 1 53 mmole) in dry methylene chloride (15 ml) at -10°C was added isobutyl chloroformate (0 208 grams, 1 53 mmole) After 20 minutes at -10°C 1- Thιophen-2-yl-ethylamιne (0 195 grams, 1 53 mmole) was added and the mixture was allowed to warm to room temperature over night The mixture was diluted with 200 ml ethyl acetate, washed with 1 N sodium hydroxide and water, dried over MgS04, filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 5% methanol/methylene chloride to give a solid Recrystalization from ethyl acetate/ hexane gave a white solid (0 191 g) M P 90-92°C, Anal calcd for C 17 H 15 N 3 0 2 S C, 62 75, H, 4 65, N, 12 91 Found C, 62 51 , H, 4 69, N, 13 10 The compounds of Examples 46-47 were prepared according to the procedure of Example 45 substituting the corresponding amine for 1-Thιophen-2-yl-ethylamιne The duration of reaction was between 1 and 24 hours EXAMPLE 46 (S)(+)-2-(Pyridin-3-yloxy)-N-(1-thiophen-2-yl-ethyl)-nicotinamide M P 196-198°C, Anal calcd for C 17 H 15 N 3 0 2 S«HCI C, 56 43, H, 4 46, N, 11 61 Found C, 59 48, H, 5 49, N, 10 04 α D = +28 3° (C=0 2, methanol) EXAMPLE 47 (R)(-)-2-(Pyridin-3-yloxy)-N-(1-thiophen-2-yl-ethyl)-nicotinamide M P 197-199°C, Anal calcd for C 17 H 15 N 3 0 2 S«HCI C, 56 43, H, 446, N, 11 61 Found C, 57 55, H, 5 12, N, 10 62 α D = +17 9° (C=0 1 , methanol) EXAMPLE 48 2-(5-Chloro-pyridin-3-yloxy)-N-(4-methyl-benzyl)-nicotinamide To a stirred solution of 2-(5-chloro-pyrιdιn-3-yloxy)-nιcotιnιc acid (0 180 grams, 0 78 mmole), 4-methylbenzylamιne (0 104 grams, 0 86 mmole), and 1 -hydroxy benzotriazole hydrate (0 116 grams, 0 86 mmole) in dry dimethylformamide (5 ml) was added 1-(3- (dιmethylamιno)-propyl)-3-ethylcarbodιιmιde chloride hydrochloride (0 165 grams, 0 86 mmole) and stirred for 18 hours The mixture was poured into 100 ml water and extracted with ethyl acetate The combined organics were washed with water and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 5% methanol/methylene chloride Recrystalization from ethyl acetate/ hexane gave light pink crystals (0 211 g) M P 119-121°C, Anal calcd for C 19 H 16 N 3 0 2 CI C, 64 50, H, 4 56, N, 11 88 Found C, 64 44, H, 4 47, N, 11 94 The compounds of Examples 49-60 were prepared according to the procedure of Example 48 substituting the corresponding amine for 4-methylbenzylamιne The duration of reaction was between 1 and 24 hours EXAMPLE 49 2-(5-Chloro-pyridin-3-yloxy)-N-[1-(5-chloro-thiophen-2-yl)-ethyl]-nicotinamide M P 110-112°C, Anal calcd for C 17 H 14 N 3 0 2 SCI 2 C, 51 66, H, 3 57, N, 10 63 Found C, 51 49, H, 3 51 , N, 10 41 EXAMPLE 50 2-(5-Chloro-pyridin-3-yloxy)-N-[1-(5-methyl-thiophen-2-yl)-ethyl]-nicotinamide M P 75-77°C, Anal calcd for C 18 H 16 N 3 0 2 SCI C, 57 83, H, 4 31 , N, 11 24 Found C, 57 88, H, 4 42, N, 11 42 EXAMPLE 51 2-(5-Chloro-pyridin-3-yloxy)-N-(5-chloro-thiophen-2-ylmethyl)-nicotinamide M P 125-127°C, Anal calcd for C^H^N^SC!;, C, 50 54, H, 2 92, N, 11 05 Found C, 50 42, H, 2 99, N, 11 07 EXAMPLE 52 2-(5-Chloro-pyridin-3-yloxy)-N-(5-methyl-thiophen-2-ylmethyl)-nicotinamide M P 81-83°C, Anal calcd for C 17 H 14 N 3 0 2 SCI C, 56 75, H, 3 92, N, 11 68 Found C, 56 94, H, 4 07, N, 11 19 EXAMPLE 53 2-(5-Chloro-pyridin-3-yloxy)-N-(5-methyl-furan-2-ylmethyl)-nicotinamide M P 103-105°C, Anal calcd for C 17 H 14 N 3 0 3 CI C, 59 40, H, 4 10, N, 12 22 Found C, 59 50, H, 4 15, N, 12 08 EXAMPLE 54 2-(5-Chloro-pyridin-3-yloxy)-N-(3-methyl-thiophen-2-ylmethyl)-nicotinamide M P 115-117°C, Anal calcd for C 17 H 14 N 3 S0 2 CI C, 56 75, H, 3 92, N, 11 68 Found C, 56 75, H, 4 02, N, 11 37 EXAMPLE 55 2-(5-Chloro-pyridin-3-yloxy)-N-(4-chloro-thiophen-2-ylmethyl)-nicotinamide M P 94-96°C, MS (m/e) 380/382 (M + +1) EXAMPLE 56 N-Benzo[b]thiophen-2-ylmethyl-2-(5-chloro-pyridin-3-yloxy)-nicotinamide M P 160-162°C, Anal calcd for C 20 H 14 N 3 S0 2 CI C, 60 68, H, 3 56, N, 10 61 Found C, 60 90, H, 3 67, N, 1049 EXAMPLE 57 N-(5-Chloro-furan-2-ylmethyl)-2-(5-chloro-pyridin-3-yloxy)-nicotinamide M P 111-113°C, Anal calcd for C^nN^CI;, C, 52 77, H, 3 04, N, 11 54 Found C, 53 04, H, 3 16, N, 11 21 EXAMPLE 58 2-(5-Chloro-pyridin-3-yloxy)-N-cyclohexylmethyl-nicotinamide M P 95-97°C, Anal calcd for C 18 H 20 N 3 O 2 CI C, 62 52, H, 5 83, N, 12 15 Found C, 62 51 , H, 5 80, N, 12 10 EXAMPLE 59 2-(5-Chloro-pyridin-3-yloxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]- nicotinamide M P 78-80°C, Anal calcd for C 21 H 20 N 3 O 3 CI C, 63 40, H, 5 07, N, 10 56 Found C, 63 24, H, 5 00, N, 10 33 EXAMPLE 60 N-[3-Chloro-5-(1-hydroxy-1-methyl-ethyl)-thiophen-2-ylmethyl]-2-(5-chloro- pyridin-3-yloxy)-nicotinamide M P 72-74 , Anal calcd for C 19 H 17 N 3 0 3 SCI 2 C, 52 66, H, 3 91 , N, 9 59 Found C, 50 27, H, 4 10, N, 9 01 EXAMPLE 61 N-(5-Chloro-thiophen-2-ylmethyl)-2-(4-fluoro-phenoxy)-nicotinamide To a stirred solution of 2-(4-Fluoro-phenoxy)-nιcotιnιc acid (0 200 grams, 1 02 mmole), C-(5-Chloro-thιophen-2-yl)-methylamιne (0 151 grams, 1 02 mmole), and 1- hydroxy benzotriazole hydrate (0 138 grams, 1 02 mmole) in dry dimethylformamide (3 ml) was added 1-(3-dιmethylamιno)-propyl)-3-ethylcarbodιιmιde hydrochlonde (0 212 grams, 1 11 mmole) and stirred over night The mixture was poured into 100 ml water and extracted with ethyl acetate The combined organics were washed with 1 N NaOH, water and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 30% ethyl acetate/ hexane Recrystalization from ethyl acetate/ hexane gave a white solid (0 216 g) M P 91-93°C, Anal calcd for C 17 H 12 N 2 0 2 SFCI C, 56 28, H, 3 33, N, 7 72 Found C, 56 34, H, 3 36, N, 7 41 The compounds of Examples 62-91 were prepared according to the procedure of Example 61 substituting the corresponding amine for C-(5-Chloro-thιophen-2-yl)-methylamιne The duration of reaction was between 1 and 24 hours EXAMPLE 62 N-(4-Chloro-thiophen-2-ylmethyl)-2-(4-fluoro-phenoxy)-nicotinamide M P 99-101°C, Anal calcd for C 17 H 12 N 2 S0 2 FC1 C, 56 28, H, 3 33, N, 7 72 Found C, 56 40, H, 3 38, N, 7 60 EXAMPLE 63 N-(5-Chloro-furan-2-ylmethyl)-2-(4-fluoro-phenoxy)-nicotinamide M P 116-118°C, Anal calcd for C 17 H 12 N 2 0 3 FCI C, 58 89, H, 3 49, N, 8 08 Found C, 59 07, H, 3 53, N, 7 97 EXAMPLE 64 N-(2.3-Difluoro-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide M P 71-73°C, Anal calcd for C 15 H 13 N 2 0 2 F 3 C, 63 69, H, 3 66, N, 7 82 Found C, 63 60, H, 3 64, N, 7 70 EXAMPLE 65 N-Benzo[b]thiophen-2-ylmethyl-2-(4-fluoro-phenoxy)-nicotinamide M P 109-111°C, Anal calcd for C 21 H 15 N 2 0 2 SF C, 66 65, H, 4 00, N, 7 40 Found C, 66 52, H, 4 02, N, 7 24 EXAMPLE 66 N-(3.5-Difluoro-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide M P 116-118°C, Anal calcd for C 15 H 13 N 2 θ 2 F 3 C, 63 69, H, 3 66, N, 7 82 Found C, 65 57, H, 4 24, N, 7 73 EXAMPLE 67 2-(4-Fluoro-phenoxy)-N-(2.4.6-trifluoro-benzyl)-nicotinamide M P 128-130°C, Anal calcd for C 19 H 12 N 2 0 2 F 4 C, 60 64, H, 3 21 , N, 7 44 Found C, 60 83, H, 3 15, N, 7 25 EXAMPLE 68 N-(3.4-Dichloro-thiophen-2-ylmethyl)-2-(4-fluoro-phenoxy)-nicotinamide M P 132-134°C, Anal calcd for C^Hn^SO^F C, 51 40, H, 2 79, N, 7 05 Found C, 51 36, H, 2 86, N, 7 05 EXAMPLE 69 N-(3-Chloro-thiophen-2-ylmethyl)-2-(4-fluoro-phenoxy)-nicotinamide M P 134-136°C, Anal calcd for C 17 H 12 N 2 S0 2 CIF C, 56 28, H, 3 33, N, 7 72 Found C, 56 17, H, 3 30, N, 7 70 EXAMPLE 70 N-(2-Chloro-benzyl)-2-(4-fluoro-benzyloxy -nicotinamide M.P. 64-66°C; Anal, calcd. for C 20 H 16 N 2 O 2 CIF: C, 64.78; H, 4.35; N, 7.55. Found: C, 64.88; H, 4.36; N, 7.48. EXAMPLE 71 2-(4-Fluoro-phenoxy)-N-(1H-indol-5-ylmethyl)-nicotinamide M.P. 128-130°C; Anal, calcd. for C 21 H 16 N 3 0 2 F: C, 69.80; H, 4.46; N, 11.63. Found: C, 69.46; H. 4.29; N, 11.55. EXAMPLE 72 2-(4-Fluoro-phenoxy)-N-(4-nitro-benzyl)-nicotinamide M.P. 155-157°C; Anal, calcd. for C 19 H 14 N 3 0 4 F: 1 H NMR (400mhz, CDCI 3 ) d 4.80 (d, J=6.02 Hz, 2H), 7.21 (m, 5H), 7.51 (m, 2H), 8.20 (m, 3H), 8.35 (s.broad , 1 H), 8.65 (m, 1 H). EXAMPLE 73 2-(4-Fluoro-phenoxy)-N-(2-oxo-2.3-dihydro-1H-indol-5-ylmethyl)-nicotinamide M.P. 180-182°C; Anal, calcd. for C 21 H 16 N 3 0 3 F: C, 66.84; H, 4.27, N, 11.13. Found: C, 66.31 ; H, 4.31 ; N, 10.76. EXAMPLE 74 2-(4-Fluoro-phenoxy)-N-(2-oxo-2.3-dihydro-benzooxazol-6-yπ-nicotinamide M.P. 289-291°C; Anal, calcd. for C 19 H 12 N 3 0 4 F: C, 62.47; H, 3.31 , N, 11.50. Found: C, 61.83; H, 3.08; N, 11.56. EXAMPLE 75 5-({[2-(4-Fluoro-phenoxy)-pyridine-3-carbonyl1-amino}-methyl)-1H-indole-2- carbox ylic acid ethyl ester M.P. 185-187°C; Anal, calcd. for C 24 H 20 N 3 O 4 F: C, 66.51 ; H, 4.65, N, 9.98. Found: C, 66.61 ; H, 4.66; N, 9.55. EXAMPLE 76 N-(3.5-Di-tert-butyl-4-hydroxy-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide M.P. 45-47°C; Anal, calcd. for C 27 H 31 N 2 0 3 F: C, 71.98; H, 6.93, N, 6.22. Found: C, 72.05; H, 7.08; N, 6.28. EXAMPLE 77 2-(4-Fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide M.P. 106-108°C; Anal, calcd. for C 22 H 21 N 2 0 3 F: C, 69.46; H, 5.56, N, 7.36. Found: C, 69.39; H, 5.48; N, 7.16. EXAMPLE 78 2-(4-Fluoro-phenoxy)-N-(4-hydroxy-3.5-dimethyl-benzyl)-nicotinamide M.P. 142-144°C; Anal, calcd. for C 2 ιH 19 N 2 0 3 F: C, 68.84; H, 5.23, N, 7.65. Found: C, 68.42; H, 5.23; N, 7.61. EXAMPLE 79 2-(4-Fluoro-phenoxy)-N-[5-(1-hydroxy-1-methyl-ethyl)-furan-2-ylmethyl]- nicotinamide M.P. 88-90°C; Anal, calcd. for C 20 H 19 N 2 O 4 F: C, 64.86; H, 5.17, N, 7.56. Found: C, 64.50; H, 4.99; N, 7.69. EXAMPLE 80 N-[5-(1-Ethyl-1-hydroxy-propyl)-thiophen-2-ylmethyl]-2-(4-fluoro-phenoxy)- nicotinamide M.P. 95-97°C; Anal, calcd. for C 22 H 23 N 2 0 3 SF: C, 63.75; H, 5.59, N, 6.76. Found: C, 63.42; H, 5.27; N, 7.07. EXAMPLE 81 N-[4-Chloro-5-(1-hydroxy-1-methyl-ethyl)-thiophen-2-ylmethyl]-2-(4-fluoro- phenoxy)-nicotinamide M.P. 115-117°C; Anal, calcd. for C 20 H 18 N 2 0 3 SCIF: C, 57.08; H, 4.31 , N, 6.66. Found: C, 57.03; H, 4.10; N, 6.75. EXAMPLE 82 N-[1-(4-Bromo-phenyl)-ethyiy2-(4-fluoro-phenoxy)-nicotinamide M.P. 120-122°C; H NMR (CDCI 3 ) d 1.60 (3 H, d, J = 6.85 Hz), 5.25 (1 H, m), 7.1-7.5 (9 H, m), 8.10 (1 H, bs), 8.20 (1 H, m), 8.60 (1 H, m). EXAMPLE 83 2-(4-Fluoro-phenoxy)-N-[4-(1-methoxy-1-methyl-ethyl)-benzyl]-nicotinamide Anal, calcd. for C 23 H 23 N 2 0 3 F: MS (m/e) 395 (M + +1 ); 1 H NMR (CDCI 3 ) d 1.50 (6 H, s), 3.05 (3 H, s), 4.72 (2 H, d, J= 5.81 Hz), 7.1-7.4 (9 H, m), 8.2 (9 H, m), 8.65 (1 H, m). EXAMPLE 84 N-[3-Chloro-5-(1-hydroxy-1-methyl-ethyl)-thiophen-2-ylmethyl]-2-(4-fluoro- phenoxy)-nicotinamide M.P. 85-87°C; Anal, calcd. for C 20 H 18 N 2 O 3 SCIF: C, 57.08; H, 4.31 , N, 6.66. Found: C, 57.30; H, 4.36; N, 6.46. EXAMPLE 85 2-(4-Fluoro-phenoxy)-N-[4-(1-hydroxy-cyclobutyl)-benzyl1-nicotinamide M P 95-97°C, Anal calcd for C 23 H 21 N 2 0 3 F C, 70 40, H, 5 39, N, 7 14 Found C, 70 28, H, 5 45, N, 7 03 EXAMPLE 86 N-[2-Chloro-4-(1-hydroxy-1-methyl-ethy0-benzyl]-2-(4-fluoro-phenoxy)- nicotinamide M P 102-104°C, Anal calcd for C 22 H 20 N 2 O 3 FCI C, 63 69, H, 4 86, N, 6 75 Found C, 63 69, H. 4 99, N, 6 72 EXAMPLE 87 N-(4-Azetidin-1-yl-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide M P 128-129°C, Anal Calcd for C 22 H 20 N 3 O 2 F C, 70 01 , H, 5 34, N, 11 13 Found C, 69 64, H, 5 27, N, 11 13 EXAMPLE 88 2-(4-Fluoro-phenoxy)-N-[4-(3-hydroxy-azetidin-1-yl)-benzyl]-nicotinamide M P 157-159°C, 1 H NMR (CDCI 3 ) d 2 08 (1 H, d, J = 7 Hz), 3 62-3 65 (2 H, m), 4 09- 4 16 (2 H, m), 4 59 (2 H, d, J = 5 Hz), 4 70-4 75 (1 H, m), 6 42 (2 H, d, J = 8 Hz), 7 07-7 24 (7 H, m), 8 03 (1 H, br s), 8 16-8 18 (1 H, m), 8 61-8 64 (1 H, m), MS (m/e) 394 (M + +1 ) EXAMPLE 89 2-(4-Fluoro-phenoxy)-N-(4-pyrrolidin-1-yl-benzyl)-nicotinamide M P 127-128°C, 1 H NMR (CDCI 3 ) d 1 93-2 03 (4 H, m), 3 21-3 30 (4 H, m), 4 59 (2 H, d, J = 5 Hz), 6 43-6 60 (2 H, m), 7 06-7 24 (7 H, m), 8 00 (1 H, br s), 8 16-8 18 (1 H, m), 8 62- 8 64 (1 H, m), MS (m/e) 392 (M + + 1) EXAMPLE 90 2-(4-Fluoro-phenoxy)-N-(4-piperidin-1-yl-benzyl)-nicotinamide M P 118-119°C, 1 H NMR (CDCI 3 ) d 1 51-1 74 (6 H, m), 3 09-3 15 (4 H, m), 4 61 (2 H, d, J = 5 Hz), 6 82-6 90 (2 H, m), 7 05-7 24 (7 H, m), 8 04 (1 H, br s), 8 17-8 18 (1 H, m), 8 62- 8 64 (1 H, m), MS (m/e) 406 (M + + 1) EXAMPLE 91 2-(4-Fluoro-phenoxy)-N-(4-morpholin-4-yl-benzyl)-nicotinamide M P 163-165°C, Anal Calcd for C 23 H 22 N 3 0 3 F C, 67 80, H, 5 44, N, 10 31 Found C, 67 42, H, 5 38, N, 10 37 EXAMPLE 92 2-(4-Fluoro-phenoxy)-N-[4-(4-oxo-piperidin-1-yl)-benzyl]-nicotinamide The crude product was further treated in a refluxmg mixture of 2 5 aqueous I N hydrochloric acid solution tetrahydrofuran for 2 days to effect hydrolysis of the ketal, work-up was accomplished by partitioning the mixture between EtOAc and saturated aqueous sodium hydrogencarbonate solution, drying the organic layer (MgS0 4 ), and evaporation M P 138- 139°C, Anal Calcd for C 24 H 22 N 3 0 3 F C, 68 72, H, 5 29, N, 10 02 Found C, 68 60, H, 5 22, N, 10 01 EXAMPLE 93 2-(4-Fluoro-phenoxy)-N-{4-[(2-hydroxy-2-methyl-propyl)-methyl-amino]-benzyl}- nicotinamide 1 H NMR (DMSO-d 6 ) d 1 04 (6 H, s), 2 98 (3 H, s), 3 32 (2 H, s), 4 01 (2 H, d, J = 6 Hz), 7 01-7 11 (2 H, m), 7 06-7 25 (7 H, m), 8 07-8 16 (2 H, m), 8 85 (1 H, t, J = 6 Hz), MS (m/e) 424 (M + + 1) EXAMPLE 94 2-(4-Fluoro-phenoxy)-N-[4-(2-methyl-[1.3]dioxolan-2-yl)-benzyl]-nicotinamide M P 78-80°C, MS (m/e) 408 (M + ) EXAMPLE 95 N-(1.4-Dioxa-spiro[4.5]dec-8-ylmethyl)-2-(4-fluoro-phenoxy)-nicotinamide M P 88-90°C, MS (m/e) 487 (M + +1 ) EXAMPLE 96 N-(4.5-Dichloro-thiophen-2-ylmethyl)-2-(4-fluoro-phenoxy)-nicotinamide M P 127-129°C, Anal Calcd for C 17 H 11 N 2 0 2 FSCI 2 C, 51 40, H, 2 79, N, 7 05 Found C, 51 65 H, 3 01 , N, 6 93 EXAMPLE 97 N-(3.5-Dichloro-thiophen-2-ylmethyl)-2-(4-fluoro-phenoxy)-nicotinamide M P 132-134°C, MS (m/e) 397 (M + ) EXAMPLE 98 2-(5-Chloro-pyridin-3-yloxy)-N-cyclopropylmethyl-nicotinamide To a stirred solution of 2-(5-chloro-pyrιdιn-3-yloxy)-nιcotιnιc acid (0 200 grams, 0 88 mmole), aminomethylcyclopropane hydrochlonde (0 094 grams, 0 88 mmole), triethylamine (0 089 grams, 0 88 mmole) and 1-hydroxybenzotπazole hydrate (0 119 grams, 0 88 mmole) in dry dimethylformamide (3 ml) was added 1-(3-dιmethylamιno)-propyl)-3-ethylcarbodιιmιde hydrochlonde (0 164 grams, 0 96 mmole) and stirred over night The mixture was poured into 100 ml water and extracted with ethyl acetate The combined organics were washed with 1 H NaOH, water and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 2 5% methanol/methylene chloride Recrystalization from ethyl acetate/ hexane gave a white solid (0 163 g) M P 105-107°C, Anal calcd for C 15 H 14 N 3 0 2 CI C, 59 31 , H, 4 65, N, 13 83 Found C, 59 41 , H, 4 68, N, 13 44 Example 99 2-(3-Cyano-4-fluoro-phenoxy)-N-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]- nicotinamide Prepared from 2-(3-Cyano-4-fluoro-phenoxy)-nιcotιnιc acid and 2-(4-Amιnomethyl-3- fluoro-phenyl)-propan-2-ol according to methods analogous to those used in Example 318 MP 157-159°C, MS m/e 422 (M + +1 ) EXAMPLE 100 2-(5-Chloro-pyridin-3-yloxy)-nicotinic acid benzyl ester A 15 ml flask was charged with 2-(5-chloro-pyrιdιn-3-yloxy)-nιcotιnιc acid (0 056 grams, 0 22 mmole), benzyl alcohol (0 052 grams, 0 44 mmole), 4-DMAP (~ 3 mg), 1-(3- dιmethylamιnopropyl)-3-ethyl carbodiimide hydrochloride (0 048 grams, 0 25 mmole), diethyl ether (4 ml) and pyndine (1 ml) and stirred at room temperature After 1 hour the mixture was concentrated under reduced pressure and purified by column chromatography on silica gel eluting with 9/1 ethyl acetate/ hexane to give 0 060 g of the title compound as a colorless oil Anal calcd for C 18 H 13 CIN 2 0 3 M S m/z [M+] 341 , 1 H NMR (CD 3 OD) d 4 58 (s, 2H), 7 45 (m, 7H), 7 71 (s, 1 H), 8 28 (m, 2 H), 8 38 (m, 2 H) The compounds of Examples 101-102 were prepared according to the procedure of Example 100 substituting the corresponding alcohol for benzyl alcohol The duration of reaction was between 1 and 6 hours EXAMPLE 101 2-(5-Chloro-pyridin-3-yloxy)-nicotinic acid 4-fluoro-benzyl ester Anal calcd for C 18 H 12 N 2 0 3 CIF, M S m/z [M+] 359, 1 H NMR (CD 3 OD) d 4 56 (s, 2H), 7 88 (m, 2H), 7 29 (m, 2 H), 7 47 (m, 2 H), 7 72 (s, 1 H), 8 37 (m, 3 H) EXAMPLE 102 2-(5-Chloro-pyridin-3-yloxy)-nicotinic acid 3.5-difluoro-benzyl ester Anal calcd for C iB H„ 2 0 3 C\F 2 , M S m/z [M+] 377, 1 H NMR (CD 3 OD) d 4 59 (s, 2H), 6 77 (m, 2H), 6 85 (m, 3 H), 7 07 (m, 1 H), 7 30 (m, 1 H), 8 35 (m, 2 H) EXAMPLE 103 2-(4-Fluoro-phenoxy)-N-(4-hydroxy-benzyl)-nicotinamide A solution of 1 M boron tribromide (1 7 ml, 1 7 mmole) in methylene chloride was added over 2 minutes to a solution of 2-(4-Fluoro-phenoxy)-N-(4-methoxy-benzyl)- nicotinamide (0 200 grams, 0 568 mmole) in dry methylene chloride at - 78°C The resulting slurry was allowed to warm to room temperature over night The reaction was quenched with water (5 ml) and diluted with ethyl acetate The organics were filtered, washed with water and brine, dried over Na 2 S0 4 , filtered and concentrated to an oil which was purified by chromatography on silica gel eluting with 60% ethyl acetate/ hexane Recrystalization from ethyl acetate/ hexane gave white crystals (0 0 058 g) M P 185-187°C, Anal calcd for C 19 H 15 N 2 0 3 F C, 67 45, H, 4 47, N, 8 28 Found C, 67 24, H, 4 45, N, 8 28 The compound of Example 104 was prepared according to the procedure of Example 103 substituting the corresponding ether for 2-(4-Fluoro-phenoxy)-N-(4-methoxy-benzyl)- nicotinamide The duration of reaction was between 1 and 24 hours EXAMPLE 104 N-(4-Hydroxy-benzyl)-2-(pyridin-3-yloxy)-nicotinamide M P 156-158°C, Anal calcd for C 18 H 15 N 3 0 3 C, 67 28, H, 4 70, N, 13 08 Found C, 66 86, H, 4 57, N, 12 89 EXAMPLE 105 2-(3-Nitro-phenoxy -N-[4-(2.2.2-trifluoro-ethoxy)-benzyl]-nicotinamide To a stirred solution 2-(3-Nιtro-phenoxy)-nιcotιnιc acid (0 200 grams, 0 77 mmole), 4- (2,2,2-Trιfluoro-ethoxy)-benzylamιne (0 173 grams, 0 85 mmole), and 1-hydroxybenzotrιazole hydrate (0 125 grams, 0 92 mmole) in dry dimethylformamide (4 ml) was 1-(3-dιmethylamιno)- propyl)-3-ethylcarbodιιmιde chloride hydrochlonde (0 192 grams, 1 00 mmole) and stirred over night The mixture was diluted with 50 ml water and extracted with ethyl acetate The combined organics were washed with 1 NaOH, water and brine, and concentrated to give a yellow solid that was purified by chromatography on silica gel eluting with 35% methanol/ methylene chloride Recrystalization from ethyl acetate/ hexane gave a white solid (0 340 g) M P 90-92°C, Anal calcd for C 21 H 16 N 3 0 5 F 3 C, 56 38, H, 3 60, N, 9 39 Found C, 56 35, H, 3 60, N, 9 47 The compounds of Examples 106-109 were prepared according to the procedure of Example 105 substituting the corresponding amine for 4-(2,2,2-Trιfluoro-ethoxy)-benzylamιne The duration of reaction was between 1 and 24 hours EXAMPLE 106 2-(3-Nitro-phenoxy)-N-(2-oxo-2.3-dihydro-1H-indol-5-ylmethyl)-nicotinamide M P 190-192°C, Anal calcd for C 21 H 16 N 4 0 5 C, 62 17, H, 3 99, N, 13 85 Found C, 62 24, H, 4 12, N, 13 73 EXAMPLE 107 N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(3-nitro-phenoxy)-nicotinamide M P 43-45°C, Anal calcd for C 22 H 21 N 3 0 5 C, 64 86 H, 5 20, N, 10 31 Found C, 64 14, H, 5 19, N, 10 23 EXAMPLE 108 N-(4-Hydroxy-3.5-dimethyl-benzyl)-2-(3-nitro-phenoxy)-nicotinamide M P 128-130°C, Anal calcd for C 21 H 19 N 3 0 5 C, 64 12 H, 4 87, N, 10 68 Found C, 63 86, H, 4 71 , N, 10 90 EXAMPLE 109 N-(5-Chloro-thiophen-2-ylmethyl)-2-(3-nitro-phenoxy)-nicotinamide M P 115-117°C, Anal calcd for C 17 H 12 N 3 0 4 SCI C, 52 44 H, 3 11 , N, 10 80 Found C, 52 35, H, 3 06, N, 10 78 EXAMPLE 110 N-(2-Chloro-benzyl)-2-(3-cyano-phenoxy)-nicotinamide To a stirred solution 2-(3-Cyano-phenoxy)-nιcotιnιc acid (0 085 grams, 0 35 mmole), 2-Chloro-benzylamιne (0 055 grams, 0 38 mmole), and 1 -hydroxy benzotriazole hydrate (0 057 grams, 0 42 mmole) in dry dimethylformamide (5 ml) was 1-(3-dιmethylamιno)-propyl)-3- ethylcarbodnmide hydrochlonde (0 046 grams, 0 87 mmole) and stirred over night The mixture was diluted with 50 ml water and extracted with ethyl acetate The combined organics were washed with 1 N NaOH, water and brine, dried over Na 2 S0 4 , filtered and concentrated to give a white solid that was purified by chromatography on silica gel Recrystalization from ethyl acetate/ hexane gave a white solid (0 067 g) M P 135-137°C, Anal calcd for C 20 H 14 N 3 O 2 CI C, 66 03, H, 3 88, N, 11 55 Found C, 65 40, H, 3 89, N, 11 50 The compounds of Examples 111-117 were prepared according to the procedure of Example 110 substituting the corresponding amine for 2-Chloro-benzylamιne The duration of reaction was between 1 and 24 hours EXAMPLE 111 N-(5-Chloro-thiophen-2-ylmethyl)-2-(3-cyano-phenoxy)-nicotinamide M P 145-147°C, Anal calcd for C 18 H 12 N 3 0 2 CIS C, 58 46, H, 3 27, N, 11 36 Found C, 58 43, H, 3 06, N, 11 30 EXAMPLE 112 2-(3-Cyano-phenoxy)-N-(2-oxo-2.3-dihydro-1H-indol-5-ylmethyh-nicotinamide M P 197-199°C, Anal calcd for C 22 H 16 N 4 0 3 C, 68 74, H, 4 20, N, 14 58 Found C, 67 71 , H. 4 09, N, 14 50 EXAMPLE 113 2-(3-Cyano-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl1-nicotinamide M P 97-99°C, Anal calcd for C 23 H 21 N 3 0 3 C, 70 30, H, 5 46, N, 10 85 Found C, 70 43, H, 5 39, N, 10 75 EXAMPLE 114 N-[3-Chloro-5-(1-hydroxy-1-methyl-ethyl)-thiophen-2-ylmethyl]-2-(3-cyano- phenoxy)-nicotinamide M P 71-73°C, Anal calcd for C 21 H 18 N 3 0 3 SCI C, 58 95, H, 4 24, N, 9 82 Found C, 58 97, H. 4 19, N, 9 67 EXAMPLE 115 2-(3-Cyano-phenoxy)-N-[4-(1-hydroxy-cyclobutyl)-benzyl]-nicotinamide M P 161-163°C, Anal calcd for C 26 H 21 N 3 0 3 C, 72 17, H, 5 30, N, 10 52 Found C, 72 23, H, 5 13, N, 1046 EXAMPLE 116 N-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(3-cyano-phenoxy)- nicotinamide M P 121-123°C, Anal calcd for C 23 H 20 N 3 O 3 CI C, 6548, H, 4 78, N, 9 96 Found C, 65 35, H, 4 89, N, 9 83 EXAMPLE 117 2-(3-Cyano-phenoxy)-N-(1-cyclohexyl-3-ethyl-1 H-indazol-5-ylmethyl)- nicotinamide M P 56-58°C, H NMR (400mhz, CDCI 3 ) d 1 20-2 10 (m, 13H), 2 95 (q, J=7 68 Hz, 2H), 4 30 (m, 1 H), 4 80 (d J=5 81 Hz, 2H), 6 05 (m, 1 H), 7 10-7 70 (m, 8H), 8 0 (bs, 1 H), 8 20 (m, 1 H), 8 70 (m, 1 H) EXAMPLE 118 N-(2-Chloro-benzyl)-2-(3-dimethylamino-phenoxy)-nicotinamide To a stirred solution 2-(3-Dιmethylamιno-phenoxy)-nιcotιnιc acid (0 200 grams, 0 775 mmole), 2-Chloro-benzylamιne (0 120 grams, 0 85 mmole), and 1-hydroxybenzotrιazole hydrate (0 126 grams, 0 93 mmole) in dry dimethylformamide (4 ml) was added 1-(3- dιmethylamιno)-propyl)-3-ethylcarbodιιmιde chloride hydrochlonde (0 193 grams, 1 00 mmole) and stirred over night The mixture was diluted with 50 ml water and extracted with ethyl acetate The combined organics were washed with 1 N NaOH, water and brine, dried over Na 2 S0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica gel Recrystalization from ethyl acetate/ hexane gave an oil The product was dissolved in diethyl ether and hydrochloric acid (g) was used to precipitate the salt, which was filtered, dissolved in methylene chloride and concentrated to a solid (0 075 g) M P 85-87°C, Anal calcd for C 21 H 20 N 3 O 2 CkHCI C, 60 30, H, 5 06, N, 10 04 Found C, 60 58, H, 5 60, N, 9 28 EXAMPLE 119 N-(2-Chloro-benzyl)-2-(4-cyano-phenoxy)-nicotinamide To a stirred solution 2-(4-Cyano-phenoxy)-nιcotιnιc acid (0 130 grams, 0 54 mmole), 2-Chloro-benzylamιne (0 083 grams, 0 59 mmole), and 1-hydroxybenzotrιazole hydrate (0 088 grams, 0 65 mmole) in dry dimethylformamide (4 ml) was added 1-(3-dιmethylamιno)-propyl)- 3-ethylcarbodιιmιde hydrochlonde (0 134 grams, 0 70 mmole) and stirred over night The mixture was diluted with 50 ml water and extracted with ethyl acetate The combined organics were washed with 1 N NaOH, water and brine, dried over Na 2 S0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 50/50 ethyl acetate/ hexane Recrystalization from ethyl acetate/ hexane gave a white solid (0 139 g) M P 112- 114°C, Anal calcd for C 20 H 14 N 3 O 2 CI C, 66 03, H, 3 88, N, 11 55 Found C, 65 90, H, 3 92, N, 11 67 The compound of Example 120 was prepared according to the procedure of Example 119 substituting the corresponding amine for 2-Chloro-benzylamιne The duration of reaction was between 1 and 24 hours EXAMPLE 120 2-(4-Cyano-phenoxy)-N-f4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide M P 137-139°C, Anal calcd for C 23 H 21 N 3 0 3 C, 71 30, H, 5 46, N, 10 85 Found C, 70 95, H, 5 69, N, 10 96 EXAMPLE 121 N-(4-Amino-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide To a degassed solution of 2-(4-Fluoro-phenoxy)-N-(4-nιtro-benzyl)-nιcotιnamιde (0 800g 2 17 mmole) in ethyl acetate was added 10% palladium on carbon ( 0 160 g) This was shaken under 40 psi hydrogen for 30 minutes The catalyst was removed by filtration, and the solution was concentrated to give an oil that was purified by chromatography on silica gel eluting with 4% methanol/ methylene chloride Recrystalization from ethyl acetate/ hexane gave a solid (0 562 g) 1 H NMR (400mhz, CDCI 3 ) d 3 64 (s, 2H), 4 58 (d, J=5 60 Hz, 2H), 6 64 (d, J=8 30 Hz, 2H), 7 05 (m, 7H), 8 02 (s, broad , 1 H), 8 20 (m, 1 H), 8 62 (d, 1 H) EXAMPLE 123 N-Allyl-2-(3-chloro-phenoxy)-nicotinamide To a stirred solution of 2(3-chloro-phenoxy)-nιcotιnamιde (0 084g, 0 34 mmole) in methylsulfoxide (2 ml) was added potassium hydroxide powder (0 074 grams, 1 32 mmole) followed by allyl bromide ((0 082 grams, 0 68 mmole) After 1 hour the mixture was poured into water and extracted with methylene chloride The combined organics were washed with brine, dried over MgS0 , filtered and concentrated to give a clear film (0 011 g) 1 H NMR (400mhz, CD 3 OD) d 4 37 (q, J=7 26 Hz, 1 H), 4 82 (d, J=5 60 Hz, 1 H), 5 26 (d J=10 58 Hz, 1 H), 5 40 (d J=17 0 Hz, 1 H), 6 05 (m, 1 H), 7 03 (m, 1 H), 7 13 (m, 1 H), 7 21 (m, 2H), 7 38 (t 8 1 Hz, 1 H), 8 30 (m, 2H) EXAMPLE 124 N-(4-Acetylamino-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide A solution of N-(4-Amιno-benzyl)-2-(4-fluoro-phenoxy)-nιcotιnamιde (0 105 grams, 0 31 mmole) and tnethyl amine (0 047 grams, 0 46 mmole) in methylene chloride was cooled to 0°C, and Acetyl chloride (0 029 grams, 0 37 mmole) was added The mixture was stirred for 10 minutes and then allowed to warm to room temperature for 30 minutes The mixture was diluted with water and extracted with methylene chloride The combined organics were washed with brine, dried over Na 2 S0 4 , filtered and concentrated to give a solid Recrystalization from ethyl acetate/ hexane gave a white solid (0 082 g) M P 128-130°C, Anal calcd for C 21 H 18 N 3 0 3 F C, 66 48, H, 4 78, N, 11 08 Found C, 66 14, H, 4 47, N, 11 08 EXAMPLE 125 2-(3-Acetylamino-phenoxy)-N-(2-chloro-benzyl)-nicotinamide To a stirred solution 2-(3-Acetylamιno-phenoxy)-nιcotιnιc acid (0 400 grams, 1 47 mmole), 2-Chloro-benzylamιne (0 228 grams, 1 62 mmole), and 1-hydroxybenzotrιazole hydrate (0 238 grams, 1 76 mmole) in dry dimethylformamide (10 ml) was added 1-(3- dιmethylamιno)-propyl)-3-ethylcarbodιιmιde chloride hydrochloride (0 367 grams, 1 91 mmole) and stirred over night The mixture was diluted with water, extracted with ethyl acetate and concentrated to give a product that was purified by chromatography on silica gel eluting with 3% methanol methylene chloride Recrystalization gave a solid (0 351 g) M P 177-179°C, Anal calcd for C 21 H 18 N 3 0 3 CI C, 63 72, H, 4 58, N, 10 62 Found C, 63 47, H, 4 55, N, 10 56 The compound of Example 126 was prepared according to the procedure of Example 125 substituting the corresponding amine for 2-Chloro-benzylamιne The duration of reaction was between 1 and 24 hours EXAMPLE 126 2-(3-Acetylamino-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]- nicotinamide M P 155-157°C, Anal calcd for C 24 H 25 N 3 0 4 C, 68 72, H, 6 01 , N, 10 02 Found C, 67 98, H, 6 04, N, 9 92 EXAMPLE 127 (R)-2-(3-Chloro-phenoxy)-N-(2-hydroxy-1-phenyl-ethyl)-nicotinamide A solution of 2-(3-chloro-phenoxy)-nιcotιnιc acid (0 25 grams, 1 0 mmole) in thionyl chloride (10 ml) was heated to reflux After 1 hour the reaction mixture was cooled to room temperature and concentrated under reduced pressure The resulting residue was dissolved in tetrahydrofuran (5 ml) and added dropwise to a solution of (S)-2-hydroxy-1 -phenyl ethylamme (0 14 grams, 1 0 mmole) in pyndine (5 ml) at 0°C After 30 minutes the mixture was warmed to room temperature After 1 hour the mixture was poured into 1 N hydrochloric acid and extracted with ethyl acetate The combined organics were washed with 1 M hydrochloric acid followed by brine and dried over Na 2 S0 4 Concentration under reduced pressure resulted in a yellow oil that was purified by chromatography on silica gel eluting with 1 1 ethyl acetate/hexane to give a colorless oil Anal calcd for C 20 H 17 N 2 O 3 CI C, 65 13, H, 4 65, N, 7 60 Found C, 65 20, H, 4 78, N, 7 38, M S m/z [M+] 369, 1 H NMR (400 MHz, CDCI 3 ) d 2 54 (s, broad, 1 H), 3 95 (m, 2H), 5 32 (m, 1 H), 7 23 (m, 10H), 8 22 (m, 1 H), 8 58 (m, 2H) EXAMPLE 128 (R)-2-(3-Chloro-phenoxy)-3-(4-phenyl-4.5-dihydro-oxazol-2-yl)-pyridine A solution of (R)-2-(3-Chloro-phenoxy)-N-(2-hydroxy-1-phenyl-ethyl)-nιcotιnamιde (0 30 grams, 0 813 mmole) and phosprorus oxychlonde (10 ml) in toluene (10 ml) was stirred for 10 hours The mixture was concentrated to dryness and dissolved in methanol (15 ml) and 1 N sodium hydroxide (5 ml) and refluxed for 2 hours The methanol was evaporated, and the residue was dissolved in water and extracted with ethyl acetate The combined organics were washed with water and brine, dried over Na 2 S0 4 , and concentrated to give a product that was purified by chromatography on silica gel eluting with 1 3 ethyl acetate/ hexane to give a colorless oil , Anal calcd for C 20 H 17 N 2 O 2 CI C, 68 48, H, 4 31 , N, 7 99 Found C, 68 58, H, 4 50, N, 7 63, M S m/z [M+] 351 , α = +24 1° c=5 6 mg/ml in methylene chloride, 1 H NMR (400 MHz, CDCI 3 ) d 4 29 (dd, J=8 4, 9 5 Hz, 1 H), 5 43 (dd, J=8 1 , 10 1 Hz, 1 H), 7 22 (m, 10H), 8 30 (m, 2H) The compound of Example 129 was prepared according to the procedure of Example 128 substituting the corresponding hydroxy nicotmamide for (R)-2-(3-Chloro-phenoxy)-N-(2- hydroxy-1-phenyl-ethyl)-nιcotιnamιde The duration of reaction was between 1 and 24 hours EXAMPLE 129 (S)-2-Phenoxy-3-(4-phenyl-4.5-dihydro-oxazol-2-yl)-pyridine Anal calcd for C 20 H 16 N 2 O 2 C, 75 93, H, 5 10, N, 8 85 Found C, 76 12, H, 5 44, N, 8 17, M S m/z [M+] 317, ot = +21 3° c=8 3 mg/ml in methylene chloride, 1 H NMR (400 MHz, CDCI 3 ) d 4 30 (t, J=8 3 Hz, 1 H), 4 82 (dd, J=8 5, 10 2 Hz, 1 H), 5 43 (dd, J=8 2, 10 3 Hz, 1 H), 7 06 (m, 1 H), 7 29 (m, 10H), 8 28 (m, 2H) EXAMPLE 130 2.2-Dimethyl-propionic acid 4-({[2-(4-fluoro-phenoxy)-pyridine-3-carbonylT|- amino}-methyl)-phenyl ester A solution 2-(4-Fluoro-phenoxy)-N-(4-hydroxy-benzyl)-nιcotιnamιde (0 050 grams, 0 148 mmole), tnmethylacetyl chloride (0 019 grams, 0 163 mmole) and tnethyl amine (0 022 grams, 0 222 mmole) in methylene chloride (5 ml) was stirred for 30 minutes The mixture was diluted with 50 ml 1.N sodium hydroxide and extracted with ethyl acetate The combined organics were washed with water and brine, dried over Na 2 S0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 40% ethyl acetate/ hexane Recrystalization from ethyl acetate/ hexane gave a solid (0 043 g) M P 91-93°C, Anal calcd for C 24 H 23 N 2 0 4 F C, 68 24, H, 5 49, N, 6 63 Found C, 66 07, H, 5 24, N, 6 42 EXAMPLE 131 2-(4-Fluoro-phenoxy)-N-(4-methanesulfonylamino-benzyl)-nicotinamide To a solution of N-(4-Amιno-benzyl)-2-(4-fluoro-phenoxy)-nιcotιnamιde (0 150 grams, 0 445 mmole) and tnethyl amine (0 089g, 0 89 mmole) in methylene chloride (5 ml) was added methanesulfonic anhydride (0 100 grams, 0 578 mmole) and stirred over night The mixture was concentrated to dryness, dissolved in methanol (10 ml) and 1 N sodium hydroxide (15 ml) and extracted with ethyl acetate The product was purified by chromatography on silica gel eluting with 5% methanol methylene chloride Recrystalization gave white crystals (0 043 g) M P 107-109°C, Anal calcd for C 20 H 18 N 3 O 4 SF C, 57 82, H, 4 37, N, 10 11 Found C, 57 88, H, 4 39, N, 9 78 EXAMPLE 132 (S)-2-(3-Chloro-phenoxy)-N-(2-hydroxy-1-phenyl-ethyl)-nicotinamide A solution 2-(3-chloro-phenoxy)-nιcotιnιc acid (0 500 g)ιn thionyl chloride (10 ml) was refluxed for 1 hour The mixture was concentrated to dryness, dissolved in 10 ml tetrahydrofuran and used immediately To a solution of (S)-2-phenylglycιnol (0 140 grams, 1 0 mmole) in dry pyndine (5 ml) at 0°C was added a solution of 2-(3-Chloro-phenoxy)-nιcotιnoyl chloride ( 270 grams, 1 0 mmole) in tetrahydrofuran (5 ml) dropwise, stirred at 0°C for 30 minutes and allowed to warm to room temperature over night The mixture was concentrated under reduced pressure The resulting residue was taken up in ethyl acetate, washed with 1N HCl, water, and brine, dried over Na 2 S0 4 , and concentrated to an oil that was purified by chromatography on silica gel eluting with 1/3 ethyl acetate/hexane to give a colorless oil , Anal calcd for C 20 H 17 N 2 O 3 CI C, 65 13, H, 4 65, N, 7 60 Found C, 65 16, H, 4 63, N, 6 95, α = -63 2° c=11 0 mg/ml in methylene chloride, 1 H NMR (400 MHz, CDCI 3 ) d 2 47 (t, J=5 9 Hz, 1 H), 3 96 (m, 2H), 5 33 (m, 1 H), 7 23 (m, 9H), 8 23 (m, 1 H), 8 58 (m, 2H) The compound of Example 133 was prepared according to the procedure of Example 132 substituting the corresponding amine for (S)-2-phenylglycιnol The duration of reaction was between 30 minutes and 3 hours EXAMPLE 133 2-(3-Chloro-phenoxy -N-(2-hydroxy-2-phenyl-ethyl)-nicotinamide M P 118-119°C, Anal calcd for C 20 H 17 N 2 O 3 CI C, 65 13, H, 4 65, N, 7 59 Found C, 65 37, H, 4 46, N, 7 35 EXAMPLE 134 (S)-2-(3-Chloro-phenoxy)-3-(4-phenyl-4.5-dihydro-oxazol-2-yl)-pyridine A solution of (S)-2-(3-Chloro-phenoxy)-N-(2-hydroxy-1-phenyl-ethyl)-nιcotιnamιde (0 340 grams, 0 922 mmole) and phosprorus oxychlonde (0 7 ml) in toluene (10 ml) was stirred over night The mixture was concentrated to dryness and dissolved in methanol (10 ml) and potassium carbonate was added The mixture was stirred for 2 hours at room temperature and refluxed for 30 minutes The methanol was evaporated, and the residue taken up in ethyl acetate It was washed with water and brine, dried over Na 2 S0 4 , and concentrated to give a product that was purified by chromatography on silica gel eluting with 1/3 ethyl acetate/hexane to give a pale yellow oil (0 013 g) , HRMS 351 0917, M P 78-80°C, Anal calcd for C 20 H 15 N 2 O 2 CI C, 57 37, H, 3 74, N, 7 42 Found C, 57 31 , H, 3 80, N, 7 39 EXAMPLE 135 2-(3-Chloro-phenoxy)-3-(5-phenyl-4.5-dihydro-oxazol-2-yl)-pyridine A solution of 2-(3-Chloro-phenoxy)-N-(2-hydroxy-2-phenyl-ethyl)-nιcotιnamιde (0 320 grams, 0 868 mmole) and phosprorus oxychlonde (0 7 ml) in toluene (10 ml) was stirred over night The mixture was concentrated to dryness and dissolved in methanol (10 ml) and potassium carbonate was added The mixture was stirred for 2 hours at room temperature and refluxed for 30 minutes The methanol was evaporated, and the residue taken up in ethyl acetate It was washed with water and brine, dried over Na 2 S0 4 , and concentrated to give a product that was purified by chromatography on silica get eluting with 1/3 ethyl acetate/hexane to give a pale yellow oil (0 102 g) HRMS 351 0897, 1 H NMR (400 MHz, CDCI 3 ) d 4 06 (dd, J=8 1 , 15 0 Hz, 1 H), 4 56 (dd, J= 10 3, 15 0 Hz, 1 H), 5 66 (dd, =8 0, 10 3 Hz, 1 H), 7 24 (m, 10H), 8 8 27 (m, 2H) EXAMPLE 136 2-(2-Chloro-phenyl)-N-[2-(4-fluoro-phenoxy)-pyridin-3-yl]-acetamide To a stirred solution 2-Chloro-benzoιc acid (0 228g, 1 34 mmole), 2-(4-Fluoro- phenoxy)-pyrιdιn-3-ylamιne (0 300 grams, 1 47 mmole), and 1-hydroxybenzotrιazole hydrate (0 217 grams, 1 61 mmole) in dry dimethylformamide (10 ml) was added 1-(3-dιmethylamιno)- propyl)-3-ethylcarbodιιmιde hydrochlonde (0 335 grams, 1 74 mmole) and stirred over night The mixture was diluted with 50 ml water and extracted with ethyl acetate The combined organics were washed with 1 N NaOH, water and brine, dried over Na 2 S0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica Recrystalization from ethyl acetate/ hexane gave a solid (0 230 g) M P 73-75°C, Anal calcd for C 19 H 14 N 2 0 2 CIF C, 63 96, H, 3 95, N, 7 85 Found C, 63 64, H, 3 85, N, 8 41 The compound of Example 137 was prepared according to the procedure of Example 136 substituting the corresponding carboxylic acid for 2-Chloro-benzoιc acid The duration of reaction was between 1 and 24 hours EXAMPLE 137 2-(4-Acetyl-phenyl)-N-[2-(4-fluoro-phenoxy)-pyridin-3-yl1-acetamide M P 118-120°C, Anal calcd for C 21 H 17 N 2 0 3 F C, 69 22, H, 4 70, N, 7 69 Found C, 68 90, H, 5 75, N, 8 54 EXAMPLE 138 N-(2-Chloro-benzyl)-2-{3-[3-(2-methoxy-phenyl)-ureidol-phenoxy}-nicotinamide A solution of 2-(3-Amιno-phenoxy)-N-(2-chloro-benzyl)-nιcotιnamιde (0 100 grams, 0 28 mmole) and 1-lsocyanato-2-methoxy-benzene (0 063 grams, 0 42 mmole) in dioxane (10 ml) was refluxed over night The mixture was cooled to room temperature and concentrated to an oil which was purified by chromatography on silica gel eluting with 2% methanol/ methylene chloride to give a solid Recrystalization from ethyl acetate/ hexane gave a solid (0 083 g) M P 180-182°C, Anal calcd for C 27 H 23 N 4 0 4 CI C, 64 48, H, 4 61 , N, 11 14 Found C, 64 55, H, 4 60, N, 10 74 The compound of Example 139 was prepared according to the procedure of Example 138 substituting the corresponding isocyanate for 1-lsocyanato-2-methoxy-benzene The duration of reaction was between 1 and 24 hours EXAMPLE 139 N-(2-Chloro-benzyl)-2-[3-(3-naphthalen-1-yl-ureido)-phenoxy]-nicotinamide M P 121-123°C, Anal calcd for C 30 H 23 N 4 O 3 CI C, 68 90, H, 4 43, N, 10 71 Found C, 69 24, H. 4 52, N, 10 28 EXAMPLE 140 (-)-N-f1-(5-Chloro-thiophen-2-yl)-ethyl]-2-(4-fluoro-phenoxy)-nicotinamide N-[1-(5-Chloro-thιophen-2-yl)-ethyl]-2-(4-fluoro-phenoxy)-nιcotιnamιde (0 750 g) was separated on a Chiral Cel AS Column eluting with 95 % hexane/ isopropanol M P 78-80°C, Anal calcd for C 18 H 14 N 2 0 2 CISF C, 57 37, H, 3 74, N, 7 42 Found C, 57 32, H, 3 68, N, 7 42 α D = -53 9°(C=0 2, chloroform) The compound of Example 141 was prepared according to the procedure of Example 140 EXAMPLE 141 (+)-N-[1-(5-Chloro-thiophen-2-yl)-ethyl]-2-(4-fluoro-phenoxy)-nicotinamide M P 78-80°C, Anal calcd for C 18 H 14 N 2 0 2 CISF C, 57 37, H, 3 74, N, 7 42 Found C, 57 31 , H, 3 80, N, 7 39 α D = +52 8°(C=0 3, chloroform) EXAMPLE 142 cis-2-(3-Chloro-phenoxy)-3-(-4-phenyl-[1.3]dioxolan-2-yl)-pyridine A solution of 2-(3-Chloro-phenoxy)-pyrιdιne-3-carbaldehyde (0 182 grams, 0 8 mmole), (S)-1-Phenyl-ethane-1 ,2-dιol (0 110 grams, 0 8 mmole) and pTSA (0 005 g) in toluene (10 ml) was refluxed for 48 hours The mixture was concentrated and purified by chromatography on silica gel eluting with 4/1 hexane/diethyl ether to give a colorless oil Anal calcd for C 20 H 16 NO 3 CI C, 67 90, H, 4 56, N, 3 96 Found C, 68 57, H, 5 16, N, 3 52, α = +49 5°, 1 H NMR (400 MHz, CDCI 3 ) d 3 97 (dd, J=7 0, 7 8 Hz, 1 H), 4 41 (dd, J=7 1 , 7 7 Hz, 1 H), 5 24 (t , J=7 0 Hz, 1 H), 6 36 (s, 1 H), 7 25 (m, 10H), 8 09 (m, 1 H), 8 19 (m, 1 H) The compound of Example 143 was prepared according to the procedure of Example 142 substituting the corresponding diol for (S)-1-Phenyl-ethane-1 ,2-dιol The duration of reaction was between 1 and 48 hours EXAMPLE 143 trans-2-(3-Chloro-phenoxy)-3-(-4-phenyl-[1.3]dioxolan-2-yl)-pyridine Anal calcd for C 20 H 16 N0 3 CI HRMS 354 0894, α = +40 5°, 1 H NMR (400 MHz, CDCI 3 ) d 3 91 (t, J=8 1 Hz, 1 H), 4 57 (dd, J=6 2, 8 3 Hz, 1 H), 5 27 (t, J=7 0 Hz, 1 H), 6 52 (s, 1 H), 7 25 (m, 10H), 8 05 (m, 1 H) 8 17 (m, 1 H) EXAMPLE 144 2-(3-Amino-phenoxy)-N-(2-chloro-benzyl)-nicotinamide To a solution of 2-(3-Nιtro-phenoxy)-N-(2-chloro-benzyl)-nιcotιnamιde ( 0 530 g 1 38 mmole) in methanol (15 ml) and tetrahydrofuran (20 ml) was added 10% Pt0 2 ( 0 0 50 g) This was shaken under 35 psi hydrogen for 1 hour 40 minutes The catalyst was removed by filtration, and the solution was concentrated to give an oil that was purified by chromatography on silica gel eluting with 2 5% methanol/ methylene chloride Recrystalization from ethyl acetate/ hexane gave crystals (0 327 g) M P 101-103°C, Anal calcd for C 19 H 16 N 3 0 2 CI C, 64 5, H, 4 56, N, 11 88 Found C, 64 15, H,4 07, N,11 80 EXAMPLE 145 (-)-N-[1-(5-Chloro-thiophen-2-yl)-ethyl]-2-(pyridin-3-yloxy)-nicotinamide N-[1-(5-Chloro-thιophen-2-yl)-ethyl]-2-(pyrιdιn-3-yloxy)-nιcotιnamιde(0 776 g) was separated on a Chiral Cel AD Column eluting with 9/1 heptane/ isoPropanol to give the product as an oil Recrystalization from ethyl acetate/ hexane gave a white solid (0 217 g) M P 82-84°C, α = -51 5° (c= 0 2, CHCI 3 ) The compound of Example 146 was prepared according to the procedure of Example 145 EXAMPLE 146 (+)-N-[1-(5-Chloro-thiophen-2-yl)-ethyl]-2-(pyridin-3-yloxy)-nicotinamide M P 83-85°C, α = +49 8° (c= 0 3, CHCI 3 ) EXAMPLE 147 (-)-2-(5-Chloro-pyridin-3-yloxy)-N-[1-(5-chloro-thiophen-2-yl)-ethyl]-nicotinamide 2-(5-Chloro-pyrιdιn-3-yloxy)-N-[1-(5-chloro-thιophen-2-yl)-ethyl]-nιcotιnamιde (0 800 g) was separated on a Chiral Cel AS Column eluting with 90/9 9/0 1 heptane/ isopropanol/diethyl ether to give a solid Recrystalization from ethyl acetate/ hexane gave a solid (0 393 g) M P 133-135°C, α = -48 8° (c= 0 2) The compound of Example 148 was prepared according to the procedure of Example 147 EXAMPLE 148 (+)-2-(5-Chloro-pyridin-3-yloxy)-N-[1-(5-chloro-thiophen-2-yl)-ethyl1- nicotinamide M P 133-135°C, α = +40 6° (c= 0 2) EXAMPLE 149 (R)-N-(2-Hydroxy-1-phenyl-ethyl)-2-(pyridin-3-yloxy)-nicotinamide A solution of 2-(Pyrιdιn-3-yloxy)-nιcotιnιc acid (0 250 grams, 1 2 mmole) in thionyl chloride (10 ml) was heated to reflux After 1 hour the reaction mixture was cooled to room temperature and concentrated under reduced pressure The resulting residue was suspended in tetrahydrofuran (10 ml) and added dropwise to a solution of (R)-2-hydroxy-1 -phenyl ethylamme (0 160 grams, 1 2 mmole) in pyndine (5 ml) at 0°C After 30 minutes the mixture was warmed to room temperature, stirred at room temperature for 1 hour and concentrated to remove pyndine The crude product was purified by chromatography on silica gel eluting with ethyl acetate to give a yellow oil HRMS 336 1324, α = +63 9° 12 3 mg/ml in methylene chloride 1 H NMR (400mhz, CDCI 3 ) d 2 76 (bs, 1 H), 3 95-4 02 (m, 2H), 5 31-5 36 (m, 1 H), 7 16-7 40 (m, 1 H), 8 19 (dd , J=2 1 Hz, 4 8 Hz, 1 H), 8 48-8 61 (m, 4H) EXAMPLE 150 (R)- 3-(4-Phenyl-4.5-dihydro-oxazol-2-yl)-2-(Pyridin-3-yloxy)-pyridine A solution of (R)-N-(2-Hydroxy-2-phenyl-ethyl)-2-(pyrιdιn-3-yloxy)-nιcotιnamιde (0 050 grams, 0 16 mmole) and phosphorus oxychlonde (150 μl, 1 6 mmole) in toluene (10 ml) was stirred over night The mixture was concentrated to dryness and dissolved in methanol (10 ml) and potassium carbonate (250 ml) was added The mixture was stirred for 24 hours at room temperature The methanol was evaporated, and the residue taken up in ethyl acetate It was washed with water and brine, dried over Na 2 S0 4 , and concentrated to give a product that was purified by chromatography on silica gel eluting with 1/1 ethyl acetate/hexane to give a colorless oil (0 020 g) HRMS 318 1227, α = +21 2° ,9 5 mg/ml in methylene chloride 1 H NMR (400mhz, CDCI 3 ) d 4 31 (t, J=8 3 Hz, 1 H), 4 83 (dd, J=8 3 Hz, 10 2 Hz, 1 H), 5 46 (dd, J=8 1 Hz, 10 2 Hz, 1 H), 7 07-7 20 (m, 1 H), 7 27-7 43 (m, 6H), 7 53-7 57 (m, 1 H), 8 22-8 53 (m, 4H) The compound of Example 151 was prepared according to the procedure of Example 150 substituting the corresponding hydroxy nicatinimide for (R)-N-(2-Hydroxy-2-phenyl-ethyl)- 2-(pyrιdιn-3-yloxy)-ntcotιnamιde The duration of reaction was between 1 and 24 hours EXAMPLE 151 (S)- 3-(4-Phenyl-4.5-dihydro-oxazol-2-yl)-2-(Pyridin-3-yloxy)-pyridine HRMS 318 1267, α = -19 2° ,11 2 mg/ml in methylene chloride, 1 H NMR (400mhz, CDCI 3 ) d 4 31 (t, J=8 3 Hz, 1 H), 4 83 (dd, J=10 2 Hz, 8 3 Hz, 1 H), 5 46 (dd, J=10 2 Hz, 8 1 Hz, 1 H), 7 09-7 57 (m, 7H), 7 54-7 57 (m, 1 H), 8 23 (dd , J= 4 8 Hz, 1 9 Hz, 1 H), 8 32-8 53 (m, 3H) EXAMPLE 152 (S)- N-(2-Hydroxy-1-phenyl-ethyl)-2-(pyridin-3-yloxy)-nicotinamide A solution 2-(Pyrιdιn-3-yloxy)-nιcotιnιc acid (0 500 g)ιn thionyl chloride (10 ml) was refluxed for 1 hour The mixture was concentrated to dryness, dissolved in 10 ml tetrahydrofuran and used immediately To a solution of (S)-2-phenylglycιnol (0 190 grams, 1 4 mmole) in dry pyndine (5 ml) at 0°C was added a solution of 2-(3-pyrιdιn-3-yloxy)-nιcotιnoyl chloride ( 325 grams, 1 4 mmole) in tetrahydrofuran (5 ml) and pyridine (5 ml), stirred at 0°C for 30 minutes and allowed to warm to room temperature over night The mixture was concentrated under reduced pressure and concentrated to a crude product that was purified by chromatography on silica gel eluting with 1 1 ethyl acetate/hexane to give a colorless oil HRMS 336 1358, α = -69 2° c=6 2 mg/ml in methylene chloride, 1 H NMR (400mhz, CDCI 3 ) d 2 77 (bs, 1 H), 3 98-4 08 (m, 2H), 5 31-5 36 (m, 1 H), 7 14-7 40 (m, 7H), 7 57-7 60 (m, 1 H), 8 19 (dd, J= 1 9 Hz, 4 8 Hz, 1 H), 8 44-8 61 (m, 4H) The compounds of Examples 153-156 were prepared according to the procedure of Example 152 substituting the corresponding amine for (S)-2-phenylglycιnol The duration of reaction was between 1 and 24 hours EXAMPLE 153 (R)-N-(1-Hydroxymethyl-2-methyl-propyl)-2-(pyridin-3-yloxy)-nicotinamide HRMS 302 15050, α = +6 1° ,8 7 mg/ml in methylene chloride 1 H NMR (400mhz, CDCI 3 ) d 1 00 (dd, J=14 9 Hz, 6 8 Hz, 6H), 1 98-2 07 (m, 1 H), 2 99 (bs, 1 H), 3 73-3 83 (m, 2H), 4 01-4 11 (m, 1 H), 7 18-7 24 (m, 1 H), 7 38 7 42 (m, 1 H), 7 55-7 58 (m, 1 H), 7 98 (d, J=6 6 Hz, 1 H), 8 18 (dd, J= 4 8 Hz, 2 1 Hz, 1 H), 8 52-8 62 (m, 3H) EXAMPLE 154 (S)-N-(1-Hydroxymethyl-2-methyl-propyl)-2-(pyridin-3-yloxy)-nicotinamide HRMS 302.1475; α = -6.3° ,10.4 mg/ml in methylene chloride. 1 H NMR (400mhz, CDCl 3 ) d 1.00 (dd, J=14.9 Hz, 6.8 Hz, 6H), 2.00-2.07 (m, 1 H), 3.09 (bs, 1 H), 3.75-3.78 (m, 2H), 4.01-4.07 (m, 1 H), 7.18-7.25 (m, 1 H), 7.38.7.41 (m, 1 H), 7.54-7.57 (m, 1 H), 7.98 (d, J=6.8 Hz, 1 H), 8.17-8.19 (m, 1 H), 8.48-8.53 (m, 2H), 8.59-8.61 (m, 1 H). EXAMPLE 155 (S)-N-(1-Hydroxymethyl-2-methyl-butyl)-2-(pyridin-3-yloxy)-nicotinamide HRMS 316.1661 ; α = -10.8° ,10.0 mg/ml in methylene chloride. 1 H NMR (400mhz, CDCI 3 ) d 0.91 (t, J=7.3 Hz, 3H), 0.99 (d, J=8.8 Hz, 3H), 1.15-1.27 (m, 1 H), 1.53-1.60 (m, 1 H), 1.74-1.84 (m, 1 H), 2.78 (bs, 1 H), 3.74-3.87 (m, 2H), 4.08-4.14 (m, 1 H), 7.19-7.24 (m, 2H), 7.41 (dd, J= 8.1 Hz, 4.57 Hz, 1 H), 7.55-7.58 (m, 1 H),8.00 (d, J=7.3 Hz, 1 H), 8.19 (dd, J= 4.8 Hz, 1.9 Hz, 1 H), 8.53 (s, 1 H), 8.60-8.63 (m, 1 H). EXAMPLE 156 N-(2-Hydroxy-1.1-dimethyl-ethyl)-2-(pyridin-3-yloxy)-nicotinamide HRMS 288.1376; 1 H NMR (400mhz, CDCI 3 ) d 1.41 (s, 6H), 3.70 (d, J=5.6 Hz, 2H), 4.54 (bs, 1 H), 7.19 (dd, J= 6.6 Hz, 4.8 Hz, 1 H), 7.39-7.42 (m, 1 H), 7.55-7.58 (m, 1 H), 7.94 (bs, 1 H), 8.18 (dd, J= 4.8 Hz, 2.1 Hz„ 1 H), 8.53-8.59 (m, 3H). EXAMPLE 157 N-(2-Chloro-benzyl)-2-(1H-indol-4-yloxy)-nicotinamide To a stirred solution 2-(1 H-lndol-4-yloxy)-nicotinic acid (0.055g, 0.216 mmole) 2- chlorobenzylamine (0.034 grams, 0.238 mmole), and 1-hydroxybenzotriazole hydrate (0.035 grams, 0.259 mmole) in dry dimethylformamide (5 ml) was added 1-(3-dimethylamino)-propyl)- 3-ethylcarbodiimide hydrochloride (0.054 grams, 0.281 mmole) and stirred over night. The mixture was diluted with 100 ml water and extracted with ethyl acetate. The combined organics were washed with 1 N NaOH, water and brine, dried over Na 2 S0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica. Recrystalization from ethyl acetate/ hexane gave a pink/white solid. (0.053 g). M.P. 185-187°C; Anal, calcd. for C 21 H 16 N 3 0 2 CI: C, 66.76; H, 4.27; N, 11.12. Found: C, 66.42; H, 4.14; N, 10.95. The compound of Example 158 was prepared according to the procedure of Example 157 substituting the corresponding amine for 2-chlorobenzylamine. The duration of reaction was between 1 and 24 hours. EXAMPLE 158 N-(5-Chloro-thiophen-2-ylmethyl)-2-(1H-indol-4-yloxy)-nicotinamide M.P. 157-159°C; Anal, calcd. for C 19 H 14 N 3 0 2 CIS: C, 59.45; H, 3.68; N, 10.9. Found: C, 59.38; H, 3.94; N, 10.95. EXAMPLE 159 N-(5-Acetyl-thiophen-2-ylmethyl)-2-(pyridin-3-yloxy)-nicotinamide A solution of N-[5-(2-Methyl-[1 ,3]dιoxolan-2-yl)-thιophen-2-ylmethyl]-2-(pyrιdιn-3- yloxy)-nιcotιnamιde (0 680 g) in 2 N hydrochloric acid (20 ml) and methylene chloride (20 ml) was stirred at room temperature over night The mixture was extracted with chloroform, washed with water, dried over MgS0 4 , filtered and concentrated to give a solid which was triturated in diethyl ether to give a white solid (0 480 g) M P 201-203°C, Anal calcd for C 18 H 15 N 3 0 3 S C, 61 18, H. 4 28, N, 11 89 Found C, 60 09, H. 4 25, N, 11 61 EXAMPLE 160 N-[5-(1-Hydroxy-ethyl)-thiophen-2-ylmethyl]-2-(pyridin-3-yloxy)-nicotinamide To a stirred suspension of N-(5-Acetyl-thιophen-2-ylmethyl)-2-(pyπdιn-3-yloxy)- nicotmamide (0 300 grams, 0 85 mmole) in methylene chloride (25 ml) and tetrahydrofuran (25 ml) at room temperature was added sodium borohydride ( 035 grams, 0 93 mmole) and stirred for 2 hours The mixture was quenched with saturated NH 4 CI (~1 ml) and concentrated under reduced pressure to about 15 ml This mixture was poured into water and extracted with ethyl acetate The combined organics were washed with water and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica eluting with 5% methanol/ methylene chloride Recrystalization from ethyl acetate/ hexane gave a white solid (0 207 g) M P 92-94°C, Anal calcd for C 18 H 17 N 3 0 3 S C, 60 83, H, 4 82, N, 11 82 Found C, 60 68, H, 4 77, N, 11 89 EXAMPLE 161 3-(5-Phenyl-4.5-dihydro-oxazol-2-yl)-2-(Pyridin-3-yloxy)-pyridine A solution of N-(2-Hydroxy-2-phenyl-ethyl)-2-(pyrιdιn-3-yloxy)-nιcotιnamιde (0 450 grams, 1 3 mmole) and phosphorus oxychlonde (1 25 ml, 13 mmole) in toluene (5 ml) was stirred over night The mixture was concentrated to dryness and dissolved in methanol (5 ml) and potassium carbonate (0 500 g) was added The mixture was stirred at room temperature over night The mixture was poured into water and extracted with ethyl acetate The combined organics were washed with water and brine, dried over Na 2 S0 4 , and concentrated to give an oil that was purified by chromatography on silica gel eluting with ethyl acetate to give a colorless oil (0 042 g) HRMS 318 1269, 1 H NMR (400mhz, CDCI 3 ) d 4 09 (dd, J=15 1 Hz,8 1 Hz, 6H), 4 57 (dd, J= 15 1 Hz, 10 3 Hz, 1 H), 5 67 (dd, J= 10 2 Hz, 7 9 Hz, 1 H), 7 09- 7 13 (m, 1 H), 7 32-7 39 (m, 6H), 7 54-7 57 (m, 1 H), 8 20-8 22 (m, 1 H), 8 29-8 31 (m, 1 H), 8 46 (dd, J= 4 6 Hz, 1 0 Hz, 1 H), 8 61-8 64 (m, 1 H) EXAMPLE 162 (S) 3-(4-lsopropyl-4.5-dihydro-oxazol-2-yl)-2-(Pyridin-3-yloxy)-pyridine A solution of N-(1-Hydroxy-2-methyl-propyl)-2-(pyrιdιn-3-yloxy)-nιcotιnamιde (0 090 grams, 0 299 mmole) and phosphorus oxychlonde (1 0 ml,) in toluene (5 ml) was stirred over night The mixture was concentrated to dryness and dissolved in methanol (5 ml) and potassium carbonate (0 250 g) was added The mixture was stirred at room temperature over night The mixture was poured into water and extracted with ethyl acetate The combined organics were washed with brine and concentrated to give a product that was purified by chromatography on silica gel eluting with ethyl acetate to give a colorless oil (0 053 g) MS m/z [M+] 284, α = +47 1° ,5 5 mg/ml in methylene chloride 1 H NMR (400mhz, CDCI 3 ) d 0 98 (dd, J=32 8 Hz, 6 6 Hz, 6H), 1 78-1 89 (m, 1 H), 4 12-4 19 (m, 2H), 4 39-4 46 (m, 1 H), 7 07-7 10 (m, 1 H), 7 31-7 34 (m, 1 H), 7 51-7 54 (m, 1 H), 8 18-8 22 (m, 2H), 8 44-8 50 (m, 2H) The compound of Example 163 was prepared according to the procedure of Example 162 substituting the corresponding hydroxy nicatinamide for N-(1-Hydroxy-2-methyl-propyl)-2- (pyrιdιn-3-yloxy)-nιcotιnamιde The duration of reaction was between 1 and 24 hours EXAMPLE 163 (R) 3-(4-lsopropyl-4.5-dihydro-oxazol-2-yl)-2-(Pyridin-3-yloxy)-pyridine HRMS 284 13915, =-52 7° ,10 0 mg/ml in methylene chloride 1 H NMR (400mhz, CDCI 3 ) d 0 98 (dd, J=32 8 Hz, 6 6 Hz, 6H), 1 86-1 92 (m, 1 H), 4 12-4 19 (m, 2H), 4 39-4 45 (m, 1 H), 7 08 (dd, J= 7 5 Hz, 4 8 Hz, 1 H), 7 31-7 34 (m, 1 H), 7 51-7 5 (m, 1 H), 8 18-8 22 (m, 2H), 8 44 (dd, J= 4 6 Hz, 1 2 Hz, 1 H), 8 50 (d, J= 2 7 Hz, 1 H) EXAMPLE 164 (R)-3-(4-sec-Butyl-4,5-dihydro-oxazol-2-yl)-2-(Pyridin-3-yloxy)-pyridine A solution of N-(1-Hydroxymethyl-2-methyl-butyl)-2-(pyrιdιn-3-yloxy)-nιcotιnamιde (0 120 grams, 0 400 mmole) and phosphorus oxychlonde (400 μl, 4 0 mmole) in toluene (5 ml) was stirred over night The mixture was concentrated to dryness and dissolved in methanol (5 ml) and potassium carbonate (0 250 g) was added The mixture was concentrated to give a crude product that was purified by chromatography on silica gel eluting with ethyl acetate to give a colorless oil (0 060 g) , Anal calcd for C 17 H 19 N 3 0 2 C, 68 67, H,6 44, N, 14 13 Found C, 68 28, H, 6 82, N, 13 33, HRMS 298 1530, α = -42 9°, 11 2 mg/ml in methylene chloride, 1 H NMR (400mhz, CDCI 3 ) d 0 95 (t, J=7 3 Hz, 3H), 1 19-1 30 (m, 1 H), 1 54-1 62 (m, 1 H), 1 71- 1 77 (m, 1 H), 4 14-4 18 (m, 1 H), 4 25-4 31 (m, 1 H), 4 40 (dd, J= 9 8 Hz, 7 1 Hz„ 1 H), 7 08 (dd, = 7 5 Hz, 5 0 Hz,, 1 H), 7 31-7 35 (m, 1 H), 7 51-7 54 (m, 1 H), 8 18-8 22 (m, 2H), 8 44- 8 50 (m, 2H) EXAMPLE 165 5-({[2-(4-Fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-1H-indole-2- carboxylic acid A solution of 5-({[2-(4-Fluoro-phenoxy)-pyrιdιne-3-carbonyl]-amιno}-methyl)-1 H-mdole- 2-carboxylιc acid ethyl ester (0 043 grams, 0 099 mmole) in 1 N sodium hydroxide (0 25 ml, 0 25 mmole) and ethanol (5 ml) was refluxed for 9 hours The mixture was concentrated under reduced pressure to dryness and dissolved in water (2 ml) The mixture was acidified with 2 N hydrochloric acid giving a white solid which was isolated by filtration (0 032 g) M P 236-238, Anal calcd for C 22 H 16 N 3 0 4 F C, 65 18, H,3 98, N, 10 37 Found C, 65 12, H, 4 08, N, 10 20 EXAMPLE 166 (R)-3-(4-Phenyl-[1.31dioxolan-2-yl)-2-(Pyridin-3-yloxy)-pyridine A solution of 2-(Pyrιdιn-3-yloxy)-pyrιdιne-3-carbaldehyde (0 150 grams, 0 75 mmole), (R)-1-Phenyl-ethane-1 ,2-dιol (0 105 grams, 0 75 mmole) and pTSA (0 005 g) in toluene (10 ml) was refluxed over night The mixture was concentrated under reduced pressure and dissolved in ethyl acetate The organics were washed with sat'd bicarb and brine, dried over Na 2 S0 4 and purified by chromatography on silica gel eluting with diethyl ether to give a yellow oil (mixture of cis and trans) HRMS 321 1260, α = -46 3° 9 2 mg/ml in methylene chloride, 1 H NMR (400mhz, CDCI 3 ) d 3 93-4 00 (m, 1 H), 4 42 (dd, J= 7 9 Hz, 7 0 Hz,, 1/2 H), 4 56-4 60 (m, 1/2H), 5 25-5 30 (m, 1 H), 6 39 (s, 1/2H), 6 56 (s, 1/2H), 7 10-7 12 (m, 1 H), 7 30-7 40 (m, 6H), 7 49-7 55 (m, 1 H), 8 02-8 16 (m, 2H), 8 43-8 52 (m, 2H) The compounds of Examples 167-169 were prepared according to the procedure of Example 166 substituting the corresponding diol for (R)-1-Phenyl-ethane-1 ,2-dιol The duration of reaction was between 1 and 24 hours EXAMPLE 167 (S)-3-(4-Phenyl-[1.31dioxolan-2-yl)-2-(Pyridin-3-yloxy)-pyridine Anal calcd for C 19 H 16 N 2 0 3 C, 71 24, H, 5 03, N, 8 74 Found C, 71 02, H, 5 32, N, 8 03, α = -48 8° 12 8 mg/ml in methylene chloride, 1 H NMR (400mhz, CDCI 3 ) d 3 90-4 00 (m, 1 H), 4 42 (dd, J= 7 9 Hz, 7 1 Hz, 1/2H), 4 56-4 58 (m, 1/2H), 5 20-5 28 (m, 1 H), 6 40 (s, 1/2H), 6 57 (s, 1/2H), 7 08-7 12 (m, 1 H), 7 32-7 41 (m, 6H), 7 53-7 55 (m, 1 H), 8 10-8 15 (m, 2H) 8 44-8 54 (m, 2H) EXAMPLE 168 (S)-3-[4-(2-Chloro-phenyl)-[1.3]dioxolan-2-yl]-2-(Pyridin-3-yloxy)-pyridine Anal calcd for C 19 H 15 N 2 0 3 CI, HRMS 355 0864, α = +55 5° 12 1 mg/ml in methylene chloride, 1 H NMR (400mhz, CDCI 3 ) d 3 80-3 96 (m, 1 H), 4 56-4 60 (m, 1/2H), 4 78-4 82 (m, 1/2H), 5 58-5 62 (m, 1 H), 6 39 (s, 1/2H), 6 53 (s, 1/2H), 7 11-7 15 (m, 1 H), 7 20-7 38 (m, 5H), 7 53-7 60 (m, 1 H), 8 06-8 18 (m, 2H) 844-8 54 (m, 2H) EXAMPLE 169 (R)-3-[4-(2-Chloro-phenyl)-[1.31dioxolan-2-yl1-2-(Pyridin-3-yloxy)-pyridine Mixture of cis and trans isomers, Anal calcd for C 19 H 15 N 2 0 3 C1, C, 64 32, H, 4 26, N, 7 90 Found C, 64 31 , H, 4 42, N, 7 72, α = -61 1° 10 2 mg/ml in methylene chloride, 1 H NMR (400mhz, CDCI 3 ) d 3 82 (dd, J= 8 2 Hz, 7 3 Hz„ 1/2 H), 3 95 (dd, J= 7 2 Hz, 6 2 Hz,, 1/2 H), 4 58 (dd, J= 8 0 Hz, 7 3 Hz„ 1/2 H), 4 80 (dd, J= 8 5 Hz, 6 4 Hz, 1/2 H), 5 58-5 62 (m, 1 H), 6 39 (s, 1/2H), 6 53 (s, 1/2H), 7 10-7 15 (m, 1 H), 7 24-7 38 (m, 4H), 7 55-7 68 (m, 2H), 8 06- 8 18 (m, 2H) 8 45-8 55 (m, 2H) EXAMPLE 170 2-[2-(Pyridin-3-yloxy)-pyridin-3-yl]-3-oxa-1-aza-spiro[4.41non-1-ene A solution of N-(1-Hydroxymethyl-cyclopentyl)-2-(pyrιdιn-3-yloxy)-nιcotιnamιde (0 045 grams, 0 144 mmole) and phosphorus oxychlonde in toluene (5 ml) was stirred over night The mixture was concentrated to dryness and dissolved in methanol (5 ml) and potassium carbonate was added The mixture was concentrated to give a crude product that was purified by chromatography on silica gel eluting with ethyl acetate to give a yellow oil (0 021 g) HRMS 296 1417, 1 H NMR (400mhz, CDCI 3 ) d 1 65-1 74 (m, 4H), 1 86-1 91 (m, 2H), 1 96-2 03 (m, 2H), 4 25 (s, 2H), 7 08 (dd, J= 7 5 Hz, 5 0 Hz, 1H), 7 32 (dd, J= 8 3 Hz, 4 8 Hz, 1H), 7 51-7 54 (m, 1 H), 8 15-8 22 (m, 2H), 8 43-8 50 (m, 2H) EXAMPLE 171 N-Propyl-2-(pyridin-3-yloxy)-nicotinamide To a solution of 2-(pyrιdιn-3-yloxy)-nιcotιnιc acid (0 100 g 0 462 mmole), BOP (0 205 grams, 0 463 mmole) and DIEA (0 242 μl) in dimethylformamide (5 ml) was added n-propyl amine (40 μl, 0 486 mmole) and stirred for 4 hours at room temperature The reaction was quenched with 10 μl water and extracted with ethyl acetate The combined organics were washed with alternating portions of 5% citric acid and sat'd bicarb, dried over Na 2 S0 4 , filtered and concentrated to a product which was purified by chromatography on silica gel eluting with diethyl ether to give a white crystalline solid ( 0 068 g) M P 55-56°C, 1 H NMR (400mhz, CDCI 3 ) d 0 98 (t, J= 7 3 Hz, 3H), 1 61-1 70 (m, 2H), 3 45-3 50 (m, 2H), 7 19 (dd, J= 7 5 Hz, 4 8 Hz, 1 H), 7 38-7 41 (m, 1 H), 7 52-7 55 (m, 1 H), 7 72 (bs, 1 H), 8 16 (dd, J= 4 8 Hz, 2 1 Hz, 1 H), 8 52-8 63 (m, 3H) The compounds of Examples 177-182 were prepared according to the procedure of Example 171 substituting the corresponding amine for n-propyl amine The duration of reaction was between 1 and 24 hours EXAMPLE 172 N-lsopropyl-2-(pyridin-3-yloxy>-nicotinamide 1 H NMR (400mhz, CDCI 3 ) d 1.27 (d, J= 6.4 Hz, 6H), 4.29-4.34 (m, 1 H), 7.18 (dd, J= 7.7 Hz, 4.8 Hz, 1 H), 7.39-7.42 (m, 1 H), 7.51 (bs, 1 H), 7.53-7.57 (m, 1 H), 8.16 (dd, J= 4.8 Hz, 2.1 Hz, 1 H), 8.53-8.62 (m, 3H). EXAMPLE 173 N-lsobutyl-2-(pyridin-3-yloxy)-nicotinamide Anal, calcd. for C 15 H 17 N 3 0 2 ; 1 H NMR (400mhz, CDCI 3 ) d 0.97 (d, J= 6.6 Hz, 6H), 1.71-1.95 (m, 1 H), 3.35 (dd, J= 6.6 Hz, 5.8 Hz, 2H), 7.19 (dd, J= 7.8 Hz, 4.8 Hz, 1 H), 7.39- 7.42 (m, 1 H), 7.53-7.56 (m, 1 H), 7.76 (bs, 1 H), 8.16 (dd, J= 4.8 Hz, 1.9 Hz, 1 H), 8.52-8.63 (m, 3H). EXAMPLE 174 N-Butyl-2-(pyridin-3-yloxy)-nicotinamide M.P. 55-56°C; Anal, calcd. for C 15 H 17 N 3 0 2 ; 1 H NMR (400mhz, CDCI 3 ) d 0.93 (t, J= 7.5 Hz, 3H), 1.37-1.44 (m, 2H), 1.57-1.65 (m, 2H), 3.48-3.53 (m, 2H), 7.16-7.19 (m, 1 H), 7.38- 7.42 (m, 1 H), 7.52-7.55 (m, 1 H), 7.70 (bs, 1 H), 8.15 (dd, J= 4.8 Hz, 1.9 Hz, 1 H), 8.51-8.63 (m, 3H). EXAMPLE 175 N-Pentyl-2-(pyridin-3-yloxy)-nicotinamide M.P. 61-62°C; Anal, calcd. for C 16 H 19 N 3 0 2 ; C, 67.32 H, 6.71 ; N, 14.72. Found: C, 67.52; H, 6.88; N, 14.23 EXAMPLE 176 (S)-N-sec-Butyl-2-(pyridin-3-yloxy)-nicotinamide M.P. 64-65°C; Anal, calcd. for C 15 H 17 N 3 0 2 ; C, 66.40 H, 6.32; N, 15.49. Found: C, 66.66; H, 6.48; N, 14.89. α = +9.0° 10.9 mg/ml in methylene chloride. EXAMPLE 177 (R)-N-sec-Butyl-2-(pyridin-3-yloxy)-nicotinamide M.P. 55-56°C; Anal, calcd. for C 15 H 17 N 3 0 2 ; C, 66.40 H, 6.32; N, 15.49. Found: C, 67.14; H, 6.37; N, 14.70. α = -8.48° 12.5 mg/ml in methylene chloride. EXAMPLE 178 2-(Pyridin-3-yloxy)-N-(4-sulfamoyl-benzyl)-nicotinamide M.P. 196-197°C; Anal, calcd. for C 18 H 16 N 4 0 4 S: C, 56.24 H, 4.20; N, 14.75. Found: C, 54.95; H, 4.30; N, 14.11. EXAMPLE 179 2-(Pyridin-3-yloxy)-N-(1-sulfamoyl-piperidin-4-ylmethyl)-nicotinamide M.P. 165-166°C; HRMS 392.1382. EXAMPLE 180 N-(1 H-lndol-4-ylmethyl)-2-(pyridin-3-yloxy)-nicotinamide M P 134-135°C, Anal calcd for C 20 H 16 N 4 O 2 C, 69 76 H, 4 68, N, 16 27 Found C, 69 45, H. 4 63, N, 16 15 EXAMPLE 181 N-Pyridin-2-ylmethyl-2-(pyridin-3-yloxy)-nicotinamide M P 118-119°C, Anal calcd for C 17 H 14 N 4 0 2 C, 66 66 H, 4 61 , N, 18 29 Found C, 66 24, H. 4 58, N, 18 21 EXAMPLE 182 N-Benzo[1.3]dioxol-5-ylmethyl-2-(pyridin-3-yloxy)-nicotinamide M P 130-131 °C, Anal calcd for C 19 H 15 N 3 0 4 C, 65 32, H, 4 33, N, 12 03 Found C, 64 62, H, 4 14, N, 11 87 EXAMPLE 183 N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(3-trifluoromethyl-phenoxy)- nicotinamide To a stirred solution 2-(3-Trιfluoromethyl-phenoxy)-nιcotιnιc acid (0 311g, 1 1 mmole) 2-(4-Amιnomethyl-phenyl)-propan-2-ol (0 200 grams, 1 21 mmole), and 1- hydroxybenzotnazole hydrate (0 178 grams, 1 32 mmole) in dry dimethylformamide (15 ml) was added 1-(3-dιmethylamιno)-propyl)-3-ethylcarbodιιmιde hydrochlonde (0 275 grams, 1 43 mmole) and stirred over night The mixture was diluted with 250 ml water and extracted with ethyl acetate The combined organics were washed with water and brine, dried over Na 2 S0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica eluting with 4% methanol/ methylene chloride to give a foam (0 350 g) M P 37-39°C, 1 H NMR (CDCI 3 ) d 1 56 (6 H, s), 4 69 (2 H, d, J= 5 81 Hz), 7 2-7 6 (9 H, m), 8 02 (1 H, s), 8 20 (1 H, m), 8 64 (1 H, m) The compound of Example 184 was prepared according to the procedure of Example 183 substituting the corresponding amine for ) 2-(4-Amιnomethyl-phenyl)-propan-2-ol The duration of reaction was between 1 and 24 hours EXAMPLE 184 N-(2-Chloro-benzyl)-2-(3-trifluoromethyl-phenoxy)-nicotinamide M P 88-90°C, Anal calcd for C 20 H 14 N 2 O 2 F 3 CI, C, 59 05 H, 3 47, N, 6 89 Found C, 58 89, H, 3 39, N, 6 94 EXAMPLE 185 2-(2-Chloro-phenyl)-N-[2-(pyridin-3-yloxy)-pyridin-3-yll-acetamide To a stirred solution 2-chloro-benzoιc acid (0 200g, 1 17 mmole), 2-(Pyrιdιn-3-yloxy)- pyrιdιn-3-ylamιne (0 239 grams, 1 28 mmole), and 1 -hydroxy benzotriazole hydrate (0 190 grams, 1 40 mmole) in dry dimethylformamide (15 ml) was added 2-dιethylamιnoethyl chloride hydrochlonde (0 292g, 1 52 mmole) and stirred over the weekend The mixture was diluted with 200 ml water and extracted with ethyl acetate The combined organics were washed with 1 N NaOH, water and brine, dried over Na 2 S0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica Recrystalization from ethyl acetate/ hexane gave a solid (0 093 g) M P 137-139°C, Anal calcd for C 18 H 14 N 3 0 2 CI C, 63 63, H, 4 15, N, 12 37 Found C, 63 30, H, 4 30, N, 12 34 The compound of Example 186 was prepared according to the procedure of Example 187 substituting the corresponding carboxylic acid for 2-chloro-benzoιc acid The duration of reaction was between 1 and 24 hours EXAMPLE 186 2-(4-Acetyl-phenyl)-N-[2-(pyridin-3-yloxy)-pyridin-3-yl]-acetamide M P 110-112°C, 1 H NMR (CDCI 3 ) d 2 6 (3 H, s), 3 90 (2 H, s), 7 0-8 7 (12 H, m) EXAMPLE 187 2-(3-Chloro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide To a stirred solution 2-(3-chloro-phenoxy)-nιcotιnιc acid (0 301g, 1 21 mmole) 2-(4- Amιnomethyl-phenyl)-propan-2-ol (0 200 grams, 1 21 mmole), and 1-hydroxybenzotrιazole hydrate (0 178 grams, 1 32 mmole) in dry dimethylformamide (15 ml) was added 1-(3- dιmethylamιno)-propyl)-3-ethylcarbodιιmιde hydrochlonde (0 275 grams, 1 43 mmole) and stirred over night The mixture was diluted with 200 ml water and extracted with ethyl acetate The combined organics were washed with water, 1 sodium hydroxide and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica eluting with 6% methanol/ methylene chloride to give a solid (0 258 g) M P 57-59°C, Anal calcd for C 22 H 21 N 2 0 3 CI C, 66 50, H, 5 33, N, 7 06 Found C, 67 15, H, 5 95, N, 6 68 The compound of Example 189 was prepared according to the procedure of Example 188 substituting the corresponding amine for2-(4-Amιnomethyl-phenyl)-propan-2-ol The duration of reaction was between 1 and 3 hours EXAMPLE 189 N-(2-Chloro-benzyl)-2-(3-chloro-phenoxy)-nicotinamide M P 126-128°C, Anal calcd for C 19 H 14 N 2 0 2 CI 2 C, 61 14, H, 3 78, N, 7 51 Found C, 61 07, H, 3 73, N,7 51 EXAMPLE 190 (S)-2-(4-{2-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-[1.3]dioxolan-4-yl}-phenyl)- propan-2-ol To a solution of (S)-4-{2-[2-(4-Fluoro-phenoxy)-pyrιdιn-3-yl]-[1 ,3]dιoxolan-4-yl}- benzoic acid ethyl ester (0 085 grams, 0 2 mmole) in tetrahydrofuran (5 ml) at -78°C 1 4 M methyl lithium in diethyl ether (0 45 ml, 0 6 mmole) was added dropwise to keep the temperature below -60°C and stirred at -78°C for 90 minutes The mixture was warmed to 0°C, quenched with sat'd NH 4 CI and extracted with ethyl acetate The combined organics were washed with water and brine, dried over MgS0 4 , filtered and concentrated to an oil which was purified by chromatography on silica eluting with 1/4 ethyl acetate/ hexane to give a colorless oil (0 45 g), Anal calcd for C 23 H 22 N0 4 F C, 69 86, H, 5 61 , N, 3 54 Found C,70 85, H, 6 22, N, 3 15, 1 H NMR (400mhz, CDCI 3 ) d 1 58 (s, 6 H), 3 90-4 00 (m, 1 H), 4 38-4 42 (m, 1/2 H), 4 54-4 58 (m, 1/2 H), 5 21-5 28 (m, 1 H), 6 37 (s, 1/2H), 6 55 (s, 1/2H), 6 98-7 15 (m, 5H), 7 34-7 38 (m, 2H), 7 44-7 52 (m, 2H), 7 99-8 16 (m, 2H) The compounds of Examples 191-192 were prepared according to the procedure of Example 190 substituting the corresponding ester for of (S)-4-{2-[2-(4-Fluoro-phenoxy)- pyrιdιn-3-yl]-[1 ,3]dιoxolan-4-yl}-benzoιc acid ethyl ester The duration of reaction was between 1 and 3 hours EXAMPLE 191 cis-(R)-2-(4-{2-[2-(4-Fluoro-phenoxy)-pyridin-3-yl1-[1.3]dioxolan-4-yl}-phenyl)- propan-2-ol Anal calcd for C 23 H 22 N0 4 F α = -45 3° 15 2 mg/ml in methylene chloride, 1 H NMR (400mhz, CDCI 3 ) d 1 58 (s, 6 H), 3 96-4 00 (m, 1 H), 4 39-4 42 (m, 1 H), 5 21-5 24 (m, 1 H), 6 38 (s, 1 H), 7 04-7 14 (m, 5H), 7 40 (d, J= 8 1 Hz, 2H), 7 50 (d, J= 8 5 Hz, 2H), 8 05-8 16 (m, 2H) EXAMPLE 192 trans-(R)-2-(4-{2-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-[1.3]dioxolan-4-yl}-phenyl)- propan-2-ol Anal calcd for C 23 H 22 N0 4 F 1 H NMR (400mhz, CDCI 3 ) d 1 58 (s, 6 H), 3 92 (t, J= 7 9 Hz, 1 H), 4 55-4 58 (m, 1 H), 5 23-5 28 (m, 1 H), 6 54 (s, 1 H), 7 03-7 19 (m, 5H), 7 40 (d, J= 8 3 Hz, 2H), 7 51 (d, J= 8 1 Hz, 2H),7 99-8 15 (m, 2H) EXAMPLE 193 2-(4-Fluoro-phenoxy)-N-(4-sulfamoyl-benzyl)-nicotinamide To a solution of 2-(4-Fluoro-phenoxy)-nιcotιnιc acid (0 110 g 0 470 mmole), BOP (0 205 grams, 0 470 mmole) and DIEA (0 242 μl, 1 42 mmole) in dimethylformamide (5 ml) was added 4-Amιnomethyl-benzenesulfonamιde (0 105 grams, 0 470 mmole) and stirred at room temperature over night The reaction was quenched with water and extracted with ethyl acetate The combined organics were washed with alternating portions of 5% citric acid and sat'd bicarb, dried over Na 2 S0 4 , filtered and concentrated to a product which recrystalized from ethyl acetate to give white crystals ( 0 100 g) M P 222-223°C, Anal calcd for C 19 H 16 N 3 0 4 SF, C, 56 85, H, 4 02, N, 10 47 Found C, 55 52, H, 4 14, N, 10 16 The compounds of Examples 194-195 were prepared according to the procedure of Example 193 substituting the corresponding amine for 4-Amιnomethyl-benzenesulfonamιde The duration of reaction was between 1 and 3 hours EXAMPLE 194 2-(4-Fluoro-phenoxy)-N-(1-sulfamoyl-piperidin-4-ylmethyl)-nicotinamide M P 225-226°C, Anal calcd for C 18 H 21 N 4 0 4 SF C, 52 93 H, 5 18, N, 13 72 Found C, 52 73, H, 5 16, N, 13 72 EXAMPLE 195 N-(3.4-Dihydro-2H-pyran-2-ylmethyl)-2-(4-fluoro-phenoxy)-nicotinamide M P 55-57°C, HRMS 329 1324 EXAMPLE 196 2-(3-Cyano-phenoxy)-N-(4-sulfamoyl-benzyl)-nicotinamide To a solution of 2-(3-Cyano-phenoxy)-nιcotιnιc acid (0 140 g 0 600 mmole), BOP (0 260 grams, 0 600 mmole) and DIEA (0 310 μl, 1 8 mmole) in dimethylformamide (5 ml) was added 4-Amιnomethyl-benzenesulfonamιde (0 135 grams, 0 600 mmole) and stirred at room temperature over night The reaction was quenched with water and extracted with ethyl acetate The combined organics were washed with alternating portions of 5% citric acid and sat'd bicarb, dried over Na 2 S0 4 , filtered and concentrated to a product which was recrystalized from ethyl acetate to give a white solid ( 0 100 g) M P 179-180°C, Anal calcd for C 20 H 16 N 4 O 4 S, C, 58 81 , H, 3 95, N, 13 72 Found C, 57 47, H, 4 15, N, 1345 EXAMPLE 197 N-(4-Sulfamoyl-benzyl)-2-(3-tetrazol-1-yl-phenoxy)-nicotinamide To a stirred solution 2-(3-Tetrazol-1-yl-phenoxy)-nιcotιnιc acid (0 050g, 0 180 mmole) 4-Amιnomethyl-benzenesulfonamιde (0 060 grams, 0 26 mmole), and 1 -hydroxy benzotriazole hydrate (0 031 grams.O 23 mmole) in dry dimethylformamide (2 ml) was added 2- diethylammoethyl chloride hydrochloride (0 044 grams, 0 23 mmole) and stirred over night The mixture was diluted with 200 ml water and extracted with ethyl acetate The combined organics were washed with water, 1 N sodium hydroxide and brine, dried over MgS0 4 , filtered and concentrated to give a product that was purified by chromatography on silica eluting with 5% methanol/ methylene chloride to give a white solid (0 013 g) M P 72-74°C, 1 H NMR (400mhz, CDCI 3 ) d 4 55 (d, J= 6 0 Hz, 2H), 6 74-6 84 (m, 2 H), 7 21-7 37 (m, 4H), 7 49 (d, J= 8 5 Hz, 2H), 7 72 (d, J= 8 3 Hz, 2H), 8 10-8 21 (m, 2H), 9 05 (t, J= 6 0 Hz, 1 H) EXAMPLE 198 N-[4-(1-Hydroxy-1-methyl-ethyl)-cyclohexylmethyl1-2-(3-methoxy-phenoxy)- nicotinamide To a solution 4-({[2-(3-Methoxy-phenoxy)-pyrιdιne-3-carbonyl]-amιno}-methyl)- cyclohexanecarboxylic acid ethyl ester ( 0 260 grams, 0 63 mmole) in tetrahydrofuran (5 ml) at -78°C 1 4 M methyl lithium in diethyl ether (1 4 ml, 1 89 mmole) was added dropwise to keep the temperature below -60°C and stirred at -78°C for 2 hours and allowed to warm to room temperature over the weekend The mixture was quenched with sat'd NH 4 CI and extracted with ethyl acetate The combined organics were washed with water and brine, dried over Na 2 S0 4 , filtered and concentrated to a product which was purified by chromatography on silica eluting with 1/1 ethyl acetate/ hexane to give a pale yellow oil (0 077 g), 1 H NMR (400mhz, CDCy d 1 02-1 22 (m, 10H), 1 52-1 56 (m, 2 H), 1 82-1 88 (m, 4H), 3 32-3 36 (m, 2H), 3 80 (s, 3H), 6 70-6 74 (m, 2H), 6 80-6 83 (m, 1 H), 7 12-7 16 (m, 1 H),7 33 (t, J= 8 1 Hz, 1 H), 7 93 (bs, 1 H), 8 20-8 22 (m, 1 H), 8 60-8 61 (m, 1 H) EXAMPLE 199 2-(3-Chloro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]- nicotinamide To a 4-({[2-(3-Chloro-phenoxy)-pyrιdιne-3-carbonyl]-amιno}-methyl)- cyclohexanecarboxylic acid ethyl ester ( 0 220 grams, 0 53 mmole) in tetrahydrofuran (5 ml) at -78°C 1 4 M methyl lithium in diethyl ether (1 13 ml, 1 58 mmole) was added dropwise to keep the temperature below -60°C and stirred at -78°C for 2 hours and allowed to warm to room temperature The mixture was quenched with sat'd NH 4 CI and extracted with ethyl acetate The combined organics were washed with water and brine, dried over Na 2 S0 4 , filtered and concentrated to a product which was purified by chromatography on silica eluting with 2/3 ethyl acetate/ hexane to give an off-white oil (0 040 g), 1 H NMR (400mhz, CDCI 3 ) d 0 84-1 70 (m, 12H), 1 83-1 87 (m, 4 H), 3 30-3 37 (m, 2H), 7 04-7 07 (m, 1 H), 7 11-7 19 (m, 2H), 7 24- 7 27 (m, 1 H), 7 35-7 39 (m, 1 H), 7 79 (bs, 1 H),8 19-8 21 (m, 1 H), 8 60-8 62 (m, 1 H) EXAMPLE 200 2-(3-Methoxy-phenoxy)-N-(4-sulfamoyl-benzyl)-nicotinamide To a solution of 2-(3-Methoxy -phenoxy)-nιcotιnιc acid (0 200 g 0 820 mmole), BOP (0 360 grams, 0 820 mmole) and DIEA (425 μl, 2 45 mmole) in dimethylformamide (5 ml) was added 4-Amιnomethyl-benzenesulfonamιde (0 182 grams, 0 820 mmole) and stirred at room temperature over night The reaction was quenched with water and extracted with ethyl acetate The combined organics were washed with alternating portions of 5% citric acid and sat'd bicarb, dried over Na 2 S0 4 , filtered and concentrated to a product which recrystalized from ethyl acetate to give a white solid ( 0 260 g) M P 142-143°C, Anal calcd for C 20 H 19 N 3 O 5 S, C, 58 10, H, 4 63, N, 10 16 Found C, 58 11 , H, 4 91 , N, 9 83 The compound of Example 201 was prepared according to the procedure of Example 200 substituting the corresponding amine for 4-Amιnomethyl-benzenesulfonamιde The duration of reaction was between 1 and 3 hours EXAMPLE 201 N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(3-methoxy-phenoxy)-nicotinamide M P 69-71°C, Anal calcd for C 23 H 24 N 2 0 4 C, 72 39, H, 6 16, N, 7 14 Found C, 69 42, H, 6 34, N,7 17 EXAMPLE 202 2-(3-Fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl1-nicotinamide To a stirred solution 2-(3-Fluoro-phenoxy)-nιcotιnιc acid (0 250g, 1 07 mmole), 2-(4- Amιnomethyl-phenyl)-propan-2-ol (0 195 grams, 1 18 mmole) and 1 -hydroxy benzotriazole hydrate (0 173 grams, 1 28 mmole) in dry dimethylformamide (15 ml) was added 1-(3- dιmethylamιno)-propyl)-3-ethylcarbodιιmιde hydrochlonde (0 173 grams, 1 28 mmole) and stirred over night The mixture was diluted with 300 ml water and extracted with ethyl acetate The combined organics were washed with water and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica Recrystalization from ethyl acetate/ hexane gave a solid (0 400 g) M P 106-108°C, Anal calcd for C 22 H 21 N 2 0 3 F C, 69 46, H, 5 56, N, 7 36 Found C, 69 05, H, 5 68, N, 7 25 EXAMPLE 203 N-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl1- acetamide To a 2-(4-Acetyl-phenyl)-N-[2-(4-fiuoro-phenoxy)-pyrιdιn-3-yl]-acetamιde (0 270 grams, 0 741 mmole) in tetrahydrofuran (15 ml) at -78°C 1 0 M methyl lithium in tetrahydrofuran (1 63 ml, 1 63 mmole) was added via syringe and stirred at -78°C for 75 minutes Another 0 8 ml methyl lithium was added and the mixture was warmed to 0°C for 10 minutes and cooled to -78°C The mixture was quenched with water, allowed to warm to room temperature and extracted with ethyl acetate The combined organics were washed with water and brine, dried over MgS0 4 , filtered and concentrated to a white solid which was purified by chromatography on silica eluting with 2% methanol/ methylene chloride to give a white solid Recrystalization from ethyl acetate/ hexane gave a solid (0 032 g) M P 135-137°C, Anal calcd for C 22 H 21 N 2 θ 3 F C, 69 46, H, 5 56, N, 7 36 Found C, 69 46, H, 5 92, N, 7 73 EXAMPLE 204 (-)-N-[5-(1-Hydroxy-ethyl)-thiophen-2-ylmethyl1-2-(pyridin-3-yloxy)-nicotinamide N-[5-(1-Hydroxy-ethyl)-thιophen-2-ylmethyl]-2-(pyrιdιn-3-yloxy)-nιcotιnamιde (0 287 g) was separated on a Chiral Cel OJ Column eluting with 70/30 heptane/ isopropanol to give a product Recrystalization from ethyl acetate/ hexane gave a solid (0 070 g) M P 85-87°C, Anal calcd for C 18 H 17 N 3 0 3 S C, 60 83, H, 8 82, N, 11 82 Found C, 55 38, H, 4 68, N, 10 82 α = -7 02° The compound of Example 205 was prepared according to the procedure of Example 204 EXAMPLE 205 (+)-N-[5-(1-Hydroxy-ethyl)-thiophen-2-ylmethvn-2-(pyridin-3-yloxy)-nicotinamide M P 88-90°C, Anal calcd for C 18 H 17 N 3 0 3 S C, 60 83, H, 8 82, N, 11 82 Found C, 57 80, H, 5 06, N,11 21 α = +7 73° EXAMPLE 206 N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(3-methylsulfanyl-phenoxy)- nicotinamide To a stirred solution 2-(3-Methylsulfanyl-phenoxy)-nιcotιnιc acid (2 5 grams, 9 58 mmole), 2-(4-Amιnomethyl-phenyl)-propan-2-ol (1 896 grams, 11 50 mmole) and 1- hydroxybenzotnazole hydrate (1 55 grams, 11 50 mmole) in dry dimethylformamide (60 ml) was added 1-(3-dιmethylamιno)-propyl)-3-ethylcarbodιιmιde hydrochlonde (2 39 grams, 12 45 mmole) and stirred over night The mixture was diluted with 300 ml water and extracted with ethyl acetate The combined organics were washed with water and brine, dried over MgS0 , filtered and concentrated to give a yellow oil that was purified by chromatography on silica eluting with 3 5% methanol/ methylene chloride to give a white solid Recrystalization from ethyl acetate/ hexane gave a solid (0 550 g) M P 107-109°C, Anal calcd for C 23 H 24 N 2 0 3 S C, 67 62, H, 5 92, N, 6 86 Found C, 67 53, H, 5 76, N, 6 91 EXAMPLE 207 N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(3-methanesulfonyl-phenoxy)- nicotinamide A solution of N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(3-methylsulfanyl-phenoxy)- nicotmamide (3 5 grams, 8 5 mmole) and MCPBA (3 945 grams, 18 8 mmole) in methylene chloride (40 ml) was stirred at room temperature for 1 hour The mixture was diluted with ethyl acetate, washed with water, 1 N sodium hydroxide and brine, dried over MgS0 4 , filtered and concentrated to give a white solid that was purified by chromatography on silica eluting with 2% methanol/ methylene chloride to give a white solid (1 64 g) M P 51-53°C, Anal calcd for C 23 H 24 N 2 0 5 S C, 62 71 , H, 5 49, N,6 38 Found C, 61 87, H, 5 48, N, 6 29 EXAMPLE 208 N-Pyridin-4-ylmethyl-2-(pyridin-3-yloxy)-nicotinamide A solution of 2-(Pyrιdιn-3-yloxy)-nιcotιnιc acid (0 0664 grams, 0 31 mmole) in thionyl chloride (1 12 ml, 15 4 mmole) was heated to 50°C After 1 5 hours the reaction mixture was cooled to room temperature and concentrated under reduced pressure Pyndine (2 5 ml) was added followed by C-Pyrιdιn-4-yl-methylamιne (47 μl, 0 47 mmole) at room temperature After 2 hours the mixture was concentrated to remove pyndine The crude product was purified by chromatography on silica gel eluting with 9/1 ethyl acetate/ methanol to give a solid (0 0331 g) M P 142-144°C, Anal calcd for C 17 H 14 N 4 0 2 C, 66 66, H, 4 61 , N, 18 29 Found C, 66 40, H. 4 56, N, 17 94 EXAMPLE 209 2-(4-Fluoro-phenoxy)-N-(5-methyl-pyrazin-2-ylmethyl)-nicotinamide A solution of 2-(4-Fluoro-phenoxy)-nιcotιnιc acid (0 0766 grams, 0 33 mmole) in thionyl chloride (2 ml) was heated to 50°C After 1 5 hours the reaction mixture was cooled to room temperature and concentrated under reduced pressure The resulting residue was dissolved in pyridine (2 ml) and C-(5-Methyl-pyrazιn-2-yl)-methylamιne (0 14 grams, 1 0 mmole) was added After 1 5 hours the mixture was concentrated under reduced pressure and purified by chromatography on silica gel eluting with 1 1 ethyl acetate/hexane to give a white solid M P 159°C, Anal calcd for C 18 H 15 N 4 0 2 F C, 63 90, H, 4 47, N, 16 56 Found C, 63 78, H, 4 39, N, 16 26 The compound of Example 63a was prepared according to the procedure of Example 63 substituting the corresponding amine for Methyl-pyrazιn-2-yl)-methylamιne The duration of reaction was between 1 and 24 hours EXAMPLE 210 5-{[2-(4-Fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-pentanoic acid ethyl ester Anal calcd for C 19 H 21 N 2 0 4 F C, 63 32, H, 5 87, N, 7 77 Found C, 62 42, H, 5 62, N,7 52, 1 H NMR (CDCI 3 ) d 1 21 (3H, t, J=7 1 Hz), 1 69 (4 H, m), 2 33 (2 H, t, J=6 2 Hz), 3 49 (2 H, m), 4 08 (2 H, q, J= 7 06, 14 11), 7 13 (4 H, m), 7 86 (1 H, s),8 17 (1 H, dd, J= 2 08, 4 77), 8 59 (1 H, dd, J= 2 07, 7 67) EXAMPLE 211 2-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-N-[2-(pyridin-3-yloxy)-pyridin-3-yl]- acetamide To a solution of 2-(4-Acetyl-phenyl)-N-[2-(pyrιdιn-3-yloxy)-pyrιdιn-3-yl]-acetamιde (0 130 grams, 0 374 mmole) in tetrahydrofuran (10 ml) at -78°C 1 0 M methyl lithium in tetrahydrofuran (1 123 ml, 1 123 mmole) was added and stirred at -78°C for 30 minutes, allowed to warm to room temperature for 30 minutes and cooled to -78°C The mixture was quenched with water and extracted with ethyl acetate The combined organics were washed with water and brine, dried over MgS0 4 , filtered and concentrated to a product which was purified by chromatography on silica eluting with 3% methanol/ methylene chloride Recrystalization from ethyl acetate/ hexane gave a solid (0 045 g) M P 122-124°C, Anal calcd for C 21 H 21 N 3 0 3 C, 69 41 , H, 5 82, N, 11 50 Found C, 69 02, H, 6 12, N, 11 30 EXAMPLE 212 2-(4-Fluoro-phenoxy)-N-(5-hydroxy-5-methyl-hexyl)-nicotinamide To a solution of 5-{[2-(4-Fluoro-phenoxy)-pyrιdιne-3-carbonyl]-amιno}-pentanoιc acid ethyl ester (0 0231 grams, 0 06 mmole) in tetrahydrofuran (1 ml) at -78°C 1 4 M methyl lithium in diethyl ether (186 μl, 0 26 mmole) was added via syringe and stirred at -78°C for 2 hours, 200 μl water was added and the mixture warmed to room temperature The reaction was diluted with ethyl acetate, dried over MgS0 4 , filtered and concentrated to give a clear oil Anal calcd for C 19 H 23 N 2 0 3 F C, 65 88, H, 6 69, N, 8 09 Found C, 63 17, H, 5 73, N, 7 46, 1 H NMR (CDCI 3 ) d 1 21 (6H, m), 1 51 (3 H, m), 1 67 (2 H, m), 3 52 (2 H, m), 4 10 (1 H, q, J= 7 17, 14 30), 7 17 (4 H, m), 7 86 (1 H, s), 8 20 (1 H, dd, J= 2 11 , 4 89), 8 58 (1 H, dd, J= 2 16, 7 67) EXAMPLE 213 N-[2-(3-Acetyl-phenoxy)-pyridin-3-yl]-2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]- acetamide To a solution of 2-(4-Acetyl-phenyl)-N-[2-(3-cyano-phenoxy)-pyrιdιn-3-yl]-acetamιde (0 250 grams, 1 484 mmole) in tetrahydrofuran (15 ml) at -78°C 1 0 M methyl lithium in tetrahydrofuran (5 2 ml, 5 2 mmole) was added and stirred at -78°C for 1 hour Another 2 0 ml methyl lithium was added and stirred for 5 minutes allowing to warm to room temperature The reaction was quenched with water and extracted with ethyl acetate The combined extracts were washed with water and brine, dried over MgS0 4 , filtered and concentrated to give an oil which was purified by chromatography on silica eluting with 30% ethyl acetate/ hexane Recrystalization from ethyl acetate/ hexane gave white crystals (0 082 g) M P 85- 87°C, Anal calcd for C 24 H 24 N 2 0 4 C, 71 27, H, 5 98, N, 6 93 Found C, 68 61 , H, 6 30, N, 6 19 EXAMPLE 214 2-(3-Cyano-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]- nicotinamide To a solution of 4-{[2-(3-Cyano-phenoxy)-pyrιdιn-3-ylcarbamoyl]-methyl}- cyclohexanecarboxy c acid ethyl ester (0 180 grams, 0 46 mmole) in tetrahydrofuran (6 ml) at -78°C 1 4 M methyl lithium in diethyl ether (980 μl, 1 37 mmole) was added via syringe and stirred at -78°C for 2 hours The reaction was quenched with 200 μl sat'd NH 4 CI and warmed to room temperature The reaction was diluted with ethyl acetate, dried over MgS0 4 , filtered and concentrated to give a light yellow oil which crystalized on standing M P 129-130°C, Anal calcd for C 23 H 27 N 3 0 3 C, 70 21 , H, 6 92, N, 10 68 Found C, 69 23, H, 6 88, N, 10 37 EXAMPLE 215 3-{3-[4-(1-Hydroxy-1-methyl-ethyl)-benzylcarbamoyl]-pyridin-2-yloxy>- benzoicacid methyl ester To a stirred solution of 2-(3-Methoxycarbonyl-phenoxy)-nιcotιnιc acid (0 400 grams, 1 463 mmole), 2-(4-Amιnomethyl-phenyl)-propan-2-ol (0 266 grams, 1 61 mmole), and 1- hydroxybenzotnazole hydrate (0 237 grams, 1 755 mmole) in dry dimethylformamide (20 ml) was added 2-dιethylamιnoethyl chloride hydrochlonde (0 365 grams, 1 90 mmole) and stirred over night The mixture was diluted with water and extracted with ethyl acetate The combined extracts were washed with water and brine, dried over MgS0 4 , filtered and concentrated to give a white foam (0 360 g), MS (m/e) 420 (M + +1 ), 1 H NMR (CDCI 3 ) d 1 50 (6 H, s), 3 90 (3 H, s), 4 70 (2 H, d, J= 5 60 Hz), 7 20-8 65 (12 H, m) EXAMPLE 216 2-(4-Fluoro-phenoxy)-N-(5-oxo-morpholin-2-ylmethyl)-nicotinamide A solution of 6-Amιnomethyl-morpholιn-3-one hydrochlonde (0 200 grams, 1 2 mmole) and tnethyl amine (0 150 grams, 1 5 mmole) in dimethylformamide was stirred at room temperature for 30 minutes To the stirring solution 2-(4-Fluoro-phenoxy)-nιcotιnιc acid (0 280 grams, 1 2 mmole), 1-hydroxybenzotrιazole hydrate (0 237 grams, 1 755 mmole) and 2- diethylammoethyl chloride hydrochloride (0 30 grams, 1 56 mmole) was added and stirred over night The mixture was diluted with water and extracted with ethyl acetate The combined extracts were washed with 1 N NaOH, water and brine, dried over MgS0 4 , filtered and concentrated to give a white solid which was purified by chromatography on silica eluting with 5 % methanol/ methylene chloride Recrystalization from ethyl acetate/ hexane gave white crystals (0 175 g), M P 157-159°C, Anal calcd for C 17 H 16 N 3 0 4 F C, 59 14, H, 4 67, N, 12 17 Found C, 59 00, H, 4 69, N, 12 19 EXAMPLE 217 2-(3-Cyano-phenoxy)-N-(5-methyl-pyrazin-2-ylmethyl)-nicotinamide A solution of 2-(3-Cyano-phenoxy)-nιcotιnιc acid (0 0067 grams, 0 03 mmole) in thionyl chloride (500 μl, 6 9 mmole) was stirred at room temperature for 3 hours and concentrated under reduced pressure to give a white solid To the residue was added pyridine (300 μl) and C-(5-Methyl-pyrazιn-2-yl)-methylamιne (0 0038 grams, 0 03 mmole) The mixture stood at room temperature for 3 hours and then was concentrated under reduced pressure to white solid ( 0 0093 g), Anal calcd for C 19 H 15 N 5 0 2 C, 66 08, H, 4 38, N, 20 26 Found C, 56 89, H, 5 02, N, 18 31 EXAMPLE 218 N-[2-(3-Cyano-phenoxyl-pyridin-3-yl]-2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]- acetamide To a solution of 2-(4-Acetyl-phenyl)-N-[2-(3-cyano-phenoxy)-pyrιdιn-3-yl]-acetamιde (0 360 grams, 0 96 mmole) in tetrahydrofuran (15 ml) at -78°C 1 0 M methyl lithium (2 03 ml, 2 03 mmole) in tetrahydrofuran (20 ml) was added and stirred at -78°C for 1 hour The reaction was quenched with water and extracted with ethyl acetate The combined extracts were washed with water and brine, dried over MgS0 4 , filtered and concentrated to give a white solid which was purified by chromatography on silica eluting with 40% ethyl acetate/ hexane Recrystalization from ethyl acetate/ hexane gave white crystals (0 115 g) M P 97- 99°C, Anal calcd for C 23 H 21 N 3 0 3 C, 71 30, H, 5 46, N, 10 85 Found C, 70 96, H, 5 30, N, 10 69 EXAMPLE 219 2-(Pyridin-3-yloxy)-N-(4-trifluoroacetyl-benzyl)-nicotinamide To a stirred solution of 2-(Pyrιdιn-3-yloxy)-N-[4-(2,2,2-trιfluoro-1-hydroxy-ethyl)- benzyl]-nιcotιnamιde (0 350 grams, 0 87 mmole), NMO (0 153 grams, 1 3 mmole) and 4 A molecular sieves (0 5 g) in methylene chloride was added TPAP (0 015 grams, 0 04 mmole) and stirred at room temperature for 4 hours The mixture was filtered through celite, washed with water, dried over MgS0 4 , filtered and concentrated under reduced pressure to give an oil which was purified by chromatography on silica eluting with 5% methanol/ methylene chloride to give a solid (0 151 g) M P 134-136°C, Anal calcd for C 20 H 14 N 3 O 3 F 3 C, 59 85, H, 3 52, N, 10 47 Found C, 59 56, H, 3 63, N, 10 20 EXAMPLE 220 2-(3-Acetyl-phenoxy)-N-pyridin-4-ylmethyl-nicotinamide A solution of 2-(3-Acetyl-phenoxy)-nιcotιnιc acid (0 356 grams, 1 39 mmole C-Pyπdin- 4-yl-methylamιne (0 150 grams, 1 39 mmole), and 1 -hydroxy benzotriazole hydrate (0 224 grams, 1 66 mmole) in dry dimethylformamide was added 1-(3-dιmethylamιno)-propyl)-3- ethylcarbodumide hydrochloride (0 319 grams, 1 66 mmole) and stirred over night The mixture was diluted with 100 ml water and extracted with ethyl acetate The combined organics were washed with water and brine, dried over MgS0 4 , filtered and concentrated to give a white solid that was purified by chromatography on silica eluting ethyl acetate to give a white solid Recrystalization from ethyl acetate/ hexane gave a white solid (0 220 g) M P 148- 150°C, Anal calcd for C 20 H 17 N 3 0 3 C, 67 15, H, 4 93, N,12 10 Found C, 66 57, H, 4 55, N, 11 43 The compound of Examples 221-224 was prepared according to the procedure of Example 220 substituting the corresponding amine for C-Pyrιdιn-4-yl-methylamιne The duration of reaction was between 1 and 24 hours EXAMPLE 221 2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide M P 52-54°C, Anal calcd for C 24 H 24 N 2 0 4 C, 71 27, H, 5 98, N, 6 93 Found C, 69 78, H, 5 54, N, 6 83 EXAMPLE 222 2-(3-Acetyl-phenoxy)-N-(2-chloro-benzyl)-nicotinamide M P 140-142°C, Anal calcd for C 21 H 17 N 2 0 3 CI C, 66 23, H, 4 50, N, 7 36 Found C, 65 84, H, 4 22, N, 6 88 EXAMPLE 223 2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-ethyl)-benzvπ-nicotinamide M P 105-107°C, MS (m/e) 391 (M + +1 ) EXAMPLE 224 2-(3-Acetyl-phenoxy)-N-(4-sulfamoyl-benzyl)-nicotinamide M P 162-164°C, MS (m/e) 425 (M + ), 1 H NMR (DMSO-d 6 ) d 2 55 (3H, s), 4 56 (2 H, d, J= 6 0 Hz), 7 2-9 2 (12 H, m) EXAMPLE 225 2-[3-(1-Hydroxy-1-methyl-ethyl)-phenoxy]-N-pyridin-4-ylmethyl-nicotinamide To a solution of 2-(3-Acetyl-phenoxy)-N-pyrιdιn-4-ylmethyl-nιcotιnamιde (0 180 grams, 0 51 mmole) in tetrahydrofuran (20 ml) at -78°C 1 0 M methyl lithium in THF/cumene (1 14 ml, 1 14 mmole) was added and stirred at -78°C for 1 hour The reaction was quenched with water and diluted with ethyl acetate The organics were washed with water and brine, dried over MgS0 , filtered and concentrated to give a product which was purified by chromatography on silica eluting with ethyl acetate to give a white foam MS (m/e) 364 (M + +1), 1 H NMR (CDCI 3 ) d 1 58 (6H, s), 4 70 (2 H, d, J= 5 81 Hz), 7 0-8 7 (12 H, m) EXAMPLE 226 N-(2-Chloro-benzyl)-2-[3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-nicotinamide To a solution of 2-(3-Acetyl-phenoxy)-N-(2-chloro-benzyl)-nιcotιnamιde (0 410 grams, 1 307 mmole) in tetrahydrofuran (20 ml) at -78°C 1 0 M methyl lithium (2 7 ml, 2 697 mmole) was added, stirred at -78°C for 1 hour and allowed to warm to room temperature for 1 hour The reaction was quenched with water and diluted with ethyl acetate The organics were washed with water and brine, dried over MgS0 4 , filtered and concentrated to give an oil which was purified by chromatography on silica eluting wirth 2% methanol/ methylene chloride to give an oil MS (m/e) 397 (M + +1 ), 1 H NMR (CDCI 3 ) d 1 60 (6H, s), 4 78 (2 H, d, J= 6 01 Hz), 7 0-7 5 (9 H, m), 8 20 (1 H, m), 8 55 (1 H, bs), 8 62 (1 H, m) The compound of Examples 227 was prepared according to the procedure of Example 226 substituting the corresponding ketone for 2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy- 1-methyl-ethyl)-benzyl]-nιcotιnamιde The duration of reaction was between 1 and 24 hours EXAMPLE 227 N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-[3-(1-hydroxy-1-methyl-ethyl)- phenoxy] nicotinamide MS (m/e) 421 (M + +1), 1 H NMR (CDCI 3 ) d 1 54 (6H, s), 1 57 (6H, s), 4 67 (2 H, d), 7 0- 7 5 (9 H, m), 8 10-8 70 (3 H, m) EXAMPLE 228 N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl1-2-(3-trifluoromethoxy-phenoxy)- nicotinamide A solution of 2-(3-Trιfluoromethoxy-phenoxy)-nιcotιnιc acid (0 409 grams, 1 366 mmole) 2-(4-Amιnomethyl-phenyl)-propan-2-ol (0 200 grams, 1 24 mmole), and 1- hydroxybenzotπazole hydrate (0 185 grams, 1 366 mmole) in dry dimethylformamide was added 1-(3-dιmethylamιno)-propyl)-3-ethylcarbodιιmιde hydrochloride (0 286 grams, 1 50 mmole) and stirred over night The mixture was diluted ethyl acetate which was washed with water and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica eluting with 3 5% methanol/ methylene chloride to give an oil (0 430g) MS (m/e) 447 (M + +1), 1 H NMR (CDCI 3 ) d 1 50 (6H, s), 4 70 (2 H, d, J= 5 81 Hz), 7 0-7 5 (9 H, m), 8 00 (1 H, bs), 8 20 (1 H, m), 8 65 (1 H, m) EXAMPLE 229 N-(4-Acetyl-cyclohexylmethyl)-2-(4-fluoro-phenoxy)-nicotinamide To 4-{[2-(4-Fluoro-phenoxy)-pyrιdιn-3-ylcarbamoyl]-methyl}-cyclohexanecarboxylιc acid ethyl ester (3 01 grams, 7 5 mmole) in tetrahydrofuran (40 ml) at -78°C 1 4 M methyl lithium in diethyl ether (16 1 ml, 22 5 mmole) was added slowly, stirred at -78°C for 1 hour and slowly warmed to -30°C The reaction was quenched with 600 μl sat'd NH 4 CI and warmed to room temperature The reaction was diluted with ethyl acetate, dried over MgS0 4 , filtered and concentrated to give a light yellow oil which was purified by chromatography on silica eluting with 3/2 hexane/ ethyl acetate to 1/3 hexane/ ethyl acetate to give a clear oil that solidified on standing (0 3500g) M P 110-111°C, Anal calcd for C 21 H 23 N 2 0 3 F C, 68 09, H, 6 26, N, 7 56 Found C, 67 32, H, 6 26, N, 7 40 EXAMPLE 230 2-(2.4-Difluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl1-nicotinamide A solution of 2-(2,4-dιfluoro-phenoxy)-nιcotιnιc acid (0 300 grams, 1 19 mmole) 2-(4- Amιnomethyl-phenyl)-propan-2-ol (0 217 grams, 1 31 mmole), and 1 -hydroxy benzotriazole hydrate (0 177 grams, 1 31 mmole) in dry dimethylformamide was added 1-(3-dιmethylamιno)- propyl)-3-ethylcarbodιιmιde hydrochlonde (0 273 grams, 1 43 mmole) and stirred over night The mixture was poured into 100 ml water and extracted with ethyl acetate The combined extracts were washed with 1 N NaOH, water and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica eluting with 40% ethyl acetate/ hexane to give a white solid Recrystalization from ethyl acetate/ hexane gave a white solid (0 336g) M P 92-94°C, Anal calcd for C 22 H 20 N 2 O 3 F 2 C, 66 32, H, 5 06, N, 7 03 Found C, 66 28, H, 4 92, N, 6 89 EXAMPLE 231 2-(3.4-Difluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl1-nicotinamide A solution of 2-(2,3-dιfluoro-phenoxy)-nιcotιnιc acid (0 300 grams, 1 19 mmole), 2-(4- Amιnomethyl-phenyl)-propan-2-ol (0 217 grams, 1 31 mmole), and 1-hydroxybenzotrιazole hydrate (0 177 grams, 1 31 mmole) in dry dimethylformamide was added 1-(3-dιmethylamιno)- propyl)-3-ethylcarbodιιmιde hydrochlonde (0 273 grams, 1 43 mmole) and stirred over night The mixture was poured into 100 ml water and extracted with ethyl acetate The combined extracts were washed with 1 N NaOH, water and brine, dried over MgS0 , filtered and concentrated to give an oil that was purified by chromatography on silica eluting with 40% ethyl acetate/ hexane to give an oil Recrystalization from ethyl acetate/ hexane gave a white solid (0 337g) M P 98-100°C, Anal calcd for C 22 H 20 N 2 O 3 F 2 C, 66 32, H, 5 06, N, 7 03 Found C, 66 40, H, 4 94, N, 6 89 The compounds of Example 232-233 were prepared according to the procedure of Example 231 substituting the corresponding amine for 2-(4-Amιnomethyl-phenyl)-propan-2-ol The duration of reaction was between 1 and 24 hours EXAMPLE 232 2-(3.4-Difluoro-phenoxy)-N-[4-(1-hydroxy-cyclobutyl)-benzyl]-nicotinamide M P 74-76°C, Anal calcd for C 23 H 20 N 2 O 3 F 2 C, 67 31 , H, 4 91 , N, 6 83 Found C, 67 14, H. 4 93, N,6 67 EXAMPLE 233 N-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(3.4-difluoro-phenoxy)- nicotinamide M P 119-211°C, Anal calcd for C 22 H 19 N 2 0 3 F 2 CI C, 61 65, H, 4 42, N, 6 47 Found C, 61 31 , H, 4 56, N,6 65 EXAMPLE 234 4-({[2-(3-Acetyl-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)- cyclohexanecarboxylic acid ethyl ester A solution of 4-Amιnomethyl-cyclohexanecarboxylιc acid ethyl ester hydrochlonde (0 410 grams, 1 853 mmole), 2-(3-Acetyl-phenoxy)-nιcotιnιc acid (0 500 grams, 1 946 mmole), 1 -hydroxy benzotriazole hydrate (0 275 grams, 2 04 mmole) and 1-(3-dιmethylamιno)-propyl)- 3-ethylcarbodιιmιde hydrochlonde (0 330 grams, 2 22 mmole) in dimethylformamide (30ml) was stirred for 10 minutes To the stirring solution was added tnethyl amine (0 280 grams, 2 78 mmole) and stirred over night at room temperature The mixture was diluted with water (200 ml) and extracted with ethyl acetate The combined extracts were washed with water and brine, dried over MgS0 4 , filtered and concentrated to give a yellow solid which was purified by chromatography on silica eluting with 40% ethyl acetate/ hexane Recrystalization from ethyl acetate/ hexane gave white crystals (0 680g), M P 118-120°C, 1 H NMR (CDCI 3 ) d 1 02 (2H, q, J= 12 866 Hz),1 2 (3 H, t), 1 4 (2 H, q), 1 6 (1 H, m), 1 85 (2 H, d, J= 12 5 Hz), 2 0 (2 H, d, J= 12 5 Hz), 2 2 (1 H, m), 2 6 (3 H, s), 3 4 (2 H, m), 4 10 (2 H, t), 7 2-8 7 (7 H, m) The compounds of Examples 235-237 were prepared according to the procedure of Example 234 substituting the corresponding amine for 4-Amιnomethyl-cyclohexanecarboxylιc acid ethyl ester hydrochlonde The duration of reaction was between 1 and 24 hours EXAMPLE 235 2-(3-Acetyl-phenoxy)-N-[2-chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]- nicotinamide M P 102-104°C, Anal calcd for C 24 H 23 N 2 0 4 CI C, 65 68, H, 5 28, N, 6 38 Found C, 65 39, H, 5 08, N. 6 15 EXAMPLE 236 2-(4-Acetyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide M P 95-97°C, Anal calcd for C 24 H 24 N 2 0 4 C, 71 27, H, 5 98, N, 6 93 Found C, 70 19, H, 5 93, N, 7 02 EXAMPLE 237 2-(3-Acetyl-phenoxy)-N-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]- nicotinamide M P 68-70°C, MS (m/e) 423 (M + +1 ) EXAMPLE 238 2-(3.5-Difluoro-phenoxy)-N-f4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide A solution of 2-(3,5-dιfluoro-phenoxy)-nιcotιnιc acid (0 300 grams, 1 19 mmole), 2-(4- Amιnomethyl-phenyl)-propan-2-ol (0 197 grams, 1 19 mmole) and 1-hydroxybenzotrιazole hydrate (0 177 grams, 1 31 mmole) in dry dimethylformamide was added 1-(3-dιmethylamιno)- propyl)-3-ethylcarbodιιmιde hydrochloride (0 273 grams, 1 43 mmole) and stirred over night The mixture was poured into 100 ml water and extracted with ethyl acetate The combined extracts were washed with 1 N NaOH, water and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica eluting with 40% ethyl acetate/ hexane to give an oil Recrystalization from ethyl acetate/ hexane gave a white solid (0 328g) M P 68-70°C, Anal calcd for C 22 H 20 N 2 O 3 F 2 C, 66 32, H, 5 06, N, 7 03 Found C, 67 30, H, 5 39, N, 6 56 EXAMPLE 239 trans-2-(2.4-Difluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)- cyclohexylmethyl -nicotinamide To trans-4-({[2-(2,4-Dιfluoro-phenoxy)-pyrιdιne-3-carbonyl]-amιno}-methyl)- cyclohexanecarboxy c acid ethyl ester (0 516 grams, 1 23 mmole) in tetrahydrofuran (20 ml) at 0°C 3 0 M methyl magnesium chloride (1 2 ml, 3 7 mmole) was added dropwise and stirred 1 hour The reaction was poured into 150 ml water, acidified with oxalic acid to pH=3 and extracted with ethyl acetate The combined extracts were washed with 1JSJ HCl, 1JN NaOH, water and brine, dried over MgS0 4 , filtered and concentrated to give an oil which was purified by chromatography on silica eluting with 50% hexane/ ethyl acetate to give an oil Recrystalization from ethyl acetate/ hexane gave a white solid (0 207g) M P 92-94°C, Anal calcd for C 22 H 26 N 2 0 3 F 2 C, 65 33, H, 6 48, N, 6 93 Found C, 65 27, H, 6 26, N, 6 73 The compound of Example 240 was prepared according to the procedure of Example 239 substituting the corresponding ester for trans-4-({[2-(2,4-Dιfluoro-phenoxy)-pyrιdιne-3- carbonyl]-amιno}-methyl)-cyclohexanecarboxylιc acid ethyl ester The duration of reaction was between 1 and 24 hours EXAMPLE 240 trans-2-(3.4-Difluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)- cyclohexylmethyl]-nicotinamide M P 80-82°C, MS (m/e) 405 (M + +1) EXAMPLE 241 4-({[2-(3-Nitro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)- cyclohexanecarboxylic acid ethyl ester To a stirred solution of 4-Amιnomethyl-cyclohexanecarboxylιc acid ethyl ester hydrochloride (0 500 grams, 2 26 mmole), 2-(3-Nιtro-phenoxy)-nιcotιnιc acid (0 588 grams, 2 26 mmole), 1-hydroxybenzotrιazole hydrate (0 366 grams, 2 71 mmole) and 1-(3- dιmethylamιno)-propyl)-3-ethylcarbodιιmιde hydrochlonde (0 564 grams, 2 93 mmole) in dimethylformamide (50ml) was was added tnethyl amine (0 456 grams, 4 52 mmole) and stirred over the weekend at room temperature The mixture was diluted with water (150 ml) and extracted with ethyl acetate The combined extracts were washed with water and brine, dried over MgS0 4 , filtered and concentrated to give an oil which was purified by chromatography on silica eluting with 40% ethyl acetate/ hexane to give an oil (1 05 g) MS (m/e) 428 (M + +1 ), 1 H NMR (CDCI 3 ) d 1 01 (2H, m), 1 2 (3 H, t), 1 4 (2 H, q), 1 6 (1 H, m), 1 90 (2 H, d, J= 12 5 Hz), 2 0 (1 H, d, J= 12 5 Hz), 2 2 (1 H, m), 3 4 (2 H, m), 4 10 (2 H, q), 7 20-8 7 (7 H, m) EXAMPLE 242 2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]- nicotinamide A solution of N-[4-(1-Hydroxy-1-methyl-ethyl)-cyclohexylmethyl]-2-[3-(2-methyl- [1 ,3]dιoxolan-2-yl)-phenoxy]-nιcotιnamιde (0 400 grams, 0 88 mmole) in acetic acid (10 ml) was stirred for 3 hours at room temperature The mixture was diluted with 250 ml ethyl acetate, washed with 1 N NaOH, water and brine, dried over MgS0 4 , filtered and concentrated to an oil which was purified by chromatography on silica eluting with 40% ethyl acetate/ heaxane Recrystalization gave a solid (0 055g) M P 105-107°C, Anal calcd for C 24 H 30 N 2 O 4 C, 70 22, H, 7 37, N, 6 82 Found C, 68 43, H, 7 32, N, 6 71 EXAMPLE 243 2-(3-Cyano-4-fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]- nicotinamide A solution of 2-(3-Cyano-4-fluoro-phenoxy)-nιcotιnιc acid (0 300 grams, 1 16 mmole) 2-(4-Amιnomethyl-phenyl)-propan-2-ol (0 192 grams, 1 16 mmole), and 1- hydroxybenzotnazole hydrate (0 172 grams, 1 28 mmole) in dry dimethylformamide was added 1-(3-dιmethylamιno)-propyl)-3-ethylcarbodιιmιde hydrochlonde (0 267g, 1 39 mmole) and stirred over night The mixture was poured into 100 ml water and extracted with ethyl acetate The combined extracts were washed with 1 N NaOH, water and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica eluting with 50% ethyl acetate/ hexane to give an oil Recrystalization from ethyl acetate/ hexane gave a white solid (0 276g) M P 147-149°C, Anal calcd for C 23 H 20 N 3 O 3 F C, 68 14, H, 4 97, N, 10 36 Found C, 67 77, H, 5 00, N, 10 15 The compound of Example 244 was prepared according to the procedure of Example 243 substituting the corresponding amine for 2-(4-Amιnomethyl-phenyl)-propan-2-ol The duration of reaction was between 1 and 24 hours EXAMPLE 244 N-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(3-cyano-4-fluoro-phenoxy)- nicotinamide M P 151-153°C, Anal calcd for C 23 H 19 N 3 0 3 FCI C, 62 80, H, 4 35, N, 9 55 Found C, 63 16, H, 4 44, N, 9 49 EXAMPLE 245 2-(4-Fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]- nicotinamide To 4-({[2-(4-Fluoro-phenoxy)-pyrιdιne-3-carbonyl]-amιno}-methyl)- cyclohexanecarboxyhc acid methyl ester (0 0221 grams, 0 06 mmole) in tetrahydrofuran (1 ml) at -78°C 1 4 M methyl lithium in diethyl ether (171 μl, 0 24 mmole) was added and stirred at - 78°C for 2 hours The reaction was quenched with 200 μl sat'd NH 4 CI and warmed to room temperature The reaction was filtered through a pad of magnesium sulfate and concentrated to give a light brown foam which was purified by chromatography on silica eluting with 1/1 hexane/ ethyl acetate to 95/5 methylene chloride/ methanol to give a clear film (0 0111 g) M P 78-80°C, Anal calcd for C 22 H 27 N 2 0 3 F C, 68 37, H, 7 04, N, 7 25 Found C, 68 32, H, 7 04, N, 7 27 EXAMPLE 246 N-(2-Chloro-benzyl)-2-(pyridin-3-ylmethoxy)-nicotinamide A solution of 2-(Pyπdιn-3-ylmethoxy)-nιcotιnιc acid (0 300 grams, 1 3 mmole) 2- Chloro-benzylamine (0 202 grams, 1 43 mmole), and 1-hydroxybenzotrιazole hydrate (0 210 grams, 1 56 mmole) in dry dimethylformamide (10 ml) was added 1-(3-dιmethylamιno)-propyl)- 3-ethylcarbodιιmιde hydrochlonde (0 324 grams, 1 69 mmole) and stirred over night The mixture was diluted with 50 ml water and 50 ml 1 N sodium hydroxide and extracted with ethyl acetate The combined extracts were washed with 1 N NaOH, water and brine, dried over Na 2 S0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica eluting with 5% methanol/ methylene chloride Recrystalization from ethyl acetate/ hexane gave white crystals (0 116g) M P 91-93°C, Anal calcd for C 19 H 16 N 3 0 2 CI C, 64 50, H, 4 56, N, 11 88 Found C, 64 38, H, 4 58, N, 11 97 EXAMPLE 247 N-[[4-(Dimethylamino)phenyl]methyl]-2-(4-fluorophenoxy)-3- pyridinecarboxamide To a solution of 1 00 g (2 96 mmol) N-(4-Amιno-benzyl)-2-(4-fluoro-phenoxy)- nicotmamide in 20 mL of acetonitrile was added 1 44 mL (17 8 mmol) of aqueous 37% formaldehyde solution followed by 0 558 g (4 45 mmol) of NaCNBH 3 After stirring for 16 h at rt, the mixture was acidified to destroy excess NaCNBH 3 and was partially evaporated to remove acetonitrile The residue was adjusted to pH 6-7 and then extracted with EtOAc (2 x 200 mL) The combined extracts were washed with saturated aqueous sodium hydrogencarbonate solution (1 x 100 mL), brine (1 x 100 mL), dried (Na 2 S0 4 ), and evaporated to 1 55 g of an oil Purification by flash chromatography using a 40% EtOAc- hexane eluant gave 992 mg of an oil which slowly solidified Trituration in hexane afforded 872 mg (81 % yield) of the title compound as a white solid, mp 99 5-101 5°C Anal Calcd for C 21 H 20 N 3 O 2 F C, 69 03, H, 5 51 , N, 11 50 Found C, 69 32, H, 5 52, N, 11 58 EXAMPLE 248 2-(4-Fluorophenoxy)-a-[2-(4-methoxyphenyl)ethyl]-3-pyridinemethanol A solution of 0 250 g (1 15 mmol) 2-(4-Fluorophenoxy)-3-pyrιdιnecarboxaldehyde in 5 mL of tetrahydrofuran was cooled to -78 °C and treated dropwise with 1 0 mL of a solution of the Gngnard reagent prepared from 2 62 g (15 3 mmol) of 1-(2-chloroethyl)-4- methoxybenzene and 0 559 g (23 0 mmol) of magnesium tunnmgs in 13 mL of THF After 2 h of stirring, an additional 0 5 mL of Gπgnard reagent was added, and the mixture was quenched by the addition of 2 mL of saturated aqueous NH 4 CI solution After warming to rt, the mixture was partitioned between 50 mL of water and 200 mL of EtOAc, and the separated organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, brine, dried (Na 2 S0 ), and evaporated to give 0 53 g of a colorless oil Two purifications by flash chromatography using 25% EtOAc-hexane and 25% ether-toluene, respectively, as eluants afforded 339 mg (64% yield) of the the title compound as an oil Thermospray MS m/e 354 (M + + 1) EXAMPLE 249 1-f2-(4-Fluorophenoxy)-3-pyridinyl]-3-(4-methoxyphenyl)-1-propanone A solution of 353 mg (1 00 mmol) 2-(4-Fluorophenoxy)-a-[2-(4-methoxyphenyl)ethyl]- 3-pyrιdιnemethanol in 5 mL of acetone was cooled to 0 °C and treated with 1 6 mL (2 00 mmol) of 1 25 M Jones Reagent solution The mixture was allowed to warm to rt and then quenched by the addition of 5 mL of isopropanol The precipitate was removed by filtration, and the filtrate was evaporated and partitioned between 50 mL of saturated aqueous sodium hydrogencarbonate solution and 100 mL of EtOAc The separated organic layer was combined with a 100 mL EtOAc backwash of the aqueous layer, washed with brine (50 mL), dried (Na 2 S0 4 ), and evaporated Trituration of the residue in hexane gave 271 mg (77% yield) of the title compound, mp 73-74°C 1 H NMR (CDCI 3 ) d 3 03 (2 H, t, J = 7 Hz), 3 43 (2 H, t, J = 7 Hz), 3 78 (3 H, s), 6 75-7 18 (9 H, m), 8 17 (1 H, dd, J = 2, 8 Hz), ), 8 25 (1 H, dd, J = 2, 4 Hz), Anal Calcd for C 21 H 18 NO 3 F « 0 25 H 2 0 C, 70 87, H, 5 10, N, 3 94 Found C, 70 88, H, 4 79, N, 3 79 EXAMPLE 250 3-(2-Chlorophenyl)-1-f2-(4-fluorophenoxy)-3-pyridinyl]-1-propanone A solution of 226 mg (0 496 mmol) a-[(2-Chlorophenyl)methyl]-2-(4-fluorophenoxy)-β- oxo-3-pyrιdιnepropanoιc Acid f-Butyl Ester in 5 mL of trifluoroacetic acid was stirred at rt for 4 h The mixture was evaporated, and the residue was diluted with 5 mL of toluene, heated to reflux for 2 h, and evaporated The residue was dissolved in 100 mL of EtOAc, washed successively with saturated aqueous sodium hydrogencarbonate solution (1 x 50 mL) and brine (1 x 50 mL), dried (Na 2 S0 4 ), and and evaporated to 125 mg of an oil Purification by flash chromatography using 40% ether-hexane as eluant yield 120 mg (68% yield) of the title compound as a colorless oil 1 H NMR (CDCI 3 ) d 3 20 (2 H, t, J = 8 Hz), 3 49 (2 H, t, J = 8 Hz), 7 06-7 32 (9 H, m), 8 19 (1 H, dd, J = 2, 7 Hz), 8 25 (1 H, dd, J = 2,5 Hz), Thermospray MS (m/e) 356,358 (M + +1 ) The compounds of Examples 251-255 were prepared according to the procedure of Example 250 substituting the indicated substrate for the compound of Preparation 60. Mass spectra were determined by the thermospray method. EXAMPLE 251 1-[2-(4-Fluoro-phenoxy)-pyridin-3-yl1-3-(4-fluoro-phenyl)-propan-1-one 1 H NMR (CDCI 3 ) d 3.07 (2 H, t, J = 7 Hz), 3.45 (2 H, t, J = 7 Hz), 6.92-7.20 (9 H, m), 8.18 (1 H, dd, J = 2, 8 Hz), 8.25 (1 H, dd, J = 2, 5 Hz); MS (m/e) 340 (M + +1 ). EXAMPLE 252 1-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-3-(4-trifluoromethyl-phenyl)-propan-1-one M.P. 94-95°C; Anal. Calcd for C 21 H 15 F 4 N0 2 : C, 64.78; H, 3.88; N, 3.60. Found: C, 64.44; H, 3.93; N, 3.45. EXAMPLE 253 1-[2-(4-Fluoro-phenoxy)-pyridin-3-yl1-3-(4-trifluoromethoxy-phenyl)-propan-1- one M.P. 79-81°C; Anal. Calcd for C 21 H 15 F 4 N0 3 : C, 62.23; H, 3.73; N, 3.46. Found: C, 62.11 ; H, 3.77; N, 3.57. EXAMPLE 254 3-(3.5-Difluoro-phenyl)-1-[2-(4-fluoro-phenoxy)-pyridin-3-yl]-propan-1-one M.P. 69-70°C; Anal. Calcd for C 20 H 14 F 3 NO 2 : C, 67.22; H, 3.95; N, 3.92. Found: C, 67.19; H, 3.74; N, 3.92. EXAMPLE 255 1-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-3-(2.4.6-trifluoro-phenyl)-propan-1-one M.P. 84-85°C; Anal. Calcd for C 20 H 13 F 4 NO 2 : C, 64.00; H, 3.49; N, 3.73. Found: C, 64.07; H, 3.31 ; N, 3.66. EXAMPLE 256 1-[2-(4-Fluorophenoxy)-3-pyridinyl]-3-phenyl-1-propanone To the sodium hydride obtained by washing 351 mg (7.73 mmol) of 50% sodium hydride dispersion in mineral oil with pentane was added 10 mL of dimethylformamide followed by 867 mg (7.73 mmol) of p-fluorophenol. After the hydrogen evolution ceased, 886 mg (3.87 mmol) 1-(2-Fluoro-pyridin-3-yl)-3-phenyl-propan-1-one was added dissolved in a minimum amount of DMF. The mixture was heated to 80 °C for 3 h, and the solvent was evaporated under high vaccum. The residue was partitioned between 200 mL of ether and 50 mL of aqueous 1 N sodium hydroxide solution, and the separated organic layer was washed with aqueous 1 N sodium hydroxide solution (1 x 50 mL), brine (1 x 100 mL), dried (Na 2 S0 ), and evaporated to 1.16 g of a white solid. Recrystallization from hexane gave 1.06 g (85% yield) of the title compound as a white solid, mp 82-83°C. Anal. Calcd for C 20 H 16 FNO 2 : C, 74.75; H, 5.02; N, 4.36. Found: C, 74.63; H, 4.97; N, 4.31. The compounds of examples 257-270 were prepared according to the procedure of Example 256 substituting the indicated substrate for the compound of Preparation 63a and, when indicated, 3-hydroxypyhdine for p-fluorophenol. Products were purified by direct trituration and/or flash chromatography. Mass spectra were determined by the APCI method. EXAMPLE 257 3-Phenyl-1-[2-(pyridin-3-yloxy)-pyridin-3-yl]-propan-1-one M.P. 45-46°C; Anal. Calcd for C 19 H 16 N 2 0 2 : C, 74.98 H, 5.36; N, 9.20. Found: C, 74.80; H, 5.35; N, 9.11. EXAMPLE 258 3-(4-Fluoro-phenyl)-1-[2-(pyridin-3-yloxy)-pyridin-3-yl1-propan-1-one M.P. 62-64°C; Anal. Calcd for C 19 H 15 FN 2 0 2 : C, 70.80; H, 4.69; N, 8.69. Found: C, 70.55; H, 4.80; N, 8.69. EXAMPLE 259 1-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-2-methyl-3-phenyl-propan-1-one H NMR (CDC d 1.19 (3 H, d, J = 7 Hz), 2.92 (2 H, ABX pattern, J AB = 13 Hz, J AX = 6 Hz, J BX = 8 Hz), 3.87-3.94 (1 H, m), 7.02-7.24 (10 H, m), 7.95 (1 H, dd, J = 2, 7 Hz), 8.19 (1 H, dd, J = 2, 5 Hz); MS (m/e) 336 (M + +1). EXAMPLE 260 2-Methyl-3-phenyl-1-[2-(pyridin-3-yloxy)-pyridin-3-yl]-propan-1-one 1 H NMR (CDCI 3 ) d 1.20 (3 H, d, J = 7 Hz), 2.93 (2 H, ABX pattern, J AB = 14 Hz, J AX = 7 Hz, J BX = 8 Hz), 3.86-3.95 (1 H, m), 7.06-7.49 (8 H, m), 7.94-7.97 (1 H, m), 8.16-8.18 (1 H, m), 8.47-8.50 (2 H, m); MS (m/e) 319 (M + +1 ). EXAMPLE 261 1-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-3-phenyl-butan-1-one 1 H NMR (CDCI 3 ) d 1.31 (3 H, d, J = 7 Hz), 3.30-3.52 (3 H, m), 7.02-7.27 (10 H, m), 8.01 (1 H, dd, J = 2, 8 Hz), 8.20 (1 H, dd, J = 2, 5 Hz); MS (m/e) 336 (M + +1). EXAMPLE 262 3-Phenyl-1-[2-(pyridin-3-yloxy)-pyridin-3-yl]-butan-1-one 1 H NMR (CDCI 3 ) d 1.31 (3 H, d, J = 7 Hz), 3.32-3.52 (3 H, m), 7.06-7.53 (8 H, m) , 8.05 (1 H, dd, J = 2, 8 Hz), 8.19 (1 H, dd, J = 2, 5 Hz); 8.49-8.51 (2 H, m); MS (m/e) 319 (M + +1). EXAMPLE 263 3-f4-(1-Hydroxy-1-methyl-ethyl)-phenyl]-1-[2-(pyridin-3-yloxy)-pyridin-3-yl]- propan-1-one 1 H NMR (CDCI 3 ) d 1 54 (6 H, s), 1 88 (1 H, br s), 3 07 (2 H, t, J = 8 Hz), 3 44 (2 H, t, J = 8 Hz), 7 11-7 55 (7 H, m), 8 17-8 21 (2 H, m), 8 21-8 49 (2 H, m), MS (m/e) 345 (M + +1 -18 (H 2 0)) EXAMPLE 264 1-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-2-phenyl-ethanone M P 81-82°C, Anal Calcd for C 19 H 14 FN0 2 C, 74 26, H, 4 59, N, 4 56 Found C, 74 13, H. 4 61 , N, 4 56 EXAMPLE 265 1-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-2-phenoxy-ethanone M P 105 5-106 5°C, 1 H NMR (CDCI 3 ) d 5 34 (2 H, s), 6 73-7 28 (10 H, m), 8 28-8 33 (2 H, m), MS (m/e) 324 (M + +1) EXAMPLE 266 2-(2-Chloro-phenoxy)-1-[2-(4-fluoro-phenoxy)-pyridin-3-yl]-ethanone M P 92-93°C, Anal Calcd for C 19 H 13 N0 3 CIF C, 63 79, H, 3 66, N, 3 91 Found C, 63 43, H, 3 52, N, 3 94 EXAMPLE 267 1-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-3-phenyl-propenone M P 110-111 °C, 1 H NMR (CDCI 3 ) d 7 07-7 58 (11 H, m), 7 75 (1 H, d, J = 16 Hz), 8 13 (1 H, dd, J = 2,7 Hz), 8 27 (1 H, dd, J = 2,5 Hz), MS (m/e) 320 (M + +1) EXAMPLE 268 Benzofuran-2-yl-[2-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone M P 102-103°C, Anal Calcd for C 20 H 12 NO 3 F C, 72 07, H, 3 63, N, 4 20 Found C, 71 84, H, 3 43, N. 4 15 EXAMPLE 269 [2-(4-Fluoro-phenoxy)-pyridin-3-yl]-(1H-indol-2-yl)-methanone M P 169-170°C, 1 H NMR (CDCI 3 ) d 7 04-7 17 (7 H, m), 7 36 (1 H, dd, J = 1 , 8 Hz), 7 46 (1 H, d, J = 8 Hz), 7 67 (1 H, d, J = 8 Hz), 7 95 (1 H, dd, J = 2, 8 Hz), 8 28 ( 1 H, dd, J = 2, 5 Hz), 9 20 (1 H, s), MS (m/e) 333 (M + +1 ) EXAMPLE 270 1-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-2-(methyl-phenyl-amino)-ethanone M P 126-128°C, 1 H NMR (CDCI 3 ) d 3 10 (3 H, s), 4 85 (2 H, s), 6 61-6 73 (3 H, m), 7 09-7 21 (7 H, m), 8 22 (1 H, dd, J = 2, 8 Hz), 8 27 (1 H, dd, J = 2, 5 Hz), MS (m/e) 337 (M + +1) EXAMPLE 271 1-[2-(4-Fluorophenoxy)-3-pyridinyl1-3-hydroxy-3-phenyl-1-propanone A solution of 0 114 mL (111 mg, 1 10 mmol) of dnsopropylamine in 8 mL of tetrahydrofuran was cooled to -78 °C and treated dropwise with 0 440 mL (1 10 mmol) of a solution of 2 5 M n-butyl thium in hexane After stirring for 30 m , a solution of 231 mg (1 00 mmol) 1-[2-(4-Fluorophenoxy)-3-pyπdιnyl]-ethanone in 2 mL of tetrahydrofuran was added dropwise After stirring for 30 mm, 0 112 mL (1 07 mmol) of benzaldehyde was added dropwise, and stirring was continued for 1 h The mixture was quenched by the addition of 2 mL of saturated aqueous NH 4 CI solution and was allowed to warm to rt The mixture was partitioned between 50 mL of saturated aqueous NH 4 CI solution and 300 mL of EtOAc The separated organic layer was washed with 50 mL of saturated aqueous sodium hydrogencarbonate solution, 50 mL of brine, dried (Na 2 S0 4 ), and evaporated to 259 mg of an oil Purification by flash chromatography using a 40% EtOAc-hexane eluant afforded 211 mg (63% yield) of the title compound as an oil, 1 H NMR (CDCI 3 ) d 3 23 (1 H, br s), 3 54-3 56 (2 H, m), 5 34-5 37 (1 H, m), 7 07-7 41 (10 H, m), 8 21-8 26 (2 H, m), APCI MS (m/e) 338 (M + +1 ) EXAMPLE 272 1-[2-(3-Pyridyloxy)-3-pyridinyl]-3-hydroxy-3-phenyl-1-propanone 1 H NMR (CDCI 3 ) d 3 29 (1 H, br s), 3 52-3 57 (2 H, m), 5 35-5 38 (1 H, m), 7 13-7 51 (8 H, m), 8 23-8 26 (2 H, m), 8 46-8 49 (2 H, m), APCI MS (m/e) 321 (M + +1 ) EXAMPLE 273 a-[2-(2-Chlorophenyl)ethyl]-2-(4-fluorophenoxy)-3-pyridinemethanol A solution of 76 0 mg (0 214 mmol) 3-(2-Chlorophenyl)-1-[2-(4-fluorophenoxy)-3- pyrιdιnyl]-1-propanone in 5 mL of methanol was cooled to 0 °C and treated with 8 0 mg (0 21 mmol) of NaBH The mixture was stirred for 30 min at 0 °C and quenched by the addition of 1 mL of aqueous 1 N hydrochloric acid solution The mixture was evaporated, and the residue was partitioned between 100 mL of EtOAc and 50 mL of saturated aqueous sodium hydrogencarbonate solution The organic layer was washed with brine, dried (Na 2 S0 4 ), and evaporated to give 79 mg (100%) of the title compound as an oil 1 H NMR (CDCI 3 ) d 2 10- 2 32 (2 H, m), 2 35 (1 H, ό, J = 6 Hz), 2 83-3 08 (2 H, m), 5 06-5 15 (1 H, m), 7 01-7 33 (9 H, m), 7 85 (1 H, dd, J = 2, 7 Hz), 8 05 (1 H, dd, J = 2, 5 Hz), thermospray MS (m/e) 358 and 360 (M + +1) The compounds of Examples 274-276 were prepared according to the procedure of Example 273 substituting the indicated substrate for the compound 3-(2-Chlorophenyl)-1-[2- (4-fluorophenoxy)-3-pyrιdιnyl]-1-propanone EXAMPLE 274 1-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-3-(2.4.6-trifluoro-phenyl)-propan-1-ol M.P. 90-91°C; 1 H NMR (CDCI 3 ) d 2.00-2.20 (2 H, m), 2.31 (1 H, d, J = 5 Hz), 2.71- 2.90 (2 H, m), 4.98-5.08 (1 H, m), 6.56-6.61 (2 H, m), 6.99-7.10 (5 H, m), 7.81 (1 H, dd, J = 1 , 8 Hz), 8.02 (1 H, dd, J = 2, 5 Hz); thermospray MS (m/e) 378 (M + +1 ). EXAMPLE 275 1-f2-(4-Fluoro-phenoxy)-pyridin-3-yl]-3-phenyl-propan-1-ol 1 H NMR (CDCy d 2.10-2.25 (2 H, m), 2.20 (1 H, br s), 2.72-2.92 (2 H, m), 5.01-5.09 (1 H, m), 6.99-7.30 (10 H, m), 7.79 (1 H, dd, J = 1 , 7 Hz), 8.03 (1 H, dd, J = 2, 5 Hz); AMPI MS (m/e) 324 (M + +1). EXAMPLE 276 3-Phenyl-1-[2-(pyridin-3-yloxy)-pyridin-3-yl]-propan-1-ol 1 H NMR (CDCI 3 ) d 2.08-2.23 (2 H, m), 2.60 (1 H, br s), 2.73-2.89 (2 H, m), 5.07-5.12 (1 H, m), 7.04-7.48 (8 H, m), 7.86-7.89 (1 H, m), 8.01 (1 H, dd, J = 2, 5 Hz), 8.40-8.43 (2 H, m); AMPI MS (m/e) 307 (M + +1). EXAMPLE 277 (Ε)-2-(4-Fluorophenoxyϊ-3-[3-(4-methoxyphenyl)-1-propenyl]-pyridine A mixture of 0.97 g (2.7 mmol) 2-(4-Fluorophenoxy)-a-[2-(4-methoxyphenyl)ethyl]-3- pyridinemethanol, 0.93 g (3.9 mmol) of Burgess Reagent, and 20 mL of benzene was heated to reflux for 4 h. The cooled mixture was partitioned between 300 mL of EtOAc and 100 mL of saturated aqueous sodium hydrogencarbonate solution, and the separated organic layer was washed with 100 mL of brine, dried (Na 2 S0 4 ), and evaporated to 1.10 g of an oil. Purificaiton by flash chromatography using 15% EtOAc-hexane as eluant gave 0.39 g (42% yield) of the title compound as an oil. 1 H NMR (CDCI 3 ) d 3.60 (2 H, d, J = 7 Hz), 3.82 (3 H, s), 6.48 (1 H, dt, J = 7, 16 Hz), 6.78 (1 H, d, J = 16 Hz), 6.86-7.18 (9 H, m), 7.79 (1 H, dd, J = 2, 8 Hz), 7.99 (1 H, dd, J = 2, 5 Hz). Example 278 was prepared according to the procedure of Example 277 substituting the corrsponding alcohol for 2-(4-Fluorophenoxy)-a-[2-(4-methoxyphenyl)ethyl]-3- pyridinemethanol. EXAMPLE 278 fE)-2-(4-Fluorophenoxy)-3-[3-phenyl-1-propenyl]-pyridine 1 H NMR (CDCI 3 ) d 3.62 (2 H, d, J = 7 Hz), 6.51 (1 H, dt, J = 7, 16 Hz), 6.81 (1 H, d, J = 16 Hz), 6.83-7.35 (10 H, m), 7.78 (1 H, dd, J = 2, 8 Hz), 8.00 (1 H, dd, J = 2, 5 Hz); AMPI MS (m/e) 306 (M + +1). EXAMPLE 279 syn-3-[1.2-Dihydroxy-3-(4-methoxyphenyl)propyll-2-(4-fluorophenoxy)-pyridine To a mixture of 161 mg (1.19 mmol) of Λ/-methylmorpholine-Λ/-oxide hydrate, 0.175 g (0.0175 mmol) of a 2.5% solution of Os0 4 in .-butanol, 0.6 mL of acetone, and 0.4 mL of water was added 200 mg (0 596 mg) (E 2-(4-Fluorophenoxy)-3-[3-phenyl-1-propenyl]-pyrιdιne dissolved in 2 mL of acetone and 0 5 mL of water The mixture was stirred for 16 h at rt, at which time 5 g of solid sodium sulfite was added The suspension was stirred for 5 mm, and the solids were removed by filtration rinsing with 100 mL of acetone The filtrate was concentrated, and the residue was partitioned between 100 mL of EtOAc and 50 mL of brine The organic layer was separated, combined with a 100 mL EtOAc backwash of the aqueous layer, dried (Na 2 S0 4 ), and evaporated to 195 mg of a solid Recrystallization from toluene gave 140 mg (64% yield) of the title compound as a white solid, mp 125-126°C 1 H NMR (CDCy d 2 13 (1 H, d, J = 4 Hz), 2 87 (2 H, d, J = 6 Hz), 2 94 (1 H, d, J = 6 Hz), 3 78 (3 H, s), 4 05-4 14 (1 H, m), 5 02 (1 H, \, J = 5 Hz), 6 80-7 16 (9 H, m), 7 89 (1 H, dd, J = 2, 7 Hz), 8 08 (1 H, dd, J = 2, 4 Hz) Example 280 was prepared according to the procedure of Example 279 substituting the corresponding starting material EXAMPLE 280 syn-3-(1.2-Dihydroxy-3-phenylpropyl)-2-(4-fluorophenoxy)-pyridine M P 125-126°C, Anal Calcd for C 20 H 18 N0 3 F C, 70 78 H, 5 35, N, 4 13 Found C, 70 68, H, 5 19, N, 4 24 EXAMPLE 281 3-[(Benzyloxy)methyl1-2-(4-fluorophenoxy)-pyridine To a suspension of 122 mg (2 53 mmol) of 50% sodium hydride dispersion in mineral oil in 10 mL of dimethylformamide was added 500 mg (2 30 mmol) 2-(4-Fluorophenoxy)-3- pyridmemethanol followed by 0 343 mL (396 mg, 2 53 mmol) of 4-methoxybenzyl chloride and 420 mg (2 53 mmol) of Kl After stirring 1 h at rt, the mixture was partitioned between 100 mL of water and 100 mL of EtOAc The separated organic layer was washed with brine, dried (Na 2 S0 4 ), and evaporated to 949 mg of a yellow oil Purification by flash chromatography using a 20% EtOAc-hexane eluant gave 552 mg of a colorless oil which solidified on standing Trituration in hexane afforded 464 mg (59% yield) of the title compound as a white solid, mp 49-50°C Anal Calcd for C 20 H 18 NO 3 F C, 70 78 H, 5 35, N, 4 13 Found C, 70 79, H, 5 09, N, 4 03 EXAMPLE 282 1-[2-(4-Fluorophenoxy)-3-pyridinyl)-3-(4-methoxyphenyl)propane To a solution of 60 mg (0 18 mmol) (ΕJ-2-(4-Fluorophenoxy)-3-[3-(4-methoxyphenyl)- 1-propenyl]-pyrιdιne in 50 mL of ethanol was added 50 mg of 10%Pd/C, and the mixture was hydrogenated at 45 psi on a Parr Shaker Apparatus for 2h The catalyst was removed by filtration, and the filtrate was concentrated to afford 50 mg (83% yield) of the title compound as a colorless oil H NMR (CDCI 3 ) d 1 92-2 06 (2 H, m), 2 67 (2 H, t, J = 8 Hz), 2 75 (2 H, t, J = 8 Hz), 3 80 (3 H, s), 6 82-7 14 (9 H, m), 7 52 (1 H, dd, J = 2, 7 Hz), 7 99 (1 H, dd, J = 2, 5 Hz), thermospray MS m/e 338 (M + + 1) EXAMPLE 283 N-(2-Chloro-benzyl)-2-(3-methoxy-phenoxy)-nicotinamide To a solution of 2-(3-methoxy-phenoxy)-nιcotιnιc acid (0 300 grams, 1 224 mmole) 2- Chloro-benzylamme (0 166 grams, 1 160 mmole), and 1-hydroxybenzotrιazole hydrate (0 173 grams, 1 283 mmole) in dry dimethylformamide (30 ml) was added 1-(3-dιmethylamιno)- propyl)-3-ethylcarbodιιmιde hydrochlonde (0 269 grams, 1 399 mmole) and stirred over night The mixture was diluted with 200 ml water and extracted with ethyl acetate The combined extracts were washed with water and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica eluting with 30% ethyl acetate/ hexane to give an oil which solidified on standing (0 300g) M P 71-74°C, Anal calcd for C 2 oH 17 N 2 0 3 CI C, 65 13, H, 4 65, N, 7 60 Found C, 64 94, H, 4 69, N, 7 63 EXAMPLE 284 N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(1-oxo-indan-4-yloxy)-nicotinamide To a solution of 2-(1-Oxo-ιndan-4-ylmethoxy)-nιcotιnιc acid (0 220 grams, 0 818 mmole), 2-(4-Amιnomethyl-phenyl)-propan-2-ol (0 128 grams, 0 779 mmole), and 1- hydroxybenzot azole hydrate (0 116 grams, 0 857 mmole) in dry dimethylformamide (30 ml) was added 1-(3-dιmethylamιno)-propyl)-3-ethylcarbodιιmιde hydrochloride (0 1795 grams, 0 935 mmole) and stirred over night The mixture was diluted with water and extracted with ethyl acetate The combined extracts were washed with water and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica eluting with 60% ethyl acetate/ hexane to give a yellow solid (0 078g) M P 145-147°C, Anal calcd for C 25 H 24 N 2 0 4 C, 72 10, H, 5 81 , N, 6 73 Found C, 71 79, H, 5 67, N, 6 61 EXAMPLE 285 N-(4-Acetyl-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide A solution of 2-(4-Fluoro-phenoxy)-N-[4-(2-methyl-[1 ,3]dιoxolan-2-yl)-benzyl]- nicotinamide (1 2 grams, 2 9 mmole) in 2 N hydrochloric acid (3 7 ml, 7 35 mmole) and tetrahydrofuran (30 ml) was stirred at room temperature for 3 hours The mixture was diluted with 100 ml water and extracted with ethyl acetate The combined extracts were washed with 1 NaOH, water and brine, dried over MgS0 4 , filtered and concentrated to give a solid which was recrystalized from ethyl aceate/ hexane to give a white solid (0 78 0 g) M P 106-108°C, Anal calcd for C 21 H 17 N 2 0 3 F C, 69 22, H, 4 70, N, 7 69 Found C, 68 87, H, 4 70, N, 7 55 The compound of Example 286 was prepared according to the procedure of Example 285 substituting the corresponding ketal for 2-(4-Fluoro-phenoxy)-N-[4-(2-methyl- [1 ,3]dιoxolan-2-yl)-benzyl]-nιcotιnamιde The duration of reaction was between 1 and 24 hours EXAMPLE 286 2-(4-Fluoro-phenoxy)-N-(4-oxo-cyclohexylmethyl)-nicotinamide M P 157-159°C, MS m/e 343 (MA 1 ) EXAMPLE 287 2-(4-Fluoro-phenoxy)-N-[4-(1-hydroxy-ethyl)-benzyl1-nicotinamide To a stirred solution of N-(4-Acetyl-benzyl)-2-(4-fluoro-phenoxy)-nιcotιnamιde (0 300 grams, 0 823 mmole) in methanol (10 ml) and tetrahydrofuran (10 ml) at room temperature was added sodium borohydride ( 121 grams, 3 993 mmole) and stirred for 1 hour This mixture was poured into ice water and extracted with ethyl acetate The combined organics were washed with water and brine, dried over MgS0 4 , filtered and concentrated to give a solid Recrystalization from ethyl acetate/ hexane gave a solid (0 180 g) M P 112-114°C, Anal calcd for C 21 H 17 N 2 0 3 F C, 68 84, H, 5 23, N, 7 65 Found C, 68 58, H, 5 15, N, 7 44 The compound of Example 288 was prepared according to the procedure of Example 289 substituting the corresponding ketone for N-(4-Acetyl-benzyl)-2-(4-fluoro-phenoxy)- nicotinamide The duration of reaction was between 1 and 24 hours EXAMPLE 288 2-(4-Fluoro-phenoxy)-N-(4-hydroxy-cyclohexylmethyl)-nicotinamide M P 110-112°C, MS m/e 345 (M* + 1) EXAMPLE 289 2-(3-Carbamoyl-phenoxy)-N-(2-chloro-benzyl)-nicotinamide To a stirred solution of 2-(3-Carbamoyl-phenoxy)-N-(2-chloro-benzyl)-nιcotιnιc acid (0 300 grams, 1 25 mmole), o-chlorobenzylamine (0 195 grams, 1 375 mmole), and 1- hydroxybenzot azole hydrate (0 203 grams, 1 50 mmole) in dry dimethylformamide (3 ml) was added 1-(3-dιmethylamιno)-propyl)-3-ethylcarbodιιmιde hydrochlonde (0 311 grams, 1 63 mmole) and stirred over night The mixture poured into 100 ml water and extracted with ethyl acetate The combined extracts were washed with 1 N NaOH, water and brine, dried over Na 2 S0 4 , filtered and concentrated to give a white solid that was purified by chromatography on silica gel eluting with 7% methanol/methylene chloride Recrystalization from ethyl acetate/ hexane gave a white solid (0 239 g) M P 153-155°C, Anal calcd for C 20 H 16 N 3 O 3 CI C, 62 91 , H, 4 22, N, 11 01 Found C, 62 92, H, 4 30, N, 11 09 EXAMPLE 290 2-(3-Dimethylcarbamoyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]- nicotinamide To a stirred solution of 2-(3-Dιmethylcarbamoyl-phenoxy)-N-[4-(1-hydroxy-1-methyl- ethyl)-benzyl]-nιcotιnιc acid (0 300 grams, 1 05 mmole), 2-(4-Amιnomethyl-phenyl)-propan-2- 01 (0 190 grams, 1 15 mmole), and 1-hydroxybenzotrιazole hydrate (0 155 grams, 1 15 mmole) in dry dimethylformamide (5 ml) was added 1-(3-dιmethylamtno)-propyl)-3- ethylcarbodnmide hydrochloride (0 242 grams, 1 26 mmole) and stirred over night The mixture poured into 100 ml water and extracted with ethyl acetate The combined extracts were washed with 1 N NaOH, water and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 2 5% methanol/methylene chloride (0 360 g) 1 H NMR (CDCI 3 ) d 1 54 (6 H, s), 3 00 (3 H, s), 3 08 (3 H, s), 4 66 (2 H, d), 7 20 (3 H, m), 7 29 (4 H, m), 7 43 (2 H, m) 8 08 (1 H, m), 8 18 (1 H, dd), 8 63 (1 H, dd), MS m/e 433 (M + ) EXAMPLE 291 N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(3-trifluoroacetyl-phenoxy)- nicotinamide To a stirred solution of N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-[3-(2,2,2-trιfluoro-1- hydroxy-ethyl)-phenoxy]-nιcotιnamιde (0 520 grams, 1 13 mmole), NMO (0 192 grams, 1 7 mmole) and 4 A molecular sieves (0 5 g) in methylene chloride (15 ml) was added TPAP (0 020 grams, 0 06 mmole) and stirred at room temperature for 1 hour The mixture was filtered through celite, washed with methylene chloride The filtrate was diluted with 150 ml methylene chloride, washed with water, dried over MgS0 4 , filtered and concentrated under reduced pressure to give an oil which was purified by chromatography on silica eluting with 2 5% methanol/ methylene chloride to give a foam (0 506 g) 1 H NMR (CDCI 3 ) d 1 54 (6 H, s), 4 69 (2 H, d), 7 50-7 15 (9 H, m), 8 16 (1 H, m), 8 64 (1 H, m), MS m/e 458 (M + ) EXAMPLE 292 N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl1-2-[3-(2.2.2-trifluoro-1-hydroxy-ethyl)- phenoxy] nicotinamide To a stirred solution of N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-[3-(2,2,2-trιfluoro-1- hydroxy-ethyl)-phenoxy]-nιcotιnιc acid (0 400 grams, 1 28 mmole), 2-(4-Amιnomethyl-phenyl)- propan-2-ol (0 232 grams, 1 40 mmole), and 1 -hydroxy benzotriazole hydrate (0 189 grams, 1 40 mmole) in dry dimethylformamide (5 ml) was added 1-(3-dιmethylamιno)-propyl)-3- ethylcarbodiimide hydrochlonde (0 294 grams, 1 54 mmole) and stirred over night The mixture poured into 100 ml water and extracted with ethyl acetate The combined extracts were washed with water and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 2 5% methanol/methylene chloride (0 550 g) 1 H NMR (CDCI 3 ) d 1 54 (6 H, s), 3 53 (1 H, d), 4 66 (2 H, d), 4 92 (1 H, m), 7 46-7 15 (9 H, m), 8 12 (1 H, m), 8 16 (1 H, dd) 8 62 (1 H, dd) MW 313 25 MS (m/e) 313 (M + ) EXAMPLE 293 2-(Benzo[1.3]dioxol-5-yloxy)-N-f4-(1-hydroxy-1-methyl-ethyl)-benzyl]- nicotinamide To a stirred solution 2-(Benzo[1 ,3]dιoxol-5-yloxy)-nιcotιnιc acid (0 300 grams, 1 158 mmole 2-(4-Amιnomethyl-phenyl)-propan-2-ol (0 182 grams, 1 103 mmole), and 1- hydroxybenzotnazole hydrate (0 163 grams, 1 20 mmole) in dry dimethylformamide (15 ml) was added 1-(3-dιmethylamιno)-propyl)-3-ethylcarbodιιmιde hydrochloride (0 254 grams, 1 32 mmole) and stirred over night The mixture was diluted with 200 ml water and extracted with ethyl acetate The combined organics were washed with water, 1.N sodium hydroxide and brine, dried over MgS0 4 , filtered and concentrated to give an oil that was purified by chromatography on silica eluting with 30% ethyl acetate/ hexane to give an oil Recrystalization from ethyl acetate/ hexane gave a white solid (0 323 g) M P 118-120°C, MS 407 (M + +1) EXAMPLE 294 2-(3-Carbamoyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide To a stirred solution of 2-(3-Carbamoyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)- benzyl]-nιcotιnιc acid (0 400 grams, 1 549 mmole), 2-(4-Amιnomethyl-phenyl)-propan-2-ol (0 243 grams, 1 475 mmole), and 1-hydroxybenzotrιazole hydrate (0 219 grams, 1 623 mmole) in dry dimethylformamide (15 ml) was added 1-(3-dιmethylamιno)-propyl)-3- ethylcarbodnmide hydrochlonde (0 3401 grams, 1 77 mmole) and stirred over night The mixture poured into water and extracted with ethyl acetate The combined extracts were washed with 1 .N NaOH, water and brine, dried over Na 2 S0 , filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 7% methanol/methylene chloride (0 250 g) M P 145-147°C, MS (m/e) 387 (M + -18) The compound of Example 295 was prepared according to the procedure of Example 294 substituting the corresponding amine for 2-(4-Amιnomethyl-phenyl)-propan-2-ol The duration of reaction was between 1 and 24 hours EXAMPLE 295 4-({[2-(3-Carbamoyl-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)- cyclohexanecarboxylic acid ethyl ester M P 160-162°C, MS (m/e) 426 (M + +1 ) EXAMPLE 296 2-(3-Acetyl-phenoxy)-N-(4-sulfamoyl-benzyl)-nicotinamide A solution of 4-Amιnomethyl-benzenesulfonamιde (0 248 grams, 1 11 mmole), 2-(3- Acetyl-phenoxy)-nιcotιnιc acid (0 300 grams, 1 167 mmole), 1-hydroxybenzotrιazole hydrate (0 165 grams, 1 22 mmole) and 1-(3-dιmethylamιno)-propyl)-3-ethylcarbodιιmιde hydrochlonde (0 256 grams, 1 33 mmole) in dimethylformamide (15 ml) was stirred for 10 minutes To the stirring solution was added tnethyl amine (0 280 grams, 2 78 mmole) and stirred over night at room temperature The mixture was diluted with ethyl acetate and washed with water and brine, dried over MgS0 4 , filtered and concentrated to give a solid Recrystalization from ethyl acetate/ hexane gave a solid (0 280g), M P 162-164°C, MS (m/e) 425 (M + ) EXAMPLE 297 2-(4-Fluoro-phenoxy)-N-[4-(1 -hydroxy-1 -methy l-ethyl)-cyclohex-1 -eny Imethy I]- nicotinamide A solution of 2-(4-Amιnomethyl-cyclohex-3-enyl)-propan-2-ol (0 360 grams, 2 127 mmole), 2-dιethylamιnoethyl chloride hydrochlonde (0 530 grams, 2 765 mmole), 2-(4-Fluoro- phenoxy)-nιcotιnιc acid (0 645 grams, 2 765 mmole), 1-hydroxybenzotrιazole hydrate (0 374 grams, 2 765 mmole) and tnethyl amine (0 430 grams, 4 254 mmole) in methylene chloride (40 ml) was added and stirred over night The mixture was concentrated and partitioned between ethyl acetate and 1 N HCl The organic extracts were washed with saturated sodium hydrogencarbonate and brine, dried over MgS0 4 , filtered and concentrated to give an oil which was purified by chromatography on silica eluting with 50 % ethyl acetate/ hexane to 100% ethyl acetate to give a yellow oil (0 080 g), M W 384455 , MS 385 (M + +1 ) Compounds in Examples 298-317 were synthesized in a manner analogous to that in Example 183 using the indicated carboxylic acid and amine Example 298 N-(4-(1-Hydroxy-1-methyl-ethyl-)-benzyl)-2-(3-oxo-indan-5-yloxy)-nicotinamide. Prepared from 2-(3-Oxo-ιndan-5-yloxy)-nιcotιnιc acid and 2-(4-amιnomethyl-phenyl)- propan-2-ol MS (m/e) 435 (M + +NH 3 ), 417 (M + +1), 400 (100) NMR (CDCI 3 ) 8 62 (dd, J=2,8 Hz, 1 H), 8 15 (dd, J=2,5 Hz, 1 H), 8 07 (m, 1 H), 7 32 (m, 8H), 4 67 (d, J=6 Hz, 2H), 3 13 (t, J=6 Hz, 2H), 2 72 (dt, J=2,4 Hz, 2H), 1 53 (s, 6H) Example 299 N-(4-(1-Hydroxy-1-methyl-ethyl-)-benzyl)-2-(2-methyl-benzothiazol-5-yloxy)- nicotinamide. Prepared from 2-(2-Methyl-benzothιazol-5-yloxy)-nιcotιnιc acid and 2-(4-amιno- methyl-phenyl)-propan-2-ol mp 124-6°C Anal Calcd for C 24 H 23 N 3 S0 3 C, 66 49, H, 5 35, N, 9 69 Found C, 66 34, H, 5 38, N, 9 57 Example 300 N-(4-(1-Hydroxy-1-methyl-ethyl-)-benzyl)-2-(2-methyl-benzothiazol-6-yloxy)- nicotinamide. Prepared from 2-(2-Methyl-benzothiazol-6-yloxy)-nicotinic acid and 2-(4-amino- methyl-phenyl)-propan-2-ol. mp 131-3°C. Anal. Calcd. for C 24 H 23 N 3 S0 3 : C; 66.49, H; 5.35, N; 9.69. Found: C; 66.43, H; 5.42, N; 9.72. Example 301 2-(Benzothiazol-6-yloxy)-N-(4-(1-hydroxy-1-methyl-ethyl)-benzyl)-nicotinamide. Prepared from 2-(Benzothiazol-6-yloxy)-nicotinic acid and 2-(4-aminomethyl-phenyl)- propan-2-ol. mp195-7°C. Anal. Calcd. for C 23 H 21 N 3 S0 3 : C; 65.85, H; 5.05, N; 10.02. Found: C; 68.74, H; 5.49, N; 9.96. Example 302 2-(Benzooxazol-6-yloxy)-N-(4-(1-hydroxy-1-methyl-ethyl)-benzyl)-nicotinamide. Prepared from 2-(Benzooxazol-6-yloxy)-nicotinic acid and 2-(4-aminomethyl-phenyl)- propan-2-ol. mp 92-4°C. Anal. Calcd. for C 23 H 21 N 3 0 4 : C; 68.47, H; 5.25, N;10.42. Found: C; 68.47, H; 5.32; N, 10.42. Example 303 2-(3-Acetyl-4-chloro-phenoxy)-N-(4-(1-hydroxy-1-methyl-ethyl)-benzyl)- nicotinamide. Prepared from 2-(3-Acetyl-4-chloro-phenoxy)-nicotinic acid and 2-(4-aminomethyl- phenyl)-propan-2-ol. MS (m/e): 456/458 (M + +NH 3 , 100). NMR (CDCI 3 ): 8.64 (dd, J=2,8 Hz, 1 H), 8.18 (dd, J=2,5 Hz, 1 H), 7.95 (m, 1 H), 7.46 (m, 3H), 7.31 (m, 3H), 7.19 (m, 2H), 4.68 (d, J=6 Hz, 2H), 2.66 (s, 3H), 1.56 (s, 6H). Example 304 N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-2-(3-methyl-benzo(d)isoazol-7-yloxy)- nicotinamide. Prepared from 2-(3-Methyl-benzo-(d)isoxazol-7-yloxy)-nicotinic acid and 2-(4- aminomethyl-phenyl)-propan-2-ol. mp 194-6°C. Anal. Calcd. for C 24 H 23 N 3 0 4 : C; 69.05, H; 5.55, N; 10.07. Found: C; 68.70, H; 5.64, N; 9.81. Example 305 2-(3-Acetyl-5-chloro-phenoxy)-N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)- nicotinamide. Prepared from 2-(3-Acetyl-5-chloro-phenoxy)-nιcotιnιc acid and 2-(4-amιno-methyl- phenyl)-propan-2-ol mp 110-2°C Anal Calcd for C 24 H 23 N 2 0 4 CI C, 65 68, H, 5 28, N, 6 38 Found C, 65 69, H, 5 35, N, 6 35 Example 306 (S)-(-)-2-(3-Acetyl-phenoxy)-N-(4-(1-hydroxy-ethyl)-benzyl)-nicotinamide. Prepared from 2-(3-Acetyl-phenoxy)-nιcotιnιc acid and (S)-(-)-1-(4-Amιnomethyl- cyclohexyl)-ethanol mp 102-4°C α D (CHCI 3 ) -13 8° Anal Calcd for C 23 H 22 N 2 0 4 C, 70 75, H, 5 68, N, 7 17 Found C, 70 48, H, 5 70, N, 7 12 Example 307 (R)-(+)-2-(3-Acetyl-phenoxy)-N-(4-(1 -hydroxy -ethyl)-benzyl)-nicotinamide. Prepared from 2-(3-Acetyl-phenoxy)-nιcotιnιc acid and (R)-(+)-1-(4-Amιnomethyl- cyclohexyl)-ethanol mp 104-6°C α D (CHCI 3 ) + 14 0° Anal Calcd for C 23 H 22 N 2 0 4 C, 70 75, H, 5 68, N, 7 17 Found C, 70 30, H, 5 71 , N, 7 10 Example 308 2-(3-Acetyl-5-chloro-phenoxy)-N-(frans-4-(1-hydroxy-1-methyl-ethyl)- cyciohexylmethyh-nicotinamide. Prepared from 2-(3-Acetyl-5-chloro-phenoxy)-nιcotιnιc acid and frans-2-(Amιno- methyl-cyclohexyl)-propan-2-ol mp 133-5°C Anal Calcd for C 24 H 29 N 2 0 4 CI C, 64 78, H, 6 57, N, 6 30 Found C, 64 75, H, 6 57, N, 6 17 Example 309 2-(3-Acetyl-4-chloro-phenoxy)-N-(frans-4-(1-hydroxy-1-methyl-ethyl)- cyclohexylmethyl)-nicotinamide. Prepared from 2-(3-Acetyl-4-chloro-phenoxy)-nιcotιnιc acid and .ra/ιs-2-(Amιno- methyl-cyclohexyl)-propan-2-ol mp 106-8°C Anal Calcd for C 24 H 29 N 2 0 4 Cl C, 64 78, H, 6 57, N, 6 30 Found C, 64 66, H, 6 58, N, 6 11 Example 310 (R)-(-)-2-(3-Acetyl-phenoxy)-N- trans-4-(1-hydroxy-ethyl)-cyclohexylmethyl)- nicotinamide. Prepared from 2-(3-Acetyl-phenoxy)-nιcotιnιc acid and (R)-(-)-frans-1-(4-Amιno- methyl-cyclohexyl)-ethanol mp 101-3°C α D (CHCI 3 ) - 1 5° Example 311 (S)-(+)-2-(3-Acetyl-phenoxy)-N-Ctrans-4-(1-hydroxy-ethyh-cyclohexylmethyl)- nicotinamide. Prepared from 2-(3-Acetyl-phenoxy)-nιcotιnιc acid and (S)-(+)-frans-1-(4- Amιnomethyl-cyclohexyl)-ethanol mp 103-5°C α D (CHCI 3 ) + 1 5° Example 312 2-(3-Acetyl-phenoxy)-N-(2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzyl)- nicotinamide. Prepared from 2-(3-Acetyl-phenoxy)-nιcotιnιc acid and 2-(4-Amιnomethyl-3-fluoro- phenyl)-propan-2-ol mp 68-70°C Anal Calcd for C 24 H 23 N 2 0 4 F C, 68 24, H, 5 49, N, 6 63 Found C, 67 17, H, 5 93, N, 5 97 Example 313 2-(3-Acetyl-5-chloro-phenoxy)-N-(2-chloro-4-(1-hydroxy-1-methyl-ethyl-)- benzyl)-nicotinamide. Prepared from 2-(3-Acetyl-5-chloro-phenoxy)-nιcotιnιc acid and 2-(4-Amιno-methyl-3- chloro-phenyl)-propan-2-ol mp 58-60°C Anal Calcd for C 24 H 22 N 2 0 4 CI 2 C, 60 90, H, 4 68, N, 5 92 Found C, 60 73, H, 4 79, N, 5 78 Example 314 2-(3-Acetyl-4-chloro-phenoxy)-N-(2-chloro-4-(1-hydroxy-1-methyl-ethyl-)- benzyl)-nicotinamide. Prepared from 2-(3-Acetyl-4-chloro-phenoxy)-nιcotιnιc acid and 2-(4-Amιnomethyl-3- chloro-phenyl)-propan-2-ol MS (m/e) 490/492 (M + +NH 3 , 100) NMR (CDCI 3 ) 8 60 (dd, J=2,8 Hz, 1 H), 8 31 (m, 1 H), 8 17 (dd, J=2,5 Hz, 1 H), 7 46 (m, 3H), 7 33 (m, 2H), 7 20 (m, 2H), 4 73 (d, J=6 Hz, 2H), 2 67 (s, 3H), 1 54 (s, 6H) Example 315 N-(4-(1-Hydroxy-1-methyl-ethyl)-cyclohexylmethyl)-2-(3-methyl-benzo(d)- isoxazol-5-yloxy)-nicotinamide. Prepared from 2-(3-Methyl-benzo-(d)ιsoxazol-5-yloxy)-nιcotιnιc acid and trans-2- (Amιnomethyl-cyclohexyl)-propan-2-ol mp 135-7°C Anal Calcd for C 24 H 29 N 3 0 4 C, 68 07, H, 6 90, N, 9 92 Found C, 68 07, H, 7 04, N, 9 64 Example 316 N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-2-(3-methyl-benzo(d)-isoxazol-5-yloxy)- nicotinamide. Prepared from 2-(3-Methyl-benzo-(d)ιsoxazol-5-yloxy)-nιcotιnιc acid and 2-(4- amιnomethyl-phenyl)-propan-2-ol mp 128-30°C MS (m/e) 418 (M + +1) Example 317 N-(4-(1-Hydroxy-1-methyl-ethyl)-cyclohexylmethyl)-2-(3-methyl-benzo(d)- isoxazol-7-yloxy)-nicotinamide. Prepared from 2-(3-Methyl-benzo-(d)ιsoxazol-7-yloxy)-nιcotιnιc acid and trans-2- (Amιnomethyl-cyclohexyl)-propan-2-ol mp 170-2°C Anal Calcd for C 24 H 29 N 3 0 4 C, 68 07, H, 6 90, N, 9 92 Found C, 68 04, H, 6 89, N, 9 80 Example 318 N-[4-(1-Hydroxy-1-methyl-ethyl)-cyclohexylmethyl]-2-(3-nitro-phenoxy)- nicotinamide A solution of 2-(3-nιtro-phenoxy)-nιcotιnιc acid (86 9 mg, 0 33 mmol), trans-2-(4- Amιnomethyl-cyclohexyl)-propan-2-ol (57 2 mg, 0 33 mmol), benzotrιazol-1-yloxy- trιs(dιmethylamιno)phosphonιum hexafiuorophosphate (148 mg, 0 33 mmol), and diisopropylethyl amine (0 29 mL, 1 67 mmol) in 10 mL of dry DMF was stirred overnight The solution was then diluted with ethyl acetate and washed with water, 5% citric acid, saturated sodium bicarbonate, and brine, dried over magnesium sulfate and concentrated to an oil Purified through a pad of silica eluted with ethyl acetate to give a clear oil (120mg ) 1 HNMR (CDCI 3 ) δ 1 04 (4H, dd), 1 14 (6H, s), 1 55 (2 s), 1 88 (4 m), 3 37 (2H, t), 7 23 (1 H, m), 7 51 (1 H, d), 7 64 (1H, t), 8 07 (1H, t), 8 16 (2H, m), 8 63 (1H, dd), MS m/e 414 (M + +1 ) The compounds for examples 319-328 were synthesized in a manner analagous to that in Example 318 using the indicated carboxylic acid and amine Example 319 (+)-2-(Benzo[1.3]dioxol-5-yloxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]- nicotinamide Prepared from 2-(Benzo[1 ,3]dιoxol-5-yloxy)-nιcotιnιc acid and (+)-trans-1-(4- Amιnomethyl-cyclohexyl)-ethanol 1 HNMR (CDCI 3 ) δ 0 97 (1 ,m), 1 10 (3, m), 1 17 (4, m), 1 19 (4,m), 3 23 (1 ,t), 3 44(2,q), 6 00(2,s), 6 58 (1 , dd), 6 64 (1 ,s), 6 8 (1 , d), 7 10 (1 ,m), 7 9 (1 ,m), 8 18 (1 ,m), 8 53 (1 , d), MS m/e 399 (M + +1) Example 320 (-)-2-(3-Cyano-4-fluoro-phenoxy)-N-[4-(1-hydroxy-ethyl)- cyclohexylmethyl]- nicotinamide Prepared from 2-(3-cyano-4-fluoro-phenoxy)-nιcotιnιc acid and (-)-trans-1-(4- Amιnomethyl-cyclohexyl)-ethanol MP 134-135 °C, MS m/e 398 (M + +1 ) Example 321 (+)-2-(3-Cyano-4-fluoro-phenoxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]- nicotinamide Prepared from 2-(3-Cyano-4-fluoro-phenoxy)-nιcotιnιc acid and (+)-trans-1-(4- Amιnomethyl-cyclohexyl)-ethanol MP 134-135°C, MS m/e 398 (M + +1 ) Example 322 2-(3-Cyano-4-fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)- cyclohexylmethyl]-nicotinamide Prepared from 2-(3-Cyano-4-fluoro-phenoxy)-nιcotιnιc acid and 2-trans-(4- Amιnomethyl-cyclohexyl)-propan-2-ol MP 85-88°C, MS m/e 410 (M + +1) Example 323 2-(2.3-Dihydro-benzo[1.4]dioxin-6-yloxy)-N-[4-(1-hydroxy-1-methyl-ethyl)- benzyl]-nicotinamide Prepared from 2-(2,3-Dιhydro-benzo[1 ,4]dιoxιn-6-yloxy)-nιcotιnιc acid and 2-(4- Amιnomethyl-phenyl)-propan-2-ol MS m/e 421 (M + +1 ), 1 HNMR (CDCI 3 ) δ 1 51 (6H, s), 4 24 (4H, s), 4 66(2H, d), 6 57 (1 H, dd), 6 85 (1 h, d), 7 11 (1 H, dd), 7 28(2H, d), 7 41(2H, d), 8 19(2H, m), 8 61 (1 H, d) Example 324 (+)-2-(2.3-Dihydro-benzo[1.4]dioxin-6-yloxy)-N-[4-(1-hvdroxy-ethyl)- cyclohexylmethyl]-nicotinamide Prepared from 2-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yloxy)-nicotinic acid and (+)-trans-1- (4-Aminomethyl-cyclohexyl)-ethanol. MS: m/e 413 (M + +1 ), 'HNMR (CDCI 3 ) δ 0.98(4H, m),1.11(3H, m), 1.22(2H, m), 1.70(2H, m), 1.84(2H, m), 3.33(2H, m), 3.51 (1 H, m), 4.25(4H, s), 6.65(1 H, m), 6.87(1 H, d), 7.11(1 H, m), 7.90(1 H, m), 8.20(1 H, m), 8.60(1 H, d). Example 325 2-(2.3-Dihydro-benzo[1.4]dioxin-6-yloxy)-N-[4-(1-hydroxy-1-methyl-ethyl)- cyclohexyimethyl]-nicotinamide Prepared from 2-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yloxy)-nicotinic acid and 2-trans-(4- Aminomethyl-cyclohexyl)-propan-2-ol. MS: m/e 427 (M + +1), 1 HNMR (CDCI 3 ) δ 1.03(4H, m), 1.13(6H, s), 1.85(4H, m), 3.33(2H, t), 4.26(4H, s), 6.61 (1 H, d), 6.70(1 H, s), 6.88(1 H, d), 7.11 (1 H, dd), 7.90(1 H, m), 8.20(1 H, dd), 8.58(1 H, dd) Example 326 (-)-2-(2.3-Dihydro-benzo[1.4]dioxin-6-yloxy)-N-[4-(1-hydroxy-ethyl)- cyclohexylmethyl]-nicotinamide Prepared from 2-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yloxy)-nicotinic acid and (-)-trans-l- (4-Aminomethyl-cyc!ohexyl)-ethanol. MP:57-59°C, MS: m/e 422 (M + +1) Example 327 2-(Benzo[1.3]dioxol-5-yloxy)-N-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]- nicotinamide Prepared from 2-(Benzo[1 ,3]dioxol-5-yloxy)-nicotinic acid and and 2-(4-Aminomethyl- 3-fluoro-phenyl)-propan-2-ol. MP: 94-95 °C MS: m/e: 425 (M + +1) Example 328 N-[2-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(4-fluoro-phenoxy)- nicotinamide Prepared from 2-(4-Fluoro-phenoxy)-nicotinic acid and 2-(4-Aminomethyl-3-fluoro- phenyl)-propan-2-ol. MP: 93-94 °C MS: m/e 399 (M + +1 )

Claims: CLAIMS A compound of the formula or the pharmaceutically acceptable salt thereof, wherein the broken line represents an optional double bond, o is O, 1 , 2, 3 or 4, p is 0 or 1 , q is O, 1 , 2 or 3, r is O, 1 , 2, 3, or 4, t is 0 or 1 , A is oxygen, >NH or sulfur, B is oxygen or NH, D is oxygen or NR 9 , wherein R 9 is hydrogen or (C r C 6 )alkyl, E is CH 2 , O, NH or S(0) a wherein a is 0, 1 or 2, R 1 is hydrogen, (C r C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkenyl, (C 6 -C 10 )aryl, brιdged(C 7 -Cg)bιcycloalkyl or a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocyclιc group, wherein said saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocyclιc group contains from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above, wherein said R 1 cycloalkyl, cycloalkenyl, cycloalkanone, aryl, bicycloalkyl and heterocyclic groups are optionally substituted by one to three substituents independently selected from the substituents consisting of halo, cyano, carboxy, am o, nitro, hydroxy, (C r C 6 )alkyl, (C C^alkoxy, (C 3 -C 7 )cycloalkyl, hydroxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkylamιno, (C r C 6 )alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C-,- C 6 )acylamιno, (C C 6 )acyloxy, (C r C 6 )alkylamιno, ((C 1 -C 6 )alkyl) 2 amιno, (C r C 6 )alkyl-NH-(C=0)-, ((C 1 -C 6 )alkyl) 2 -N-(C=0)-, aminosulfonyl, (C r C 6 )alkylamιnosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 ) heterocycle, wherein said saturated or unsaturated cyclic or bicyclic (C 3 - C 7 )heterocycle substituents on said R 1 cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups contain from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above, and wherein the heterocycles are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, ammo, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C r C 6 )alkoxy, (C 1 -C 6 )alkylthιo, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C 6 -C 10 )aryl, (C r C 6 )acylamιno, (C r C 6 )acyloxy, (C 1 -C 6 )alkylamιno, ((C 1 -C 6 )alkyl) 2 amιno, (C r C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylamιnosulfonyl, ((C r C 6 )alkyl) 2 amιnosulfonyl or (C 2 -C 9 )heteroaryl, wherein said alkyl, alkoxy or cycloalkyl substituents on said R 1 cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups are optionally further independently substituted by one to three sub-substituents independently selected from halo, cyano, carboxy, ammo, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkyIthιo, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C 6 - C-ιo)aryl, (C r C 6 )acylamιno, (C r C 6 )acyloxy, (C 1 -C 6 )alkylamιno, ((C r C 6 )alkyl) 2 amιno, (C C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylamιnosulfonyl, ((C 1 -C 6 )alkyl) 2 amιnosulfonyl or (C 2 - C 9 )heteroaryl, or said R 1 cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups are additionally optionally independently substituted with from one to three substituents of the formula ,10 wherein R is hydrogen, (C r C 6 )alkyI, (C C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 - C 7 )cycloalkenyl, (C 6 -C 10 )arylamιno, (C 6 -C 10 )aryl, brιdged(C 7 -C 9 )bιcycloalkyl or a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocycle, wherein said R 10 saturated or unsaturated cyclic or bicyclic (C 3 - C 7 )heterocycle contains from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above, wherein said R 10 alkyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocycle groups are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, am o, nitro, hydroxy, (C 1 -C 6 )alkyl (C r C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, hydroxy(C r C 6 )alkyl, hydroxy(C r C 6 )alkylamιno, (C r C 6 )alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C 1 -C 6 )acylamιno, (C r C 6 )acyloxy, (C r C 6 )alkylamιno, ((C r C 6 )alkyl) 2 amιno, aminosulfonyl, (C r C 6 )alkylamιnosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocycle, wherein said saturated or unsaturated cyclic or bicyclic (C 3 -C 7 ) heterocycle contains from one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above, wherein the heterocycle is optionally substituted by from one to three substituents independently selected from halo, cyano, carboxy, ammo, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkylthιo, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6 )acyl, (C 6 -C 10 )aryl, (C r C 6 )acylamιno, (C r C 6 )acyloxy, (C r C 6 )alkylamιno, (C 1 -C 6 )alkylsulfonyl, aminosulfonyl, (C C 6 )alkylamιnosulfonyl, ((C r C 6 )alkyl) 2 amιnosulfonyl or (C -C 9 )heteroaryl, wherein the alkyl, alkoxy or cycloalkyl substituents on said R 10 alkyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, ammo, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkylthιo, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C 6 -C 10 )aryl, (C r C 6 )acylamιno, (C r C 6 )acyloxy, ((C 1 -C 6 )alkyl) 2 amιno, (C 1 -C 6 )alkylsulfonyl, aminosulfonyl, (C 1 -C 6 )alkylamιnosulfonyl, ((C 1 -C 6 )alkyl) 2 amιnosulfonyl or (C 2 -C 9 )heteroaryl, or R 1 is a group of the formula wherein u is O or 1, and G, J, K and L are each independently oxygen, sulfur, nitrogen, NR 9 , wherein R 9 is as defined above, carbonyl or CHR 16 , wherein the dashed lines represent optional double bonds and where it is understood that when a double bond exists between G and J, J and K or K and L that R 9 is absent, >CHR 16 is >CR 16 and G, J, K or L cannot be carbonyl, wherein R 16 is hydrogen, halo, cyano, carboxy, ammo, nitro, hydroxy, (C 1 -C 6 )alkyl (C C 6 )aIkoxy, (C 3 -C 7 )cycloalkyl, hydroxy(C r C 6 )alkyl, hydroxy(C r C 6 )alkylamιno, (C 1 -C 6 )alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C CeJacylamino, (C r C 6 )acyloxy, (C C 6 )alkyiamιno, ((^-C^alkyl^amino, aminosulfonyl, (C 1 -C 6 )alkylamιnosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 ) heterocycle containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R is as defined above, wherein said heterocycle is optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C 6 -C 10 )aryl, (C r C 6 )acylamino, (C C 6 )acyloxy, (C C 6 )aIkylamino, ((C r C 6 )alkyl) 2 amino, (C r C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylaminosulfonyl, ((C r C 6 )alkyI) 2 aminosulfonyl or (C 2 -C 9 )heteroaryl; wherein said R 16 alkyl, alkoxy or cycloalkyl substituents are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6 )acyl, (C 6 -C 10 )aryl, (C r C 6 )acylamino, (C C 6 )acyloxy, (C r C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino, (C r C 6 )alkylsulfonyl, aminosulfonyl, (C C 6 )alkylaminosulfonyl, ((C C 6 )alkyl) 2 aminosulfonyl or (C 2 -C 9 )heteroaryl; wherein each R 2 , R 3 and R 4 is independently hydrogen, hydroxy, halo, cyano, carboxy, nitro, amino, (C r C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino, hydroxyamino, (C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, or a group of the formula wherein R 10 is as defined above; or R 2 and R 3 can be taken together with the carbon to which they are attached to form a carbonyl group or R 2 and R 3 taken together with the carbon to which they are attached form a (C 3 -C 7 )cycloalkyl ring; or when m is 1 , n is 1 , o is 1 and p is 0, A and R 2 can be taken together to form a group of the formula wherein the broken lines represent optional double bonds and q, A, B, R 1 , R 3 and R 4 are as defined above and when a double bond contains the carbon atom to which R 3 is attached then R 3 is absent; or when m is 1 , n is 1 , o is 1 and p is 0, A and R 2 are taken together and R 3 and -[R 4 ] q -R 1 are taken together to form a group of the formula R 5 is a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocyclιc group containing one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above, wherein the heterocyclic group is optionally substituted by one to three substitutents independently selected from halo, cyano, carboxy, ammo, nitro, hydroxy, (C r C 6 )alkyl (C C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, hydroxy(C r C 6 )alkyl, (C r C 6 )alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C r C 6 )acylamιno, (C r C 6 )acyloxy, (C r C 6 )alkylamιno, ((C r C 6 )alkyl) 2 amιno, (C C 6 )alkyl-NH-(C=0)-, ((C r C 6 )alkyl) 2 -N-(C=0)-, aminosulfonyl, (C r C 6 )alkylamιnosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C 3 - C 7 )heterocycle containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above, wherein the heterocycle substituent on said R 5 saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocyclιc group is optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, ammo, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkylttιιo, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6 )acyl, (C 6 -C 10 )aryl, (C r C 6 )acylamιno, (C C 6 )acyloxy, ((C 1 -C 6 )alkyl) 2 amιno, (C r C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylamιnosulfonyl, ((C r C 6 )alkyl) 2 amιnosulfonyl or (C 2 -C 9 )heteroaryl, wherein the alkyl, alkoxy or cycloalkyl substituents on said R 5 saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocyclιc group, are optionally substituted by one to three sub-substituents independently selected from halo, cyano, carboxy, am o, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C 1 -C 6 )alkoxy, (C r C 6 )alkylthιo, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C C 6 )acyl, (C 6 -C 10 )aryl, (C r C 6 )acylamιno, (C r C 6 )acyloxy, (C 1 -C 6 )alkylamιno, ((C 1 -C 6 )alkyl) 2 amιno, (C r C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylamιnosulfonyl, ((C 1 -C 6 )alkyl) 2 amιnosulfonyl or (C 2 -C 9 )heteroaryl, or said R 5 saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocyclιc group is additionally optionally substituted by a group of the formula wherein R 10 is as defined above, or R 5 is a group of the formula wherein R 11 , R 12 , R 13 , R 14 and R 15 are each substituents independently selected from the group consisitng of hydrogen, halo, cyano, carboxy, ammo, nitro, hydroxy, (C r C 6 )alkyl (C r C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, hydroxy (C r C 6 )alkyl, (C r C 6 )alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C.,-C 6 )acyl, (C r C 6 )acylamιno, (C r C 6 )alkyl- (C=0)-NH-(C=0)-, (C 6 -C 10 )aryI-(C=O)-NH-(C=O)-, (CrCβJacyloxy, (CrC^alkylammo, ((C r C 6 )alkyl) 2 amιno, (C r C 6 )alkyl-NH-(C=0)-, ((C r C 6 )alkyl) 2 -N-(C=0)-, aminosulfonyl, (C r C 6 )alkylamιnosulfonyl, ((C r C 6 )alkyl) 2 amιnosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocycle containing one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is as defined above, and wherein said heterocycle is optionally substituted by one to three substituents independently selected from the group consisting of halo, cyano, carboxy, ammo, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C r C 6 )alkoxy, (C 1 -C 6 )alkylthιo, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 6 )acyl, (C 6 -C 10 )aryl, (C 1 -C 6 )acylamιno, (C r C 6 )acyloxy, (C C 6 )alkylamιno, ((C 1 -C 6 )alkyl) 2 amιno, (C r C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylamιnosulfonyl, ((C 1 -C 6 )alkyl) 2 amιnosulfonyl or (C 2 -C 9 )heteroaryl, or R 11 , R 12 , R 13 , R 14 and R 15 are optionally independently a group of the formula wherein R > 10 , is as defined above, wherein the alkyl, alkoxy or cycloalkyl groups of said R 11 , R 12 , R 13 , R 14 and R 15 groups are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, ammo, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkylthιo, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C 6 -C 10 )aryl, (C 1 -C 6 )acylamιno, (C^C^acyloxy, (C 1 -C 6 )alkylamιno, ((C r C 6 )alkyl) 2 amιno, (C 1 -C 6 )alkylsulfonyl, aminosulfonyl, (C 1 -C 6 )alkylamιnosulfonyl, ((C r C 6 )alkyl) 2 amιnosulfonyl or (C 2 -C 9 )heteroaryl, or R 12 and R 13 can be taken together with the carbons to which they are attached to form a group of the formula wherein u, G, J, K and L are as defined above, R 6 , R 7 , and R 8 are each independently hydrogen, halo, cyano, carboxy, am o, nitro, hydroxy, (C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C r C 6 )alkoxy, (C r C 6 )alkylthιo, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C r C 6 )acyl, (C 6 -C 10 )aryl, (C r C 6 )acylamιno, (C r C 6 )acyloxy, (C r C 6 )alkylamιno, ((C r C 6 )alkyl) 2 amιno, (C r C 6 )alkylsulfonyl, aminosulfonyl, (C r C 6 )alkylamιnosulfonyl, ((C 1 -C 9 )alkyl) 2 amιnosulfonyl or (C 2 -C 9 )heteroaryl, or R 7 and R 8 may be taken together with the carbons to which they are attached to form a fused bicyclic ring of the formula wherein the dashed lines represent optional double bonds, and M, P, Q and T are each independently oxygen, nitrogen or CR 17 wherein R 17 is hydrogen or (C r C 6 )alkyl, with the proviso that when m is 1 , n is 1 , o is 1 , p is 0, q is 0, r is 0, A is oxygen, B is NH, R 2 and R 3 are hydrogen, R 1 is phenyl substituted by methyl, methoxy, chloro or fluoro, E is oxygen and R 5 is phenyl optionally substituted by one or two fluoro or chloro, then R 1 must be at least di - substituted by substituents other than methyl, methoxy or halo, with the proviso that when t is one that the compound of formula I is a zwitenonic N- oxide, with the proviso that adjacent positions defined by G, J, K and L cannot both be defined by oxygen, and with the proviso that when the broken line of formula I represents a double bond, p is 0 and R 3 is absent 2 A compound according to claim 1 , wherein m is 1 , n is 1 , o is 1 , p is 0, q is 0, r is 0, A is oxygen or nitrogen, B is NH, R 2 is hydrogen or (Ci-CβJalkyl, R 3 is hydrogen, R 1 is (C 6 - C 10 )aryl, (C 3 -C 7 )cycloalkyl or a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR , wherein R is hydrogen or (C r C 6 )alkyl, wherein the aryl, cycloalkyl and heterocyclic groups are optionally substituted by halo, (C r C 6 )alkyl, (C r C 6 )alkoxy, hydroxy(C r C 6 )alkyl, amino, (C r C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino or hydroxy(C r C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C C 6 )alkyl. 3. A compound according to claim 1 , wherein m is 0; n is 0; o is 3; p is 0; q is 0; r is 0; R 2 and R 3 are hydrogen; R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C C 6 )alkyl, (C r C 6 )alkoxy, hydroxy(C r C 6 )alkyl, amino, (C 1 -C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino or hydroxy(C r C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R 5 is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C r C 6 )alkyl. 4. A compound according to claim 1 , wherein m is 1 ; n is 0; o is 2; p is 0; q is 0; r is 0; A is oxygen; R 2 and R 3 are hydrogen; R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, amino, (C 1 -C 6 )alkylamino, ((C r C 6 ) 2 amino or hydroxy(C C 6 )alkylamino; E is oxygen and R ε is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C r C 6 )alkyl 5 A compound according to claim 1 , wherein m is 0, n is 0, 0 is 1 , p is 1 , q is 1 , r is 0, R 2 and R 3 are hydrogen, D is oxygen, R 4 is hydrogen, R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C 1 -C 6 )alkyl, (C C 6 )alkoxy, hydroxy(C r C 6 )alkyl, ammo, ((C C 6 )alkyl) 2 amιno or hydroxy(C 1 -C 6 )alkylamιno, E is oxygen and R 5 is a group of the formula or R is or a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C r C 6 )alkyl 6 A compound according to claim 1 , wherein m is 0, n is 0, o is 3, p is 0, q is 0, r is 0, R 2 is hydrogen or hydroxy, R 3 is hydrogen, R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C r C 6 )alkyl, (C C 6 )alkoxy, hydroxy(C r C 6 )alkyl, ammo, (C r C 6 )alkylamιno, ((C r C 6 )alkyl) 2 amιno or hydroxy(C r C 6 )alkylamιno, E is oxygen and R 5 is a group of the formula or R 5 is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 )heterocyclιc group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C r C 6 )alkyl 7 A compound according to claim 1 , wherein m is 1 , n is 0, o is 1 , p is 1 , q is 0, r is 0, A is oxygen, R 2 and R 3 are hydrogen, D is oxygen, R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C r C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C C 6 )alkyl, am o, (C r C 6 )alkylamιno, ((C C 6 )alkyl) 2 amιno or hydroxy(C r C 6 )alkylamιno, E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C r C 6 )alkyl 8 A compound according to claim 1 , wherein m is 1 , n is 1 , o is 1 , p is 0, q is 0, r is 0, A is oxygen, B is oxygen, R 2 and R 3 are hydrogen , R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C r C 6 )alkyl, (C r C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, ammo, (C r C 6 )alkylamιno, ((C r C 6 )alkyl) 2 amιno or hydroxy(C r C 6 )alkylamιno, E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C C 6 )alkyl 9 A compound according to claim 1 , wherein m is 1 , n is 1 , o is 0, p is 1 , q is 0, r is 0, A is oxygen, B is NH, D is NR 8 wherein R 8 is hydrogen or (C r C 6 )alkyl, R 1 is (C 6 -C 10 )aryl optionally substituted by halo, (C r C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C r C 6 )alkyl, ammo, (C r C 6 )alkylamιno, ((C r C 6 )alkyl) 2 amιno or hydroxy(C r C 6 )alkylamιno, E is oxygen and R 5 is a group of the formula or R 5 is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C r C 6 )alkyl 10 A compound according to claim 1 , wherein m is 0, n is 1 , o is 1 , p is 0, q is 1 , r is 0, B is NH, R 2 and R 3 are taken together to form a carbonyl group, R 4 is hydrogen, R 1 is (C 6 - C 10 )aryl optionally substituted by halo, (C r C 6 )alkyl, (C C 6 )alkoxy, hydroxy(C r C 6 )alkyl, ammo, (C r C 6 )alkylamιno, ((C r C 6 )alkyl) 2 amιno or hydroxy(C r C 6 )alkylamιno, E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C r C 6 )alkyl 11 A compound according to claim 1 , wherein m is 1 , n is 1 , o is 1 , p is 0, q is 0, r is 0, A and R 2 are taken together to form a group of the formula wherein A is nitrogen, B is NH, R 1 is (C r C 6 )alkyl or (C r C 10 )aryl wherein the aryl group is optionally substituted by halo, (C r C 6 )alkyl, (C r C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, ammo, (C r C 6 )alkylamιno, ((C r C 6 )alkyl) 2 amιno or hydroxy(C r C 6 )alkylamιno, E is oxygen and R 5 is a group of the formula or R 5 is a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C C 6 )alkyl 12. A compound according to claim 1 , wherein m is 0; n is 0; o is 1 ; p is 0; q is 2; r is 0; R 2 is hydrogen or hydroxy; R 3 is hydroen; R 4 is independently hydrogen or hydroxy; R 1 is (C 6 - C 10 )aryl optionally substituted by halo, (C 1 -C 6 )alkyl, (C C 6 )alkoxy, hydroxy(C r C 6 )alkyl, amino, (C r C 6 )alkylamino, ((CrCe^lkyl^amino or hydroxy(C r C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R 5 is a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C r C 6 )alkyl. 13. A compound according to claim 1 , wherein m is 1 ; n is 1 ; o is 1 , 2, 3 or 4; p is 0; q is 1, 2 or 3; r is 0; A is oxygen; B is oxygen; R 2 , R 3 , R 4 and R 1 are hydrogen; E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated cyclic or bicyclic (C 3 -C 7 )heterocyclic group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C C 6 )alkyl. 14. A compound according to claim 1 , wherein m is 1 ; n is 1 ; o is 1 ; p is 0; q is 0; r is 0; A and R 2 are taken together to form a gro )uupp of the formula wherein A is nitrogen; B is oxygen; R 1 is (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl wherein the aryl group is optionally substituted by halo, (C C 6 )alkyl, (C r C 6 )alkoxy, hydroxy(C C 6 )alkyl, amino, (C r C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino or hydroxy(C r C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 )heterocyclic group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C r C 6 )alkyl. 15. A compound according to claim 1 , wherein m is 1 ; n is 1 ; o is 1 ; p is 0; q is 0; r is 0; A and R 2 are taken together to form a group of the formula wherein A is oxygen; B is oxygen; R 1 is (C|-C 6 )alkyl or (C 6 -C 10 )aryl wherein the aryl group is optionally substituted by halo, (C r C 6 )alkyl, (C r C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, amino, (C r C 6 )alkylamino, ((C r C 6 )alkyl) 2 amino or hydroxy(C r C 6 )alkylamino; E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 )heterocyclic group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C r C 6 )alkyl. 16. A compound according to claim 1 , wherein m is 1 ; n is 0; o is 0; p is 0; q is 0; r is 0; A is oxygen; R 1 is (C 6 -C 10 )aryl or a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 ) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR 9 wherein R 9 is a hydrogen or (C CgJalkyl wherein the aryl or heterocyclic group is optionally substituted by halo, (C-|-C 6 )alkyl, (C r C 6 )alkoxy, hydroxy(C r C 6 )alkyl, ammo, (C r C 6 )alkylamιno, ((C r C 6 )alkyl) 2 amιno or hydroxy(C r C 6 )alkylamιno, E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 )heterocyclιc group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C r C 6 )alkyl 17 A compound according to claim 1 , wherein m is 1 , n is 1 , o is 0, p is 0, q is 1 , r is 0, A is oxygen, B is NH, R 4 is hydroxy (C r C 6 )alkyl, R 1 is (C r C 6 )alkyi, E is oxygen and R 5 is a group of the formula or R is a saturated or unsaturated, cyclic or bicyclic (C 3 -C 7 )heterocyclιc group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR 9 , wherein R 9 is hydrogen or (C r C 6 )alkyl 18 A compound according to claim 1 , selected from the group consisting of N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-2-(3-methyl-benzo(d)ιsoxazol-7-yloxy)- nicotinamide, N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-2-(3-oxo-ιndan-5-yloxy)-nιcotιnamιde, 2-(3-(1-Hydroxyιmιno-ethyl)-phenoxy)-N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)- nicotinamide, N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-2-(4-oxo-chroman-6-yloxy)-nιcotmamιde, (±) 2-(3-Acetyl-phenoxy)-N-(1-hydroxy-ιndan-5-ylmethyl)-nιcotιnamιde, 2-(2,3-Dιhydro-benzo(1 ,4)dιoxιn-6-yloxy)-N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)- nicotmamide, N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-2-(3-(1-methoxyιmιno-ethyl)-phenoxy)- nicotinamide, N-(2-Chloro-benzyl)-2-(4-fluoro-phenoxy)-nιcotιnamιde, N-(5-Chloro-thιophen-2-ylmethyl)-2-(pyrιdιn-3-yloxy)-nιcotmamιde, 2-(4-Fluoro-phenoxy)-N-[4-(3-hydroxy-azetιdιn-1-yl)-benzyl]-nιcotιnamιde, N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(3-nιtro-phenoxy)-nιcotιnamιde, 2-(4-Fluoro-phenoxy)-N-(2-oxo-2,3-dιhydro-1 H-ιndol-5-ylmethyl)-nιcotιnamιde, N-[2-(3-Acetyl-phenoxy)-pyrιdιn-3-yl]-2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]- acetamide, 3-{3-[4-(1-Hydroxy-1-methyl-ethyl)-benzylcarbamoyl]-pyrιdιn-2-yloxy}-benzoιc acid methyl ester, 2-(4-Fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nιcotιnamιde, 2-(4-Fluoro-phenoxy)-N-(1-thιophen-2-yl-ethyl)-nιcotιnamιde, N-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(3-cyano-phenoxy)-nιcotιnamιde, 2-(3-Cyano-4-fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nιcotιnamιde, N-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(3,4-dιfluoro-phenoxy)- nicotmamide, N-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(3-cyano-4-fluoro-phenoxy)- nicotmamide, 2-(3-Acetyl-phenoxy)-N-[2-chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nιcotιnamιde, 2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]-nιcotιnamιde, 2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nιcotιnamιde, 2-(3,4-Dιfluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nιcotιnamιde, 2-(4-Fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]-nιcotιnamιde, 2-(3-Cyano-phenoxy)-N-[4-( 1 -hydroxy-1 -methy l-ethy l)-cyclohexy Imethyl]- nicotmamide, (+)-2-(Benzo[1 ,3]dιoxol-5-yloxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]- nicotinamide, (-)-2-(3-Cyano-4-fluoro-phenoxy)-N-[4-(1-hydroxy-ethyl)- cyclohexylmethyl]- nicotmamide, (+)-2-(3-Cyano-4-fluoro-phenoxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]- nicotinamide, (+)-2-(2,3-Dιhydro-benzo[1 ,4]dιoxιn-6-yloxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]- nicotmamide, (-)-2-(2,3-Dιhydro-benzo[1 ,4]dιoxιn-6-yloxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]- nicotmamide, 2-(Benzo[1 ,3]dιoxol-5-yloxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nιcotιnamιde, 2-(Benzo[1 ,3]dioxol-5-yloxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]- nicotinamide; 2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-ethyl)- cyclohexylmethyl]-nicotinamide; and 2-(3-Cyano-4-fluoro-phenoxy)-N-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]- nicotinamide; N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(3-methoxy-phenoxy)-nicotinamide; 2-(3-Cyano-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide; N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(pyridin-3-yloxy)-nicotinamide; and 2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide. 19. A pharmaceutical composition for the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS in a mammal, including a human, comprising an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in such preventions or treatment and a pharmaceutically acceptable carrier. 20. A method for the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS in a mammal, including a human, comprising administering to said mammal an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in such treatment. 21. A pharmaceutical composition for selective inhibition of PDE4 D isozymes which regulate the activation and degranulation of human eosinophils useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS in a mammal, including a human, comprising administering to said mammal a PDE4 D isozyme inhibiting effective amount of a PDE4 D isozyme inhibiting compound or a pharmaceutically acceptable salt thereof, effective in such treatment and a pharmaceutically acceptable carrier. 22 A method for selective inhibition of PDE4 D isozymes which regulate the activation and degranulation of human eosmophils useful in the treatment of respiratory, allergic, rheumatoid, body weight regulafion, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS in a mammal, including a human, comprising administering to said mammal a PDE4 D isozyme inhibiting effective amount of a PDE4 D isozyme inhibiting compound or a pharmaceutically acceptable salt thereof, effective in such treatment

Inventors: CHAMBERS ROBERT JAMES, CHENG JOHN BIN, DUPLANTIER ALLEN JACOB, KLEINMAN EDWARD FOX, MARFAT ANTHONY, WATSON JOHN WESLEY, CHAMBERS, ROBERT, JAMES, CHENG, JOHN, BIN, DUPLANTIER, ALLEN, JACOB, KLEINMAN, EDWARD, FOX, MARFAT, ANTHONY, WATSON, JOHN, WESLEY
Applicants: CHAMBERS ROBERT JAMES, CHENG JOHN BIN, DUPLANTIER ALLEN JACOB, KLEINMAN EDWARD FOX, MARFAT ANTHONY, PFIZER PROD INC, WATSON JOHN WESLEY, CHAMBERS, ROBERT, JAMES, CHENG, JOHN, BIN, DUPLANTIER, ALLEN, JACOB, KLEINMAN, EDWARD, FOX, MARFAT, ANTHONY, PFIZER PRODUCTS INC., WATSON, JOHN, WESLEY
Application year: 1998
Main classification: C07D213
IPC codes: A61K31, A61K45, A61P1, A61P3, A61P7, A61P11, A61P17, A61P19, A61P25, A61P29, A61P31, A61P37, A61P43, C07D213, C07D401, C07D405, C07D409, C07D413, C07D417