Title of Invention	4-PHENYL-PYRIDINE DERIVATIVES
Abstract	171/CHENP/2003 4-PHENYL-PYRIDlNE DERIVATIVES" This invention relates to substituted 4-phenyl-pyridine compounds of the formula having substituents as described in the specification. The compounds of this invention show activity as antagonists of Neurokinin 1 receptors.

Full Text

4-Phenyl-pyridine derivatives The present invention relates to compounds of the general formula wherein R is hydrogen or halogen; B} is -(OC)mR^'or-(CR'=CR")mR^" wherein R is a) halogen, b) cyano, or the following groups: —(C).R' L 0 ^ , d) -C(0)NR'R", e) -C(0)6(CH2):nR^ f) -C(0)R^ g) -N(0H)-(CH2)^R^ h) -NR'C(0)-(CH2kR', i) -N[C(0)-R']2, j) -0R^ k) -(CH2)m-SR^ -(CH2)^^-S(0)R^ Or -(CH2)m-S(0)2R', 1) aryl, optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR'R", nitro, -(CH2)nOR', -C(0)NR'R", -C(0)OR' or -C(0)R', m) is a five or six membered heteroaryl group, containing one to four heteroatoms, selected firom N, O or S and maybe optionally substituted by one or more substituents, selected firom halogen, trifluoromethyl, lower alkyl, lower alkoxy. cyano, hydroxy, -NR'R", nitro, -(CH2)nOR', -C(0)OR\ -C(0)NR'R" or ^U^o JK , n) is a five or six membered saturated qrclic tertiary araine of the group which may contain one additional heteroatom, selected from N, O or S, R7R" are independently from each other hydrogen, hydroxy, lower alkyl, cydoalkyl or aryl, wherein the lower alkyl, cycloalkyl or aryl group maybe optionafly substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR'"R"", nitro, -(CH2)nOR"\ -C(0)NR"'R"", "C(0)OR"' or -C(0)R"', R'"/R"" are independentiy from each other hydrogen, lower alkyl, cydoalkyl or aryl, R^ is hydrogen, cyano, hydroxy, halogen, trifluoromethyl, -C(0)OR', -OC(0)R or aryl, optionally substituted by one or more substituents, sdected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR'R", nitro, -(CH2)nOR', ^C(0)NR'R", -C(0)OR' or "C(0)R', or is a five or six membered heteroaryl group, containing one to four heteroatoms, selected fron N, O or S and may be optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower aUcjd, lower alkoxy, cyano, hydroxy, -NR'R*', nitro, -(CH2)nOR', -C(0)NR'R", -C(0)OR' or-C(0)R', R^ is hydrogen, lower alkyl, trifluoromethyl, or aryl, wherein the lower alkyl or aryl group may be optionally substituted by one or more substituents, sdected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR'R", nitro, •C(0)NR'R", -(CH2)nOR\ -C(0)OR^ or -C(0)R\ or is a five or sbc membered heteroaryl group, containing one to four heteroatoms, selected fron N, O or S and may be optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR'R**, nitro, -(CH2)nOR', -C(0)NR^R", -C(0)OR' or "C(0)RR^ is -C(0)-(CH2)mOH or an oxo group; R^ hydrogen, lower alkyl, lower alkoxy, halogen or CF3; are independently from each other hydrogen, lower alkyl or form together with the carbon atom to which they are attached a cydoalkyl group; R'^/R^ are independently from each other hydrogen, halogen, CF3, lower alkyl or lower alkoxyi ; R and R^ or R^ and R^' may be together -CH=CH"CH=CH-, optionally substituted by one or two substituents selected from lower aDcyl, halogen or lower alkoxy^, X is -C(0)N(R^)., (CH2)pO-, -(CH2)pN(R^)-, -N(R^)C(0)- or -N(R^)-(CH2)p-; wherein R^ is hydrogen or lower alkyl; n is 1 or 2; m isO, 1,2,3 or 4; o is 1 or 2; and p is 1 or 2; and to pharmaceutically acceptable acid addition salts thereof. The compounds of formula I and their salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors. The neuropeptide receptor for substance P (NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a nimiber of diverse biological processes. The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson's disease (Neurosd. Res,, 1996,7,187-214), anxiety (Can. J, Phys., 1997,75,612-621) and depression (Science, 1998,281,1640-1645). Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn's disease, ocular injury and ocular inflammatory diseases reviewed in "Tachykinin Receptor and Tachykinin Receptor Antagonists'*, J. Auton. Pharmacol, 13,23-93,1993. ; Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been impHcated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798). The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting. In addition, in The New En^and Journal of Medicine, Vol. 340, No. 3 190-195,1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. Furthermore, US 5,972,938 describes a method for treating a psychoimmtmologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist. The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in "Neuropeptides, 32(1), 1-49, (1998)" and "Eur. J. Pharmacol., 383(3), 297-303, (1999)". The compounds of formula I can also be used in form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like. The prodrugs may add to the value of the present compounds advantages in adsorption, pharmacokinetics in distribution and transport to the brain. Objects of the present invention are the compounds of formula I and pharma-ceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments. As used herein, the term 'lower alkyl" denotes a saturated straight- or branched-chain alkyl group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms. The term "cydoalkyr denotes a saturated carbocydic group, containing 3-6 carbon atoms. ; The term "halogen" denotes chlorine, iodine, fluorine and bromine. The term 'lower alkoxy" denotes a group wherein the allcyl residue is as defined above, and which is attached via an oxygen atom. The term "five or six membered heteroaryl group, containing one to four heteroatoms, selected firom N, O or S' denotes, for example, the following groups: pyrrol-1-yl, imidazol-1 or 2-yl, pyrazol-l-yl, pyridin-2,3 or 4-yl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl, thienyl, l,2,3-tria2olyl, 1,2,4-oxadiazolyl, tetrahydro-pyridinyl, isoxazolyl or fiiryi. The term "five or six membered saturated cyclic tertiary amine" denotes, for example, pyrroUdinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyi, morpholinyl, thiomorpholinyl, thiomorpholin-l,l-dioxo or thiomorpholin-1-oxo. The term "aryl" denotes a monocycHc aromatic hydrocarbon radical or a bicyclic or tricyclic ring system in which at least one ring is aromatic, preferred are phenyl, benzyl or naphthyl rings. The term "pharmaceutically acceptable acid addition salts" embraces salts with inorganic and organic adds, such as hydrochloric add, nitric acid, sulfuric add, phosphoric add, dtric acid, formic add, fumaric acid, maleic add, acetic add, succinic add, tartaric add, methane-sulfonic acid, p-toluenesulfonic add and the like. The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders or emesis by the administration of NK-1 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities. Preferred are compounds of formula I, in which X is "C(0)N(CH3)" and '-(R'*)n is 3,5-di-CF3, Exemplary preferred compounds of this group are those, wherein R /R are *\ both hydrogen and R is methyl, for example the following compoxmds: N-(3,5-bis-trifluoromethyI-benzyl)-6-(4-hydroxyacetyl-pipera2in-l-yl)-N-methyI-4-o-tolyl-nicotinamide, N-(3,5-bis-trifiuoromethyl-benzyl)"6-chloro-N"methyl-4-o-tolyl"nicotinamide, N*(3,5-bis-trifluoromethyl-benzyl)-6-cyanomethyl-N"methyl-4-o-tolyl-nicotinamide, N-(3,5"bis-1xifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyi-nico1inamide, 4-o-tolyl-[2,4']bipyridinyl-5-carboxyHcadd(3,5-bis-1xifluoromethyl-be amide, 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridine-2-carboxyH^ add methyl ester, N-(3,5-bis-trifluoromethyl-benzyl)-6-hydroxymethyl-N-methyl-4-o-tolyl-iiicotinam 6-(5-acetyl-thiophen-2-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl"4-o-tolyl- nicotinamide, 4-o-tolyl-1^2^3^6'-t€trahydro-[2,4']bipyTidiny^5-ca^boxyiicadd(3>5-bis-trifluoromethyl-benzyl)-methyl-amide, N- (3,5-bis-trifluoromethyl"benzyl) -6- (4-hydroxymethyl-phenyl)-N-methyl-4-o-tolyl- nicotinamide, 2^-methyl-4-o-tolyl-[2,4*]bipyridinyl-5-carbox7Hcadd(3,5-bis-trifluoromethyl-benzj^ methyl-amide, N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl"6-(3-methyl-[l,2,4]oxadiazol-5"yl)-4-o- tolyl-nicotinamide, 6-(3-amino-prop-l-ynyl)-N-(3,5-bis-trifluoromethyl-ben2yl)-N-methyl-4-o-tolyl- nicotinamide, (RS)-N-(3,5-bis-trifluoromethyl-benzyl)-6-(2-hydroxy-ethanesulfinylmethyl)-N-met^^ 4'O-tolyl-nicotinamide, N-(3,5-bis-trifluoromethyl-ben2yl)-N-methyl-6-(l-methyl-lH-imidazol-2' ylsulfanylmethyl) "4-o-tolyl-nicotinamide, (RS)"N"(3,5-bis--trifluoromethyl-benzyl)-N-methyl-6-(pyridine-2-siilfinyl)"4-o-tolyl- nicotinamide, N"(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(pyridine"2-sulfonyl)-4-o-tolyl- nicotinamide or N-(3,5-bis-trifluoromethyl-benzyl)-6-(3-hydroxy-propoxy)-N-methyl-4-o-tolyl- nicotinamide. Further preferred are compounds of formula I, in which X is —N{CH3)C(0)-and -(R^)ri is 3,5-di-CF3. Exemparly preferred compounds of this group are those, wherein are both methyl and R^ is methyl, for example the following compoimds: 2-(3,5-bis-trifluoromethyl-phenyl)-N-{6'[hydroxy-(2-hydroxy"ethyl)-araino]-4-o-tolyl-pyridin-3-yl}-N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(3-oxo-morpholin-4-yl)"4-o-tolyl-pyridin-3-yl] -isobutyramide. cetic acid (5-{ [2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl"propionyl]-methyl-ainino}" "0"tolyl-pyridin-2-ylcarbamoyl)-methyl ester, -(3,5-bis-trifluorometiiyl-phenyl)-N-[6-(2-hydroxy-acetylainino)-4-o-tolyl-p 1] -N-methyl-isobutyramide, ,-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(hydroxyacetyl-methyl-aiiiino)-4-o-tol^^^ >yridin-3-yl] -N-methyl-isobutyramide, :-(3,5-bis-trifluorometiiyl-phenyl)-N-[6-(2,5-dioxo-pyrroUdin-l"yl)-4-o-tolyl^^ 1] -N-methyl-isobutyramide, yclopropanecarboxylic acid (5-{ [2-(3,5-bis-tri£luoromethyl-phenyl)-2-methyl- )ropionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-cydopropanecarbonyl-amide, i-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl- sobutyramide, ^(3,5-biS"trifluorometbyl-phenyl)-N-[4-(2-cUoro-phenyl)-2'"methyl-[2,4']bipyridiny^^ fl] -N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-ethynyl-4-o-tolyl-pyridin"3-yl)-N-methyl- Lsobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxjnmethyl4soxazol-5-yl)-4-0"tolyl- pyridin-3-}d] -N-methyl-isobutyramide, 1-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-prop-l-ynyl)"4"0-tolyl-pyridin-3- ^]-N-methyl-isobutyramide or ;RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-methoxy-benzen€sulfinyl)-4-o-tolyl- pyridin-3-yll -N-methyl-isobutyramide. Preferred compounds of this group are further those, wherein R /R are both methyl and R is chloro, for example the following compounds: 2-(3,5-bis-trifluoromethyl-phenyl)-N-{4-(2-chloro-phenyl)-6-[hydroxy-(2-hydroxy-ethyl)-amino]-pyridin-3-yl}-N-methyl-isobutyramideor 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-oxo-morpholin-4-yl)-pyridin-3-yl] -N-methyl-isobutyramide, The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises a) reacting a compound of formula wherein the substituents are described above-In accordance with process variant a) DIPEA (N-ethyldiisopropyl-amine) is added to a mixture of a compound of formula II and of a compound of formula III in dichloromethane and the mixture is stirred at temperatures between 25-40°C. The desired compound of formula la is isolated after purification in good yields. Process variant b) describes the reaction of a compound of formula TV with a compound of formula V to a compoimd of formula lb. The reaction is carried out in conventional manner, for example in a solvent, such as a mixture of toluene and triethyi-amine. The mixture is refluxed for about 1 hour. In accordance with process variant c) a compound of formula lb is reduced to a compound of formula Ic. This reaction is carried out with a reducing agent, such as LiAlH^ or BHs^THF, in conventional manner. Process variant d) describes the reaction of a compound of formula VI with a compound of formula VII to a compound of formula lb. This reaction is carried out by deprotonation of a compound of formula VI with KHMDS (potassium hexamethyldisilazide) and subsequent addition of a compound of formula VII. A suitable solvent is tetrahydrofiiran. The reaction is carried out at room temperature. In accordance with process variant e) a compoimd of formula Id is prepared. This reaction is carried out by deprotonation of a compound of formula VIII with NaH and susequent addition of a compoimd of formula VTI. This reaction is carried out in conventional manner. A further method for the preparation of a compound of formula I is described in process variant f). A compound of formula la is reduced to a compound of formula le in conventional manner, for example with LiAlH4 or BHs^THF. The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic adds, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methan-sulphonates, p-toluenesulphonates and the like are examples of such salts. The following schemes 1-18 describe the processes for preparation of compounds of formula I in more detail. These reactions are carried out in conventional manner under conditions, described in the following schemes. The starting materials are known compounds or maybe prepared according to methods known in the art In the schemes the following abbreviations have been used: r . PivCl pivaloyi chloride THF tetrahydrofuran ' TMEDA N,N,N',N'-tetramethylethylene diamine DIPEA N-ethyldiisopropyl-amine KHMDS potassium hexamethyldisilazide LDA lithium diisopropylamide DPPA diphenylphosphoryl azide EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride MCPBA m-chloroperbenzoic acid Z = CI, Br, 1 or OS(0)2CgH4CH3 or OS(0:^CH3 The substituents are described above. The substituents have the significances given above. As mentioned earlier, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1> substance P) receptor. The compounds were investigated in accordance with the tests given hereinafter. The affinity of test compounds for the NKi receptor was evaluated at human NKi receptors in CHO cells infected with the human NKi receptor (using the Semliki virus expression system) and radiolabelled with [^H] substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04 %) leupeptin (8 fxg / ml), MnCl2 (3mM) and phosphoramidon (2 ^M). Binding assays consisted of 250 yl of membrane suspension (1.25x10^ cells I assay tube), 0,125 \£L of buffer of displacing agent and 125 pi of [^Hjsubstance P. Displacement curves were determined "with at least seven concentrations of the compound. The assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered tmder vacuum through GF/C filters presoaked for 60 min with PEI (0.3 %) with 2 x 2 ml washes of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in tripKcate in at least 2 separate experiments. The af&nity to the NK-1 receptor for preferred compounds, given as pKi, is in the scope oi%30 - 9.50 for the described coxxxpoxm^. The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions. The compounds of foraiula I and their pharmaceutically usable add addition salts can be processed with phannaceutically inert, inorganic or organic excipients for the production oftablets, coated tablets, dragees and hard gelatine capsules. Lactose, com starch or derivatives thereof, talc, stearic acid or its salts etc can he used as such excipients e.g. for tablets, dragees and hard gelatine capsules. Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc. Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc. Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc. Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc. Moreover, the pharmaceutical preparations can contain preservatives, solubiKzers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buifers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary. The following Examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius. Compounds of examples 39,54,65,81, 83,92, 108,109,117 and 118 are out of the scope of the present formula I. Example 1 N"(3,5-Bis-trifluoromethyl-benzyl)-6-(4-hydroxyacetyl-pipera2in-l-yl)-N-methyl-4-0" tolyl-nicotinaraide a) 6-ChlorO"N-methyl-nicotinamide To 50 g (317 mmol) of 2-chloronicotinic acid was added 230 ml (3.16 mol) thionyl chloride at 0 °C. After heating the mixture at reflux for 2h excess thionyl chloride was removed by distillation. The oily brown residue was dissolved in 250 ml dichloromethane. The solution was treated with methylamine gas at 0 °C until no exothermic reaction was observed any longer. The resulting suspension was diluted with 1000 ml dichloromethane/water. The layers were separated and the aqueous layer extracted with three 300 ml portions of dichloromethane. Drying of the organic layer with sodium sulfate and concentration gave 53.2 g (98 %) of the title compound as a light yellow solid. MS m/e (%): 171 (M+H^ 15). b) 6-ChIoro-N-methvI-4"0-tolv]-nicotinamide To a solution of 3.41 g (20.0 mmol) 6-chloro-N-methyl-nicotinamide in 80 ml tetrahydrofuran 50 ml (50 mmol) of a 1 M solution of o-tolyl magnesium chloride in tetrahydrofuran was added dropwise at 0 °C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred for 1.5 L The mixture was again cooled to 0 ®C> followed by the dropwise addition of 5.7 ml (100 mmol) acetic add and a solution of 5.1 g (22 mmol) 2,3-dichloro-5,6-dicyano-l,4"ben2oquinone in 18 ml tetrahydrofuran. After completed addition the reaction mixture was allowed to warm to room temperature and stirred for 15 min. Addition of 30 ml 2 N aqueous sodium hydroxide solution was followed by dilution with 11 ethyl acetate and 200 ml water. The layers were separated and the organic washed with 4 250-ml portions of 2 N aqueous sodium hydroxide solution. The combined aqueous layers were extracted with 3 500-ml portions of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution and dried with sodium sulfate. Concentration gave 5.44 g of a brown-red oil. Hash colunrn chromatography afforded 2,15 g (41.3 %) of the title compound as a light yellow solid. MS m/e (%): 260 (M'^> 11). M.p. 91 - 93X. c) 4-f5-Methvlcarbamoyl'4-Q-tolvI-pvridin"2-yl)"piperazine-l-carboxylic acid tert-butvl ester A mixture of 8.31 g (31.9 mmol) 6-chloro-N-methyl-4-o-tolyl"nicotinamide, 6.53 g (35.0 mmol) l-tert-butoxycarbonylpiperazine, 16.7 ml (95.6 mmol) N-ethyldiisopropylamine and a catalytic amount of 4-(N,N-dimethylamino)-pyridine was heated at reflux over night. After cooling to room temperature the mixture was dissolved in dichloromethane and washed with two portions of 0.1 M aqueous hydrochloric acid solution. Drying with sodixim sulfate and concentration gave 10.7 g of the crude product Flash column chromatography afforded 6.28 g (48.0 %) of the title compound as an off-white solid- MS m/e (%): 411 (M+H% 100). d) 4-^5-f(3.5-Bis-trifluoromethvl-benzvD-methvl"Carbamovn-4-o-tolvl-pvridin-2'Vn- piperazine-l-carboxvlic acid tert-butvl ester To a solution of 6.28 g (15.3 mmol) 4-(5-methylcarbamoyl"4-o-tolyl-pyridin-2"yl)-piperazine-1-carboxylic acid tert-butyl ester in 250 ml tetrahydrofuran 20 ml of a 1 M solution (20 mmol) of potassium hexamethyldisilazide in tetrahydrofuran were added at 0 °C. After 30 min> 2-81 ml (15.3 mmol) 3,5-bis(trifluoromethyl)ben2yl bromide were added dropwise. The reaction mixture was allowed to warm to room temperatxire over night. Addition of water and 1 M aqueous sodium hydroxide solution was followed by extraction with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated Flash column chromatography gave 6.89 g (70.8 %) of the title compound as a white solid. MS m/e (%): 637 (M+H"", 100). e) N-f3.5-Bis-trifluoromethvI-ben2yl)-N*methvl-6'-pipera2in-l-yl*4-o-tolvl-nicotinamide To a solution of 6.60 g (104 mmol) 4-{5-[(3,5"bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-0"tolyl-pyridin-2-yl}-piperazine-l-carboxyHc acid tert-butyl ester and 8.40 ml (207 mmol) methanol in 50 ml ethyl acetate 14.7 ml (207 mmol) acetyl chloride were added dropwise at 0 ^'C. After 4h the reaction mixture was diluted with ethyl acetate and treated with 1 M sodium hydroxide solution. The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated to give 5.36 g of crude product Flash colxmin chromatography afforded 4.86 g (87.4 %) of the title compound as a light brown solid. MS m/e (%): 537 (M-^H^ 100). f) N-(3>5-BiS"trifluoromethvl-benzvl)-6"f4-bromoacetvl-piperazin"l-vlVN--methvl-4"0- tolyl-nicotinamide To a solution of 0.30 g (0.56 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl"6-piperazin-l-yl-4-o-tolyl-nicotinamide in 4 ml dichloromethane 0.055 ml (0.62 mmol) bromoacetyl bromide and 4 ml of a 2M aqueous sodium carbonate solution were consecutively added dropwise at 10 °C. After 2h the reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was dried with sodium sulfate and concentrated to give 0.36 g of crude product Flash column chromatography afiforded 0.26 g (69 %) of the title compound as a white soUd. MS m/e (%): 657 (M+H% 100,1 Br). glN-(3,5"Bis-trifluoromethvl-benzvlV6-(4-hvdroxvacetyl-piperazin-l-vl)-N-methvl-4-^ tolyl-nicotinamide A mixture of 0.12 g (0.18 namol) N-(3,5-bis-trifluoromethyl-benzyl)-6-(4-bromoacetyl-pipera2in"l-yl)-N-methyl-4-o-tolyl-nicotinamide, 1.2 ml l-methyl-2-pyrrolidone and 0.2 ml half-saturated aqueous sodixim bicarbonate solution was stirred at 100 °C over night After cooling to room temperature and dilution with water the noixture was extracted with five portions of tert-butyl methyl ether. The combined organic extracts were dried with sodium sulfate, concentrated and dried in vacuo (0.5 mbar) at 70 °. Flash column chromatography afforded 71 mg (64 %) of the title compound as a white solid. MS m/e (%): 595 (M+H^ 100). Example 2 N-(3,5-Bis-trifluoromethyl-benzyl)"6-chloro-N-methyl-4-o-tolyl-nicotinaniide To a solution of 10.0 g (38.4 nunol) 6-chloro-N-methyl-4-o-tolyi-nicotinamide in 190 ml tetrahydrofiiran 46 ml of a 1 M solution (46 mmol) of potassium hexamethyldisilazide in tetrahydrofiiran were added at 0 °C. After 30 min, 8.5 nd (46 monol) 3,5-bis(trifluoromethyl)benzyl bromide were added dropwise to the resulting suspension. After completed addition the ice-water cooling bath was removed and the reaction mixture was allowed to warm to room temperature. After 2h the reaction was quenched with water. The mixture was adjusted to pH 3 with 1 M aqueous hydrochloric add solution and stirred for 10 min. Basification with 1M aqueous sodium hydroxide solution to pH 8 was followed by concentration to remove tetrahydrofiiran. The aqueous residue was extracted with four portions of dichloromethane. The combined organic extracts were dried with sodium sulfate and concentrated to give 21.4 g of crude product. Column chromatography afforded 18.4 g (98.5 %) of the title compound as a white soUd. MS m/e (%): 485 ([M-H]^ 2). Example 3 N"(3,5-Bis-trifluoromethyl-benzyl)-6-cyanomethyl-N-methyl-4-o-tolyl-nicotinamide a) fRS)-l5"ff3,5-Bis-trifluorometfavI"benzvl)-methyI-carbamovn-4-o-tolvl-pyridin-2-vU-cvano-acetic acid ethyl ester A mixture of 1.00 g (2.05 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chIoro-N-methyl-4-o-tolyl-nicotinamide, 0.44 ml (4.1 mmol) ethyl cyanoacetate and 0.46 g (4.1 namol) potassiimi tert-butoxide in 2 ml dimethyl sulfoxide was stirred at 100 °C over night. After cooling to room temperature 10 ml of a half-concentrated aqueous solution of ammonium chloride was added. The mixture was extracted with 3 portions of ethyl acetate. The combined organic extracts were washed with two portions of water, dried with sodium sulfate and concentrated to give 1.2 g of crude product. Flash chromatography afforded 0.681 g (58.8 %) of the title compound as a yellow foam. MS m/e (%): 563 (M^ 80). b) N-(3.5-Bis-trifluoromethvl-benzvl)-6-cyanomethvl-N-methvl-4-o-tolvl-nicotinamide A mixture of 650 mg (1.15 mmol) (RS)-{5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o--tolyl-pyridin-2-yl}-cyano-acetic add ethyl ester and 0.20 g (4.6 mtmol) lithium chloride in wet dimethyl sulfoxide was stirred at 120 °C over night After cooling the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The layers were separated and the aqueous layer was extracted with two portions of ethyl acetate. The combined organic extracts were washed with two portions of water, dried with magnesiima sulfate and concentrated to give 595 mg of crude product Flash chromatography afforded 396 mg (69.9 %) of the title compoimd as a white solid. MS m/e (%): 492 (M-^-H^ 100). Example 4 N-(3,5-Bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide To a solution of 1.00 g (2.05 mmol) N-(3,5-bis-trifluoromethyl-ben2yl)-6"Chloro-N-methyl-4-o-tolyl-nicotinamide in 10 ml 2-butanone 1.1 g (7.2 mmol) sodium iodide and 0.28 ml (2.1 mmol) hydroiodic acid (57 % in water) were added at room temperature. The mixture was heated at 80 °C for 2 h. After cooKng to room temperature the mixture was diluted with ethyl acetate and treated with saturated aqueous sodium bicarbonate solution. The layers were separated, the organic layer washed with water, dried with magnesium sulfate and concentrated to give 1,5 g of crude product. Flash column chromatography gave 1-11 g (93.6 %) of the title compound as a yellow oil. MS m/e (%): 579 (M+H"", 100). 4-o-Tolyl-[2,4']bipyridinyl-5-carboxylic acid (3,5-bis-trifluoromethyl-benz7l)-meth7l-amide A mixture of 100 m§ (0,173 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide, 21 mg (0,17 mmol) 4-pyridylboronic acid, 5 ml dimethoxyethane and 5 ml of a 2 M aqueous solution of sodium carbonate was deoxygenated by three fireeze-thaw cycles- After addition of 20 mg (0.017 nunol) tetrakis(triphenylphosphine)paUadium(0) the reaction mixture was stirred at 90 **C for 60 h. Cooling to room temperature was followed by dilution with water and extraction with 3 portions of ethyl acetate. The organic extract was washed with water, dried with magnesium sulfate and concentrated. Column chromatography afforded 59 mg (64 %) of the tide compound as a yellow solid. MS m/e (%):530 (M+H^ 100). Example 6 5-[(3,5-Bis-trifluoromethyl-berizyl)-methyl-carbamoyl]-4-o-tolyl-pyridine-2-carboxylic acid methyl ester A solution of 690 mg (1.19 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide, 0.33 ml (2.4 mmol) triethylamine and 1,9 ml (48 mmol) methanol in 10 ml N,N-dimethylformamide was deoxygenated by three freeze-thaw cycles. Filling the flask with carbon monoxide gas from a balloon was followed by addition of 31 mg (0.12 mmol) triphenylphosphine and 23 mg (0.102 mmol) palladium(II) acetate. The reaction mixture was stirred for 60 h under an atmosphere of carbon monoxide gas at room temperature. The mixture was diluted with water and extracted with 3 portions of tert-butyl methyl ether. The combined organic extracts were washed with water, dried with sodium sulfate and concentrated. Flash chromatography afforded 407 mg (66.8 %) of the title compound as a light-yellow solid. MS m/e (%): 511 (M+H% 100). Example 7 N-(3,5-Bis-trifluoromethyl-benzyl)-6"hydroxymethyl-N-methyl-4-o-tolyl-nicotinamide To a solution of 9 mg (4 mmol) Uthium borohydride in 0.5 ml diethyl ether was added a solution of 346 mg (0,678 mmol) 5-[(3,5*bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridine-2-carboxylic acid methyl ester in 0.6 ml toluene. The mixture was gradually heated to 100 ^'C, whereby diethyl ether was distilled off. After heating for 2h at 100 °C the resulting suspension was concentrated. The residue was treated with 5 ml of a 1 M aqueous solution of hydrochloric acid for 5 min. Basification with potassium carbonate was followed by extraction with tert-butyi methyl ether. The combined organic extracts were dried with sodium sulfate and concentrated. Flash chromatography afforded 240 mg (73.4 %) of the title compound as a Hght brown oil. MS m/e (%): 481 (M-H\ 6). Example 8 2-(3,5-Bis-trifluoromethyl-phenyl)-N"{6-[hydroxy-(2-hydroxy-ethyl)-amino]-4-o-tolyl- pyridin-3-yl}-N-methyl-isobutyramide a) 4-(5-Nitro-2-pvridvlVmorpholine To a solution of 20 g (126 mmol) of 2-chloro-5-nitropyridine in 150 ml tetrahydrofuran were added dropwise 27 ml (315 mmol) morpholine within 10 min. The reaction mixture was refluxed for additional 2 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was re-dissolved in 200 ml ethyl acetate. The organic phase was washed with 200 ml 1 N sodium bicarbonate solution, dried (magnesium sulfate) and evaporated to give 27.3 g (quantitative) of the title compound as a yellow solid, M.p. 142-143 °C. b) 2.2-Dimethvl-N-f6-morpholin-4-yl-pvridin-3'-vlVpropionamide To a solution of 27.3 g (126 mmol) of4-(5-nitro-2-pyridyl)-morpholinein 600 ml methanol were added 2.5 g of 10 % of palladium on activated charcoal. The reaction mixture was hydrogenated (room temperature to ca. 45 ®C> 1 bar) until the theoretical amount of hydrogen was taken up (about 3 h). The catalyst was filtered off and was washed twice with 100 ml portions of methanol. The filtrate was evaporated in vacuo to give 22.6 g of a purple oil which consisted to ca. 95 % of the desired aniline derivative according to analysis by thin layer chromatography. This crude product was dissolved in a mixture of 240 ml tetrahydrofuran and 60 ml diethyl ether. After cooling to 0 °C, 26 ml (189 nmiol) of triethylamine were added in one portion. Stirring was continued while 23 g (189 mmol) of pivaloyl chloride were added dropwise within a period of 10 min. The ice bath was removed and the reaction mixture was stirred for 1 h at room temperature. Then, the solvent was removed in vacuo and the residue was suspended in 200 ml 1N soditun bicarbonate solution. The product was extracted three times with 200 ml portions of dichloromethane, dried (sodiima sulfate) and evaporated. iecrystallization of the solid residue from ethyl acetate/hexane 1:8 gave 28.6 g (86 %) of iie title compound as white crystals. MS m/e (%): 264 (M+H^, 100). :)N-(4-Iodo-6-morpholin-4-yl-pvridin-3-ylV2.2-dimethyl-propionamide \ solution of 28.4 g (108 mmol) 2,2"dimethyl-N-(6-morpholin-4-yl-pyridin-3-yl)-propionamide and 49 ml (324 nmiol) N,N,N',N*-tetramethylethylenediamine under argon in 600 ml tetrahydrofuran was cooled in a dry ice bath to -78 °C. Within 1 h, 202 ml (324 mmol) of a 1.6 N n-butyUithium solution in hexane were added dropwise. The reaction mixture was allowed to warm up to -35 °C overnight After cooling again to -78 °C, 37 g (146 mmol) iodine dissolved in 60 ml tetrahydroftiran were added dropwise during 15 min. The dry ice bath was replaced by an ice bath and a solution of 90 g (363 mmol) sodium thiosulfate pentahydrate in 250 ml water were added within 10 min when the temperature of the reaction mixture had reached 0 °C. Then, 1000 ml diethyl ether were added and the organic layer was separated. The aqueous layer was extracted twice with 500 mi dichloromethane and the combined organic layers were dried (magnesium sulfate) and evaporated. Flash chromatography gave 15.6 g (37 %) of the title compound as a light brown oil which crystallized upon standing at room temperature. MS m/e (%): 389 (M^, 71), 358 (25), 304 (43), 57 (100). d')2.2-Dimethyl-N-(6-morpholin-4-vl-4*Q-tolvl-pvridin-3-vl)-propionamide A mixture of 3.50 g (9.0 mmol) N-(4-iodo-6-morpholin-4-yl"pyridin-3-yl)-2,2-dimethyl-propionamide, 35 ml toluene, 18 ml 2 N sodium carbonate solution, 312 mg (0.27 mmol) tetrakis(triphenylphosphine)palladium(0) and 1.34 g {9S mmol) o-tolylboronic acid was heated under argon at 80 °C for 12 h. After cooling to room temperature, the aqueous phase was separated and washed twice with ethyl acetate. The combined organic layers were washed with 50 ml brine, dried (soditmi sulfate) and evaporated. PuriJBcation by flash-chromatography gave 3.23 g (quantitative) of the title compoxmd as a white foam. MS m/e (%): 354 (M+lT, 100). e) 6-MorphoIin-4-yl-4-o-tolvl-pvridin'3-vlamine A suspension of 2,93 g (8.28 mmol) 2,2-dimethyl-N-(6-morpholin-4-yl-4-o-tolyl"pyridin-3-yl)-propionamide in 80 ml 3 N hydrochloric acid solution and 5 ml 1-propanol was heated to 90-95 **C overnight. The reaction mixture was cooled to room temperature, washed with three 20 ml portions diethyl ether and filtered over celite. The filtrate was diluted with 20 ml water and was adjusted to pH 7-8 by addition of 28 % sodium hydroxide solution under ice cooling. The product was extracted with four 100 ml portions of dichloromefhane. The combined organic layers were washed with 50 ml brine, dried (magnesium sulfate) and evaporated to give 2.31 g (quantitative) of the title compound as a white foam. MS m/e (%): 269 (M^ 100). f)Methyl-(6-mQrpholin-4-vI-4-0"tolvl-pyridin"3-yl)-amine A solution of 2.24 g (8.3 mmol) 6-morphoIin-4-yl-4-o-toIyl-pyridin-3-ylamine in 17 ml trimethyl orthoformate and 3 drops trifluoroacetic acid was heated for 2 h at 130 °C. The reaction mixtiu-e was evaporated and dried in vacuo for 30 min. The residual oil was dissolved in 5 ml tetrahydrofuran and was added dropwise under ice cooling to 630 mg (16.6 nunol) lithium aluminum hydride in 20 ml tetrahydrofuran. The reaction mixture was stirred for 1 h at room temperature, cooled to 0 °C again and acidified (pH 1-2) by addition of 28 % hydrochloric add solution. After stirring for 5 min, 28 % sodium hydroxide solution was added to reach pH 10, The solution was filtered over celite, evaporated and purified by flash chromatography to give 1.56 g (66 %) of the title compoimd as a white foam. MS m/e (%): 283 (M^ 100). g) 2-(3.5-Bis-trifluoromethyl-phenylVN-methvl-N-(6"morpholin-4-yl-4-o-tolvl-pvridin-3 -vl) -isobutvramide A solution of 1.46 g (5.15 mmol) methyl-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-amine and L32 ml (7.73 mmol) N-ethyldiisopropylamine in 15 ml dichloromethane was cooled in an ice bath and 1.8 g (5.67 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride were added dropwise. The reaction mixture was warmed to 35-40 ^C for 3 h, cooled to room temperature again and was stirred with 25 ml saturated sodixma bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 2.9 g (quantitative) of the title compound as white crystals. M.p. 131-132 ^'C. h)2-(3.5-Bis-trifluoromethvl-phenyl)-N"f6-f2-hvdroxv-ethvlamino)-4-o-tolyl-pvridin-3-yll -N-methvl-isobutvramide A mixture of 1.0 g (1.76 mmol) 2-(3,5-biS"trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, 100 mg (0.48 mmol) ruthenimn(in)chloride hydrate, 832 mg (3.87 mmol) sodium periodate, 3.5 ml carbon tetrachloride, 3.5 ml acetonitrile and 5.3 ml water was stirred for 4 days at room temperature. Dichloromethane was added, the organic layer was separated, washed with sodium hydrogensulfite solution and filtered over celite. To the filtrate were added 10 ml 1 N potassium hydroxide solution and 20 ml methanol After heating the rmxture for 1 h at 40 ^C, the solvents were removed in vacuo and the residue was purified by flash-chromatography to give 352 mg (37 %) of the title compound as light brown foam. MS m/e (%): 540 (M+H^, 100). i^2-(3>5'Bis-trifluoromethvl'phenviVN-{6-fhvdroxv'-(2-hvdroxv-ethvl)"aminol-4-o-tolyl-pvridin-3-vR-N-methvl-isobutvramide To a solution of 500 mg (0.93 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N"[6-(2-hydxoxy-ethylaniino)-4-o-tolyl-pyridin-3-yl]--N-methyl-isobutyramide in 5 ml dichloromethane was added under ice cooling a solution of 240 mg (0.97 mmol) of 3-chloroperbenzoic acid {ecu 70 %) in 5 ml dichloromethane. After stirring for 2 h at 0 °C, the reaction mixture was washed twice with saturated sodium carbonate solution, dried (sodium sulfete) and evaporated. The crude material was suspended in a mixture of dichloromethane and hexane, filtered and dried in vacuo to give 345 mg (62 %) of the title compound as white crystals. MS m/e (%): 556 (M+lT, 100). Example 9 2-(3,5-Bis-trifluoromethyl-phenyl)-N-{4-(2-chloro-phenyl)-6-[hydroxy-(2-hydroxy- ethyl)-amino]-pyridin-3-yl}-N-miethyl-isobutyramide The title compound was obtained as light brown foam in comparable yield according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)- N-{6-[hydroxy-(2-hydroxy-ethyl)-amino]-4-o-tolyl-pyridin-3-yl}-N-methyl- isobutyramide using 2-chlorophenylboronic add instead of o-tolylboronic acid in step d), MS m/e (%): 576 (M+H"", 100). Example 10 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(3-oxO"morpholin-4-yl)-4-o-tolyl-pyridin-3-yl] -isobutyramide To an ice-cooled suspension of 1.2 g (7.12 mmol) ruthenium(IV)oxide hydrate in a mixture of 50 ml carbon tetrachloride and 50 ml water were added 9.0 g (42 mmol) sodium periodate. After stirring for 30 min the organic layer was separated and the aqueous layer was extracted twice with 10 nd portions of carbon tetrachloride. The combined organic layers were filtered over celite, cooled to 0°C and were added slowly to an ice-cooled solution of 2,0 g (3.54 mmol) 2-(3,5-bis-trifiuoromethyl-phenyl)-N"methyl-N-(6-morpholin-4-yI-4-o-tolyl-pyridin-3-yI)-isobutj7ramide in 20 ml carbon tetrachloride. The mixture was stirred for additional 15 min at 0 °C, was filtered over celite and was evaporated. The residue was purified by flash-chromatography and gave 704 mg (34 %) of the title compound as colourless foam. MS m/e (%): 580 (M+PT^, 100). Example 11 2- (3,5-Bis-trifIuoromethyl"phenyl)-N- [4- (2-chloro-phenyl)-6- (3-oxo-morpholin-4-yl)-pyridin-3-yl] -N-methyl-isobutyramide The title compound was obtained as light brown oil in comparable yields according to the procedures described above for the preparation of 2-(3,5-bis-trifluorom€thyl-phenyl)-N-methyi-N-[6-(3-oxo-morpholin"4-yl)-4-o-tolyl-pyridin"3-yl]-isobutyraniide. MS m/e (%): 600 (M+KT, 100), Example 12 Acetic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-anaino}-4-o-tolyl-pyridin-2-ylcarbamoyl)-methyl ester a) N2"Benzvl-N5-methvI-4-o-tolvl-pvridine-2.5-diamine The title compound was prepared following the procedures described above for the synthesis of methyl-(6-morpholin-4-yl"4-o-tolyl-pyridin-3-yl)"amine. MS m/e (%): 304 (M-hH^, 100). h) Benzyl- (5"metiivlamino-4"0-tolvl-pvridin-2-yl)-carbamic acid benzyl ester To a solution of 2.03 g (6.7 mmol) N -benzyl-N -methyl-4-o-tolyl-pyridine-2,5-diamine in 100 ml dichloromethane and 40 ml N-ethyldiisopropylamine was added dropwise at 0 **C a solution of 2,1 ml (14.09 mmol) benzyl chloroformate in 50 ml dichloromethane. After stirring for 2 h at room temperature the reaction mixture was washed with water (2 x 50 ml), brine (50 ml), dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 2,36 g (80 %) of the title compound as.Ught brown crystals. M.p. 110-112 MS m/e (%): 438 (M+KT, 100). c) Benzyl-f5-1 [2-f33-bis-trifluoromethyl-phenvl)-2-methyl-propionvn -methyl-amino}-4-o-tolvl-pyridin-2-yD-carbamic acid benzyl ester To a solution of 1.075 g (2.5 mmol) benzyl-(5-methylamino-4-o-tolyl-pyridin-2-yl)-carbamic acid ben2yl ester in 10 ml dichloromethane and 1 ml N-ethyldiisopropylamine was added dropwise at 0 °C a solution of 1.15 g (3.5 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionic add chloride in 2 ml dichloromethane and the mixture was stirred for 3 h at room temperature. The solution was washed with water (20 ml), saturated aqueous sodium hydrogencarbonate solution (20 ml) and brine (20 ml), dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 1.15 g (62 %) of the title compound as a yellow oil. MS m/e (%): 720 (M+H"", 100). d)N-(6-Benzvlamino-4-o-tolyl-pyridin-3-yl)-2-(33-bis-trifluorometfayl-phenyl)-N-methyl-isobutyramide To a solution of 973 mg (1.35 mmol) ben2yl-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-carbamic addben2yl ester in 13 ml methanol and 1 ml N,N-dimethylformamide was added 40 mg 10 % palladium on activated charcoal and the mixture was hydrogenated (room temperature, 1 bar) for 1 h. Filtration of the catalyst and evaporation of the filtrate afforded 795 mg (quantitative) of the title compound as a yellow oil. MS m/e (%): 586 (M+H^ 100). e)N-(6-Amino-4-o-tolyl-pyridin-3-yD-2-f3.5-bis-trifluoromethyl-phenyl)"N-methyl-isobutyramide A solution of 750 mg (1.28 mmol) N-(6-benzylaniino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 25 ml of a 5 N solution of hydrochloric add in ethanol was evaporated to drjnaess and the residue was dissolved in 30 ml methanol and hydrogenated in the presence of 60 mg 10 % palladium on activated charcoal (room temperature, 10 bar) for 20 h. After filtration of the catalyst and evaporation of the solvent the residue was dissolved in 30 ml ethyl acetate, washed twice with saturated aqueous sodium hydrogencarbonate solution and dried (magnesium sulfate). Evaporation of the solution afforded 514 mg (81 %) of the title compound as Hght brown crystals. ; MS m/e (%): 496 (M+H^, 100). f) Acetic acid f5-[[2-(3>5-bis-trifluoromethvl-phenvl)-2-methvI-propionvl]-methyl-amino}-4-o-tolvl-pyridin-2-'ylcarbamovn"methyl ester To a solution of 100 mg (0.20 mmol) N-(6-amino-4-o-toIyl-pyridin-3"yl)-2-(3,5-bis-trifluoromethyI-phenyI)-N-methyI-isobutyramid€ in 3 ml dichloromethane were added 27 mg (0.21 mmol) N-ethyldiisopropylamine and 30 mg (0.21 mmol) acetoxy acetyl chloride. After stirring overnight, the solvent was evaporated and the residue was purified by flash-chromatography to give 62 mg (52 %) of the title compound as white solid. MS m/e (%): 618 (M+Na^ 19), 596 (M-f iT, 100). Example 13 2- (3,5-Bis-trifluoromethyl-phenyl)-N- [6- (2-hydroxy-acetylanmio)-4-o-tolyl-pyridin-3" yl] -N-methyl-isobutyramide To a solution of 30 mg (0.05 mmol) acetic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl"propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-ylcarbamoyl)'-methyl ester in 2 ml tetrahydrofuran were added 2 ml 1 N sodium hydroxide solution at room temperature. After stirring for 15 min, ethyl acetate was added, the aqueous phase was separated and the organic layer was dried (sodiiim sulfate). After evaporation the residue was purified by flash-chromatography to give 15 mg (54 %) of the title compound as white soUd. MS m/e (%): 576 (M+Na^ 19), 554 (M+H% 100). Example 14 2-(3,5-Bis-trifluoromethyl-phenyI)-N-[6-(hydroxyacetyI-methyI-anuno)-4-o-tolyl--pyridin-3-yl]-N-methyl-isobutyramide To a solution of 70 mg (0.12 mmol) acetic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyI)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl"pyridin-2-ylcarbamoyl)-methyl ester in 4 ml tetrahydrofuran at room temperature under argon were added dropwise 0.13 ml (0.12 mmol) of a 1 M solution of potassium hexamethyldisilazide in tetrahydrofuran. Stirling was continued for 1 h at room temperature and 17 mg (0.12 mmol) methyl iodide were added. After stirring overnight, saturated ammonium chloride solution was added and the aqueous layer was extracted with diethyl ether. The diethyl ether layer was dried with sodium sulfate, evaporated, and the residue was purified by flash-chromatography to give 12 mg (18 %) of the title compound as a white solid. , MS m/e (%): 590 (M+Na"", 31), 568 (M-hH"", 100). Example 15 2-(3,5-Bis-trifluoromethyl-phenyl)-N"[6-(2,5-dioxo-pyrrolidin"l-yl)-4-o-tolyl-pyridin-3-yl] -N-methyl-isobutyramide To a solution of 100 mg (0.20 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5"bis-trifluoromethyl-phenyl)-N-methyl"isobutyramide in 3 ml pyridine were added 54 mg (0.50 mmol) trimethylchlorosilane at room temperature. After stirring for 15 min, this mixture was added slowly xmder stirring to 155 mg (1.0 mmol) succinyl chloride and stirring was continued overnight The solvent was removed in vacuo and the residue was purified by flash-chromatography to give 29 mg (25 %) of the title compound as white solid. MS m/e (%): 600 (M+Na', 16), 578 (M+H^, 100). Example 16 Cyclopropanecarboxylic acid (5-{[2-(3,5-bis-trifluoromethyI-phenyI)-2-methyI-propionyl]-metfayl-amino}-4-o-tolyi-pyridin-2-yl)-cyclopropanecafbonyl-an:iide To a solution of 100 mg (0.20 mmol) N-(6"amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 3 ml dichloromethane were added 29 mg (0.21 mmol) N-ethyldiisopropylamine and 46 mg (0.44 mmol) cyclopropanecarboxyUc acid chloride at 0 °C. After stirring overnight at room temperature, the solvent was removed in vacuo and the residue was purified by flash-chromatography to give 80 mg (63 %) of the title compound as white solid. MS m/e (%): 654 (M+Na^, 30), 632 (M+H^, 100). Example 17 4-o-TolyI- [2,3 ']bipyridinyl-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide The title compo;md was obtained as a white solid in comparable yidd according to the procedure described above for the preparation of 4-o-tolyl-[2,4*]bipyridinyl-5-carboxylic acid (3,5"bis-trifluoromethyl-ben2yl)-methyI"amide using 3-pyridyIboronic acid instead of 4-pyridylboronic acid. MS m/e (%): 530 (M+H^ 100). Example 18 N-(3,5-Bis-trifIuoromethyl-benzyI)-6-(2-methoxy-phenyl)-N-niethyl-4-o-toIyl- nicotinamide The title compound was obtained as a light brown solid in 99 % yield according to the procedure described above for the preparation of 4-o-tolyl-[2,4']bipyridinyl-5-carboxylic acid (3,5-biS"trifluoromethyl-ben2yl)-methyl-amide using 2-methoxyphenylboronic add instead of 4-pyTidylboromc add- MS m/e (%); 559 (M+lT, 100). Example 19 N-(3,5-Bis-trifluoromethyl-benzyl)-6-(3-methoxy-phenyl)-N-methyl-4-o-tolyl-nicotinamide The title compound was obtained as a light yeUow viscous oil in 81% yield according to the procedure described above for the preparation of 4-o-tolyl-[2,4']bipyridinyl-5-carboxylic add (3,5-bis-trifluoromethyl"benzyl)"methyl-amide using 3-methoxyphenylboronic add instead of 4-pyridylboronic add. MS m/e (%): 559 (M+ET, 100). Example 20 N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-methoxy"phenyl)-N-methyl"4-o-tolyl- nicotinamide The title compound was obtained as a light yellow solid in 90 % yield according to the procedure described above for the preparation of 4-o-toiyI-[2,4*]bipyridinyl-5-carboxylic add (3,5-bis-trifluoromethyl-benzyl)-methyl-amide using 4-methoxyphenylboronic acid instead of 4-pyridylboronic add, MS m/e (%): 559 (M+H^, 100). r N-(3,5-Bis-trifluoromethyl-ben2yl)-6-(2-hydroxy"phenyl)-N-metiiyl-4-o-tolyl" nicotinamide To a solution of 80 mg (0.14 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-(2-methoxy-phenyl)-N-methyl-4-o-tolyl-nicotinamide in 1.5 ml dichloromethane 0.17 ml of a IM solution of boron tribromide in dichloromefhiane (0.17 mmol) were added dropwise at 0 °C. The temperature was allowed to warm to room temperature over night Water and a IM aqueous solution of hydrochloric acid were added. After 5 min the mixture was neutralized by addition of IM aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried with sodium sulfate and concentrated. Column chromatography afforded 67 mg (86 %) of the title compound as a white sohd. MS m/e (%):545 (M+H^ 100). Example 22 N-(3,5-Bis-trifluoromethyl-benzyl)-6-(3-hydroxy-phenyl)-N-methyl"4-o-tolyl-nicotinamide The title compound was obtained as a white soUd in comparable yield according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-ben2yl)'-6-(2-hydroxy-phenyl)-N-methyl-4-o-tolyl-nicotinamide using N-(3,5-bis-trifluoromethyl-benzyi)-6"(3-methoxy-phenyl)-N-methyl-4-o-tolyl"nicotinamide instead of N-(3,5-bis-trifiuoromethyl-benzyl)-6-(2-methoxy-phenyl)-N-methyl-4-o-tolyl-nicotinamide. MS m/e (%):545 (M+H"", 100). Example 23 N-(3,5-Bis-trifluoromethyl-ben2yl)-6"(4-hydroxj^-phenyl)-N-methyI-4-o-tolyl-nicotinamide To a solution of 80 mg (0.14 mmol) N-(3,5-bis-trifluoromethyl-ben2yl)-6-(2-metiioxy-phenyl)-N-methyl-4-o-tolyl-nicotinamide in 1.5 ml dichloromethaiie 0.43 ml of a IM solution of boron tribromide in dichloromethane (0.43 mmol) were added dropwise at 0 °C. The cooling bath was removed and the mixture was stirred at 35 °C over night. Water and a IM aqueous solution of hydrochloric acid were added. After 5 min the nfiixture was neutralized by addition of IM aqueous sodium hydroxide solution and extracted with WLAWJ-LLWA.' vjjLii-1-u.aan-. xiit uigoim-iayci wi«> uxicu wiLxi soGLium suiiaie anci concentrated-Column chromatography afforded 63 mg (81 %) of the title compoimd as a white solid. MS m/e (%):545 (M+H"", 100). Example 24 2-(3,5"Bis-trifluoromethyl-phenyl)-N-[6-cMoro-4-(2-cUoro-phenyl)-pyridin-3-yi]-N-methyl-isobutyramide a) 5-Bromo-2-chloro-pvridine To a solution of 15,0 g (75.8 nmiol) 5-bromo-2-methoxypyridine in 90 nJ dry N,N-dimethylformamide 21.2 ml (227 mol) phosphorus oxychloride were slowly added at 0°C. After completed addition the reaction mixture was heated to 110 °C over a period of 30 min. At this temperature the reaction started to be exothermic. The heating bath was partly removed such that the internal temperature did not exceed 120 °C. When the internal temperature started to drop heating was resumed, and the reaction mixture was kept at an internal temperature of 100 -110 "^C for 18 h. After cooling to room temperature the reflux condenser was exchanged by a daisen condenser, and the title compound was gained as a mixture with N,N-dimethylformamide by vacuum distillation at 40-50 °C (1-10 mbar). The distillate was diluted with cyclohexane and washed with two portions of water. The combined aqueous layers were extracted with cyclohexane. The combined organic extracts were dried with sodium sulfate and concentrated to give 11.0 g (76 %) of the title compound as a white solid. MS m/e, isotope cluster (%): 191 (M^ 75), 193 (100), 195 (24). b) 5-Bromo-2-chloro-4-iodo-pvridine To a solution of 12 ml (83 mmol) diisopropylamine in 80 ml dry tetrahydrofuran 52 ml of a solution of n-but)dlithiTim in hexanes (1.6 M, 83 mmol) was added at-78 °C over a period of 15 min under argon. The mixture was stirred at -78 ^C for 10 min. A solution of 15.2 g (79-0 mmol) 5-bromo-2-chloro-pyridine in 160 ml dry tetrahydrofuran was added at a rate such that the internal temperature did not exceed —70 °C. After completed addition the reaction mixture was stirred at -78 °C for 5 h. A solution of 24 g (95 mmol) iodine in 160 ml dry tetrahydrofuran was added at a rate such that the internal temperature did not exceed -70 °C. The reaction mixture was stirred for another 30 min at -78 ®C. The reaction mixture was allowed to warm to -10 ®C and treated with 120 ml of an aqueous solution of sodium thiosulfate (1 M, 120 mmol). The layers were separated and the aqueous layer was extracted with two portions of ethyl acetate. The combined organic layers were washed twice with saturated ammonium hydroxide solution, dried with sodium sulfate and concentrated. The residue was dissolved in hot heptane and allowed to stand over night. Filtration of the precipitate and drying in vacuo gave 19.3 g (77 %) of the title compound as a light brown solid. MS m/e (%): 318 (M^ 100). c) 5"Bromo-2"Chloro-4-f2"chloro-phenvl)-pvridine A mixture of 10.8 g (33,9 mmol) 5-bromo-2-chlorO"4-iodo-pyridine, 5.84 g (37.3 mmol) 2-chlorophenylboronic acid, 200 wl dimethoxyethane and 50 ml of a 2 M aqueous solutior of sodium carbonate was deoxygenated by three freeze-thaw cydes. After addition of 381 mg (1.70 mmol) palladium(II) acetate and 917 mg (3.39 mmol) triphenylphosphine the reaction mixture was stirred at 90 ^'C for 4 h. Cooling to room temperature was followed b^ dilution with water and extraction with two portions of tert-butyl methyl ether. The combined organic extracts were washed with brine, dried with magnesium sulfate and concentrated. Column chromatography afforded 7.74 g (75 %) of the title compound as a white soUd. MS m/e, isotope cluster (%): 301 (M^, 60), 303 (100), 305 (45). d) 6-Chloro-4-(2-chloro-phenvl)-nicotinicacid ethvl ester To a solution of 2.00 g (6.60 mmol) 5-bromo-2-chIoro-4-(2-chloro-phenyl)-pyridine in 66 ml tetrahydrofiiran 4.3 ml of a solution of n-butyllithium in hexanes (1,6 M, 6.9 mmol) were added dropwise at -100 ^'C under argon. Thin layer chromatography showed complete bromine-lithitun exchange after 5 min. After addition of 0.71 ml (7.3 mmol) ethyl chloroformate the reaction mixture was allowed to slowly warm to -78 ^C and stirred at that temperature for 1 h. The reaction mixture was allowed to warm to room temperature over night. Quenching with a small amount of water was followed by dilution with tert-butyl methyl ether and washing with water and brine. The organic layer was dried with sodium sulfate and concentrated. Column chromatography afforded 1.66 g (85 %) of the title compound as a light yellow solid. MS m/e (%): 295 (M"", 97), 250 ([M-OEt] ^ 100). e) 6-Chloro-4-(2-chlorO"phenvl)-nicotinic add A mixture of 3.20 g (10.8 mmol) 6-chloro-4-(2-chloro-phenyl)-nicotinic acid ethyl ester, 50 ml dioxane and 50 ml of a 2 M aqueous sodium hydroxide solution was stirred at room temperature for 17 h. Dilution with water was followed by washing with two portions of tert-butyl methyl ether. The combined organic layers were extracted with 1M aqueous sodium hydroxide solution. The combined aqueous layers were acidified to pH 2 with 2 M aqueous hydrochloric acid solution and extracted with four portions of tert-butyi methyl ether. The combined organic extracts were dried with sodium sulfate and concentrated to give 2.90 g (100 %) of the title compound as an off-white solid. MS(ISN) m/e (%): 266 ([M-dT)]" 100). f) !"6-Chloro-4--(2-chloro-phenvl)-pvridin-3-vl1--carbamic acid tert-butyl ester A mixture of 650 mg (2.42 mmol) 6-chloro-4-(2-chloro-phenyl)-nicotinic add, 0.54 ml (2.42 mmol) diphenylphosphoryl azide, 0.34 ml (2.42 mmol) triethylamine and 8 ml tert-butanol was heated at reflux for 1 L Cooling to room temperature was followed by evaporation of the solvent in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous ammonixmi chloride solution, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried with sodium sulfete and concentrated. Column chromatography gave 695 mg (85 %) of the tide compound as a white solid. MS m/e (%): 339 (M+H^, 76). g) f6-Chloro-4-(2-chloro-phenvl)-pvridin-3-vn-metfavl-carbamic add tert-butyl ester To a solution of 1.21 g (3.57 mmol) [6-chloro-4-(2"Chloro-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester in 35 ml N>N-dimethylformamide 0.18 g (3.7 mmol) sodium hydride (55 % dispersion in mineral oil) were added at room temperature. After 30 min 0.25 ml (3.9 mmol) methyl iodide were added and the reaction mixture was stirred for 1 h. Quenching was followed by extraction with tert-butyi methyl ether. The organic layer was washed with two portions of water, and the combined aqueous layers were extracted with two portions of tert-butyl methyl ether. The combined organic layers were dried with sodium sulfate and concentrated to give 1.26 g (100 %) of the title compound as a light yellow amorphous mass, MS m/e (%): 353 (M+H^ 92). h) f6-Chloro-4-f2-chloro-phenvl)-pvridin-3-vn-methvl-amine A solution of 1.26 g (3.55 mmol) [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-carbamic add tert-butyi ester and 3.34 ml (42.8 mmol) trifluoroacetic acid in 11 ml dichloromethane was stirred at room temperature for 2 h. Addition of 2 M aqueous sodium carbonate solution was followed by extraction with two portions of dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated to give 0.89 g (99 %) of the title compound as an off-white solid. MS m/e (%): 253 (M+PT, 100). i) 2-(3,5-Bis-trifluoromethvl"phenvl)-N-[6'Chloro-4-(2-chloro-phenvlVpyridin-3-vll-N-methvl-isobutyxamide To a solution of 180 mg (0.711 mmol) [6-chloro-4-(2-chloro-phenyl)-pyridin-3'yl]-methyl-amine in 7 ml dry tetrahydrofuran 0.86 ml of a 0.91 M solution (0.78 nomol) of potassium hexamethyldisilazide in tetrahydrofuran was added at room temperature under an atmosphere of argon. After 45 min 295 mg (0,924 mmol) 2-(3,5-bis-trifluoromethyi-phenyl)-2-methyl-propionyl chloride were added. The reaction mixture was stirred at room temperature for 3 h. Quenching with water was followed by dilution with tert-butyl methyl ether and washing with 2 M aqueous sodium carbonate solution and brine. The combined aqueous layers were extracted with two portions of tert-butyl methyl ether. The combined organic extracts were dried with sodixmi sulfate and concentrated. Flash chromatography gave 254 mg (67 %) of the title compotmd as a light yellow soHd. MS m/e (%): 535 (M+U", 100), Example 25 2'(355-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-iodo-pyridin-3-yI]-N- methyl-isobutyramide A mixture of 250 mg (0.467 mmol) 2-(3>5-bis-trifluoromethyl-phenyl)"N"[6-chloro-4-(2' chloro-phenyl)-pyridin-5-yl]-N-methyl"isobutyramide (Example 24), 250 mg (1.64 mmol) sodium iodide and 0.12 ml (0.99 mmol) hydroiodic acid (57 % in water) in 5 ml 3-methyl-2-butanone was heated at 80 °C for 5 h in a sealed tube. After cooling to room temperature the mixture was diluted with tert-butyl methyl ether and treated with saturated aqueous sodium bicarbonate solution. The layers were separated, the organic layer washed with water, dried with magnesium sulfate and concentrated. Flash column chromatography gave 218 mg (48 %) of the tide compound as a Hght brown solid. MS m/e (%): 627 (M+H"", 100), 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tdlyl-pyridin-3"yl)-N-methyl- isobutyramide The title compound was obtained as a light yellow solid in comparable yields according to the procedures described above for the preparation of 2-(3,5-bis-trifluoromethyI-phenyl)-- N" [6-chIoro-4-(2-chloro-phenyl)-pyridin-3-yl]"N-methyl"isobutyramide (Example 24) using o-tolylboronic acid instead of 2-chlorophenylboronic acid in step c). MSm/e(%):514(M^5). Example 27 2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6-iodo-4-0"tolyl"pyridin-3-yi)"N-methyl-isobutyramide The title compound was obtained as a Ught yellow solid in 58 % yield according to Xhe procedure described above for the preparation of 2"(3,5"bis-t^ifluoromethyI-phenyl)-N-[4-(2-chloro-phenyl)-6-iodo-pyridin-3-yl]"N-methy^isobutyramide (Example 25) using 2-(3,5-bis-trifluoromethyl-phenyl)"N-(6"Chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide (Example 26) instead of 2-(3>5-biS"trifluoromethyl-phenyl)"N-[6-chloro-4-' (2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide. MSm/e(%):606(M\l3). Example 28 2-(3,5-BiS"trifluoromethyl-phenyl)-N"[6-chloro-4-(4-fluorO"2-methyl-phenyl)-pyridin-3-yl] "N-methyl-isobutyramide The tide compound is prepared according to the procedures described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)"N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide (Example 24) using (4-fluoro-2-methyiphenyl)boronic acid instead of 2-chlorophenylboronic acid in step c). Example 29 2-(3,5-Bis-trifluoromethyl-phenyl)"N-[4-(4-fluoro-2-methyl-phenyl)-6-iodo-pyridin-3-yl] -N-methyl-isobutyramide The title compound is prepared according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4"(2-chloro-phenyl)-6-iodo-pyridin-3-yl]-N-methyI-isobutyramide (Example 25) using2-(3,5-bis-trifiuoromethyI- phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide instead of 2-(3,5-bis-trifluoromethyl"phenyl)-N"[6-chlorO"4-(2-chloro-phenyl) -pyridin-3-yl] -N-methyl-isobutyramide. Example 30 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]"N- methyl-isobutyramide The title compound was obtained as a light brown solid in comparable yields according to the procedures described above for the preparation of 2-(3,5-bis-trifiuoromethyl-phenyl)- N- [6-chloro-4-(2"Chloro-phenyl)-pyridin-3"yl] -N-methyl-isobutyramide (Example 24) using 4-fluorophenyIboronic acid instead of 2-chlorophenylboronic acid in step c). MS m/e (%): 519 (M+H^ 100). Example 31 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4"(4-£luoro-phenyl)-6-iodo-pyridin-3-yl]-N-methyl-isobutyramide The title compoimd is prepared according to the procedure described above for the preparation of 2-(3>5-bis-trifluorom€thyl-phenyl)-N"[4-(2-chloro-phenyl)"6"iodo-pyridin-3-yl]-N-methyl"isobutyramide (Example 25) using 2-(3,5-bis-trifluoromefhyl-phenyl)-N- [6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl] -N-methyl-isobutyramide (Example 30) instead of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyi-isobutyramide. Example 32 N-(3,5-Bis-trifluoromethyl-benzyl)-6-chloro-4-(2-chloro-phenyl)-N-methyl-nicotinamide To a solution of 300 mg (1.12 mmol) 6-chloro-4-(2-chloro-phenyl)-nicotinic acid (Example 24, step e)) in 12 ml dichloromethane 0.15 ml (1.7 mmol) oxalyl chloride and one drop of N,N-dimethylformamide were added at 0 °C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated in vacuo. The residue was redissolved in 6 ml dichloromethane and added dropwise to a solution of 432 mg (1.68 mmol) (3,5-bis-trifluoromethyl-benzyl)-methyl-amine5 0.39 ml (2.2 mmol) N-ethyldiisopropylamine and 7 mg (0.06 mmol) 4-(N,N-dimethylamino)pyridine in 6 ml dichloromethane at 0 ^C. After completed addition the reaction mixture was allowed to warm to room temperature and stiixed over ni^t The reaction mixture was diluted with dichloromethane and washed with two portions of 1M aqueous hydrochloric add sohition. The combined aqueous layers were extracted with dichloromethane. The combined organic extracts were washed with two portions of 1M aqueous sodium hydroxide solution. The combined basic aqueous layers were extracted with dichloromethane. The combined organic extracts were dried with sodium sulfete and concentrated. COIUHMI chromatography afforded 475 mg (84 %) of the title compound as a light yellow amorphous mass. MS m/e (%): 507 (M+H^, 100). Example 33 N"(3>5-Bis-trifluoromethyl-benzyl)-4-(2"cUoro-phenyl)-6"iodo-N-methyl-nicotinamide The title compound was obtained as a light brown amorphous mass in 21 % yield according to the procedure described above for the preparation of N-(3,5-bis-trifiuoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) using N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-4-(2-chloro-phenyl)-N-methyl-nicotinamide (Example 32) instead of N-(3,5-bis-trifluoromethyl"ben2yl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide. MS m/e (%): 599 (M+H', 100). Example 34 N-(3,5-Bis-trifluoromethyl-benzyl)-6"chloro-4-(4-fluorO"2-methyl-phenyl)-N-methyl- nicotinamide a) 6-Chloro-4-f4-fluoro-2-methvl-phenvD-nicotinic acid The title compound was obtained as an off-white solid in comparable yields according to the procedures described above for the preparation of 6-chloro-4-(2-chloro-phenyl)-nicotinic acid (Example 24, step e)) using (4-fluoro-2-methylphenyl)boronic acid instead of 2-chlorophenylboronic acid in step c). MS(ISN) m/e (%): 264 ([M-(H^)]- 100). b)N-(3.5-Bis-trifluoromethvl-benzvI)-6-chloro-4"f4-fluoro-2-methvl-phenvl)"N-methvl- nicotinamide The title compoxmd was obtained as a white solid in 92 % yield according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-4-(2" chloro-phenyl)-N-niethyl-nicotinainide (Example 32) using 6-chloro-4"(4-fluoro-2-methyl-phenyl)-nicotinic acid instead of 6-chloro-4-(2Tchloro-phenyl)-nicotinic acid. MS m/e (%): 505 (M+lT, 100). Example 35 N-(3,5-Bis-trifluorome11iyl-beii2yl)-4-(4-fluoro-2-methyl-phenyl)-6--iodo-N-methyl- nicotinamide The tide compoimd was obtained as a yellow viscous oil in 50 % yield according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyI-benzyl)"6" iodo-N-methyI-4-o-tolyl-nicotinamide (Example 4) using N-(3,5-bis-trifluoromethyI- benzyl)-6-chloro-4-(4-fluoro-2-methyl-phenyl)-N-methyl-nicotinamide (Example 34) instead of N-(3,5-bis-trifluoromethyl"ben2yl)-6-chloro-N-methyl-4-o-tolyl"mcotinamide. MS m/e (%): 597 (M+If, 100). Example 36 N-(3,5-Bis-trifluoromethyl"ben2yi)-6-chloro-4-(4-fluoro-phenyl)-N-mediyl-nicotinamide a) 6"Chloro-4-(4-fluoro-phenyl)-nicotinic acid The title compound was obtained as a light brown solid in comparable yields according to the procedures described above for the preparation of 6"Chloro-4"(2-chlorO"phenyl)-nicotinic acid (Example 24, step e)) using 4-fluorophenylboronic acid instead of 2-chlorophenylboronic add in step c). MS(ISN) m/e (%): 250 ([M-(H^)]', 100). b) N-f3.5-Bis-trifluoromethyl-benzvI)-6-chloro--4-f4-fluoro-phenyI)-N-methvI- nicotinamide The tide compound was obtained as a light yeUow solid in 98 % yield according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-4-(2-chloro-phenyl)-N-methyl-nicotinamide (Example 32) using6-chloro-4-(4-fluoro-phenyl)-nicotinic acid instead of 6-chloro-4-(2-chloro-phenyl)-nicotinic acid. MS m/e (%): 491 (M+H% 100). N-(3>5-Bis-trifluoromethyl-beiizyl)-4-(4-fluoro-phenyl)-6-iodo-N-methyl-nicotinamide The tide compound is prepared according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyI-ben2yl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) using N-(3,5-bis-trifiuoromethyl-benzyl)-6-chloro-4-(4-fluoro-phenyl)-N-methyl-nicotinamide (Example 36) instead of N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide. Example 38 6-(5"Acetyl-thiophen-2-yl)-N-(3,5-bis-trifluoromethyl-benizyl)-N-methyl-4-o-tolyl- nicotinamide The title compound was obtained as a white solid in 49 % yield according to the procedure described above for the preparation of 4-o-tolyi-[2,4']bipyridin}d-5-carbox)dic acid (3,5- bis-trifluoromethyi-benzyl)-methyl-amide (Example 5) using 5-acetyl-2-thiopheneboronic acid instead of 4-pyridylboronic acid. MS m/e (%): 577 (M+HT, 100). Example 39 (RS)-N-(3,5-Bis-trifluoromethyl-ben2yl)-6-[5-(l-hydroxy-ethyl)-thiophen-2-yl]-N-methyl-4-o-tolyl-nicotinamide A mixture of 50 mg (0.087 mmol) 6-(5-acetyl-thiophen-2-yl)-N-(3>5-bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-nicotinamide (Example 38), 7 mg (0.2 mmol) sodium borohydride in 1 ml ethanol and a small amount of tetrahydrofuran was stirred at room temperature for 2 h. The reaction was quenched by addition of water, followed by 1 N aqueous hydrochloric add solution. The mixture was basified with sodium carbonate and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and concentrated to give 48 mg (96 %) of the title compound as a slightly yellow solid. MS m/e (%): 579 (M+H^ 100). N-(3,5-Bis-trifluoromethyl-ben2yl)-6-(3,5-dimethyl-is6xa2ol-4"yl)-N-methyl-4-o-tolyl^ nicotinamide The title compound was obtained as a light brown solid in 83 % yield according to the procedure described above for the preparation of 4-o-tolyl-[2,4']bipyridinyl-5-carboxylic acid (3,5-bis-trifluoromethyl"benzyI)-methyl-aniide (Example 5) using 3,5-dimethylisoxa2ole-4-boronic acid instead of 4-pyridyIboronic add. MS m/e (%): 548 (M+H^ 100). Example 41 5-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyI]-4-o-tolyl-3',6'-dihydro-2'H-[2,4']bipyridinyl-l'-carboxyIic add tert-butyl ester The title compoimd was obtained as a light orange soUd in 61 % yield according to the procedure described above for the preparation of 4-o-tolyl-[2,4']bipyridinyl-5-carboxylic add (3>5-bis-trifluoromethyl-benzyl)-methyl-amide (Example 5) using 4-(4,4,5>5" tetramethyl-[l,3>2]dioxaborolan-2-yl)-3>6-dihydro-2H-pyridine-l"carboxylic add tert-butyl ester instead of 4-pyridyIboronic add. MS m/e (%): 634 (M+H^, 100). Example 42 4"0-ToIyl-r,2',3',6'-tetrahydro-[2,4']bipyridinyI-5-carboxyKc acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide A solution of 258 mg (0.407 mmol) 5-[(3,5-bis-trifluoromethyl-ben2yl)-methyl-carbamoyl]-4-o-tolyl-3',6*-dihydro-2*H-[2,4']bipyridinyl-l'-carboxylic add tert-butyl ester (Example 41) and 0.26 ml (3.2 mmol) trifluoroacetic add in 2 ml dichloromethane was heated at reflux for 4 h. After cooling to room temperature the mixture was diluted with dichloromethane and washed with IN aqueous sodium hydroxide solution. The aqueous layer was extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated. Column chromatography afforded 135 mg (62 %) of the title compound as a light brown solid. MS m/e (%): 534 (M+II', 100). r-Cydopropylmethyl-4-o-tolyl-l\2\3\6'-tetrahydro-[2,4']bipyridinyl-5-carbox7licadd (3,5-biS"trifIuoromethyl-benzyl)-methyl"anude A mixture of 60 mg (0.11 mmol) 4-o-tolyl-r,2',3',6'-tetrahydro-[2,4']bipyridinyl-5-carboxyiic add (3,5-bis-trifluoromethyl"ben2yl)-methyl-amide (Example 42), 0.011 ml (0.11 mmol) (bromomethyl) cyclopropane and 19 mg (0.14 namol) potassium carbonate in 1.5 ml acetonitrile was stirred at room temperature for 15 h. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with three portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. Column chromatography afforded 28 mg (42 %) of the title compound as a Hght brown solid, MS m/e (%): 588 (M+H^> 100). Example 44 4-{5-[(3,5-Bis-1xifluoromethyl-benzyl)-melhyl-carbamoyl]-4-o-tolyl-pyridin" benzoic acid methyl ester A mixture of 200 mg (0.346 mmol) N-(3,5-bis-trifluoromethyl-ben2yl)-6-iodo-N-methyi-4-o-tolyl-nicotinamide (Example 4), 95 mg (0,52 mmol) 4- methoxycarbonylphenylboronic add and 155 mg (0,692 namol) potassium phosphate in 4 ml dioxane was deoxygenated by three freeze-thaw cycles. After addition of 9-5 mg (0.010 nmiol) tris(diben2ylideneacetone)dipalladium(0) and 0.0025 xnl (0.02 mmol) trimethyl phosphite the reaction mixture was stirred at 95 °C for 5 h. Cooling to room temperature was followed by dilution with tert*butyl methyl ether, filtration over Decalite and evaporation of the solvent in vacuo. Column chromatography afforded 50 mg (25 %) of the title compound as a light brown solid. MS m/e (%): 587 (M+H^ 100), Example 45 N"(3,5-Bis-trifluoromethyl-benzyI)"6-(4"hydroxymethyl"phenyl)-N-methyl-4-0"tolyl- nicotinamide The title compoimd was obtained as a light yellow sohd in 41 % yidd according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-benzyl)-6" hydroxymethyl-N-methyl-4-o-tolyl-nicotinamide (Example 7) using 4-{5-[(3,5-bis- trifluoromethyl-benzyi)-methyl-carbamoyl]-4-o-tolyl-pyridin-2-yi}-benzoic add methyl ester (Example 44) instead of 5-[(3,5-bis-trifluoromethy^ben2yl)-methyl-ca^bamoyl]-4-o- tolyl-py^idine"2-ca^boxylic acid methyl ester. ; MS m/e (%): 559 (M+H^, 100). Example 46 2'-Methyl-4-o-tolyl- [2,4']bipyridinyl-5-carboxyiic acid (3,5-bis-trifluoromethyl-benzyI)-methyl-amide a) 4-Iodo-2-methvl"pvridine The title compound was obtained as a red-brown sohd in 84 % yield according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl"benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) using 4-chloro-2"methyl-pyridine instead of N- (3,5"bis-trifluoromethyl-ben2yl)-6-chloro-N"methyl-4-o-tolyl-nicotinamide. MSm/e(%):219(M^100). b) 2'-Methvl-4-o-tolvl-r2,4'1bipyridinvl-5"Carboxvlic acid r3.5-b2S-trifluoromethyl- benzvD-methvl-amide A mixture of 300 mg (1.37 mmol) 4-iodO"2-methyl-pyridine, 383 mg (1.51 mmol) bis(pinacolato)diboron and 403 mg (4.11 nmiol) potassium acetate in 8.5 ml N,N-dimethylformamide was deoxygenated by three freeze-thaw cycles. After addition of 112 mg (0.137 mmol) dichloro(l,r-bis(diphenylphosphino)ferrocene)palladium(ll) dichloromethane adduct the reaction mixture was stirred at 80 °C for 3 h. Cooling to room temperature was followed by addition of 4 ml of a 2 M aqueous solution of sodium carbonate, 396 mg (0.685 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) and 56 mg (0.068 mmol) dichloro(l,r-bis(diphenylphosphino)ferrocene)palladium(n) dichloromethane adduct The reaction mixture was reheated to 80 °C for 1.5 h. After cooling to room temperature the reaction mixture was diluted with aqueous sodium bicarbonate solution and extracted with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and concentrated. Drying in high vacuo at 50 ^C and flash column chromatography gave 292 mg (78 %) of the title compound as a light brown solid- MS m/e (%): 544 (M+H^ 100). 4-(2-Chloro-phenyl)-2'-methyl-[2,4']bipyridinyl-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl"anude The title compound was obtained as a light brown amorphous mass in 42 % yield according to the procedure described above for the preparation of 2'-methyl-4-o-toIyI-[2,4']bipyridinyl-5-carboxylic acid (3,5-bis-trifluoromethyI-ben2yl)-methyl-amide (Example 46) using N-(3,5-bis-trifluoromethyl-benzyl)-4-(2-chloro-phenyl)-6-iodo-N-methyl-nicotinamide (Example 33) instead of N-(3,5-biS"trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide. MS m/e (%): 564 (M+tT, 100). Example 48 2-(3,5-Bis-trifluoromethyl-phenyl)-N"[4-(2-chloro-phenyl)-2'-methyl-[2,4']bipyridinyl-^ yl]-N-methyl-isobutyramide The title compound was obtained as a light brown solid in 31 % yield according to the procedure described above for the preparation of 2'-methyI-4"0"toIyl-[2,4']bipyridinyl-5-carboxylic add (3,5-bis-trifluoromethyI-ben2yI)"methyl-amide (Example 46) using 2-(3,5-biS"trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-iodo-pyridin-3-yI]-N-methyl-isobutyramide (Example 25) instead of N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide. MS m/e (%): 592 (M+H^ 100). Example 49 5-{[2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionyI]-methyI-amino}"4-o-tolyl-3',6'-dihydro-2'H-[2,4']bipyridinyl-r'Carboxylic acid tert-butyl ester The title compound was obtained as an orange viscous oil in 64 % yield according to the procedure described above for the preparation of 4-o-tolyl-[2,4lbipyridinyl-5-carboxyhc acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide (Example 5) using 2-(3,5-bis-trifluoromethyl-phenyI)-N-(6-iodo-4-o-toIyI-pyridin-3-yI)-N-methyI-isobutyramide (Example 27) instead of N-(3,5-bis-tri£luoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-' nicotinamide and 4-(4,4,5,5-tetramethyl- [ 1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxyUc acid tert-butyl ester instead of 4-pyridylboronic acid. MS m/e (%): 662 (M+H^, 100). i-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-cyano-phehyl)-4-o-tolyl-pyridin-3-yl]-^^ nethyl-isobutyramide The title compound was obtained as a white solid in 67 % yield according to the procedure described above for the preparation of 4-o-toIyI-[254']bipyridinyl-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide (Example 5) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-iodo-4-o-tolyl-pyridin-3"yl)-N-methyl-isobutyramide (Example 27) instead ofN-(3,5-bis-trifluoromethyl-ben2yl)-6-iodo-N-methyl-4-0"tolyl-nicotinamideand4-cyanophenylboronic acid instead of 4-pyridylboronic acid. MS m/e (%): 582 (M+H^, 100). Example 51 2"(3,5-Bis-trifluoromethyl"phenyl)-N-[6"(4-fluoro-phenyl)-4"0-tolyl-pyridin-3-yl]-N-methyl-isobutyramide The title compound was obtained as a light brown solid in 45 % yield according to the procedure described above for the preparation of 4-o-tolyl-[2>4']bipyridinyl-5"Carboxylic add (3,5-bis-trifluoromethyI"ben2yl)-methyl-amide (Example 5) using 2-(3,5-bis-trifluoromethyl"phen)d)-N-(6-iodO"4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide (Example 27) instead of N"(3,5-bis-trifluoromethyl-ben2yl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide and 4-fluorophenylboronic add instead of 4-pyridylboronic add. MS m/e (%): 575 (M+JT, 100). Example 52 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(3,4-difluoro-phenyl)-4-o-tolyl-pyridin-3-yl]-N-mefhyl-isobutyramide The title compound was obtained as a light brown solid in 85 % yield according to the procedure described above for the preparation of 4"0-tolyl-[2,4']bipyridinyl-5-carboxyiic acid (3>5-bis-trifluoromethyl-benzyl)"methyl-amide (Example 5) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-iodo-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide (Example 27) instead of N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide and 3,4-difluorophenylboronic add instead of 4-pyridylboronic acid. MS m/e (%): 593 (M+H% 100). N-[6-(4-Acetyl-thiophen-2-yl)-4-o-tolyI-pyridin-3-yl]-2-(3,5-bis-trifluoro^ N-methyl-isobutyramide The title compoimd was obtained as a light hroym solid in 59 % yield according to the procedure described above for the preparation of 4-o-tolyl-[2,4']bipyridinyl-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-niethyl-amide (Example 5) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-iodo-4-o-tolyl-pyridin-3-yl)-N-methyHsobutsn:ainide (Example 27) instead of N-(3,5-bis-trifluoromethyl-ben2yi)-6-iodo-N-methyl"4-o-tolyl-nicotinamide and 5-acetyl-2-thiopheneboronic add instead of 4-pyridylboronic acid MS m/e (%): 605 (M+H', 100). Example 54 (RS)-2-(3,5-Bis-trifluoromethyl-phenyl)-N-{6"[5'(l-hydroxy-ethyl)-thiophen-2-yl]-^ tolyi-pyridin-3-yl}-N-methyl-isobutyramide The title compound was obtained as a white solid in 64 % yield after column chromatography according to the procedure described above for the preparation of (RS)- N-(3>5-bis-trifluoromethyl-benzyl)-6-[5-(l-hydroxy-ethyl)-thiophen-2-yi]-N-methyl-4-o- tolyl-nicotinamide (Example 39) using N*[6-(4-acetyl-thiophen-2-yl)-4-o-tolyl-pyridin-3- yl]-2-(3,5-bis-trifluoromethyl-phen}d)-N-methyl-isobutyramide (Example 53) instead of 6-(5-acetyl-thiophen-2-yl)-N-(3,5-bis-tri£Iuoromethyi-benzyl)-N-methyl-4-0"tolyl- nicotinamide. MS m/e (%): 607 (M+H^, 100), Example 55 5-[(3,5-Bis-trifluoromethyl-beiizyl)-methyl-carbamoyl]-4-o-tolyl-pyridine-2-carboxylic acid A mixture of 0.50 g (0.98 mmol) 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-0"tolyl-pyridine-2-carboxylic acid methyl ester (Example 6), 10 ml methanol, 10 ml dioxane and 10 ml IN aqueous sodium hydroxide solution was stirred at room temperature for 17 h. Dilution with water was followed by washing with tert-butyl methyl ether- The aqueous layer was acidified to pH 2 with 1 M aqueous hydrochloric acid solution and extracted with four portions of dichloromethane. The combined dichloromethane extracts were dried with sodium sulfate and concentrated to give 0,38 g (78 %) of the title compound as a white solid. MS(ISN) m/e (%): 495 ([M-CfT)]", 100). *7U Example 4-o-Tolyl-pyridine"2,5-dicarboxylic acid 2-[(3,5-bis-trifluoromethyl-ben2yl)-meth7l-amide] 5-cyclopropylamide A mixture of 80 mg (0.16 mmol) 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridine-2-carboxylic acid (Example 55), 0.12 ml (1,6 mmol) cyclopropylamine, 63 mg (0.32 mmol) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and a catalytic amount of 4-(N,N-dimethylamino)pyridine in 2 ml dichloromethane was stirred at room temperature for 60 h. Addition of saturated aqueous ammonium chloride solution was followed by extraction with four portions of dichloromethane. The combined dichloronaethane extracts were washed with saturated aqueous sodium carbonate solution, dried with sodium sulfate and concentrated. Column chromatography afforded 56 mg (65 %) of the title compound as a white solid. MS m/e (%): 536 (M+tT, 100). Example 57 4-o-Tolyl-pyridine-2,5-dicarboxylic add 2-[(3,5-bis-trifluoromethyl-benzyI)-meth7l" amide] 5-(cyclopropyl--methyl-amide) To a solution of 49 mg (0.092 mmol) 4-o-tolyl-pyridine-2,5-dicarboxylic acid 2-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amide] 5-cyclopropylamide (Example 56) in 1 ml tetrahydrofiiran 0.12 ml of a 0.91 M solution (0.11 mmol) of potassium hexamethyldisilazide in tetrahydrofiiran were added at 0 °C. After 30 min, 0.007 ml (0.1 mmol) methyl iodide were added- The reaction mixture was allowed to warm to room temperature over night. Quenching with water and 1 M aqueous hydrochloric add solution and neutralization with saturated aqueous sodium bicarbonate solution was followed by extraction with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Flash column chromatography gave 38 mg (76 %) of the title compound as an off-white solid. MS m/e (%): 550 (M+lT, 100). Example 58 N-(3,5-Bis-trifluoromethyl-beii2yl)-N-methyl-6-(morpholine-4-carbon^ nicotinamide The tide compound was obtained as a white solid in 85 % yield after column chromatography according to the procedure described above for the preparation of 4-o-toIyi-pyridine-2,5-dicarboxylic acid 2-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amide] 5-cyclopropylamide (Example 56) using morpholine instead of cyclopropylamine. MS m/e (%): 566 (M-fH^, 100). Example 59 4-o-Tolyl-pyridine-2,5-dicarboxylic acid 2-[(3,5-bis-trifluoromethyl-ben2yl)-methyl-amide] 5-[(2-hydroxy-ethyl)-amide] The title compound was obtained as a white soHd in 65 % yield after colunm chromatography according to the procedure described above for the preparation of 4-o-tolyl-pyridine-2,5-dicarboxylic acid 2-[(3,S-bis-trifluoromethyl-benzyl)-methyl-amide] 5-cyclopropylamide (Example 56) using ethanolamine instead of cyclopropylamine. MS m/e (%): 540 (MH-H"", 100). Example 60 4-o-Tolyl-pyridine-2,5-dicarboxylic acid 2-[(3>5-bis-trifluoromethyl-benzyl)-methyl" amide] 5-(carbamoylmethyl-methyl-amide) The title compound was obtained as a white solid in 8 % yield after preparative thinlayer chromatography according to the procedure described above for the preparation of 4-o-tolyl-pyridine-2,5-dicarboxylic acid 2-[(3,5"bis-trifluoromethyl-benzyl)-methyl-amide] 5-cyclopropylamide (Example 56) using an equimolar mixture of sarcosine hydrochloride and triethylamine instead of cyclopropylamine. MS m/e (%): 567 (M+H"", 100). Example 61 4-o-Tolyl-pyridine-2,5-dicarboxylic acid 2-amide 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amide] To a solution of 200 mg (0.403 mmol) 5-[(3,5-bis-triflluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridine-2-carboxylic acid (Example 55) in 4 ml anhydroxis tetrahydrofuran 0.042 ml (0.48 mmol) oxalyl chloride and two drops of N,N" dimethyiformamide were added dropwise at room temperature. After stirring for L5 h the reaction mixture was cooled to 0 ""C, followed by addition of 3 ml of a 25 % aqueous solution of ammonium hydroxide. Dilution with water was followed by extraction with four portions of etiiyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated to give 199 mg (99.7 %) of the title compound as a light orange-yellow solid, MS m/e (%): 496 (M+H^, 100). Example 62 N" (3,5-Bis-trifluoromethyl-benzyl)-N-methyI-6- (3-methyl- [ 1,2,4] oxadiazoi-5"yI)-4-o-tolyl-nicotinamide A solution of 170 mg (0.343 mmol) 4-o-tolyi-pyridine-2,5-dicarboxylic acid 2-amide 5-[(3,5-bis-trifluoromethyl"benzyl)-methyI-amide] (Example 61) in 1 ml N,N-dimethylformamide dimethyl acetal was heated at 120 ^C for 1 h. After concentration in vacuo the residue was dissolved m 0.4 ml acetic acid. A solution of 29 mg (0.41 mmol) hydroxylamine hydrochloride in 0.2 ml 2N aqueous sodium hydroxide solution was added at room temperature. The mixture was heated at 90*^C for 1.5 h. After cooling to room temperature water and aqueous saturated sodium bicarbonate solution were added, followed by extraction with three portions of dichloromethane. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography and preparative HPLC afforded 6S mg (37 %) of the tide compound as a light yellow soHd. MS m/e (%): 535 (M+H', 100). Example 63 N"(3,5-Bis-trifluororaethyI-benzyI)-6-ethynyI-N-methyl-4-o-tolyl-nicotinaniide a) N-(3,5-Bis"trifluoromethyl-benzyl)'N-methvl-4-o-tolvl-6'trimethvlsilanyletiiynyl-nicotinamide To a mixture of 200 mg (0.346 mmol) N'(3,5-bis--trifluoromethyl-benzyl)-6-iodo-N" methyl-4-0"tolyl-nicotinamide (Example 4), 0.073 ml (0-52 mmol) triethylamine, 5 mg (0.007 mmol) bis(triphenylphosphine)palladium(II) chloride and 3 mg (0.014 mmol) copper(I) iodide in 1 ml tetrahydrofuran a solution of 0.098 ml (0.69 mmol) trimethylsilylacetylene in 0.5 ml tetrahydrofuran was added at room temperature. After stirring for 17 h the mixture was diluted with tert-butyl methyl ether. Washing with a saturated aqueous solution of ammonium chloride was followed by drying with sodium sulfate and evaporation of the solvent. Column chromatography afforded 158 mg (83 %) of the tide compound as a light brown solid. MS m/e (%): 549 (M+H"", 100), b) N-f3.>5--Bis-trifluorQmethvI-benzvI)'6-ethvnvl-N"methyl-4-o-toIyI-nicotinamide A mixture of 143 mg (0.261 mmol) N-(3>5-bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-6-trimethyIsilanylethynyl-nicotinamide, 2.5 ml of a 1M aqueous solution of potassium hydroxide and 2.5 ml methanol was stirred at room temperature for Ih. Acidijfying to pH 5 with a saturated aqueous solution of ammonium chloride was followed by extraction with three portions of dichloromethane. The combined organic extracts were dried with sodium sulfate and concentrated. Colunan chromatography afforded 97 mg (78 %) of the tide compound as a Ught brown soUd. MS m/e (%): 475 ([M-H] ^, 4). Example 64 N-(3,5-Bis-trifluoromethyI-ben2yI)-N-methyl-6-(3-methyI-isoxazol-5-yI)-4-o-tolyl-nicotinamide To a solution of 55 mg (0.12 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-ethynyl-N-methyl-4-o-tolyl-nicotinamide (Example 63), 0.026 ml (0.35 mmol) nitroethane and 1 mg (0.01 mmol) 4-N,N-dimethylaminopyridine in 0.5 ml acetonitrile a solution of 77 mg (0.35 mmol) di-tert-butyl dicarbonate in 0.1 ml toluene was added, and the mixture was stirred at room temperature over night Another portion of 0.026 ml (0.35 mmol) nitroethane and 77 mg (0.35 mmol) di-tert-butyl dicarbonate were added, and stirring was continued for 24 h. Quenching with water was foEowed by extraction with two portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 21 mg (34 %) of the title compound as a light yellow amorphous mass. MS m/e (%): 534 (M+H^, 100). Example 65 6-(3"Amino-prop-l-ynyl)-N-(3,5-bis-trifluoromethyI"benzyl)-N-methyl-4-o-tol^^^ nicotinamide a)N-f3,5-Bis-trifluoromethvl"ben2v])--6-'f3"fl,3--diQXO"13"dihvdro-isoindol-2-vl)-prop-: ynyll-N-methvl-4-o-tolvl-nicotinamide The title compound was obtained as a white sohd in 68 % yield after column chromatography according to the procedure described above for the preparation of N- (3,5-bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-6-trimethylsilanylethynyl- nicotinamide (Example 63, step a)) using N-propargylphthalimide instead of trimethylsiiylacetylene. MS m/e (%): 636 (M+H^ 100). b) 6-r3-Amino-prop"l-vnv])-N-f3>5-biS"trifluoromethvl-benzvI)-N-methyl-4-o-tolyl-nicotinamide A mixture of 206 mg (0-324 mmol) N--(3,5-bis-trifluoromethyl"benzyl)-6-[3-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-prop-l-ynyl]-N-methyi-4-o-tolyI-nicotinamide and 0,061 ml (0.97 mmol) hydrazine hydrate (51 % hydrazine) in 3.5 ml ethanol was stirred at room temperature for 1 h. The reaction mixture was diluted with tert-butyl methyl ether and washed with IN aqueous sodium hydroxide solution. The aqueous layer was extracted witfc three portions of tert-butyl methyl ether. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 93 mg (57 %) of the title compound as a light brown soUd. MS m/e (%): 506 (M+H^, 100). Example 66 2-(3,5-Bis-tri£luororaethyl--phenyl)-N--(6-ethynyl"4-o-tolyl-pyridin-3-yl)-N-methyl- isobutyramide a) 2-f33'Bis-trifluoromethvl--phenyl)-N-methvl-N'f4-o-tolyl-6-trimethylsilanylethynyl- pvridin-3-yl)-isobutvramide The title compound was obtained as an orange gum in quantitative yield after column chromatography according to the procedure described above for the preparation of N- (3,5-bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyI-6-trimethylsiIanylethynyl" nicotinamide (Example 63, step a)) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-iodo-4- o-tolyi-pyridin-3-yl)-N-methyl-isobutyraniide (Example 27) instead of N"(3,5-bis-trifluoromethyl-benTyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide.. MS m/e (%): 577 (M+HT, 100). b)2"f3.5-Bis-trifluorometfavl-phenvI)-N-f6-ethvnvI-4-o-tolvI-pvridin-3-vl)'-N-methyl-isobutvramide The title compoimd was obtained as a brown viscous oil in 52 % yield after column chromatography according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-ben2yl)-6-ethynyl-N-methyl-4-o-tolyI-nicotinamide (Example 63, step b)) using 2-(3,5"biS"trifluoromethyl-phenyl)-N-methyl-N-(4-o-tolyl-6-trim€thylsilanylethynyl-pyridin-3-yl)-isobutyramide instead of N-(3>5-bis--trifluoromethyl-benzyl)-N-methyI-4-o-tolyl-6-trimethyIsilanyIethynyl-nicotinamide. MS m/e (%): 505 (M+H', 100). Example 67 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(3-methyl-isoxazol-5-yI)-4-o-tolyl-pyridin-3-yl] -isobutyramide The title compound was obtained as a light brown soHd in 34 % yield after column chromatography according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl"6-(3-methyl-isoxa2ol-5-yl)-4-0"tolyl-nicotinamide (Example 64) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-ethynyl-4-o-tolyl-pyridin-3-yl)'N-methyl-isobutyramide (Example 66) instead of N-(3,5-bis-trifluoromethyl-benzyl)-6"ethynyl-N-methyl"4-o-tolyl"nicotinamide. MS m/e (%): 562 (M+H% 100). Example 68 2- (3,5-Bis-trifIuoromethyI-phenyI)-N- [6- (3-ethyl-isoxa2ol-5-yI)-4-o-toIyl-pyridiQ-3-yl]-N-methyl-isobutyramide The title compound was obtained as a viscous light yellow oil in 17 % yield after column chromatography according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(3-methyl-isoxa2ol-5-yl)-4-o-tolyl-nicotinamide (Example 64) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-ethynyl-4-o-tolyl-pyridin-3-yl)-N-methyl-isobut5n:amide (Example 66) instead of N-(3,5'bis- trifluoromethyl-benzyl)-6-ethynyl"N-methyl-4-0"tolyl-nicotinamideandl-nitropropane mstead of nitroethane. ; MS m/e (%): 576 (M+lT, 100). Example 69 2"(3,5"Bis-trifluoromethyl-phenyl)-N"[6"(3-hydroxymethyl-isoxazol-5-yl)-4-o-tolyl-pyridin-3-yl] -N-methyl-isobutyramide To a solution of 200 mg (0.396 mmol) 2-(3,5-bis-trifluoromethyl-phenyI)"N-(6-ethynyl-4-o-tolyl-pyridin-3-yl)-N-meth)d-isobutyramide (Example 66)-, 0.182 ml (1.19 mmol) 2-(2-nitroethoxy)tetrahydropyran and 5 mg (0.04 mmol) 4-N,N-dimethylaminopyTidine in 3 ml acetonitrile a solution of 260 mg (1.19 mmol) di-tert-butyl dicarbonate in 2 ml toluene was added, and the mixture was stirred at room temperature for 70 h. Quenching with water was followed by extraction with two portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. The residue was dissolved in 1.5 ml methanol and treated with 4 mg (0.02 mmol) 4-toluenesulfonic add monohydrate. After stirring for 1.5 h at room temperature the solvent was evaporated. The residue was dissolved in ethyl acetate. Washing with saturated sodium bicarbonate solution was followed by drying with sodium sulfate and concentration. Column chromatography afforded 35 mg (15 %) of the titie compovmd as a viscous orange oil. MS m/e (%): 57?, (M+H"", 100). Example 70 2-(3,5-Bis-trifluoromethyI-phenyl)-N-metiiyl-N-[4-o-tolyI-6"(lH-[l,2,3]tria2ol-4-yI)-pyridin-3-yl] -isobutyramide A mixture of 300 mg (0.595 mmol) 2"(3,5-bis-trifluoromethyl-phenyl)-N-(6-ethynyl-4-o-tolyl-pyridin-3"yl)-N-methyl-isobutyramide (Example 66) and 0.30 ml (2.3 mmol) trimethylsilyl azide was heated at 150 °C in a sealed tube over night Cooling to 0 ^'C was followed by addition of 10 ml ethanol. The mixture was allowed to warm to room temperature, stirred for Ih and conentrated. Column chromatography afforded 222 mg (68 %) of the titie compound as a light brown solid. MS m/e (%): 548 (M+H"*", 100). 2-(3,5-Bis-trifluoromethyl-phenyl)-N-meliyl-N-[6-(2-methyl-pyridin-4-ylethynyl)-4-o- tolyl-pyridin-3-yl]-isobutyramide The title compound was obtained as as a brown viscous oil in 61 % yield after column chromatography according to the procedure described above for the preparation of N- (3,5-bis-trifluoromethyl-ben2yl)-N-methyl-4-o-tolyl-6-trimethylsilanylethynyl- nicotinamide (Example 63, step a)) using 4-iodo-2-methyl-pyridine (Example 46, step a)) instead of N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyi-4-o-tolyl-nicotinaniide and2-(3,5-biS"trifluoromethyl"phenyl)-N-(6"ethynyI-4-o-tolyl-pyridin-3-yl)-N-methyI-- isobutyramide (Example 66) instead of trimethylsilylacetylene, MS m/e (%): 596 (M+H", 100). Example 72 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-phenylethynyl-4-o-tolyl-pyridin-3- yl) -isobutyramide The title compound was obtained as as a brown solid in 60 % yield after column chromatography according to the procedure described above for the preparation of N- (3,5-bis-trifluoromethyl-ben2yl)"N-methyl-4-o-tolyl-6-trimethylsilanylethynyl- nicotinamide (Example 63, step a)) using iodobenzene instead of N"(3,5-bis- trifluoromethyl"benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamideand2-(3,5-bis- trifluoromethyl-phenyl)-N-(6-ethynyl-4-o-tolyl-pyridin-3-yl)-N-methyI-isobutyramide (Example 66) instead of trimethylsilylacetylene. MS m/e (%): 581 (M+H^ 100). Example 73 (Z)"2-(3>5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-styryl-4-o-tolyl"pyridin-3-yI)" isobutyramide A mixture of 100 mg (0.198 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-phenylethynyl-4-o-tolyl-pyridin-3-yl)-isobutyramide (Example'72), 10 mg (0.17 mmol) ethylenediamine and 1 mg 10 % palladium on carbon in 2 ml methanol was stirred at room temperature under an atmosphere of hydrogen gas for 8 h. The reaction mixture was filtered and concentrated. Column chromatography afforded 28 mg (24 %) of the tide compound as an orange viscous oil. MS m/e (%): 583 (M+H"", 100). Example 74 2-(3,5"Bis-txifluoromethyl-phenyl)-N-methyl-N-(6-phenethyl-4-o^tolyl-pyri^ isobutyramide A mixture of 20 mg (0,034 mmol) (Z)-2-(3,5-biS"trifluoromethyl-phenyl)-N-methyl-N-(6-styryl-4-o-tolyl-pyridin-3-yl)-isobutyramide (Example 73) and 2 mg 10 % palladium on carbon in 1 ml methanol was stirred at room temperature tmder an atmosphere of hydrogen gas for 2 h. The reaction mixture was filtered and concentrated. Column chromatography afforded 14 mg (72 %) of the title compound as an orange waxy solid. MS m/e (%): 585 (M+H% 100). Example 75 2-(3,5-Bis-trifluoromethyl-phenyl)-N"[6-(3-hydroxy-prop-l-ynyl)-4-o-tolyl-pyridin«3-yl] -N-methyl-isobutyramide a) 2-(3>5-Bis-trifLuoromethyl-phenyl)"N-(6-[3-(tert-butvl-dimethyl-silanyloxy)-prop-l" ynyn-4-o-tolyl-pyridin-3-yn-N'methyI-isobutyramide The title compound was obtained as an orange gum in 78 % yield after column chromatography according to the procedure described above for the preparation of N-(3,5-biS"trifluoromethyl-benzyl)-N-methyl-4-o-tolyI-6-trimethyIsilanylethynyI-nicotinamide (Example 63, step a)) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-iodo-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide (Example 27) instead of N-(3,5-bis-trifluoromethyl"ben2yl)"6-iodo-N-methyl-4"0-tolyl"nicotinamide and tert-butyldimethyl(2-propynyioxy)silane instead of trimethylsilylacetylene. MS m/e (%): 649 (M+ET, 100). b)2-f3>5"Bis-trifluorQmethvl-phenyI)-N-f6'f3-hydroxv-prop-l-ynyl)-4-o-tolyl-pyridin^ yll -N-methvl "isobutyramide To a solution of 167 mg (0.257 nunol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-{6-l3-(tert-butyl-dimethyl-silanyloxy)-prop-l-ynyl]"4-o-tolyI-pyridin-3-yl}-N-methyl-isobutyrami in L5 ml tetrahydroforan a 1 M solution of tetrabutylammonium fluoride in tetrahydroforan was added at room temperature. After stirring for 0,5 h water was added, followed by extraction with four portions of ethyl acetate. The combined organic extracts Arere dried with sodium sulfate and concentrated. Column chromatography afforded 82 ng (60 %) of the title compound as a brown viscous oil. MS m/e (%): 535 (M+H^ 100). Example 76 (RS)-N-(3,5-BiS"trifluoromethyl-benzyl)-6-(hydroxy-phenyl-methyl)-N-methyl-4-o-tolyl-nicotinamide To 1.8 mJ of a 1 M solution of isopropyl magnesium bromide in tetrahydrofuran (1.8 mmol) a solution of 500 mg (0.865 mmol) N-(3,5-bis-trifluoromethyl-ben2yl)"6-iodO"N-methyl-4-o-tolyl-nicotinamide (Example 4) in 10 ml tetrahydrofuran was added drop wise at "40 °C. After 2 h 0.116 ml (1.15 mmol) benzaldehyde were added. The reaction mixture was allowed to warm to room temperature over night. Addition of water and saturated aqueous anmaonium chloride solution was followed by extraction with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 274 mg (57 %) of the title compound as an off-white foam. MS m/e (%): 559 (M+H% 100). Example 77 (RS)-N-(3,5-Bis-trifluoromethyl-ben2yl)-6-(l-hydroxy-hexyl)-N-methyl-4-o-tolyl-nicotinamide The title compound was obtained as an off-white foam in 34 % yield after column chromatography according to the procedure described above for tiae preparation of (RS)-N-(3,5-bis-trifluoromethyl-benzyl)-6-(hydroxy-phenyl-methyl)-N-methyl-4"0-tolyl-nicotinamide (Example 76) using hexanal instead of benzaldehyde. MS m/e (%): 553 (M+H^ 100). Example 78 (RS)-N-(3,5-Bis-trifluoromethyl-ben2yl)-6-(l-chloro-hexyl)-N-methyl-4-o-tolyl-nicotinamide A solution of 50 mg (0.090 mmol) (RS)-N"(3,5-bis-trifluoromethyl-benzyl)-6-(l-hydrox7-hexyl)-N-methyl-4-o-toIyl-nicotinamide (Example 77) and 0,032 ml (0.23 nmiol) triethylamine in 3 ml dichloromethane was treated with 0.008 ml (0.1 mmol) methanesulfonyl chloride at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and then allowed to warm to room temperature. After 1 h 3 ml toluene were added, and the mixture was stirred at 80 °C over night. Cooling to room temperature was followed by dilution with dichloromethane, washing with water, drying with sodium sulfate and concentration. Column chromatography gave 43 mg (83 %) of the title compoimd as a light yellow viscous oil. MS m/e (%): 571 (M+H', 100). Example 79 S-BenzoyI-N-(3,5"bis-trifluoromethyl-benzyl)-N-methyl-4-0"tolyl"nicotinamide To a solution of 0,018 ml (0.21 mmol) oxalyl chloride in 2,5 ml dichloromethane 0.03 ml (0,4 mmol) dimethylsulfoxide were added at -78 **C. After 5 min a solution of 100 mg (0.179 mmol) (RS)-N-(3,5-bis-trifluoromethyl-benzyl)-6-(hydroxy-phenyl"methyl)-N-methyl"4-o-tolyl-nicotinamide (Example 76) in 2.5 ml dichloromethane were added dropwise at -78 'C. After stirring for another 30 min at -78 °C 0.15 ml (0.90 mmol) triethylamine were added. The reaction mixture was allowed to warm to room temperature. Dilution with dichloromethane was followed by washing with three portions of 1 M aqueous hydrochloric acid solution and one portion of a saturated aqueous solution of sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated. Column chromatography afforded 69 mg (70 %) of the title compoimd as a light-yellow foam. MS m/e (%): 557 (M+H^, 100). Example 80 N-(3,5-Bis-trifluoromethyl-benzyI)-N-methyl-6--(pyridine-4-carbonyl)-4-o-tolyl-nicotinamide a) (RS)-N-(3,5-Bi$-'trifluorometfavl-benzvl)-6-fhvdrQxv-pyridin-4-vl-methyl)-N-metfavl-4- o-tolyl-nicotinamide The title compound was obtained as a light brown foam in 18 % yield after column chromatography according to the procedure described above for the preparation of (RS)-N-(3,5-bis-trifluoromethyl-benzyl)-6-(hydroxy-phenyl-methyl)-N-methyl"4-o-tolyl" nicotinamide (Example 76) using 4-pyridinecarboxaldehyde instead of benzaldehyde. MS m/e (o/o): 560 (M+H^, 100). b) N-(3,5'Bis-trifluoromethyl"benzvl')'N'methvl-6-(pyridine-4-carbonvl)-4-o-tolvl- nicotinamide The title compound was obtained as an orange-brown solid in 26 % yield after column chromatography according to the procedure described above for the preparation of 6- benzoyl-N-(3,5-bis-triQuoromethyl-ben2yI)-N"methyl-4-o-tol7l-nicotmamide (Example 79) using (RS)-N-(3,5-bis-trifluoromethyi-ben2yI)-6-(hydroxy"pyridin-4"yI-methyl)-N-methyi"4-o-toiyI-mcotinamide instead of (RS)-N-(3,5-bis-trifluoromethyl-benzyl)-6-(hydroxy-phenyI-methyl)-N-methyl-4-o-tol7l-nicotinamide. MS m/e (%): 558 (M+lT, 100). Example 81 N-(3,5-Bis-trifluoromethyl-ben2yl)"N-methyl"4-o-tolyl-6-(3-trifluoromethyl-phenoxymethyl)"nicotinamide A solution of 80 mg (0,17 mmol) N-(3>5-bis-trifluoromethyl-ben2yl)-6-hydroxymethyI-N-methyl-'4-o-toIyI-nicotinaxnide (Example 7), 0.027 ml (0.22 mmol) 3-hydroxybenzotrifluoride, 47 mg (0,17 mmol) triphenylphosphine and 32 mg (0.17 n^nol) diethyl azodicarboxylate in 2 ml tetrahydrofiiran was stirred at room temperature over night The reaction mixture was diluted with ethyl acetate and washed with IN aqueous sodium hydroxide solution. The aqueous layer was extracted with three portions of ethyl acetate. The combined organic extracts were dried with sodiimi sulfate and concentrated. Coliman chromatography afforded 62 mg (60 %) of the title compound as a light yellow amorphous mass. MS m/e (%): 627 (M+H^ 100), Example 82 N-(3,5-Bis-trifluoromethyl-ben2yI)-N-methyl-6- (2-methyi-imidazoH-yI-methyl)-4-o-tolyl-nicotiaamide To a solution of 100 mg (0.207 mmol) N-(3,5-bis-trifIuoromethyl"ben2yl)-6-hydroxymethyl-N-methyl-4-o-tolyl-nicotinamide (Example 7) in 1 ml dichloromethane 0.03 ml (0.4 mmol) thionyl chloride were added at 0 "^C, The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated and the light yellow residue was dried in high vacuo. The residue was dissolved in 1 ml dry N>N-dimethylformamide and added to a suspension of 2-methyliiQida2ole sodium salt that had previously been prepared by addition of 54 mg (1,2 mmol) sodium hydride (55 % dispersion in mineral oil) to a solution of 52 mg (0.62 mmol) 2-methylimida2ole in 3 ml dry N,N-dimethylformamide imder argon at room temperature. After stirring for 3 h the reaction was quenched by addition of excess water, followed by extraction with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chxomatography afforded 52 mg (46 %) of the title compound as an orange solid. "^o' MS m/e (%): 547 (M+H^ 100). Example 83 N-(3,5-Bis-trifluoromethyl-ben2yl)-N"methyl-6-morpholin-4-yl-methyl-4-o-toIyl- nicotinamide The title compound was obtained as a viscous brown oil in 82 % yield after column chromatography according to the procedure described above for the preparation of N- (3,5-bis-trifluoromethyl-ben2yl)-N-methyi-6-(2-methyl-imidazoI-l-yl-methyl)-4-o-tolyl- nicotinamide (Example 82) using moipholine instead of 2-methylimidazole and potassium carbonate instead of sodium hydride, MS m/e (%): 552 (M+H^ 100). Example 84 N-(3,5-Bis-trifluoromethyl-ben2yl)-6-(2-hydroxy-ethylsxdfanylmethyl)-N-methyl^ tolyl-nicotinamide The title compotmd was obtained as a viscous yellow oil in 39 % yield after column chromatography according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-benz7l)-N-methyl-6-(2-methyl-irnida2ol-l-ylmethyl)-4-o-tolyl-nicotinamide (Example 82) using 2-mercaptoethanol instead of 2-metiiylimidazole and potassium carbonate instead of sodium hydride. MS m/e (%): 543 (M+H^ 100). Example 85 (RS)-N-(3,5-BiS"trifluoromethyI-ben2yl)-6-(2-hydroxy-ethanesiiIfinyImethyl)-N-methyl-4-o-tolyl-nicotinamide and Example 86 N-(3,5-BiS"trifluoromethyl-benzyl)-6-(2-hydroxy"ethanesiilfonyl)-N-methyl-4-o-tolyl- nicotinamide To a solution of 30 mg (0.057 mmol) N-(3,5-bis-trifluoromethyl"benzyl)-6-(2-hydroxy- ethylsulfanylmethyl)-N-methyl-4"0-tolyl-nicotinamide (Example 84) in 2 ml dichloromethane a solution of 14 mg (0.057 mmol) 3-chloroperbenzoic acid (70 %) in 1 ml dichloromethane was added at 0 °C. After 30 min the reaction niixture was diluted with dichloromethane, washed with 1 M aqueous sodium hydroxide solution, dried with magnesium sulfate and concentrated Column chromatography afforded 18 mg (58 %) (RS)-N-(3,5-bis-trifluoromethyl-benzyl)-6-(2-hydrox7-ethanesulfinylmethyl)"N-methyl-4-o-tolyl-nicotinamide as a viscous colorless oil and 4.3 mg (14 %) N-(3,5-biS" trifluoromethyI-benzyI)-6-(2-hydroxy-ethanesuIfonyl)-N-methyI-4-o-toIyI-nicotinamide as a viscous light-yellow oil. (RS)-N-(3,5--Bis-trifluoromethyl-benzyl)-6-(2"hydroxy-ethanesulfinyhnethyl)-N-methyl-4-o-tolyI-nicotinamide: MS m/e (%): 559 (M+H^ 100). N-(3,5-Bis-trifluoromethyl-benzyl)-6-(2-hydroxy-ethanesulfonyl)-N-methyl-4-o-tolyl-nicotinamide: MS m/e (%): 575 (M+H"^, 100). Example 87 N-(3,5-Bis-trifluoromethyI-benzyI)-N-methyl-6-(l-methyi-lH"imidazol-2-ylsulfanylmethyl)-4-o-tolyl-nicotinamide The title compound was obtained as a viscous yellow oil in 66 % yield after column chromatography according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-ben2yl)-N-methyl-6-(2-methyl-imidazol-l-ylmethyl)-4-o-tolyl-nicotinamide (Example 82) using 2"mercapto-l-methylinaida2ole instead of 2-methylimidazole and potassium carbonate instead of sodiimi hydride. MS m/e (%): 579 (M-^H^ 100). Example 88 (RS)-N-(3,5-Bis-trifluoromethyl"benzyi)-N-methyl-6-(l-methyl-lH-imidazole-2- sulfinylmethyl)"4-o-tolyI-nicotinamide The title compoxmd was obtained as a viscous light yellow oil in 87 % yield after column chromatography according to the procedure described above for the preparation of (RS)- N-(3,5-biS"trifluoromethyl-benzyl)-6--(2-hydroxy-ethanesulfinylmethyi)-N-methyl-4"0- tolyl-nicotinamide (Example 85) using N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl"6- (l-methyl-lH-imidazol-2-ylsulfanylmethyl)-4-o-tolyl"nicotinamide (Example 87) instead ofN-(3,5-bis-trifluoromethyl"ben2yl)-6-(2-hydroxy-ethylsulfanylmethyl)-N-methyl-4-o- tolyl-nicotinamide. MS m/e (%): 595 (M+lT, 100). Example 89 N-(3,5-Bis-trifluoromethyl-benzyl)-6-[3-(4-methoxy-plienyl)-propyl]-N-methyl-4-o- tolyl-nicotinamide Deoxygenation of a solution of 89 mg (0.58 mmol) 4-allylanisole in 3 ml tetrahydrofiiran by three freeze-thaw q^cles was followed by addition of 73 mg (0.29 mmol) 9-borabiq?'clo[3.3.1]nonane dimer at room temperature under an atmosphere of argon. After 1.5 h 43 mg (0.58 mmol) potassium methoxide were added, and stirring was continued for 20 min. In one portion 250 mg (0.432 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N'meth)d-4-o-tolyl-nicotinamide (Example 4) were added, followed by a suspension of 10 mg (0.043 mmol) palladi\ma(II) acetate and 37 mg (0.086 mmol) l>3-bis-(2,6-diisopropyl-phenyl)-3H-imidazoI-l-iimi chloride in 0.5 ml tetrahydrofuran. The reaction mixture was heated at reflux for 2 h. Cooling to room temperature was followed by dilution with tert-butyl methyl ether and washing with two portions of 1 M aqueous sodium hydroxide solution. The combined aqueous layers were extracted with tert-butyl methyl ether. The combined organic extracts were dried with magnesium sulfate and concentrated. Column chromatography afforded 184 mg (71 %) of the title compoimd as a light-yellow amorphous mass. MS m/e (%): 601 (M+H% 100). Example 90 N-(3,5-Bis-trifluoromethyl-ben2yl)-6-(4,4-diinethyl-pentyl)-N"methyl-4-o-tolyl- nicotinamide The title compound was obtained as a light-yellow amorphous mass in 72 % yield after column chromatography according to the procedure described above for the preparation ofN-(3,5-bis-trifluoromethyI-benzyI)-6-[3-(4-methoxy-phenyI)-propyl]-N-methyl-4-o- tolyl-nicotinamide (Example 89) using 4,4-dimethyl-l-pentene instead of 4-aIlylanisole. MS m/e (%): 551 (M+H"", 100). Example 91 N-(3,5-Bis-trifluoromethyl-beiizyl)-6-(3-cyano-propyl)'N-niethyl-4-o-tolyl-mcotinamide The title compound was obtained as a light-yellow amorphous mass in 72 % yield after column chromatography according to the procedure described above for the preparation ofN-(3,5-bis-trifluoromethyl-benzyl)-6-[3-(4-methoxy-phenyl)-propyl]-N-methyl-4-o-tolyl-nicotinamide (Example 89) using aUylcyanide instead of 4-allylanisole. MS m/e (%): 520 (M+H^ 100). Example 92 N-(6-Acetyl-4-o-tolyl-pyridin-3-yl)"2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl" isobutyramide A solution of 300 mg (0.495 mmol) 2-(3>5-bis-trifluoromethyl-phenyl)-N-(6-iodo-4-o--tolyl-pyridin-3-yl)-N-methyl-isobutyramide (Example 27) and 0.20 ml (0.59 nmiol) 1-ethoxyvinyltri-n-butyltin in 1 ml toluene was deoxygenated by three freeze-thaw cycles. After addition of 17 mg (0.025 mmol) bis(triphenylphosphine)palladium(II) chloride the reaction mixture was heated at reflux for 16 h. Cooling to room temperature was followed by addition of 1 ml 2 M aqueous hydrochloric acid solution. After 15 min 2 ml IN aqueous sodium hydroxide solution and 35 mg (0.59 mmol) potassiima fluoride were added, followed by extraction with four portions of ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate and concentrated. Column chromatography afforded 147 mg (57 %) of the title compoimd as a colorless gum. MS m/e (%): 523 (M+H% 100). Example 93 6-(2-Amino-thiazol-4-yl)-N-(3,5-bis-trifluoromethyl-ben2yl)-N-methyl-4-o-tolyl-nicotinamide a)N-(33-Bis-trifluoromethvl-benzvl)"6-(l-ethoxy-vinvl)-N-methvl-4-o-tolyl-nicotinamide A solution of 1.00 g (1.73 mmol) N-(3,5-bis-trifluoromethyl-ben2yl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) and 0.61 ml (1.8 mmol) 1-ethoxyvinyltri-n-butyltin in 5 ml toluene was deoxygenated by three freeze-thaw cycles. After addition of 61 mg (0.087 mmol) bis(triphenylphosphine)palladium(II) chloride the reaction mixture was heated at reflux for 16 h. The mixture was cooled to room temperature, treated with 500 mg (2.25 mmol) potassium fluoride on aluminum oxide (5.5 mmol fluoride/g) and stirred for 15 min. After filtration and washing with toluene the filtrate was concentrated. Colimin chromatography afforded 592 mg (66 %) of the title compound as a light yellow foam. MS m/e (%): 523 (M+H\ 100). b) N-(3.5-Bis-trifluoromethvl-ben2vD-6-bromoacetyl-N-methvl-4-o-toIyl-nicotinamide A mixture of 592 mg (L13 mmol) N-(3,5-bis-trifluoromethyI-benzyl)-6-(l-ethoxy-vinyl)-N-methyl-4-o-tolyl-nicotinamide and 203 mg (1.13 mmol) N-bromosuccinimide, 10 ml tetrahydrofuran and 1 ml water was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with:saturated sodium bicarbonate solution. The aqueous layer was extracted with two portions of ethyl acetate. The combined organic layers were diied with sodium sulfate and concentrated. Column chromatography afiforded 586 mg (90 %) of the title compound as a light orange viscous oil. MS m/e (%): 573 (M+H^ 100). c) 6-(2-Amino-thia2ol-4'Vl)-N-(3,5-bis-trifluoromethvl-benzvD-N"methyl-4*o-tolyl-nicotinamide A mixture of 73 mg (0.13 mmol) N-(3,5-bis-trifiuoromethyl-benzyl)-6-bromoacetyl-N-metiiyl-4-o-tolyl-nicotinamide and 12 mg (0.15 mmol) thiourea in 1 ml ethanol was heated at reflux for 30 min. After cooling to room temperature the solvent was evaporated in vacuo and the residue was dissolved in etbyl acetate. Washing with 1 M aqueous sodium hydroxide solution was followed by extraction of the aqueous layer with three portions of ethyl acetate. The combined organic layers were dried with sodium sulfate and concentrated. Column chromatography afforded 62 mg (88 %) of the title compotmd as a hght orange solid. MS m/e (%): 551 (M+H^, 100). Example 94 N-(3,5-Bis-trifluoromethyl-benzyl)"N-methyl-6-(2-methyl-1iiazol-4-yl)-4-o-tolyl" nicotinamide The title compound was obtained as an off-white foam in comparable yield after column chromatography according to the procedures described above for the preparation of 6-(2-amino-thiazol-4-yl)-N-'(3,5-bis-trifluoromethyl-benzyl)"N-methyl-4-o--tolyl"nicotinamide (Example 93) using thioacetamide instead of thiourea in step c), MS m/e (%): 550 (M+H', 100). Example 95 5-{[2-(3,5-Bis-trifluoromethyl-phenyl)-2-metiiyl-propibnyI]-methyl-amino}-4-o-tol^^^ pyridine-2-carboxyiic acid methyl ester A solution of 100 mg (0.165 mmol) 2-(3,5-bis-trifluoromethyI-phenyl)-N-(6-iodo-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide (Example 27), 0.046 ml (0.33 mmol) triethylamine, 4 mg (0.02 mmol) triphenylphosphine and 0.27 ml (6.6 mmol) methanol in 2.5 ml N,N-dimethylformamide was deoxygenated in a glas flask by three freeze-thaw qrdes. After addition of 4 mg (0.02 mmol) palladium(II) acetate under argon the flask containing the reaction mixture was transferred to an autoclave which was sealed and pressurized with carbon monoxide gas to 60 bar. After stirring at 50 °C for 16 h the mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were washed with water, dried with sodium sulfate and concentrated. Hash chromatography aflforded 48 mg (54 %) of the title compotmd as an orange gum. MS m/e (%): 539 (M+H% 100). Example 96 N-(3,5-Bis-trifluoromethyl-benzyl)-6-inethanesulfonyl-N-methyl-4-o-tolyl-nicotinaniide A mixture of 369 mg (0.758 mmol) N-(3,5-bis-trifiuoromethyl-ben2yl)-6"Chloro-N-methyl-4-o-tolyl-nicotinamide (Example 2) and 176 mg (1.67 mmol) sodium methanesulfinate in 4 ml N,N-dimethylformamide was heated at reflux over night After codling to room temperature the mixture was diluted with dichloromethane and treated with saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with three portions of dichloromethane. The combined organic layers were dried with sodimn sulfate, concentrated and and dried in high vacuo. Flash colimxn chromatography gave 118 mg (29 %) of the title compound as a white solid. MS m/e (%): 531 (M+H^ 100). Example 97 6-Bexizenesiilfonyl-N-(3,5-bis-trifluoromethyl-ben2yl)-N-methyl-4-o-tolyl-nicotinanude The title compound was obtained as an off-white solid in 29 % yield after column chromatography according to the procedure described above for the preparation of N-(3,5-bis-tri£luoromethyl-benzyl)-6-methanesulfonyl-N-methyl-4-o-tolyl-nicotinamide (Example 96) using sodium benzenesulfinate instead of sodium methanesulfinate. MS m/e (%): 593 (M+JFT, 100). Example 98 N-(3,5-Bis-trifluoromethyl-beiizyl)-N"methyl-6-(pyridin-2-ylsidfanyl)-4-o-to^ nicotinamide A solution of 250 mg (0.432 mmol) N"(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-toiyl-nicotinamide (Example 4), 0.090 ml (0.65 mmol) triethylamine and 59 mg (0.52 mmol) 2-mercaptopyridine in 4 ml tetrahydrofiiran was deoxygenated by three freeze-thaw cycles. After addition of 15 mg (0.022 mmol) bis(triphenylphosphine)palladium(n) chloride the reaction naixture was heated at reflux over night. Cooling to room temperature was followed by dilution with efhyl acetate and washing with satxirated aqueous sodium carbonate solution and brine. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate and concentrated. Column chromatography afforded 210 mg (87 %) of the tide compound as a light yellow amorphous mass. MS m/e (%): 562 (M-fH% 100). Example 99 (RS)"N-(3,5-Bis-tri&uoromethyl-benzyl)-N-meliiyl-6-(pyridine-2-sulfinyl)-4-o-tol^^^ nicotinamide and Example 100 N-(3>5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(pyridine-2-sulfonyl)-4-0"tolyl-nicotinamide A mixture of 198 mg (0.353 mmol) N-(3,5"bis-trifluoromethyl-benzyl)-N-mefhyl-6-(pyridin-2-ylsulfanyl)-4-o-tolyl-nicotinamide (Example 98), 216 mg (0.353 mmol) Oxone, 3,5 ml methanol and 0.7 ml water was stirred at room temperature for 70 h. Dilution with IN aqueous sodium hydroxide solution was followed by extraction with three portions of dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated. Colunm chromatography afforded 31 mg (15 %) (RS)-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6--(pyridine-2-sulfinyl)"4-o-tolyl"nicotinaniideasan off-white amorphous mass and 80 mg (38 %) N"(3,5-biS"trifluoromethyl"benzyl)-N-methyl-6-(pyridine-2-sulfonyl)-4-o-tolyl-nicotinamide as an off-white amorphous mass. (RS)-N-(3>5-BiS"1xifluoromethyl-benzyl)-N-methyl-6-(pyridine-2-sulfinyl)-4-o-tolyl-nicotinamide: MS m/e (%): 578 (M+H^ 100). N-(3,5-BiS"lTifiuoromethyl-benzyl)-N-methyl-6-(pyridine-2-sulfonyl)"4-o-tolyl-nicotinamide: MS m/e (%): 594 (MH-H% 100), Example 101 N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-4H-[l,24]tria2ol-^ ylsulfanyl)-4-o-tolyl-nicotinamide The title compound was obtained as a light yellow solid in 49 % yield after column chromatography according to the procedure described above for the preparation of N- (3,5-biS"trifluoromethyl-benzyl)-N-methyl-6-(pyridin-2-ylsulfanyl)-4-o-tolyl- nicotinamide (Example 98) using 3-mercapto-4-methyl-4H-l,2>4-triazole instead of 2- mercaptopyridine. MS m/e (%): 566 (M+H^ 100). Example 102 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(4-methoxy-phenykiiIfanyl)-4-o-tolyl-py^ 3-yI] -N-methyl-isobutyramide The title compound was obtained as an orange gum in 22 % yield after column chromatography according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-ben2yl)"N-methyl-6*(pyridin-2-ylsulfan)d)-4-o-tolyl-nicotinamide (Example 98) using 2-(3,5-bis-trifluoromethyl-phenyl)"N-(6-iodo-4-o-tolyl" pyridin-3-yl)-N-methyl-isobutyramide (Example 27) instead of N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide and 4-methoxyfhiophenol instead of 2-mercaptopyridine. MS m/e (%): 619 (M+H"", 100). Example 103 2-(3,5"Bis-trifluoromethyl-phenyl)-N-[6-(3-methox7-phenylsxilfanyl)-4-o-tolyl-pyridin- 3-yl]-N-methyl-isobutyramide The title compound was obtained as a grey solid in 71 % yield after column chromatography according to the procedure described above for the preparation of N- (3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(pyridin-2-ylsulfanyl)-4-o-tolyl- nicotinamide (Example 98) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-iodo-4-o-tolyl- pyTidin-3-yl)-N-methyl-isobutyramide (Example 27) instead ofN-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o--tolyl-niGotinanQide and 3-methoxj^thiopbenol instead of 2-mercaptopyridine. MS m/e (%): 619 (M+H"", 100). Example 104 (RS)-2-(3,5"Bis-trifluoromethyl-plienyl)-N-[6-(3-methoxy-ben2enesuIjBnyl)-4-o-tolyl-pyridin-3-yl] -N-methyl-isobutyramide To a solution of 130 mg (0.210 mmol) 2-(3,5-bis-trifluoromethyl"phenyl)-N-[6-(3-methoxy-phenylsdfanyl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyraniide (Example 103) in 1 ml dichloromethane a solution of 52 mg (0.21 mmol) 3-chloroperbenzoic acid in 1.5 ml dichloromethane was added at 0 ®C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred over night. The reaction ntiixture was diluted with, dichloromethane and washed with saturated aqueous sodium carbonate solution. The aqueous layer was extracted with three portions of dichloromethane. The combined organic layers were dried with sodium soalfate and concentrated. Colunan chromatography afforded 9 mg (7 %) of the title compound as a colorless viscous oil. MS m/e (%): 635 (M-i-H^, 100). Example 105 (5-{[2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-anuno}-4-o-tolyl-pyridin-2-ylsulfanyl)-acetic acid methyl ester The title compound was obtained as a viscous orange oil in 12 % yield after column chromatography according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-ben2yl)-N-methyl-6"(pyridin-2-ylsulfanyl)-4-o-tolyl-nicotinamide (Example 98) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6"iodo-4-o-tolyl-pyridin-3"yl)-N-methyl-isobutyramide (Example 27) instead of N-(3,5-bis-trifIuoromethyl-ben2yl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide and methyl thioglycolate instead of 2-mercaptopyridine. MS m/e (%): 585 (M+lT, 100). Example 106 3-(5-{[2-(3,5-BiS"trifluoromethyl-phenyl)-2-methyl-prbpionyl]-methyl-amino}-4-o pyridin-2-ylsulfanyl)-propionic acid methyl ester The title compound was obtained as a viscous colorless oil in 37 % yield after column chromatography according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl"beiizyl)-N-methyl-6-(pyridin"2"-jdsvilfanyl)-4-o-tolyl-nicotinamide (Example 98) using 2-(3,5-bis-trifluoromethyI-phenyl)-N-(6-iodo-4-o-tolyl-pyridin-3-yI)-N-methyl-isobutyramide (Example 27) instead ofN-(3,5-bis-trifluoromefhyl-benzyl)"6-iodo-N"methyl-4-o-tolyl-nicotinamide and methyl 3-mercaptopropionate instead of 2-mercaptopyridine, MS m/e (%): 599 (M-fH^, 100). Example 107 N-(3,5-Bis-ttifluoromethyl-ben2yl)-6-(3-cyano-phenoxy)-N-methyl-4"0-tolyl-nicotinanaide A solution of 200 mg (0.346 nunol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) and 84 mg (0.69 mmol) 3-hydroxybenzonitrile in 4 mi pyridine was deoxygenated by three freeze-thaw cycles. After addition of 5 mg (0.04 mmol) copper(I) oxide and 96 mg (0.69 mmol) potassium carbonate under a stream of argon the reaction mixture was heated at reflux for 70 h. Cooling to room temperature was followed by dilution with tert-butyl methyl ether and washing with two portions of 1M aqueous hydrochloric acid solution. The combined aqueous layers were extracted with tert-butyl methyl ether. The combined organic layers were washed with saturated aqueous sodium carbonate solution and brine, dried with sodium sulfate and concentrated- Column chromatography afforded 174 mg (88 %) of the titie compound as a light brown solid. MS m/e (%): 570 (M+H^ 100). Example 108 2-(3,5-Bis-trifluoromethyl-phenyl)"N-meliiyl-N-[4-o-tolyl-6"(4-[l,2,4]triazol-l-yl- phenoxy)-pyridin-3-yl] -isobutyramide The title compound was obtained as a viscous light yellow oil in 78 % yield after colunan chromatography according to the procedure described above for the preparation of N- (3,5"bis-trifluorom€thyl-benzyl)-6-(3-cyano-phenoxy)-N-methyl-4-o-tolyl-nicotinainide (Example 107) using 2-(3,5-bis-trifluoromethyl-phenyl)"N-(6-iodo-4-o-tolyl-pyridin-3- yl)-N-methyl-isobutyrainide (Example 27) instead of N"(3,5-bis-trifluoromethyl-ben2yl)-6-iodO"N-methyl-4-o-tolyl-nicotinainide and 4-(l,2,4-triazol-l-yl)phenol instead of 3-hydroxybenzonitrile. MS m/e (%): 640 (M+H*", 100). Example 109 2-(3>5-Bis-trifluoromethyl-phenyl)-N-[6"(4-methanesiilfonyl-phenoxy)-4-o-tolyl^^ 3-yl] -N-methyl-isobutyramide The title compound was obtained as a light-yellow solid in 47 % yield after column chromatography according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-benzyI)"6-(3-cyano-phenoxy)-N"methyl-4-o-tolyl-nicotinanMde (Example 107) using 2"(3,5-bis-trifluoromethyl-phenyl)-N"(6-iodo-4-o-toIyI-pyridin-3-yl)-N-methyl-isobutyraniide (Example 27) instead of N-(3,5-bis-trifluoromethyl-benzyi)-6-iodo-N-methyl-4-0"tolyl-nicotinamide and 4-methylsulphonylphenol instead of 3-hydroxybenzonitrile. MS m/e (%): 651 (M+H^, 100). Example 110 2-(3,5-Bis-trifluoromethyl-phenyl)-N-{6-(4-cyano-phenoxy)-4-o-tolyl-pyridin-3-yl]-N-methyHsobutyramide The title compoxmd was obtained as a light-yeUow solid in 77 % yield after column chromatography according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-benzyl)"6"(3-cyano-phenoxy)-N-methyi-4-o-tolyl-nicotinamide (Example 107) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-iodo-4-0"tolyI-pyridin-3-yl)-N-methyl-isobutyramide (Example 27) instead of N-(3,5-bis-trifluoromethyl-ben2yl)-6-iodO"N-methyl-4-o-tolyl-nicotinamide and 4-hydroxybenzonitrile instead of 3-hydroxybenzonitrile. MS m/e (%): 598 (M+H^, 100). Example 111 N-(3,5-BiS"trifluoromethyI-ben2yl)-6-hydroxy-N-methyl-4-o-tolyl-nicotinamide a) 6-Chloro-N-methvl-nicotinamide To 50 g (317 mmol) of 2-chIoronicotimc acid were added 230 ml (3,16 mol) thionyl chloride at 0 ^C. After heating the mixture at reflux for 2 h excess thionyl chloride was removed by distillation. The oily brown residue was dissolved in 250 ml dichloromethane. The solution was treated with methyJamine gas at 0 **C until no exothermic reaction was observed any longer. The resulting suspension was diluted with 1000 ml dichloromethane/water. The layers were separated and the aqueous layer extracted with three 300-ml portions of dichloromethane. Drying of the combined organic layers with sodium sulfate and concentration gave 53.2 g (98 %) of the title compound as a light yellow solid. MS m/e (o/o): 171 (M+H^ 15). h) 6-Chloro-N-methvl-4*o-tolvl-nicotinamide To a solution of 3-41 g (20,0 mmol) 6-chloro-N-methyl-nicotinamide in 80 ml tetrahydrofuran 50 ml (50 mmol) of a 1M solution of o-tolyl magnesium chloride in tetrahydroforan was added dropwise at 0 °C. After completed addition the reaction mixtmre was allowed to warm to room temperature and stirred for 1.5 h. The mixture was again cooled to 0 ^C, followed by the dropwise addition of 5.7 ml (100 mmol) acetic acid and a solution of 5.1 g (22 mmol) 2,3-dichioro-5,6-dicyano-l,4-benzoquinone in 18 ml tetrahydrofiiran. After completed addition the reaction mixture was allowed to warm to room temperature and stirred for 15 min. Addition of 30 ml 2 N aqueous sodium hydroxide solution was followed by dilution with 11 ethyl acetate and 200 ml water. The layers were separated and the organic layer was washed with 4 250-ml portions of 2 N aqueous sodium hydroxide solution. The combined aqueous layers were extracted with 3 500-ml portions of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution and dried with sodium sulfate. Concentration gave 5.44 g of a brown-red oil. Flash colunm chromatography afforded 2.15 g (41.3 %) of the tide compound as a light yellow solid.), M.p. 91-93 °C. MSm/e(%):260(M%ll). c) N-Methyl-6-morpholin-4-vl-4-o-toIvI-nicotinamide A mixture of 1.00 g (3.84 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide, 0.37 ml (4.22 mmol) morpholine, 2.0 nJ. (12 mmol) N-ethyldiisopropylamine and a catalytic amoxmt of 4-(N>N-dimethylamino).-pyridine was heated at 100 °C over night After cooling to room temperature the mixture was dissolved in ethyl acetate and washed with two portions of water. The combined aqueous layers were extracted with 3 portions of dichloromethane. Drying with sodium sulfate and concentration gave 1.23 g of the crude product. Flash column chromatography afforded 1.11 g (92.9 %) of the title compound as an off-white solid. M.p. 156-158 ^C. MSm/e(%):311(M^64). d) N-f3.5-Bis-trifluoromethvl"benzvl)-N-methvI-6-morpholin-4-vl-4-o-tolvl-nicotinamide To a solution of 0.27 g (0.87 mmol) N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinanaide in 15 ml tetrahydrofuran, 1.12 ml of a 1 M solution (1.12 mmol) of potassium hexamethyidisilazide in tetrahydrofuran was added at 0 ""C, After 30 min, 0.16 ml (0.87 mmol) 3>5-bis(trifluoromethyl)benzyl bromide were added dropwise and the reaction mixture was allowed to warm to room temperature over night Quenching with water was followed by extraction with ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography gave 0.20 g (44 %) of the tide compound as a white solid. MS m/e (%): 538 (M+H^ 100). e)N-f3,5-Bi5'trifluoromethy]-benzyl)-N-methyl-6-f4-oxv-morpholin-4-yI)"4-o-tolyl" nicotinamide monohydrate To a solution of 0.43 g (0.81 namol) N-(3,5-bis-trifluoromefh)d-benzyl)-N-methyl-6-morpholin-4-yl-4-o*tolyl-nicotinamide in 5 ml dichloromethane 0.15 g 3-chloroperbenzoic acid (70 %; 0.76 mmol) were added at 0°C. After 1.5 h the reaction mixture was diluted with dichloromethane and washed with 3 portions of saturated sodium carbonate solution. The combined aqueous layers were extracted with dichloromethane. The combined organic extracts were washed with saturated sodiuna chloride solution, dried with sodium sulfate and concentrated. Colunm chromatography gave 0.29 g (65 %) of the title compound as a white solid. MS m/e (%): 554 (M+H*^, 100). f) N-(3,5-BiS'trifluoromethyl-benzyl)-6-hydroxv-N-methyl-4-o-tolyl-nicotinamide A solution of 0.29 g (0.52 mmol) N-(3,5-bis-trifluoromethyl-benzyI)-N-methyl"6-(4-oxy-morpholin-4-yI)-4-o-toIyl-nicotinamide monohydrate in 5 ml toluene was heated at reflux over night. After cooling to room temperature the reaction mixture was diluted with ethyl acetate and washed with 1 M aqueous hydrochloric acid solution. The organic layer was dried with sodium sulfate and concentrated. Column chromatography gave 0.17 g (71 %) of the title compound as a viscous yellow oil. : MS m/e (%): 467 ([M"H]^ 4). Example 112 6-Benzyloxy-N-(3,5-bis-trifluoromethyl-beixzyl)-N-methyl-4-o-tolyl-iucotinamid^ A mixture of 50 mg (0.11 mmol) N-(3,5-bis-trifluoromethyl-ben2yl)-6-hydroxy-N-methyl-4-o-tolyl-nicotinamide (Example HI), 0.014 ml (0.12 mmol) benzyl bromide and 59 mg (0.21 nunol) silver carbonate in 2 ml dichloromethane was heated at reflux for 2 h. Coohng to room temperature was followed by dilution with dichloromethane and filtration. The filtrate was washed with water. The aqueous layer was extracted with three portions of dichloromethane. The combined organic layers were dried with sodium sulfate, concentrated and dried in high vacuo. Column chromatography afforded 24 mg (41 %) of the title compound as a viscous light yellow oil. MS m/e (%): 559 (M+H% 100). Example 113 N-(3,5"Bis-trifluoromethyl-benzyl)-6-(3*hydroxy-propoxy)-N-methyl-4-o-tolyl-nicotinamide The title compound was obtained as a viscous light-red oil in 33 % yield after column chromatography according to the procedure described above for the preparation of 6-ben2yloxy-N-(3,5-bis-trifluoromethyl"ben2yl)-N-methyl-4-0"tolyl-nicotinamide (Example 112) using 3-iodopropanol instead of benzyl bromide. MS m/e (%): 527 (M+H"", 100). Example 114 2-(3,5-Bis-trifluoromethyl-phenyl)"N-(6-hydroxy-4-o-tolyl-pyridin-3-yl)-N-methyl- isobutyremaide a) 4-(5-Nitro-2-pvridyl)-morpholine To a solution of 20 g (126 mmol) of 2-chloro-5"nitropyridine in 150 ml tetrahydrofuran were added dropwise 27 ml (315 mmol) morpholine within 10 min. The reaction mixture was refluxed for additional 2 h. After cooling to room temperature, the solvent was removed in vaaio and the residue was re-dissolved in 200 ml ethyl acetate. The organic phase was washed with 200 ml 1 N sodium bicarbonate solution, dried (magnesium sulfate) and evaporated to give 27.3 g (quantitative) of the tide compound as a yellow solid. M,p. 142-143 °C. b)2,2-Dimethvl-N-f6-morpholin-4"yl-pvridin-3-vl)"propionamide To a solution of 27.3 g (126 mmol) of 4-(5-nitro-2-pyridyl)-morpholine in 600 ml methanol were added 2.5 g of 10 % of palladium on activated charcoal. The reaction mixture was hydrogenated (room temperature to ecu 45 °C, 1 bar) until the theoretical amount of hydrogen was taken up (about 3 h). The catalyst was filtered off and was washed twice with 100 ml portions of methanol. The filtrate was evaporated in vacuo to give 22.6 g of a purple oil which consisted to CCL 95 % of the desired aniline derivative according to analysis by thin layer chromatography. This crude product was dissolved in a mixture of 240 ml tetrahydroforan and 60 ml diethyl ether. After cooling to 0 *^C, 26 ml (189 mmol) of triethylamine were added in one portion-Stirring was continued while 23 g (189 mmol) of pivaloyl chloride were added dropwise within a period of 10 min. The ice bath was removed and the reaction mixture was stirred for 1 h at room temperature. Then, the solvent was removed in vacuo and the residue was suspended in 200 ml 1N sodium bicarbonate solution. The product was extracted three times with 200 ml portions of dichloromethane, dried (sodium sulfate) and evaporated, RecrystaUization of the solid residue firom ethyl acetate/hexane 1:8 gave 28.6 g (86 %) of the title compound as white crystals. MS m/e (%): 264 (M+H^, 100). c)N-(4-Iodo-6-morpholin-4-vl-pvridin-3-yD-2>2"dimethyl-propionamide A solution of 28.4 g (108 mmol) 2,2-dimethyl-N-(6-morpholin-4-yl"pyridin-3-yl)" propionamide and 49 ml (324 mmol) N,N,N',N'-tetramethylethylenediamine under argon in 600 ml tetrahydroforan was cooled in a dry ice hath to -78 °C. Within 1 h, 202 nil (324 mmol) of a 1.6 N n-butyUithium solution in hexane were added dropwise. The reaction mixture was allowed to warm up to -35 °C overnight After cooling again to -78 °C, 37 g (146 mmol) iodine dissolved in 60 ml tetrahydroftiran were added dropwise during 15 min. The dry ice bath was replaced by an ice bath and a solution of 90 g (363 mmol) sodium thiosulfate pentahydrate in 250 ml water were added within 10 min when the temperature of the reaction mixture had reached 0 °C. Then, 1000 ml diethyl ether were added and the organic layer was separated. The aqueous layer was extracted twice with 500 ml dichloromethane and the combined organic layers were dried (magnesium sulfate) and evaporated. Flash chromatography gave 15.6 g (37 %) of ±e title compound as a light brown oil which crystallized upon standing at room temperature. . MS m/e (%): 389 (M^, 71), 358 (25), 304 (43), 57 (100). d)2.2-Dimethvl-N-f6-morpholin-4-vl-4-Q-tolvl-pvridin-3-yl)-propionamide A mixture of 3,50 g (9.0 mmol) N-(4-iodo-6-morpholin-4-yl-pyridin-3-yl)-2,2-dimethyl-propionamide, 35 ml toluene, 18 ml 2 N sodium carbonate solution, 312 mg (0.27 mmol) tetralds(triphenylphosphine)paIladium(0) and 1.34 g (9.9 nmiol) o-tolylboronic acid was heated under argon at 80 °C for 12h. After cooHng to room temperature, the aqueous phase was separated and washed twice with ethyl acetate. The combined organic layers were washed with 50 ml brine, dried (sodium sulfate) and evaporated. Purification by flash-chromatography gave 3.23 g (quantitative) of the title compound as a white foam. MS m/e (%): 354 (M+H^ 100). e) 6-Morpholin"4-yl-4-o-tolvl-pvridin-3-vlamine A suspension of 2.93 g (8.28 mmol) 2,2-dimethyl-N"(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-propionamide in 80 ml 3 N hydrochloric acid solution and 5 ml l-propanol was heated to 90-95 °C overnight. The reaction mixture was cooled to room temperature, washed with three 20 ml portions diethyl ether and filtered over celite. The filtrate was diluted with 20 ml water and was adjusted to pH 7-8 by addition of 28 % sodiiun hydroxide solution imder ice cooling* The product was extracted with four 100 ml portions of dichloromethane. The combined organic layers were washed with 50 ml brine, dried (magnesium sulfate) and evaporated to give 2.31 g (quantitative) of the title compound as a white foam. MS m/e (%): 269 (M^ 100). f) Methyl-('6-morpholin-4-vl-4-0"tolvl-pvridin-3-yl)-amine A solution of 2.24 g (8.3 mmol) 6-morphoIin-4-yl-4-o-tolyl-pyridin-3-yl-amine in 17 ml trimethyl orthoformate and 3 drops trifluoroacetic acid was heated for 2 h at 130 °C, The reaction mixture was evaporated and dried in vacuo for 30 min. The residual oil was dissolved in 5 ml tetrahydrofuran and was added dropwise under ice cooling to 630 mg (16,6 mmol) lithium aluminum hydride in 20 ml tetrahydrofiiran. The reaction mixture was stirred for 1 h at room temperature, cooled to 0 °C again and acidified (pH 1-2) by addition of 28 % hydrochloric acid solution. After stirring for 5 min, 28 % sodium hydroxide solution was added to reach pH 10. The solution was filtered over celite, evaporated and purified by flash chromatography to give 1.56 g {66 %) of the title compound as a white foam. ; MS m/e (%): 283 (M*", 100). g) 2-(3>5-Bis-trifluoromethvl-phenvl)-N-methvl-N-f6-morpholin-4-vl-4-o-tolvl-pyridin-3-vl)-isobutvramide A solution of 1.46 g (5.15 mmol) methyl-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-amine and 1.32 ml (7.73 mmol) N-ethyidiisopropylamine in 15 ml dichloromethane was cooled in an ice bath and 1.8 g (5.67 mmol) 2-(3,5-bis-trifluoromethyI-phenyl)-2-methyl-propionyl chloride were added dropwise. The reaction mixture was warmed to 35-40 ^'C for 3 h, cooled to room temperature again and was stirred with 25 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 2.9 g (quantitative) of the title compound as white crystals. M.p. 131-132 'C. h) 2-(3,5-Bis-trifluoromethvI-phenvI)-N-methvl-N-f6-(4-oxv-morphoIin-4-vl)-4-o-toIyl-pyridin-3-vn -isobutyramide To a solution of 5.0 g (8.84 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-"N-(6" morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyrainide in 50 ml dichloromethane was added under ice cooling a soloution of 2.18 g (8.84 mmol) of 3-chlbroperbenzoic acid {ca, 70 %) in 35 ml dichloromethane. After stirring for 1 h at 0 ""C, 2.6 g (25.7 mmol) triethylamine were added slowly. The reaction mixture was concentrated to a total volume of 10 mL and the residue was purified by flash-chromatography. The crude material was suspended in 20 ml diethyl ether, filtered and dried in vacuo to give 4.2 g (82 %) of the title compound as white crystals. M.p. 149-151 °C (partial decomposition). MS m/e (o/o): 582 (M+lT, 100). i) 2-(3,5-Bis-trifluoromethvl-phenvl)-N-(6-hvdroxv-4-o-tolvl"pyridin-3-vlVN-methyI-isobutyramide A sample of 1.00 g (1.72 mmol) 2-(3,5-bis-trifluoromethyl"phenyl)-N-methyl-N-[6-(4-oxy-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide was heated at 100 ®C for 16 h and at 150 °C for 2 h. Column chromatography afforded 107 mg (13 %) of the title compound as a white foam. MSm/e(%):496(M%30). 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-hydroxy-pyridin-3-^^ methyl-isobutyramide a) 2-f3.5-Bis-trifiuoromethvl-phenvl)-N-f4-C2-chIoro-phenvl)-6-(4-oxv-morpholin-4--vI)- pyridin-S-yll -N-metfayl-isobutyramide The title compound was obtained in comparable yields according to the procedures described above for the preparation of 2-(3,5-bis-trifluoromethyI-phenyl)-N-methyl-N-[6-(4-oxy-morpholin-4-yl)-4-o-tolyl-pyridin-3"yl]-isobutyramide (Example 114, step h)) using 2-chlorophenylboronic acid instead of o-toIy]boronic acid in step d). M.p.141-143 ^C (partial decomposition). MS m/e (%): 602 (M+H^, 100), 624 (M+Na"", 10). b) 2-(3,5-Bis-trifluoromethyl-phenvl)-N-f4-r2"chloro'phenyl)-6-hydroxy-pyridin-3-yn- N-methyl-isbbutyramide A solution of 1.80 g (2.99 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro' phenyl)-6-(4-oxy-morpholin"4-yl)-pyridin-3-yl]-N-methyl-isobutyraniide in 20 ml toluene was heated at reflux for 60 h. After cooling to room temperature the solvent was evaporated. Column chromatography afforded 1.07 g of a hght yellow foam. As determined by proton NMR spectroscopy this material consisted of a 4:1 mixture of the title compound and an isomer of the starting material (characterized by MS). MS m/e (%): 517 (M+If', 100). Example 116 2-(3,5-Bis-trifluoromethyI-phenyI)-N-[4-(2-chioro-phenyl)-6-methoxy-pyridin-3-yl]-N-methyl-isobutyramide The title compotmd was obtained as a light yellow solid in 33 % yield after column chromatography according to the procedure described above for the preparation of 6-benzyloxy"N"(3,5-bis-trifluoromethyl-ben2yl)-N-methyl-4-o-tolyl-nicotinamide (Example 112) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-hydroxy-pyridin-3-yl]-N-methyl-isobutyramide (Example 115; 80% purity) instezd of N-(3,5-bis-trifluoromethyI-benzyl)-6-hydroxy-N-methyl-4-o-tolyl-nicotinamide and methyl iodide instead of benzyl bromide. MS mJe (%): 531 (M+H^, 100). Example 117 2-(3,5-Bis-txifluoromethyl-phenyl)-N-[4-(2-cUoro-phenyl)-6-(pyridin-4-yl^ pyridin-3-yl]-N-metihyl-isobutyraimde The title compound was obtained as a light orange solid in 15 % yield after column chromatography according to the procedure described above for the preparation of 6-benzyloxy"N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-4-0"tolyI-nicotinamide (Example 112) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-hydroxy"' pyridin-3-yl]"N-methyl-isobutyramide (Example 115; 80 % purity) instead of N-(3,5-bis-trifluoromethyl-benzyl)-6-hydroxy-N-methyl"4-o-tolyl-nicotinaniide and 4-(bromomethyl)pyridine hydrobromide with one additional equivalent of silver carbonate instead of ben2yl bromide. MS m/e (%): 608 (M-hH"", 100). Example 118 2-(3,5-Bis-trifluoromethyI-phenyl)-N-[4-(2-chloro-phenyl)-6-(pyridin-3-ylmethoxy)-pyridin-3-yl] -N-methyl-isobutyramide The title compoimd was obtained as an off-white foam in 35 % yield after colmnn chromatography according to the procedure described above for the preparation of 6-benzyloxy-N-(3,5-bis-trifluoromefhyl-ben2yl)-N-methyl-4-o-tolyl-nicotinamide (Example 112) using 2-(3,5-biS"trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)"6-hydroxy-pyridin-3-yl]-N-methyl-isobutyramide (Example 115; 80% purity) instead of N-(3,5"bis-trifluoromethyl-benzyl)-6-hydroxy-N-methyl-4-o-tolyl-nicotinanrLide and 3-(bromomethyl)pyridine hydrobromide with one additional equivalent of silver carbonate instead of benzyl bromide. MS m/e (%): 608 (M+H^, 100). Example 119 N- [6-Ben2yloxy-4- (2-chloro-phenyl)-pyridin-3-yl] -2- (3,5-bis-trifluoromethyl-phenyl)"N- methyl-isobutyramide The title compound was obtained as a light yellow foam in 50 % yield after column chromatography according to the procedure described above for the preparation of 6- ben2yloxy-N"(3>5-bis-trifluoromethyl-ben2yl)-N-methyl-4"0-tolyl-nicotinamide (Example 112) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-hydroxy- pyridin-3-yI]-N-methyHsobutyramide (Example 115; 80 % purity) instead of N-(3,5-bis trifluoromethyl-beii2yl)-6-hydroxy"N-methyl-4-o-tolyt-nicotinamd^ MS m/e (%): 607 (M+H^, 100). Example A Tablets of the following composition are manufectured va the usual manner: mg/tablet Active substance 5 Lactose 45 Com starch 15 Microcrystalline cellulose 34 Magnesiiun stearate 1 Tablet weight 100 Example B Capsules of the following composition are manufactured: mg/capsule Active substance 10 Lactose 155 Com starch 30 Talc 5 Capsule fill weight 200 The active substance, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer, the talc is added thereto and mixed thoroughly. The mixture is filled by machine into hard gelatine capsules. Example C Suppositories of the following composition are manufactured: mg/supp. Active substance 15 Suppository mass 1285 Total 1300 The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45°C. Thereupon, the finely powdered active substance is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool, the suppositories are then removed from the moulds and packed individually in wax paper or metal foil. WE CLAIM: 1. 4-phenyl pyridine derivatives of the general formula wherein R is hydrogen or halogen; R^ is -(OC)njR^*or-(CR*=CR")n,R^' •« ■wherein R is a) halogen, b) cj^ano, or the following groups: —(C)„R' I. 0 f^ , d) -C(0)NR'R", e) -C(0)0(CH2)«R^ f) -C(0)R^ g) -N(OH)-(CH2)„R^ h) -NR'C(0)-(CH2)mR^ i) -N[C(0)-R']2, j) -0R^ k) -(CH2)„,-SR^ -(CH2)„-S(0)R^ or -(CH2)«-S(0)2R', 1) aryi, optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alkjd, lower alkoxy, cyano, hydroxy, -NR'R", nitro, -(CH2)nOR', -C(0)NR'R", -C(0)OR' or -C(0)R', m) is a five or six membered heteroaryi group, containing one to four heteroatoms, selected from N, O or S and may be optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR'R", nitro, -(CH2)aOR', -C(0)OR', -C(0)NR'R" or -C(0)R', n) is a five or six membered saturated cyclic tertiary amine of the group which may contain one additional heteroatom, selected from N, O or S, RVR" are independently from each other hydrogen, hydroxy, lower alkyl, cycloalkyl or aryl, wherein the lower alkyl, cycloalkyl or aryl group may be optionally substituted by one or more substituents> selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR'"R"", nitro, -(CH2)nOR"', -C(0)NR"'R"", -C(0)OR^" or-C(0)R"R"'/R'"' are independendy from each other hydrogen, lower alkyl, cycloalkyl or aryl, R is hydrogen, cyano, hydroxy, halogen, triQuoromethyl, -C(0)OR*, -OC(0)R or aryl, optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR'R", nitro, -(CH2)nOR\ -C(0)NR'R", -C(0)OR' or -C(0)R'> or is a five or six membered heteroaryl group, containing one to four heteroatoms, selected fron N, O or S and maybe optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR'R", nitro, -(CH2)nOR', -C(0)NR'R", -C(0)OR' or -C(0)R', R*^ is hydrogen, lower alkyl, trifluoromethyl, or aryl, wherein the lower alkyl or aryl group may be optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR*R", nitro, -C(0)NR'R", -(CH2)nOR\ -C(0)OR' or -C(0)R\ or is a five or six membered heteroaryl group, containing one to four heteroatoms, selected fron N, O or S and may be optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR'R", nitro, -(CH2)nORN "C(0)NR'R", "C(0)OR' or-C(0)RR^is-C(0)-(CH2)mOHor an oxo group; R hydrogen, lower alkyl, lower alkoxy, halogen or CF3; R /R are independently from each other hydrogen, lower alkyl or form together with the carbon atom to which they are attached a cycloalkyl group; A A* R /R are independently from each other hydrogen, halogen, CF3, lower alkyl or lower alkoxy; R and R^ or R^ and R^' may be together -CH=CH-CH=CH-, optionally substituted by one or two substituents selected from lower alkyl, halogen or lower alkoxy; X is ^C(0)N(R^)-, {CH2)pO-, -(CH2)pN(R^)-, -N(R^)C(0)- or ^N(R^)-(CH2)p-; wherein R^ is hydrogen or lower alkyl; n is 1 or 2; m isO, 1,2,3 or 4; o is 1 or 2; and p is 1 or 2; and pharmaceutically acceptable add addition salts thereof, 2. Compounds of the general formula wherein R is hydrogen or halogen; R' is -(<: wherein r is> a) halogen, b) cyano> or the following groups: ?■ , (. c) f^ , d) -C(0)NR'R", e) -C(0)0(CH2)«R', f) -C(0)R^ g) -N(OH)-(CH2)mR', h) -NR'C(0)-(CH2)„,R^ i) -N[C(0)-R']2, j) -OR^ k) -SR^ -S(0)R^ or -S(0)2R^ 1) aryi, optionally substituted by one or more substituents> selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, -NR'R", nitro, -(CH2)nOR\ -C(0)NR'R", -C(0)OR' or -C(0)Rm) is a five or six membered heteroaryl group, containing one to four heteroatoms, selected from N, O or S and may be optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alkyl, lower aikoxy, cyano, hydroxy, -NR'R'\ nitro, -(CH2)nOR\ ^C(0)OR^ -C(0)NR^R" or -C(0)R', n) is a five or six membered saturated cyclic tertiary amine of the group which may contain one additional heteroatom, selected firom N, O or S, R'/R' are independently firom each other hydrogen, lower alkyl, cycloalkyl or aryl, optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alfcyl, lower aikoxy, cyano, hydroxy, -NR'"R"", nitro, -(CH2)nOR'", -C(0)NR"'R"", -C(0)OR'" or -C(0)R'", R"7R'"' are independently from each other hydrogen, lower alkyl, cycloalkyl or aryl, R^ is hydrogen, cyano, hydroxy, halogen, trifluoromethyl, -C(0)OR' or aryl, optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alkyl, lower aikoxy, cyano, hydroxy, -NR'R", nitro, -(CH2)nOR', -C(0)NR'R", -C(0)OR' or -C(0)R'> or is a five or six membered heteroaryl group, containing one to four heteroatoms, selected fron N, O or S and maybe optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alkyl, lower aikoxy, cyano, hydroxy, -NR*R", nitro, "(CH2)nOR', -C(0)NR'R", -C(0)OR* or-C(0)RR^ is hydrogen, lower alkyl, trifluoromethyl, or aryl, optionally substimted by one or more substituents, selected from halogen, trifluoromethyl, lower alkyl, lower aikoxy, cyano, hydroxy, -NR'R", nitro, -C(0)NR'R", -(CH2)nOR', -C(0)OR' or -C(0)R\ or is a five or six membered heteroaryl group, containing one to four heteroatoms, selected fron N, O or S and may be optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alkyl, lower aikoxy, cyano, hydroxy, -NR'R", nitro, "{CH2)^0R^ -C(0)NR'R", -C(O)0R' or -C(0)R', R^ is ^C(0)"(CH2)mOH or an oxo group; R^ hydrogen, lower alkyl, lower alkoxy, halogen or CF3; R^/R^' are independently from each other hydrogen, lower alkyl or form together with the carbon atom to which they are attached a cycloalkyl group; RVR^* are independently from each other hydrogen, halogen, CF3, lower alkyl or lower alkoxjr, R and R^ or R^ and R'^' may be together -CH=CH-CH=CH-, optionally substituted by one or two substituents selected from lower alkjd, halogen or lower alkoxy; X is-C(0)N(R^)", (CH2)pO-, -(CH2)pN(R^)^, -N(R^)C(0)- or-N(R^)-(CH2)pS wherein R^ is hydrogen or lower alkyl; n is 1 or 2; m is 0 to 4; o is 1 or 2; and p is 1 or 2; and pharmaceutically acceptable add addition salts thereof. wherein R^ is halogen, -(CH2)mCN, -C(0)0^1ower alkyi, -(CH2)niOH, -N(OH)(CH2)mOH, -N(R)C(0)-(CH2)„,OC(0)-lower alkyl, -N[C(0)-cycloalk)d]2, -N(R)C(0)"(CH2)mOH, pyridin-2,3,4-yl or phenyl, optionally substituted by lower alkyl, lower alkoxy or hydroxy or is morpholinyi or piperazinyl, substituted by-C(0)-(CH2)niOH or oxy group(s), R is hydrogen or lower alkyl; R is lower alkyl or halogen; R^/R^ are independently from each other hydrogen or lower alkyl; X is-C(0)N(R^)-or-N(R'*)C(0)s R* is hydrogen or lower alkyl; and m is 1 or 2; 4. The compound of formula I according to daim 1, wherein —(R^)n is 3,5-di-trifluorometh)d. 5. The compound of formula I according to daim 4, wherein X is -C(0)N(R)-. 6. The compoimd of formula I according to claim 5, wherein R /R are both hydrogen and R is methyl. 7. The compound of formula I according to daim 6, which is N-(3,5-biS"trifluoromethyl-benzyl)-6-(4-hydroxyacetyl-pipera2in-l-yl)-N-methyl-4-o- tolyi-nicotinamide, N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyi-nicotmaraide, N-(3,5-bis-txifluoromethyl-beii2yl)-6-cyanometh)i-N-methyi-4-o-tolyi-iiicotinaniide5 N-(3,5"bis-trifluoromethyl-ben2yl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide, 4"0-tolyl-[2,4']bipyridinyi-5-carboxylic add (3,5-bis-trifluoromethyl-benzyl)-methyl- amide, 5-[(3,5-bis-lxifluoromethyl-benzyl)-methyl-carbamo3d]-4-0"tolyl"pyridine-2-carboxyiic add methyl ester, N-(3,5"bis-trifluoromethyl-beiizyl)-6-hydrox)anethyl-N-methyl-4-o-tolyl-nicotinaniide, 6-(5-acetyl-thiophen-2-yJ)-N-(3,5-bis-trifluorometh)d-ben2yl)-N-methyl-4-o-tol)d- nicotinamide, 4-o-toIyI-^,2^3^6'"tetrahyd^o-[2,4']bipyridinyi-5-carboxy^cadd(3,5-bis-trifluo^omethyl- ben2yl)-meth3d-amide, N-(3,5-bis-trifluoromethyl-ben27l)-6-(4-hydroxymethyl-phenyi)-N-methyl-4-0"tolyl- nicotinamide^ 2*-methyI-4-o-tolyl-[2,4']bipyridinyl"5-carboxyIic add (3,5-bis-trifluoromethyl-benzyl)- methyl-amide, N-(3,5-bis-trifluoromethyl-benz7l)-N"meth)d--6-(3-methyl-[l,2,4]oxadiazol-5-yl)-4-o- tol)^-nicotinamide, 6-(3-amino-prop-l-ynyl)-N-(3,5-bis-trifluoromethyl-ben2yl)-N-methyi-4"0-tolyl- nicotinamide, (RS)-N-(3,5-bis-trifluoromethyI--benzyi)-6"(2-hydroxy"ethanesulfinyimethyl)-N-methyl- 4-o-tolyl-nicotinamide, N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(l-methyl-lH-imidazol-2- ylsulfanylmethyl)-4-o-tol)4-nicotinamide. (RS)-N-(3,5'bis-txifluorometfa)d-benz7l)'N-methyi-6-(pyridine-2-sulfi^ nicotmaraide, N-(3,5-bis-tii£luorometIi)^-benz)d)-N'methyI-6-(pyridme-2-sialfon^^ nicotinamide or N-(3,5-bis-trifluorometiiyl-benzyl)-6-(3-hydrox7-propoxy')-N-meth7l-4-0"to^^ nicotinamide. 8. The compound of formula I according to claim 4, wherein X is -N(R)C(0)". 9. The compoimd of formula I according to claim 8, wherein R^/R^ and R^ are meth-jd. 10. The compound of formula I according to claim 9, which is 2-{3,5-bis-trifluoromethyl-phenyi)"N-{6-[hydroxy-(2-hydroxy-ediyl)-anxino]-4- pyridin-3"yl}-N-methy3-isobutyramide, 2-(3,5-bis-trifluoromediyi-phenyi)'N-methyl-N-[6-(3-oxo-morpholin-4-)i)-4-o-toIyi- pyridin-3-yi] -isobutyramide, acetic add (5"{[2"(3,5-biS"trifIuoromethyI-phenyl)-2-methyi-propionyl]-methyl-amino}- 4-o-toiyl-pyridin-2-ylcarbamoyl)-methyI ester, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(2-hydroxy"acetyIaiiuno)-4-o-tolyl-pyridin-3- yl] -N-methyl-isobutyramide, 2-(3,5"bis-tri£luoromethyl-phenyl)-N-[6-(hydroxyacetyl-methyl"amino)-4-0"tolyl'- pyridin-3-yi]'N-methyl-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-[5-(2>5-dioxo-pyrrolidin"l-yl)-4-o-tolyl-pyridin-3- yl] "N-methyl-isobutyramide, cyclopropanecarboxylic add (5"{[2-(3,5-bis-trifluoromethyi-phenyi)-2-methyl- propionyl]-methyl-amino}-4-o-tolyl"pyridin-2-yl)-cydopropanecarbouyl-amide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-chloro-4-o-tolyl-pyridin"3-yl)-N-methyl- isobutyramide, 2-(3,5-bis-trifiuoromethyl-phenyi)-N-[4-(2-chloro-phenyl)-2'-metiiyl-[2,4*]bipyridinyl-5- yl J "N-methyi-isobutyramide, 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-ethynyl-4-o-tolyl-pyridin-3-yl)-N-methyl- isobutyramide, 2-(3,5-bis-trifluoromethyi-phenyi)-N-[6-(3-hydroxymethyi-isoxa2ol-5-yi)-4-o*toly]- pyridin-3 -yi] -N-meth)d-isobutyramide, 2-(3,5-bis-trifluoromethyI-phenyI)-N-[6-(3-hydroxy-prop-l-ynyI)-4-o-tolyl-pyridin-3- yl]-N-methyI-isobutyramide or (RS)"2-(3,5-bis-trifluorometiiyl-phenyl)-N-[6-(3-methoxy-ben2enesulfinyl)-4-o-tolyi" pyridin-3-yI] -N-methyl-isobutyramide, 11. The compoiind of formula I according to claim 8, wherein R^/R^ are both methyl andR^ischloro. 12. The compound of formula I according to claim 11, which is 2-(3,5-biS"trifluoromethyl-phenyl)-N"{4-(2-diloro-ph€nyi)-6-[hydroxy"(2-hydroxy-ethyl)-amino] -pyridin-3-yl}-N-methyl-isobutyramide or 2"(3,5-biS"trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(3-oxo-morpholin-4-yl)-pyridin-3-yl] -N-methyl-isobutyramide. 13. The compound of formula I according to daim 4, wherein X is -N(R)-(CH2)p-. 14. The compoimd of formula I according to claim 4, wherein X is -(CH2)pO-. 15. The compound of formula I according to daim 4, wherein X is -(CH2)pN(R)-. 16. A medicament containing one or more compounds as daimed in any one of daims 1-15 and pharmaceutically acceptable exdpients. 7. A process for preparing a compound of formula I as claimed in claim 1, which process comprises wherein the definition of substituents is given above, or h) modifying one or more substituents R -R , R or R within the definitions given above, and if desired, converting the compound obtained into a pharmaceuticany acceptable acid addition salt. 18. The compound according to any one of claims 1 to 15, wlienever prepared by a process as claimed in claim 17.

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