Title of Invention	CARBOXYARYL SUBSTITUTED DIPHENYL UREAS
Abstract	A compound selected from the group consisting of the 4-chloro-3-(trifluoromethyl)phenyl ureas: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4- pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl)-4- pyridyloxy) phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl)urea and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-N- methylcarbamoyl)(4-pyridyloxy)phenyl)urea, the 4-bromo-3(trifluoromethyl)phenyl ureas: N-(4-bromo-3-(trifluoromethyl)pheny)-N'-(3-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4- pyridylthio) phenyl)urea, N-(4-bromo-3-(trifiuoromethyl)phenyl)-N'-(2-chloro-4-2-(N- methylcarbamoyl)(4-pyridyloxy))phenyl)urea, and N-(4-bromo-3-(trifluoromethyl))phenyl)-N'-(3-chloro-4-2-(N- methylcarbamoyl)(4-pyridyloxy)phenyl)urea. the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas: N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-2-(N-methylcarbamoyl)-4-pyridylo3cy)phenyl)urea. N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea. or a pharmaceutically acceptable salt thereof.

Title of Invention

CARBOXYARYL SUBSTITUTED DIPHENYL UREAS

Abstract

A compound selected from the group consisting of the 4-chloro-3-(trifluoromethyl)phenyl ureas: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4- pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl)-4- pyridyloxy) phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl)urea and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-N- methylcarbamoyl)(4-pyridyloxy)phenyl)urea, the 4-bromo-3(trifluoromethyl)phenyl ureas: N-(4-bromo-3-(trifluoromethyl)pheny)-N'-(3-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4- pyridylthio) phenyl)urea, N-(4-bromo-3-(trifiuoromethyl)phenyl)-N'-(2-chloro-4-2-(N- methylcarbamoyl)(4-pyridyloxy))phenyl)urea, and N-(4-bromo-3-(trifluoromethyl))phenyl)-N'-(3-chloro-4-2-(N- methylcarbamoyl)(4-pyridyloxy)phenyl)urea. the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas: N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-2-(N-methylcarbamoyl)-4-pyridylo3cy)phenyl)urea. N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea. or a pharmaceutically acceptable salt thereof.

Full Text	FORM 2 THE PATENTS ACT 1970 [39 OF 1970] & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See Section 10; rule 13] "CARBOXYARYL SUBSTITUTED DIPHENYL UREAS" BAYER CORPORATION, 100 Bayer Road, Pittsburgh, Pennsylvania, 15205, U.S.A., The following specification particularly describes the invention and the manner in which it is to be performed: ©"Carboxyarylf substituted diphenyl ureas as raf Joaasc inhibitors Field of the Invention This invention relates to the use of a group of carboxvarvl substituted diphenyl ureas pryl ureas-in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy. Background of the Invention The p21™ oncogene is a major contributor to the development and progression of human solid caitaers and is mutated in 30% of all human cancers (Bolton et al. Ann. Rep. Med Chem, 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, unmutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avrucbtit al. Trends Biochem. Sci. 1994,19, .'&• 279-83). Biochemically, ras is a guanine nucleotide%nding protein, and cycling between a GTP-bound activated and a GDP-bound rcs0g form is strictly controlled by ras , ■ ^'-W:" endogenous GTPase activity and other reguIatSry^proteins. In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to the cancerous growth of the cells which carry these mutants (Magnuson et al, Semin. Cancer Biol. 1994, 5, 247-53). It has been shown that inhibiting the effect of active rai- by inhibiting the raf kinase signa/mg pathway by administration of deactivating antibodies to raf kinase or by co-expression of dominant negative raf kinase or dominant negative MEK, the substrate of raf kinase, leads to the reversion of transformed cells to the normal growth phenotype (see: Daum et al. Trends Biochem. Set 1994, JP, 474-80; Fridman ut al. J. Biol. Chem, 1994, 269, 30105-S. Kolch et al, (Nature 1991,349, 426-28) have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes. Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., Nat, Med. 1996, 2, 668-75). Summary of the Invention The present invention provides compounds which are inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector of p21fM, the inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compounds are useful in the treatment of human or animal solid cancers, e.g., murine cancer, since the progression of these cancers is dependent upon the ras protein signal transduction cascade and therefore susceptible to treatment by interruption of the cascade, i.e., by inhibiting raf kinase. Accordingly, the compounds of the invention are useful in treating cancers, including solid cancers, such as, for example, carcinomas (e.g., of the lungs^pancreas, thyroid, bladder or colon), myeloid disorders (e.g., myeloid leukemia) or adenomas (e.g., villous colon adenoma). The presont invention therefore provides compounds generally described as aryl ureas, - including both aryl and heteroaryl analogues, which inhibit the raf kinase pathway. -3%* invention also provides a-method for trcating-ft-paf mediated disease state-in humans or mammals. Thus, the invention is directed to compounds which inhibit the enzyme raf kinase and also compounds and compositions ftnd methods for the treatment of cancerous cell growth mediated by raf kinase wherein a compound of the invention Formula I M-administcrcd or can be in the form of a pharmaceutical^ acceptable salt thereof. A compound of the invention is selected from the group consisting of methvIcarbamovnf4-pyridvIoxv))phenvl') area or a pharmacegticallv acceptable salt thereof Example's of pharmaecnticallv acceptable salts include those of N^4-chloro^-ftiif[uoromethvn phe phenyl) orea of the formula; H H CI and N^chloro^-('trifluoromethvnDhenyn"N>^4^-^-methvicarbamovfM- lyridyloyy) phenylVurea pf the formula: form of » basic salt described above, such as a tofeylate salt. -A-D-B r -© In formula I> D is NH-C(O) NH t A4s—a-substitutcd moiety of up to 40 carbon atoms of the formula; L (M >-)q » where L fa a 5 or- 6 membered cyclic structure bound directly to P, L comprises a substituted cyclic-moie^-having at least 5 membcre,-M is a bridging group-having at least-one atom,—q fa-an -integer of from 1 3;-and each cyclic structure of L and-fc* contains 0 4 members of the group consisting ofna-itrogen, oxygen end sulfur, and S4s a-substitutcd or unsubstitutcdi up-to tricyclic tiryl or hctcrooryl directly to D containing 0 4 members of the group ooraisting of-nitrogen, oxygen- M1IU JUJIJUJ) wlteyem-L* is substituted by at least one gnbotttnont selected from the group consisting of SOfe C(0)R —-—R^ is hydrogen or a carbon based moiety of up to 21 carbon atoms optionally : containing octcrontoma selected from N, S-and^Q-and-optionally' halosnbstitated, up Kv-is hydrogen qr a carbon basod-hioiety of np to 30 carbon atoms optionally containing hctoroatoms selected from N,g and 0 and optionally snbstitutod by hftjogcn, hydroxy and earbqn based, substitnentsof np io-34 carbon atoms, which &fti4&&aHy-eonta»n hetcro atoms >clectftd^iHMfla-Nt-S and 0 and arc optionally Ej4^ftjre^RaRb.wherc ^-imd-RbHM'e -a) HHtefrend^ntfy-hydrogen, ^ -JSP' — a onrben based moicty-o-f np to-^^arbon atoms optionally containing hoteroatums selected from N, S and O aj^goptionally snbstitnted by halogen, hydroxy ftnd-carbon based substitnents o^upUo 24 carboi . '■. f.t. ~ ■ ■ . contain Itctcroatoma selected from N» S and O and arc optionally substituted by halogen, or _ QSiffi^ where R+ is hydrogen or a carbon based moiety of np to 34 carbon »toms optionally containing hctoroatoms selected from-N, S and Q and optionally substituted by halogen, hydfoxy-and carbon based oubstitnonts of up to and are optionally substituted by halogen; or _ ,_&.) Rg-and-Ri, together form a 5-7-mcmbcr heterocyclic strnctnrc of 1 3 hotcrontoms selected from N» S and 0, or a Hofrstifutcd 5 7 member heterocyclic contain hctcroatoma aclcctcd fromN, S-and 0 and aro optionally substituted by halogen; or e)-— one of R,- or Rb is C(O), a tVCg divalent alhyleno group or a substituted G4.-G5 divalent alltylcnc^group bound to -the moiety L to form n cyclic structure with at-least 5 member^ whorein-thc snbstitucnts of the substituted Cf-^s dtvafont-ulhylcnc gronp arc selected from the group consisting of halogon.-hydrojtyi, and—carbon based substituents of up to 24 carbon atoms^ which optionally contain hoteroatoms selected from N» S and 0 and are optionally substituted by halogen; substituents are selected from the group consisting of hfllogen,-np-to-per halo, and W-n.-where n is 0-3; jW -— whoroin-oacn-W-is independently selected from the group consisting of CN, WRy€^Q)ft?, Q Ar, and carbon based moieties of up to-24 carbon atoms, optionally containing heterontoms selected from-N.S and O and optionally substituted by one or more -substituents independently selected frjp the group-consisting of -Cty - NR?€{0)QR?-6fld-halogcn up to per halo? with'cach R? independently selected from H or a carbon based moiety of up to-24\|ffarbon atamst optionally containing heteroafaims selected from N» S and O and optionally substituted by halogen, wherein Q is O, g» NfflVWm) C(0), CH(OH) > (CHA^O-T- Ar is n 5 or 6 member-aromatic structure containing 0 3 members selected from tho group consisting of nitrogen, otygen and-sulfur, which is optionally substittHcd-by halogen, up to per-halo, and optionally substituted by Z^, wherein nl is 0 to 3 and each Z is independently selected-from the group-consisting of CN, €Q3BV-c(0)fty> C(0)PERR* NOA> oi£—$&?—3ra^V^»c(0)ORV- WR?G(Q)RV-and 0 carbon based moiety of np. to 31 carbon atoms, optfqnaljy or more tmhstituents selected from t-he-gronp consisting of CN, COUR r-€OR r~ Vvtlivvu tfuuyi;. In formula I, suitable hctaryl groups include, bat arc not limited to, 5 12 carbon atom aromatic rings or ring systems containing 13 rings, at least one of which is aromatic^ in which one or morerc-g-.) 1 4 earben-atoms in-one or more of j tbeHFHigs-efln-bc-rcplaccd by oxygen^ nitrogen or sulfur atoms,—Each ring typically has3 7 fltems.-F " 3L-, ^r- or 3-pyrrolyl) I I or S.-pyrazolyl, 3,4 or S oxflzolyl, 3 ,4 or 5 ifloxa^olyl, 3-, 1 or5 tfalqzoh/l)'3 ,'1 or 5 isothhreolyl, 3 ,3 or 4 pyridyli 3V f i 5. .or 6 pyrimidinyl, 1,23 triflfcol 1.% 1 or 5-yl, 1,2,4 triatol 1 t 3 or 5 yl; 1 pr-5-tetrazolyl, 1,2,3 ojoflwzol i or 5 y), 1,3,4 oxadioaol 3 or 5 yl, 1,3,1 thiadipufcol 2 or 5-yl, 1,2,4-psqdiflgol 3 or 5 yl, 1,3,1 tfaiadiojiol 3 -or 5 yl, 1,3,1 thiodiaaol 3 or gyl^ 1,2,3 thlodiflaoM^^r 5 yl, 3, 3-, A t S or 6 2H thiopyraiiyl, 3-, 3 or 4 1H tbiopyranyl, 3- or jQ\|pridagmyl» pyrazinyl, 3-, 3-, 4 , Si 6-or 7-benzofuryl 2 13 , 4,5 ,6 or 7 bonEqjjjipnyl, 1,2 , 3 ,4 »5 > 6 or 7 indolyl, 1 f a ,4 or 5bonzimidagolyl, 1 , 3 , 4 ,5 » ntJ\|r 7-benzopyrazobrl, 2 14->-gy6 or 7 bcnzoxoifiOlyl, 3 »4 ,5 6 or 7-bcnzUoxu&oh/la 1,3 -r 4 ,5-, 6- or 7 bongotniazolyl, 2 , 4-,-5-, 6- or 7 bcnrisothiazolyl, 2,1,5)6 or 7 benz l^oxadiazolM 3 ,3 ,-4-,5 ,6-, 7 -or S-quinolinyl, 1 > 3 ,4,5 ,6,7,8 feoquinolinyl, 1-, 3 ,3 > 4 or 9 carbazolyl) 4- r^-r3~r4 ,5-^,7,8 or 9 aeridinylt or 2 , 4-, 5,6,7 or 8 quinazolinyl» or addftiomdly optionally Substituted phenyl 2 or 3 thicnyl, 1,3,4 thiadiazotyl, 3 fyrfyts-3-pyragoIyl, 2 thiazolyl or 5 thiazolyl, etc. For example, B can be 4 methyl phenyl, 5 methyl 2-tlricnyl> 4 methyl 2 thicnyl, 1 methyl 3 pyi'iyl» 1 methyl 3 pyrazolyl, 5 methyl- 2 thiazolyl op 5 mcthyM,3,4 tbiadiazol 3 yl. Suitable alkyi groups and alky! portions of groups, cgM. nlltoxy, ate throughout inehidc-mcthyl, ethyl} propyl, butyl, ete^ including all otratght-choin and branched isomers such as taopropyI> laobutyl,see bf^l,W$butyh cfer without ftlfayl substituonts such-that,- for example, "(VeyeloalftyjT includes mctbyl substituted cyolopropyl groups—fl& well as cyctobutyl groups.—The term -■cycloalkyr, as used herein also includes saturated heterocyclic groups. Suitable hflfogfea^gFoups include Fy-GI^ Br, and/or I, from onc-to per substitution (i.e. all H atonw-on-a group replaced-by a halogen atom) being possible nvhiwo an alley! group is subfltitutcd by halogen, mixed.substitution of halogen atom TF>IO invention also relates to eompound»per sc, of formula I. The present invention is also directed to pharmaceutically acceptable salts of a compound of the invention formula I. Suitable pharrnaccutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, raethanesalphonic acid, trifluoromethanesulfonji? acid, benzenesutfonic acid, p-toJuenesulfonic acid, I-naphthalenesuJfonic acidvi\|flaphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, cMcracid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic aci$/salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li^ Na+ or K)M alkaline earth cations (e.g., Mg+2 , Ca2 or Ba+a), the ammonium cation, as well as acid salts of organic Nases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonatibn or peralkylation of triethylamine, A^-diethylamine, AW-dicyclohexylamine, lysine, pyridine, N,N-dimethyhiminopyridine (DMAP), l,4-diazabiclo[2.2.2]octane (DABCO), 1,5-diazabicyc]o[4.3.0]non-5-ene (DBN) and l,8-diazabicycloj;5.4.0]undec-7-ene (DBU). A number of the compounds of-P&waHtfa-I possess asymmetric carbons and can therefor exist in racemic and optically activeforms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art. The present invention encompasses any isolated racemic or optically active form of the compounds of the invention or pfaarmaceuticany acceptable salts thereof dtogoribod" in- Forinnla -I which possess raf inhibitory activity. General Preparative Methods The comjiounds of Formula I the invention may be prepared by the use of known chemical reactions and procedures, some from starting materials which are commercially available. Nevertheless, general preparative methods are provided below to aid one skilled in the art in synthesizing these compounds, with more detailed examples being provided in the Experimental section which follows. Substituted anilines may be generated using standard methods (March. Advanced Organic Chemistry, 3rd Ed,; John Wiley: New York (1985). Larock. Comprehensive Organic rransformations; VCH Publishers: New Y$rk (1989)). As shown in Scheme I, aryl amines are commonly synthesized by reduc\|im of nitroaiyls using a metal catalyst, such as INL, Pd, or Pt, and rfe or a hydride transf^sfgen^ such as formate, cyclohexadieue, or a borohydride (Rylander. Hydrogenation^Mjpthods; Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as UAIH4 (Seyden-Penne. Reductions by the Alumina- and BorohydHdes in Organic Synthesis; VCH Publishers: New York (1991)), or using a 2ero valent metal, such as fe, Sn or Cti, often in acidic media. Many methods exist for die synthesis of nitroaryls (March. Advanced Organic Chemistry, 3rd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). H2 / catalyst 2 ArNO: / (eg. Ni, Pd, Pt) V EtU »». ArNH2 X M(0) (eg-Fe,? * Scheme I Reduction of Nitroaryls to Aiyl Amines Nitroaryl are commonly formed by electrophilic aromatic nitration using HNO3, or an alternative N HNQ3 Ar-H —- ArN02 potential leaving groups (e.g. F„ CI, Br, etc.) may undergo substitution reactions on --Mrrealment-Avith-nueleophiles, such^miolate. (exemplified .in Scheme ID or phenoxide. Nitroaryh. may also undergo Uliman-type coupling reactions (Scheme il). ArSH 02N ■ jfW ——^ R-^^r^ base ^A cy~sH 02N R-"'^=s/ CuO / base £ Vs-Ar R Br-Ar y^ 2 $$> m MP sal Scheme JI Selected Nucleophilic Aromatic^nbstitwtion using Nitroaryls 'f$r ■".■■■ ■ ft' ■ ••■ Nitroaryl;. may also undergo transition metal mediated cross coupling reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo palladium mediated cross coupling reactions with aryl nocleophiles, such as arylboronic acids (Suzuki reactions,, exemplified below), aryltins (Stille reactions) or aiylzincs (Negishi reaction) to afford the biaryl (5). 02NV^ ArB(0ft')2 OzN t V-X — - > VAr R--W Pd(0) R-^=/ 4 5 Either nitroaryls or anilines may be converted Into the corresponding arenesulfonyl chloride (7) on treatment with chlorosalfonic acid, Reaction-ofthe sulfonyJ chloiide with : a fluoride source, such as KF then affords SUlfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with triniethylsilyl trifluoromethane in the presence of a fluoride source, such as .tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to tbe corresponding trifluoromethyisulfone (9). Alternatively, Sulfonyl chloride 7 may be reduced to the arenethiol (10), for example with zinc amalgum. Reaction of thiol 10 with CHCIF3 in the presence of base gives the difluororriethyl mercaptam (11), which may be oxidized to the sulfone (12) with any of a variety of oxidants, including Cr03-acetic anhydride (Sedovaetal, Zh. Org._Khm- A?70-M5ffi)- CIS03H (Me2N)3S Me3SiF2 Me3SiCF3 # -R Sp2CI [0] S02CHF2 O 12 Scheme QI Selected Methods of Fluorinated Aiyl Sulfone Synthesis As shown in Scheme IV, non-symmetrical V>rea formation may involve reaction pfanaryl isocyanace (14) .with.an aryl amine.03), The heteroa^l isocyanate may be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichlorpmethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or N,N ^arbonyldiimidazole (CD]). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or ant anhydride by a Curtius-type rearrangement. Thus, reaction of acid derivative 16 withan &ride source, followed by rearrangement affords the isocyanate. The corresponding carboxylk: acid (17) may also be subjected to Curtius-type rearrangements using diphenylphosphory 1 azide pPPA) or a similar reagent. J Ar^NHa 13 COCI3 H2N~Ar 0 Ar^NCO - ArV. X ;Ar14 H H '/ 15 Ar" "x Ar1' "OH N3' / \ DPPA 0 O ■ie 17 Mt ?K Scheme IV Selected Methods of Non-Syro$fe:al Urea Formation Finally, ureas may be further manipulated usi\|\|4nethods familiar to those skilled in the art. The invention also includes pharmaceutical compositions including a compound of l?eranla-J, the invention, or a pharmaceuticallv acceptable salt thereof- and a physiologically acceptable carrier. The compounds may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term 'administration by injection* includes intravenous, intramuscular, subcutaneous and parenteral injections, as we]] as use of infusion techniques. One or more compounds may be present in association -with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients. Compositions intended for oral use may be prepared according to any suitable method * known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations, Tablets contain the active ingredient in admixture with non-toxic pharmaceutical ly acceptable excipients which are suitable for the^manufacture of tablets. These excipients may be, for example, Inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; .granulating and disintegrating agents, for example, com starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc, the tabletsmay be uncoated or they may be coated by known techniques to delay dismtegration and adsorptioa in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosfearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form. $■' Formulations for oral us* may also be preselpd as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture.with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium c^rboxymethylcellulose, methylcellulose, hydroxypropyl methyJceliuJose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example polyoxy&hytene stearate, or condensation pivdacts of ethylene cokfc w'jfc Jong chain aliphatic alcohols, for sample heptadecaethylene oxycetanoly or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyeihylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl /7-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose pr saccharin. \| Dispersible powders and granules suitable for preparation of an aqueous suspension by \| the addition of water provide the active ingredient in admixture with a dispersingor i y/ethng agent, suspending agent arid one or more preservatives. Suitable dispersing or Byettiiig agents -and suspending agents are, exemplified by those already mentioned above, lAdditiohaTe^ example, sweetening, flavoring and coloring agents, may also be present. The comiJOunds may also be In the form of honjgfueous liquid formulations, e.g., oily suspensions which may be formulated by suspenM\| the. active ingredients in a vegetable \|f oil, for example arachis oil, olive oil, sesame pf^ peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may $>htain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These ipositions may be preserved by the addition of ananti-oxidant such as ascorbic acid. come em a minera Pharmaceutical compositions of the invention may also be in the form of oil-in-water ulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate,. and condensation products ~of "the said partial esi^ v^uTe^ polyoxyethylene sorbitan monooleate: The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The compounds may also be administered in the form of suppositories for rectal ^ i administration of the drug. These compositions can be prepared by mixing the drug with ,•; a suitable hon-initating excipient which is solid at ordinary temperatures but liquid at the ; rectal temperature and will therefore melt in the rectum to release the drug. Such I materials include cocoa better and polyethylene glycols. ■:; For all regimens ofuse disclosed herein for compounds of Formula I the invention or ' pharmaceiiticairv acceptable salts thereof , the ■ daiW-^ml dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight The daily dosage for administration by injection, including intravenpjy, intramusculary subcutaneous and parenteral injections, and use of infusion technio^ will preferably be from 0.01 to 200 r mg/Kg of total body weight. The daily rectal dj\|\|\|e. regime will preferably be from 0.01 fif- to 200 mg/Kg of total body weight. The danfe^pical dosage regime will preferably be from 0,1 to 200 mg administered between one to four times daily. The daily inhalation dosage regime will preferably be from 0.01 to 10 mg/Kg of total body weight. It will be appreciated by those skilled in the an that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be appreciated by one skilled in the art that the specific dose level for a given patient depends on a variety of factors, including specific activity of the compound administered, age, body weight, health, sex, diet, time end route of administration, rate of excretion, etc. It will be further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests. It will be anderslood, however, that the specific dose IeVel for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the condition undergoing therapy. ;• The entire enclosure of all applications^ patents and publications cited above and . Hcltm nru-licrcby incorporated by reference, including provisional application Serial ; No. 60/115^877, filed January 13,1909 and non provisional application Serial N-o. 0m$7£L6 filed February 2S, ippo. The compounds can be produced from known compounds (or from starting materials which, iii rum, can be produced from known compounds), e.g., through- the general preparative methods shown below. The aetivi\|wof a given compound to inhibit raf kinase can be routinely assayed, e.g., accordingflo procedures disclosed below. The following examples are for illustrative puipo\|\|??Only and are not intended, nor should they be construed to limit the invention in any\|yay. EXAMPLES All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mmHg. Unless otherwise stated, the term 'under high vacuum' refers to a vacuum of 0.4- 1.0 mmHg. All temperatures are-reported uncorrected in degrees Celsius (°C). Unless otherwise f^dicated, all parts and percentages, are by weight. Commercial grade reagents and solvents were used without further purification. N- cyclohexyI-//'-(methylpolystyrene)carbodiimide was purchased from Calbiochem- Novabiochem Corp. 3-ter/-Butylaniline, 5-fert-butyl-2-methoxyaniline, 4-bromo-3- (trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline 2-methoxyo- (trifluoromethyl)aniline, 4-/err-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-isocyanatobenzoate, Ar-acetyl-4-chloro-2-medioxy-5-(trifluoromethyl)aiiiline and 4-chloro-3-(trifluoromethyl)phenyl isocyanate were purchased and used without further purification. Syntheses of 3-amino-2-methoxyqumoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem.. 3, 1995, 129), 4- ■'4 Thin-layer chromatography (TLC) was performed using Whitman1' pre-coated glass-backed silica gel 60A F-254 250 urn plates. Visualization of plates1 was effected by one or more of the following techniques: (a) ultraviolet illumination, ^(b)1 exposure to iodine vapor, (c) ummersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazme followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science® silica gel. Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer Proton (H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (5 0.00) or residual protonated solvent (CHClj 5 7.26; MeOH S 3.30; DMSO 8 2.49) as standard. Carbon (;3C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometi. with solvent (CDC13 5 77.0; MeOD-d3; 5 49.0; DMSO-d6 5 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion source was maintained at 250 °C. Electron impact ionization was performed with electron energy of 70 eV and a trap current of 300 uA. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas (lxl 0"4 torr to 2.5x10"4 torr). The direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared ( -1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospru\ ionization. Spectra were scanned from 120-800 amu using a variable ion time according 10 the number of ions in the source. Gas chromatography - ion selective mass spectra (GC-MS) ^were obtained with a Hewlett Packard 5890 gas chiomatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25 rax 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eV). Elemental analyses are conducted by Robertson Microlit Labs, Madison NJ. All compounds displayed NMR spectra, LRMS and either elemental analysis or HRMS consistent with assigned structures. List of Abbreviations and Acronyms: AcOH acetic acid anh anhydrous atm atmosphere(s) BOC ^r?-butoxycarbony! CDI l.l'-carbonyl diimidazole cone concentrated d day(s) dec decomposition DMAC /V,jV-dimethylacetamide DMPU l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone DMF /V,jV-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDCI 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide EtOAc ethyl acetate EtOH ethanol(100%) Et20 diethyl ether EtjN triethylamine h hour(s) HOBT 1-hydroxybenzotriazole w-CPBA 3-chloroperoxybenzoic acid MeOH methanol pet. ether petroleum ether (boiling range 30-60 °C) temp. temperature ^THF tetrahydrofuran TFA trifluoroAcOH Tf trifluoromethanesulfonyl A. General Methods for Synthesis of Substituted Anilines AI. General Method for Aryl Amine Formation via Ether Formation Followed by Ester Saponification, Curtius Rearrangement, and Carbamate Deprotection. Synthesis of 2-Amino-3-methoxynaphthaleoe. C02Me OMe Step 1. Methyl 3-methoxy-2-naphthoate A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K2C03 (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temp, for 15 min., then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temp. overnight, then was treated with water (200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSCU), concentrated under reduced pressure (approximately 0.4 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10.30 g): 'H- NMR (DMSO-d6) 5 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, 7=8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, >8.09 Hz, 1H), 7.84 (d, >8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H). Step 2. 3-Metboxy-2-naphthoic acid A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room temp, was treated with a 1 N NaOH solution (33.4 mL, 33.4 mmol). The mixture was heated at the reflux temp, for 3 h, cooled to room temp., and made acidic with a 10% citric acid solution. The resulting solution was extracted with EtO.Ac (2 \ Inn mL). The combined organic layers were washed with a saturated NaCl solution, dned K(MgS04) and concentrated under reduced pressure. The residue was triturated with hexane then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): 'H-NMR (DMSO-d6) 6 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d, >8.09 Hz, 1H), 7.91 (d, 7=8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (br s, 1H). Step 3. 2-(Ar-(Carbobenzyloxy)amino-3-methoxynapbthaIene A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and EtjN (2.59 mL, 18.6 mmol) in anh toluene (70 mL) was stirred at room temp, for 15 min., then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resulting mixture was heated at 80 °C for 2 h. After cooling the mixture to room temp., benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was then warmed to 80 °C overnight. The resulting mixture was cooled to room temp., quenched with a 10% citric acid solution, and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc/86% hexane) to give 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%): 'H-NMR (DMSO-d6) 8 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H), 8.76 (s,lH). NH2 OMe Step 4. 2-Amino-3-methoxynaphthalene A slurry of 2-(/V-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a H2 atm (balloon) at room temp, overnight. The resulting mixture was filtered through Celite4, and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder (2.40 g. ^5%): 'H-NMR (DMSO-4) 5 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, 7=8.0 Hz, 1H), 7.56 (d, 7=8.0 Hz, 1H); EI-MS m/z 173 (M+). A2. Synthesis of co-Carbamyl Anilines via Formation of a Carbamylpyridine Followed by Nucleophilic Coupling with an Aryl Amine. Synthesis of 4-(2-/V-MethylcarbamyI-4-pyridyioxy)aniIine 0 clY^Y^NHMe Step la. Synthesis of 4-chloro-Ar-methyl-2-pyridinecarboxamide via the Menisci reaction Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temp, was added cone. H2SO4 (3.55 mL) to generate an exotherm. To this mixture was added H2O2 (30% wt in H20, 17 mL) followed by FeS047H20 (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temp, for 1 h, then warmed slowly over 4 h to 45 °C. When bubbling had subsided, the reaction was heated at 60 °C for 16 h. The resulting opaque brown solution was diluted with H20 (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with a saturated NaCl solution (3 x 150 mL), then they were combined, dried (MgS04) and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 4-chloro-W-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) R/0.50; 'H NMR (CDCI3) 5 3.04 (d, 7=5.1 Hz, 3H), 7.43 (dd, 7=5.4, 2.4 Hz, 1H), 7.96 (brs, 1H), 8.21 (s, 1H), 8.44 (d, 7=5.1 Hz, 1 H); CI-MS m/z 171 ((M+H)+). O Cl. CI N HCI Step lb. Synthesis of 4-chloropyridine-2-carbonyl chloride HCI salt via picolinic acid i\|f Anhydrous DMF (6.0 ml) was slowly added to SOCl2 (180 mL) between 40° and 50 °C. The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g, 487 mmol) was added in portions over 30 min. The resulting solution was heated at 72 °C (vigorous S02 evolution) for 16 h to generate a yellow solid precipitate. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and dried under high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chloride HCl salt as a yellow-orange solid (92.0 g, 89%). O CIYV^OMe I^N HCl Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HCl salt Ann DMF (10.0 mL) was slowly added to SOCl2 (300 mL) at 40-48 °C. The solution was stirred at that temp, range for 10 min., then picolinic acid (100 g, 812 mmol) was added over 30 min. The resulting solution was heated at 72 °C (vigorous S02 evolution) for 16 h to generate a yellow solid. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was Filtered, and the solids were washed with toluene (50 mL) and dried under high vacuum for 4 hours to afford 4-chloropyridine-2-carbonyl chloride HCl salt as an off-white solid (27.2 g, 16%). This material was set aside. The red filtrate was added to MeOH (200 mL) at a rate which kept the internal temperature below 55 °C. The contents were stirred at room temp, for 45 min., cooled to 5 °C and treated with Et20 (200 mL) dropwise. The resulting solids were filtered, washed with Et20 (200 mL) and dried under reduced pressure at 35 °C to provide methyl 4-chloropyndine-2-carboxylate HCl salt as a white solid (110 g, 65%); mp 108-112 °C; 'H-NMR (DMSO-db) 5 3.88 (s, 3H); 7.82 (dd, 7=5.5, 2.2 Hz, 1H); 8.08 (d, 7=2.2 Hz, 1H); 8.68 (d, 7=5.5 Hz, 1 H); 10.68 (br s, 1H); HPLC ES-MS ni/z 172 ((M+Hf). 0 c'Y^Y^NHMe Step 3a. Synthesis of 4-chloro-/V'-methyl-2-pyridinecarboxamide from methyl 4- chloropyridine-2-carboxylate A suspension of methyl 4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in MeOH (75 mL) at 0 °C was treated with a 2.0 M methylamine solution in THF (1 L) at a rate which kept the internal temp, below 5 °C. The resulting mixture was stored at 3 °C for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500 mL), dried (Na2S04) and concentrated under reduced pressure to afford 4-chloro-iV-methyl-2-pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43 °C; 'H-NMR (DMSO-d6) 5 2.81 (s, 3H), 7.74 (dd, 7=5.1,2.2 Hz, 1H), 8.00 (d, 7=2.2, 1H), 8.61 (d, 7=5.1 Hz, 1H), 8.85 (br d, 1H); Cl-MS m/z 171 ((M+Hf). O Step 3b. Synthesis of 4-chloro-iY-methyl-2-pyridinecarboxainide from 4- chloropyridine-2-carbonyl chloride 4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in portions to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0 °C. The resulting mixture was stored at 3 °C for 4 h, then concentrated under reduced pressure. The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate was washed with a saturated NaCl solution (2 x 100 mL), dried (Na2S04) and concentrated under reduced pressure to provide 4-chloro-/vr-methyl-2-pyridinecarboxamide as a yellow, crystalline solid (4.95 g, 88%): mp 37-40 °C. O Step 4. Synthesis of 4-(2-(^-methyIcarbamoyl)-4-pyridyloxy)aniline A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated with potassium re/v-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at room temp, for 2 h. The contents were treated with 4-chloro-jV-methy]-2- pyndinecarboxamide (15.0 g, 87.9 mmol) and K2C03 (6.50 g, 47.0 mmol) and then heated at 80 °C for 8 h. The mixture was cooled to room temp, and separated between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution (4 x 1000 mL), dried (Na2S04) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 °C for 3 h to afford 4-{2-(Ar-methylcarbamoyl)-4- pyridyloxy)aniIine as a light-brown solid 17.9 g, 84%): 'H-NMR (DMSO-d6) 5 2.77 (d, 7=4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB* quartet, 7=8.4 Hz, 4H), 7.06 (dd, 7=5.5, 2.5 Hz. 1H), 7.33 (d, 7=2.5 Hz, 1H), 8.44 (d, 7-5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244 ((M+H)+). A3. General Method for the Synthesis of Anilines by Nucleophilic Aromatic Addition Followed by Nitroarene Reduction. Synthesis of 5-(4- Aminophenoxy)isoindoline-l,3-dione O Step 1. Synthesis of 5-bydroxyisoindoline-l,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in cone. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120 °C for 45 min., then the clear, bright yellow mixture was heated at 160 °C for 2 h. The resulting mixture was maintained at 160 °C and was concentrated to approximately 15 mL, then was cooled to room temp, and adjusted pH 10 with a IN NaOH solution. This mixture was cooled to 0 °C and slowly acidified to pH 5 using a IN HC1 solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-l,3-dione as a pale yellow powder as product (3.24 g, 72%): 'H NMR (DMSO-d6) 8 7.00-7.03 (m, 2H), 7.56 (d, 7=9.3Hz, 1H). Step 2. Synthesis of 5-(4-nitropbenoxy)isoindoline-l,3-dione To a stirring slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 °C was added a solution of 5-hydroxyisoindoline-l,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The bright yellow-green mixture was allowed to return to room temp, and was stirred for 1 h, then 1 -fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated at 70 °C overnight, then cooled to room temp, and diluted slowly with water (150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (MgSCu) and concentrated under reduced pressure to give 5-(4-nitrophenoxy)isoindoline-l,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70% hexane) R/0.28; 1H NMR (DMSO-d6) 6 7.32 (d, 7=12 Hz, 2H). 7.52-7.57 (m, 2K), 7.89(d, 7=7.8 Hz, 1H), 8.29 (d, 7=9 Hz, 2H), 11.43 (br s, 1H); CI-MS m/z 285 ((M+H)+, 100%). H2N' ^ VV° O Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-l,3-dione A solution of 5-(4-nitrophenoxy)isoindoline-l,3-dione (0.6 g, 2.11 mmol) in cone. AcOH (12 mL) and water (0.1 mL) was stirred under stream of argon while iron powder (0.59 g, 55.9 mmol) was added slowly. This mixture stirred at room temp, for 72 h, then was diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgSO.4) and concentrated under reduced pressure to give 5-(4-aminophenoxy)isoindoline-l,3-dione as a brownish solid (0.4 g, 75%): TLC (50% EtOAc/50% hexane) R/0.27; lH NMR (DMSO-d6) 5 5.14 (br s, 2H), 6.62 (d, 7=8.7 Hz, 2H), 6.84 (d, 7=8.7 Hz, 2H), 7.03 (d, 7=2.1 Hz, 1H), 7.23 (dd, IH), 7.75 (d, 7=8.4 Hz, 1H), 11.02 (s, IH); HPLC ES-MS m/z 255 ((M+Hf, 100%). A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5-tert- Butyl-2-(2,5-dimethylpyrrolyl)aniline Step 1. Synthesis of l-(4-terNbutyl-2-nitrophenyI)-2,5-dimethyipyrroIe To a stirring solution of 2-nitro-4-ferr-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added AcOH (0.1 mL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. The reaction mixture was heated at 120 °C for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temp., diluted with CH2Ch (10 mL) and sequentially washed with a IN HC1 solution (15 mL), a IN NaOH solution (15 mL) and a saturated NaCl solution (15mL), dried ( MgS04) and concentrated under reduced pressure. The resulting orange-brown solids were purified via column chromatography (60 g SiO?; gradient from 6% EtOAc/94% hexane to 25% EtOAc/75% hexane) to give l-(4-rerr-butyl-2-nitrophenyl)-2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85% hexane) Rf 0.67; 'H NMR (CDClj) d 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, IH), 7.62 (dd, IH), 7.88 (d, 7=2.4 Hz, IH); CI-MS m/z 273 ((M+H)+, 50%). Step 2. Synthesis of 5-terr—Butyl-2-(2,5-dimethy\|pyrrolyl)aniIine A slurry of l-(4-/err-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10%Pd/C (0.056 g) and EtOAc (50 mL) under an H2 atmosphere (balloon) was stirred for 72 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give 5-/err--butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g, 99%): TLC (10% EtOAc/90% hexane) R/0.43; 'H NMR(CDClj) 5 1.28 (s, 9H), 1.87-1.91 (m. 8H). 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, 1H). General Method for the Synthesis of Anilines from Anilines by Nucleophilic Aromatic Substitution. Synthesis o(4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HC1 Salt 0 i HCI Me A solution of 4-ammo-3-methylphenol (5.45 g, 44.25 mmol) in dry dirnethylacetamide (75 mL) was treated with potassium terr-butoxide (10.86 g, 96.77 mmol) and the black mixture was stirred at room temp, until the flask had reached room temp. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 °C for 8 h. The mixture was cooled to room temp, and diluted with water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with a saturated NaCl solution (200 mL), dried (MgSOj) and concentrated under reduced pressure. The residual black oil was treated with EtiO (50 mL) and sonicated. The solution was then treated with HCI (1 M in Et20; 100 mL) and stirred at room temp, for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration from solution and stored under anaerobic conditions at 0 °C prior to use: !H NMR (DMSO-d6) 5 2.41 (s, 3H), 2.78 (d, 7=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, 7=8.5, 2.6 Hz. 1H), 7.23 (dd, .7=5.5, 2.6 Hz, 1H), 7.26 (d, 7=2.6 Hz, 1H), 7.55 (d, 7=2.6 Hz, 1H), 7.64 (d, 7=8.8 Hz, 1H), 8.55 (d, 7=5.9 Hz, 1H), 8.99 (q, 7=4.8 Hz, 1H). A6. General Method for the Synthesis of Anilines from Hydroxyanilines by -V- Protection, Nucleophilic Aromatric Substitution and Deprotection. Synthesis of4-(2-(A^-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline CI Step 1: Synthesis of 3-Chloro-4-(2,2,2-trifluoroacetylamino)phenol Iron (3.24 g, 58.00 mmol) was added to stirring TFA (200 mL). To this slurry was added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 mL). This urav slurry was stirred at room temp, tor 6 d. The iron was filtered from solution and the remaining material was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To the resulting yellow solution was added a saturated NaHCOj solution (50 mL). The solid which precipitated from solution was removed. The filtrate was slowly quenched with the sodium bicarbonate solution until the product visibly separated from solution (determined"was using a mini work-up vial). The slightly cloudy yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with a saturated NaCl solution (125 mL), dried (MgSOi) and concentrated under reduced pressure. The 'H NMR (DMSO-d6) indicated a 1:1 ratio of the nitrophenol starting material and the intended product 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol. The crude material was taken on to the next step without further purification. 0 '°W^NHMe F3cr H i. Step 2: Synthesis of 4-(2-(A:-Methylcarbamoyl)-4-pyridyloxy)-2-cblorophenyJ (222-trifluoro)acetamide A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 mL) was treated with potassium ferr-butoxide (5.16 g, 45.98 mmol) and the brownish black mixture was stirred at room temp, until the flask had cooled to room temp. The resulting mixture was treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 °C under argon for 4 d. The black reaction mixture was cooled to room temp, and then poured into cold water (100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by column chromatography (gradient from 20% EtOAc/pet. ether to 40% EtOAc/pet. ether) to yield 4-(2-(Ar-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol). O ,u. H2N ^ CI Step 3. Synthesis of 4-(2-(A'-Methylcarbarnoyl)-4-pyridyloxy)-2 MA solution of crude 4-(2-(Ar-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a IN NaOH solution (20 raL). This brown solution was allowed to stir for 8 h. To this solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x 40 mL) and the solvent was concentrated to yield 4-(2-(yV-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline as a green oil that solidified upon standing (2.86 g, 10.30 mmol): 'H NMR (DMSO-d6) 5 2.77 (d, 7=4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, 7=8.5, 2.6 Hz, IH), 6.76 (d, 7=2.6 Hz, IH), 7.03 (d, 7=8.5 Hz, IH), 7.07 (dd, 7=5.5, 2.6, Hz, IH), 7.27 (d, 7=2.6 Hz, IH), 8.46 (d, 7=5.5 Hz, IH), 8.75 (q, 7=4.8, IH). A7. General Method for the Deprotection of an Acylated Aniline. Synthesis of 4-ChIoro-2-methoxy-5-(trifluoromethyl)aniline CF3 A suspension of 3-chIoro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g, 14.95 mmol) in a 6M HC1 solution (24 mL) was heated at the reflux temp, for 1 h. The resulting solution was allowed to cool to room temp, during which time it solidified slightly. The resulting mixture was diluted with water (20 mL) then treated with a combination of solid NaOH and a saturated NaHC03 solution until the solution was basic. The organic layer was extracted with CH2CI2 (3 x 50 mL). The combined organics were dried (MgS04) and concentrated under reduced pressure to yield 4-chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g, 14.2 mmol): 'H NMR (DMSO-d6) 5 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H). A8. General Method for Synthesis of co-Alkoxy-o-carboxyphenyl Anilines. Synthesis of 4-(3-{A/-Metbylcarbamoly)-4-methoxyphenoxy)aniline. O rY0TV^oMe Step 1. 4-(3-Methoxycarbonyl-4-merhoxyphenoxy)-l-nitrobenzene: »To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-l -nitrobenzene (prepared from 2,5-dihydroxybenzoic acid in a manner analogous to that described in Method A13, Step 1,12 mmol) in acetone (50 mL) was added K2CO3 (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated at the reflux temp, overnight, then cooled to room temp, and filtered through a pad of Celite®. The resulting solution was concentrated under reduced pressure, absorbed onto SiCh, and purified by column chromatography (50% EtOAc / 50% hexane) to give 4-(3~methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene as a yellow powder (3 g): mp 115-118 °C. O jfT°I^0H Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-l-Ditrobenzene: A mixture of 4-(3-methoxycarbonyI-4-methoxyphenoxy)-l -nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temp, overnight and then heated at the reflux temp, for 4 h. The resulting mixture was cooled to room temp, and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous mixture was made acidic with a IN HC1 solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgS04) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-l-nitrobenzene (1.04 g). O Step 3. 4-(3-(Ar-Methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene: To a solution of 4-(3-carboxy-4-methoxyphenoxy)-l-nitrobenzene (0.50 g, 1.75 mmol) in CH2CI2 (12 mL) was added SOCI2 (0.64 mL, 8.77 mmol) in portions. The resulting solution was heated at the reflux temp, for 18 h, cooled to room temp., and concentrated under reduced pressure. The resulting yellow solids were dissolved in CH2CI2 (3 mL) then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02 mmol) in portions (CAUTION: gas evolution), and stirred at room temp, for 4 h. The resulting mixture was treated with a IN NaOH solution, then extracted with CHjCN (25 mL). The organic layer was dried (Na2SC>4) and concentrated under reduced pressure to give 4-(3-W(//-methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene as a yellow solid (0.50 g, 95%). O '°VY^NHMe H2N' "" ^"NjMe Step 4. 4-(3-(Ar-MethylcarbamoIy)-4-methoxyphenoxy)aniline: A slurry of 4-(3-(A'-methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene (0.7S g7 2.60 mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under I atm of H2 (balloon) for 2.5 d, then was filtered through a pad of Celite®. The resulting solution was concentrated under reduced pressure to afford 4-(3-(yV-methylcarbamoly)-4-methoxyphenoxy)aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et3N/99.9% EtOAc) R/0.36. A9. General Method for Preparation of ca-Alkylphthalimide-contaimng Anilines. Synthesis of 5-(4-Aminophenoxy)-2-metnylisoindoIine-l,3-dione O N-Me O Step 1. Synthesis of 5-(4~Nitrophenoxy)-2-methylisoindoIine-l,3-dione: A slurry of 5-(4-nitrophenoxy)isoindoline-l,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp, for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temp, overnight, then was cooled to °C and treated with water (10 mL). The resulting solids were collected and dried under reduced pressure to give 5-{4-nitrophenoxy)-2-methylisoindoline-1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) Kf 0.61. o £t.ep 2. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-I,3-dione: A slurry of nitrophenoxy)-2-methylisoindoline-l,3-dione (0.87 g, 2.78 mmol) and 10% Pd/C (0.10 g) in MeOH was stirred under 1 atm of H? (balloon) overnight. The resulting mixture was filtered through a pad of Celite and concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) and filtered through a plug of SiOi (60% EtOAc/40% hexane) to afford 5-(4-aminophenoxy)-2-methylisoindoline-l,3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc/60% hexane) R/0.27. A10. General Method for Synthesis of co-Carbamoylaryl Anilines Through Reaction of ©-Alkoxycarbonylaryl Precursors with Amines. Synthesis of 4-{2-(iV-(2-morpholin-4-ylethyl)carbamoy})pyridyloxy)aniline o "IYWG Step 1. Synthesis of 4-Chloro-2-(jV-(2-morpholin-4-ylethyl)carbamoyl)pyridine To a solution of methyl 4-chloropyridine-2-carboxylate HC1 salt (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 mmol) dropwise and the resulting solution was heated at the reflux temp, for 20 h, cooled to room temp., and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSCh) and concentrated under reduced pressure to afford 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH/90% EtOAc) Rr0.50. H,N v ^-^ A^Step 2. Synthesis of 4-(2-( ylethyI)carbamoyl)pyridyioxy)aniline. A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium terr-butoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temp, for 2 h, then was sequentially treated with 4-chloro-2-(A/-(2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and K.2COj (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 °C overnight, cooled to room temp., and separated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were washed with a saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure. The resulting brown solids were purified by column chromatography (58 g; gradient from 100% EtOAc to 25% MeOH/75% EtOAc) to afford 4-(2-(yV-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC (10% MeOH/90% EtOAc) R/0.32. All. General Method for the Reduction of Nitroarenes to Arylamines. Synthesis of 4-(3-Carboxyphenoxy)aniIine. A slurry of 4-(3-carboxyphenoxy)-l-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd/C (0.50 g) in MeOH (120 mL) was stirred under an H2 atmosphere (balloon) for 2 d. The resulting mixture was filtered through a pad of Celite®, then concentrated under reduced pressure to afford 4-(3-carboxyphenoxy)anihne as a brown solid (2.26 g, 48%): TLC (10% MeOH/90% CH2C12) Rr 0.44 (streaking). A12. General Method for the Synthesis of Isoindoiinone-Containing Anilines. Synthesis of 4-(l-Oxoisoindolin-5-yloxy)aniHoe. XJQ NH Step 1. Synthesis of 5-hydroxyisoindolin-l-one io a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the reflux temp, for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 Kg Si02; gradient from 60% EtOAc/40% hexane to 25% MeOH/75% EtOAc) to give 5-hydroxyisoindolin-l-one (3.77 g): TLC (100% EtOAc) R/0.17; HPLC ES-MS m/i 150 ((M+H)+). O Step 2. Synthesis of 4-(l-isoindolinon-5-yloxy)-l-nitrobenzene To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 °C was added 5-hydroxyisoindolin-l-one (2.0 g, 13.4 rr.mol) in portions. The resulting slurry was allowed to warn to room temp and was stirred for 45 min., then 4-fluoro-l-nitrobenzene was added and then mixture was heated at 70 °C for 3 h. The mixture was cooled to 0 °C and treated with water dropwise until a precipitate formed. The resulting solids were collected to give 4-(l-isoindolinon-5-yloxy)-l-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) R/0.35. NH H,N O Step 3. Synthesis of 4-(l-oxoisoindofin-5j-yloxy)aniline A slurry of 4-(l-isoindolinon-5-yloxy)-l-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd/C (0.20 g) in EtOH (50 mL) was stirred under an H2 atmosphere (balloon) for 4 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford 4-( 1-oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC (100% EtOAc) R/0.15. A13. General Method for the Synthesis of ©-Carbamoyl Anilines via EDO- Mediated Amide Formation Followed by Nitroarene Reduction. Synthesis of4-(3-A/-MethyIcarbamoyIphenoxy)aniline. 012 0->N x^ Step 1. Synthesis of 4-(3-etboxycarbonyiphenoxy)-l-nitrobenzene A mixture of 4-fluoro-l-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K2CO3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux temp, overnight, cooled to room temp, and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na2S04) and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g). O OH 0,N' XT Step 2. Synthesis of 4-(3-carboxyphenoxy)-l-nitrobenzene To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene (5.14 g, 17.9 mmol) in a 3:1 THF/water solution (75 mL).was added a solution LiOH'fyO (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50 °C overnight, then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2 with a 1M HC1 solution. The resulting bright yellow solids were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-l-nitrobenzene (4.40 g, 95%). O 02N' ^ ^ ^Step3. Synthesis of 4-(3-(Ar-methylcarbamoyl)phenoxy)-l-nitrobenzene A mixture of 4-(3-carboxyphenoxy)-l-nitrobenzene (3.72 g, 14.4 mmol), EDOHC1 (3.63 g, 18.6 mmol), jV-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CH2CI2 (45 mL) was stirred at room temp, for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with a 1M HC1 solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with a saturated NaCl solution (50 mL), dried (T^SClt), and concentrated under reduced pressure to give 4-(3-(/V-methylcarbamoyl)phenoxy)-l-nitrobenzene as an oil (1.89 g). 'NHMe Step 4. Synthesis of 4-(3-(Ar-metbylcarbamoyI)phenoxy)aniline A slurry of 4-(3-(yV-methylcarbamoyl)phenoxy)-l-nitrobenzene (1.89 g, 6.95 mmol) and 5% Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an H2 atm (balloon) overnight. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH/95% CH2CI2). The resulting oil solidified under vacuum overnight to give 4-(3-(N-methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%). A14. General Method for the Synthesis of ©-Carbamoyl Anilines via EDO- Mediated Amide Formation Followed by Nitroarene Reduction. Synthesis of 4-3-(5-MethyIcarbamoyl)pyridyloxy)aniline O 02N' ^ N Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-l-nitrobenzene To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a ^solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated at 70 °C overnight, cooled to room temp., and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g). O H2N v N Step 2, Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-l-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd/C in MeOH/EtOAc was stirred under an Hz atmosphere (balloon) for 72 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% EtOAc/90% hexane to 30% EtOAc/70% hexane to 50% EtO Ac/50% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): !H NMR (CDC13) 5 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H), 8.87 (d, 1H). A15, Synthesis of an Aniline via Electropbilic Nitration Followed by Reduction. Synthesis of 4-(3-Methylsulfamoylphenoxy)aniline. Br-^ ^r^ ^S. NHMe Step 1. Synthesis of A^methyl-S-bromobenzenesuIfonamide To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0 °C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was allowed to warm to room temp, and was stirred at room temp, overnight. The resulting mixture was separated between EtOAc (25 mL) and a 1 M HC1 solution (25 mL). The aqueous phase was back-extracted with EtOAc (2 x 25 mL). The combined organic phases were sequentially washed with water (2 x 25 mL) and a saturated NaCl solution (25 mL), dried (Mg,SQ4 and concentrated under reduced pressure to give M-metbM-1-bromobenzenesuifonamide as a white solid (2.8 g, 99%). V°YVS Step 2. Synthesis of 4-(3-(A-methylsuIfamoyl)phenyloxy)benzene To a slurry of phenol (1.9 g, 20 mmol), K2C03 (6.0 g, 40 mmol), and CuI (4 g, 20 mmol) in DMF (25 mL) was added Ar-methyl-3-bromobenzenesulfonamide (2.5 g, lOmmol), and the resulting mixture was stirred at the reflux temp, overnight, cooled to room temp., and separated between EtOAc (50 mL) and a 1 N.HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were sequentially washed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgS04), and conceicvt.T3.ted under reduced pressure. The residual art was. riurifted ty COVAVJW. chromatography (30% EtOAc/70% hexane) to give 4-(3-(/V- methylsulfamoyl)phenyloxy)benzene (0.30 g). 0,N - Step 3. Synthesis of 4-(3-(ALmethylsu}farnoyl)phenyloxy)-l-nitrobenzene To a solution of 4-(3-(/V-methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10°C was added NaNO; (0.097 g, 1.14 mmol) in portions over 5 min. The resulting solution was stirred at -10 °C for 1 h, then was allowed to warm to room temp., and was concentrated under reduced pressure. The residue was separated between EtOAc (10 mL) and water (10 mL). The organic phase was sequentially washed with water (10 mL) and a saturated NaCl solution (10 mL), dried (MgS04) and concentrated under reduced pressure to give 4-(3-(Ar-methylsulfamoyl)phenyloxy)-l -nitrobenzene (0.20 g). This material carried on to the next step without further purification. Step 4. Synthesis of 4-(3-(/V-methylsulfarnoyl)phenyloxy)aniline A slurry of 4-(3-(A/-methylsulfamoyl)phenyloxy)-l-nitrobenzene (0.30 g) and 10% Pd/C (0.030 g) in EtOAc (20 mL) was stirred under an H2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(Ar-methylsulfamoyl)phenyloxy)aniline (0.070 g). A16. Modification of ©-ketones. Synthesis of 4-(4-(l-(W- methoxy)iminoethyl)phenoxyaniline HC1 salt. HC! ft H2N„ O To a slurry of 4-(4-acetylphenoxy)aniIine HC1 salt (prepared in a manner analogous to Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0 mL) was added 0-methylhydroxylamine HCl salt (0.65 g, 7,78 mmol, 2.0 equiv.). The resulting solution was heated at the reflux temperature for 30 min, cooled to room temperature and concentrated under reduced pressure. The resulting solids were triturated with water (10 mL) and washed with water to give 4-(4-(l -(/V-methoxy)iminoethyl) phenoxyaniline HCl salt as a fellow solid (0.85 g): TLC (50% EtOAc/50% pet. ether) R/0.78, 'H NMR (DMSO-d6) 5 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257.((M+H)+). A17. Synthesis of ^-(co-SHyloxyalkyOamides. Synthesis of 4-(4-(2-(A/-(2- Triisopropylsilyloxy)ethylcarbarnoyl)pyridyloxyaniHne. -i'r Step 1. 4-Chloro-Ar-(2-triisopropylsilyloxy)ethyIpyridine-2-carboxamide To a solution of 4-chloro-Ar-(2-hydroxyethyl)pyridine-2-carboxamide (prepared in a manner analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp, then was concentrated under reduced pressure. The residue was separated between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried (MgSO-t), and concentrated under reduced pressure to afford 4-chloro-2-(N-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide as an orange oil (2.32 g, 88%). This material was used in the next step without further purification. H;NXJ u « ^r Step 2. 4-(4-(2-(iV-(2-Triisopropylsilyloxy)ethylcarbamoyI)pyridyloxyaniiine To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF (8 mL) was added potassium rerr-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) in one portion causing an exotherm. When this mixture had cooled to room temperature, a solution of 4-chloro-2-(jV-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) in DMF (4 mL) was added followed by K2CO3 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was heated at 80 °C overnight. An additional portion of potassium rerr-butoxide (0.34 g, 3 mmol, 0.5 equiv.) was then added and the mixture was stirred at 80 °C an additional 4 h. The mixture v.as cooled to 0 °C with an ice/water bath, then water (approx. \ mL) was slowly added dropwise. The organic layer was extracted with EtOAc (3 x 10 mL). The combined gjrganic layers were washed with a saturated NaCl solution (20 mL), dried (MgS04) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (Si02; 30% EtOAc/ 70% pet ether) to afford 4-(4-(2-(tf-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown oil (0.99 g, 38%). A18. Synthesis of 2-PryidinecarboxyIate Esters via Oxidation of 2- Methylpyridines. Synthesis of 4-(5-(2- methoxycarbonyl)pyridyloxy)aniline. Step 1. 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene. A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), \ fIuorc-4-nitrobenzcne (9.S mL, 91.6 mmol, 1.0 equiv.), K2C03 (25 g, 183 mmol, 2.0 equiv.) in DMF (100 mL) was heated at the reflux temperature overnight. The resulting mixture was cooled to room temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed with water (2 x 100 mL) and a saturated NaCl solution ((100 mL), dried (MgSOt) and concentrated under reduced pressure to give 4-(5-(2-methyl)pyridyloxy)-l-nitrobenzene as a brown solid (12.3 g). Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)-l-nitrobenzene. A mixture of 4-(5-(2-methyi)pyridyloxy)-l -nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the reflux temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered , then concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The solution was treated with a cone HC1 solution (7 mL), then heated at the reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was separated between EtOAc (50 mL) and a IN NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were sequentially gashed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgSOj) and concentrated under reduced pressure. The residue was purified by column chromatography (Si02; 50% EtOAc/50% hexane) to afford 4-(5-(2-methoxycaibonyl)pyridyloxy)-l-nitrobenzene (0.70 g). O Step 3. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)auiline. A slurry of 4-(5-(2-methoxycarbonyI)pyridyloxy)-l-nitrobenzene (0.50 g) and 10% Pd/C (0.050 g) in a mixture of EtOAc (20 mL) and MeOH (5 mL) was placed under a H2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite4', and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCh; 70% EtOAc/30% hexane) to give 4-(5-t,2-methoxycarbonyl)pyridyloxy)aniline (0.40 g). A19. Synthesis of co-Sulfonylphenyl Anilines. Synthesis of 4-(4- Methylsulfonylphenyoxy)aniline. 02N v v ,£ O O Step 1. 4-(4-Methyisulfonylphenoxy)-l-nitrobenzene: To a solution of 4-(4- methylthiophenoxy)-l-nitrobenzene (2.0 g, 7.7 mmol) in CH2CI2 (75 mL) at 0 °C was slowly added m-CPBA (57-86%, 4.0 g), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a IN NaOH solution (25 mL). The organic layer was sequentially washed with a IN NaOH solution (25 mL), water (25 mL) and a saturated NaCl solution (25 mL), dried (MgS04), and concentrated under reduced pressure to give 4- (4-methylsuIfonyiphenoxy)-l-nitrobenzene as a solid (2.1 g). Step 2. 4-(4-MethylsulfonyIphenoxy)-l-aniIine: 4-(4-Methylsulfony!phenoxy)-l- nitrobenzene was reduced to the aniline in a manner analogous to that described in Method A IS. step 3. B, Synthesis of Urea Precursors Bl_ General Method for the Synthesis of Isocyanates from Anilines Using CDI. Svnthesis of 4-Bromo-3-(trifluoromethyl)phenyI Isocyanate. NH2«HCI Step 1. Synthesis of 4-bromo-3-(trifluoromethyI)aniline HC1 salt To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et20 (500 mL) was added an HC1 solution (1 M in Et20; 300 mL) dropwise and the resulting mixture was stirred at room temp, for 16 h. The resulting pink-white precipitate was removed by filtration and washed with Et20 (50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline HC1 salt (73 g , 98%). NCO Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate A suspension of 4-bromo-3-(trifluoromethyl)aniline HC1 salt (36.8 g, 133 mmol) in toluene (278 mL) was treated with trichloromethyl chloroformate dropwise and the resulting mixture was heated at the reflux temp, for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mL), then concentrated under reduced pressure. The residue was treated with CH2CI2 (500 mL), then concentrated under reduced pressure. The CH2CI2 treatment/concentration protocol was repeated and resulting amber oil was stored at -20 °C for 16 h, to afford 4-bromo-3-(trifluoromethyl)phenyl isocyanate as a tan solid (35.1 g, 86%): GC-MS m/z 265 (M+). C. Methods of Urea Formation Cla. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of A^-(4-Chloro-3-(trifluoromethyl)phenyl)-/V'-(4-(2-(/V-methylcarbamoyl)-4-pyridyloxy)pheoyl) Urea A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol) in CH2CI2 (35 mL) was added dropwise to a suspension of 4-(2-(//-methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH2C12 (35 mL) at 0 °C. The resulting mixture was stirred at room temp, for 22 h. The resulting yellow solids were removed by filtration, then washed with CH2CI2 (2 x 30 mL) and dried under reduced pressure (approximately 1 mmHg) to afford vV-(4-chloro-3-(trifluoromethyl)phenyl)-jV'-(4-(2-(yV-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as an off-white solid (28.5 g, 93%): mp 207-209 °C; 'H-NMR (DMSO-d6) 5 2.77 (d, 7=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, 7=2.5 Hz, 1H), 7.62 (m, 4H), 8.11 (d, 7=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s. 1H), 9.21 (s, 1H); HPLC ES-MS irv'z 465 ((M+H)+). Clb. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of A^-(4-Bromo-3-(trifluoromethyl)phenyl)-yV-(4-(2-(7V-methylcarbamoyl)-4-pyridyloxy)phenyl)Urea CF3 O KK) U N N H H A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method Bl, Step 2; 8.0 g, 30.1 mmol) in CH2CI2 (80 mL) was added dropwise to a solution of 4-(2-(7V-methylcarbamoyl)-4- pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH2C12 (40 mL) at 0 °C. The resulting mixture was stirred at room temp, for 16 h. The resulting yellow solids were removed by filtration, then washed with CH2CI2 (2 x 50 mL) and dried under reduced pressure (approximately 1 mmHg) at 40 °C to afford jV-(4-bromo-3-(trifluoromethyl)pheny 1 )- /V'-(4-(2-(yV-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-yellow solid (13.2 g. 90%): mp 203-205 °C; 'H-NMR (DMSO-d6) 5 2.77 (d, 7=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d. 7=2.5 Hz, IH), 7.58 (m, 3H), 7.77 (d, 7=8.8 Hz, 1H), 8.11 (d, 7=2.5 Hz, JH). 8.49 (d. 7=5.5 Hz,- lH),8.77(brd, lH),8.99(s, IH), 9.21 (s. IH); HPLC ES-MS m/z 509 ((M-H)'). General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of/V-(4-Chloro-3-(trifluoromethyl)phenyl)-A"-(2-methyl-4-(2-(N-methykarbamoyl)(4-pyridyloxy))phenyl) Urea CF3 0 O f VJV^T NHMe A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method A5; 0.11 g, 0.45 mmol) in CH2C12 (1 mL) was treated with Et3N (0.16 mL) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temp, for 6 d, then was treated with water (5 mL). The aqueous layer was back-extracted with EtOAc (3x5 mL). The combined organic layers were dried (MgSCU) and concentrated under reduced pressure to yield Ar-(4-chloro-3-(trifluoromethyl)phenyl)-/Vr'-(2 niethyl-4-(2-(N-mc;:hylcarbamoyl)(4-p^Tidyloxy))phenyi) irea as a brown oil ^0.11 g, 0.22 mmol): 'H NMR (DMSO-d6) 5 2.27 (s, 3H), 2.77 (d, 7=4.8 Hz, 3H), 7.03 (dd, 7=8.5, 2.6 Hz, 1H), 7.11 (d, .7=2.9 Hz, 1H), 7.15 (dd, 7=5.5, 2.6, Hz, 1H), 7.38 (d, 7=2.6 Hz, 1H), 7.62 (app d, 7-2.6 Hz, 2H), 7.84 (d, 7=8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50 (d, 7=5.5 Hz, 1H), 8.78 (q, 7=5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H)+). Cld. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of /y-(4-Chloro-3-(trifluoromethyr)phenyl)-A"-(4-aminophenyI) Urea CF3 To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in CH2CI2 (308 mL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The resulting mixture was stirred at room temp, for 1 h, treated with CH2G2 (100 mL), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc (110 mL) and MeOH (15mL), and the clear solution was washed with a 0.05 N HC1 solution. The organic layer was concentrated under reduced pressure to afford impure %--(4-chloro-3-(trifiuoromethyl)phenyl)-jV'-(4-aniinophenyl) urea (3.3 g): TLC (100% EtOAc) R.y-0.72. Cle. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of A-(4-Chloro-3-(trifluorornethyl)phenyI)-/V-(4-ethoxycarbonylphenyl) Urea CF3 0 H H To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH2CI2 (30 mL) was added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution was stirred at room temp, overnight. The resulting slurry was diluted with CH2CI2 (50 mL) and filtered to afford A'-(4-chloro-3-(trifluoromethyl)phenyl)-yV'-(4-ethoxycarbonylphenyl) urea as a white solid (5.93 g, 97%): TLC (40% EtOAc/60% hexane) R/0.44. Clf. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of A^-Chloro-S-ttrifluoromethyOphenylHV'-(3-carboxyphenyl) Urea H H To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21g, 5.46 mmol) in CH2CI2 (8 mL) was added 4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76 mmol) and the resulting mixture was stirred at room temp, overnight, then treated with MeOH (8 mL), and stirred an additional 2 h. The resulting mixture was concentrated under reduced pressure. The resulting brown solids were triturated with a 1:1 EtOAc/hexane solution to give /V-(4-chloro-3-(trifluoromethyl)phenyl)-/Y'-(3-carboxyphenyl) urea as an off-white solid (1.21 g, 76%). C2a. General Method for Urea Synthesis by Reaction of an Aniline with V./V'- Carbonyl Diimidazole Followed by Addition of a Second Aniline. Synthesis of/V-(2-Methoxy-5-(trifluoromethyl)pbenyl)-Ar'-(4-(2-(/V-methylcarbamoyl)-4-pyridyloxy)phenyI) Urea CF3 0 9 ff TJYr NHMe To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH2C12 (15 mL) at 0 °C was added CDI (0.13 g). The resulting solution was allowed to warm to room temp, over 1 h, was stirred at room temp, for 16 h, then was treated with 4-(2-(iV-methylcarbamoyI)-4- pyridyloxy)aniline (0.18 g). The resulting yellow solution was stirred at room temp, for 72 h, then was treated with H2O (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCl solution (100 mL), dried (MgS04) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The fiitrate was concentrated under reduced pressure and the residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane to 100% EtOAc) to give M(2-memoxy-5-(trifluoromethyl)phenyl)- yV'-(4-(2-(Ar-methylcarbamoyI)-4-pyridyloxy)phenyl) urea as a light tan solid (0.098 g, 30%): TLC (100% EtOAc) R/0.62; H NMR (DMSO-d«) 5 2.76 (d, 7=4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, 7=4.8 Hz, IH), 9.55 (s, 1 H); FAB-MS m/z 461 ((M+H)). ) C2b. General Method for Urea Synthesis by Reaction of an Aniline with A',/V'-Carbonyl Diimidazole Followed by Addition of a Second Aniline. Symmetrical Urea's as Side Products of a tyA/'-Carbonyl Diimidazole Reaction Procedure. Synthesis of Bis(4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea o o MeHN-AY^Y°Y^ o ff"Y°Y'V^NHMe "V kJWU U H H •To a stirring solution of 3-amino-2-methoxyquinoIine (0.14 g) in anhydrous CH2CI2 (15 mL) at 0 C was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over 1 h then was stirred at room temp, for 16 h. The resulting mixture was treated with 4-(2-(/V-methylcarbamoyl)-4-pyridyloxy)anilme (0.18 g). The resulting yellow solution stirred at room temp, for 72 h, then was treated with water (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with a saturated NaCl solution (100 ml), dried (MgSO^j) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis(4-(2-0V-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) R/0.50; lH NMR (DMSO-d6) 6 2.76 (d, J=5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, >5.4 Hz, 1H), 8.75 (d, y-4.8 Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m/r 513 ((M+H)+). C2c. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of Ar-(2-Methoxy-5-(trifluoromethyl)phenyWv'-(4-(l,3-dioxoisoindolin-5-yloxy)pheny!) Urea u H H O' To a stirring solution of 2-methoxy-5-(trifluoromethyi)phenyl isocyanate (0.10 g, 0.47 mmol) in CH2CI2 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-l,3-dione (Method A3, Step 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h, then was treated with CH2CI2 (10 mL) and MeOH (5 mL). The resulting mixture was sequentially washed with a IN HCl solution (15 mL) and a saturated NaCl solution (15 mL), dried (MgS04) and concentrated under reduced pressure to afford N-(2-methoxy-5- (trifluoromethyl)phenyl-iV'-(4-(l13-dioxoisoindolm-5-yloxy)phenyl) urea as a white solid (0.2 g, 96%): TLC (70% EtOAc/30% hexane) R/0.50; 'H NMR (DMSO-d6) 5 3.95 (s, 3H), 7.31- 7.10 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), [{.27(brs. IH); HPLC ES-MS 472.0 ((M+Hf. 100%). General Method for Urea Synthesis by Reaction of an Aniline with N,N'-Carbonyl Diimidazole Followed by Addition of a Second Aniline. Synthesis of iV-(5-(rerr-Buryl)-2-(2,5-dimethylpyrrolyl)phenyl)-.'V'-(4-(2-(A^-methylcarb?moyl)-4-pyridyloxy)phenyl) Urea To a stirring solution of CDI (0.21g, 1.30 mmol) in CH2CI2 (2 mL) was added 5-(/err-butyl)-2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one portion. The resulting mixture was stirred at room temp, for 4 h, then 4-(2-(Ar-methylcarbamoyi)-4-pyridyloxy)aniline (0.065 g, 0>267mnol) was then added in one portion The resulting mixture was heated at 36 °C overnight, then cooled to room temp, and diluted with EtOAc (5 mL). The resulting mixture was sequentially washed with water (15 mL) and a IN HC1 solution (15mL), dried (MgSO-O, and filtered through a pad of silica gel (50 g) to afford ;V-(5-(/e«-butyl)-2-(2,5-dimethylpyrfolyl)phenyl)-A^'-(4-(2-(Af-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc/60% hexane) R/0.24; lH NMR (acetone-dfl) 6 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J=4.8Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, 7=5.4Hz, 1H), 8.57 (d, 7=2.1Hz,■ 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M+H)+, 100%). C3. Combinatorial Method for the Synthesis of Diphenyl Ureas Using Triphosgene One of the anilines to be coupled was dissolved in dichloroethane (0.10 M). This solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a bis(trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The vial was capped and heat at 80 °C for 5 h, then allowed to cool to room temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 mL. 1.0 equiv), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting Mixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC. C4. General Method for Urea Synthesis by Reaction of an Aniline with Phosgene Followed by Addition of a Second Aniline. Synthesis of yV-(2-Methoxy-5-(trifluoromethyl)pbenyl)-iV'-(4'(2-(N-methykarbamoyl)-4-pyridyioxy)phenyl) tjrea £ CF3 O NxNXJ U H H To a stirring solution of phosgene (1.9 M in toluene; 2.07 mL0.21g, 1.30 mmol) in CH^Ci: (20 mL) at 0 °C was added anh pyridine (0.32 mL) followed by 2-methoxyo-(tnfluoromethyl)aniline (0.75 g). The yellow solution was allowed to warm to room temp during which a precipitate formed. The yellow mixture was stirred for 1 h, then concentrated under reduced pressure. The resulting solids were treated with anh toluene (20 mL) followed by 4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline (prepared as described in Method A2; 0.30 g) and the resulting suspension was heated at 80 °C for 20 h, then allowed to cool to room temp. The resulting mixture was diluted with water (100 mL), then was made basic with a saturated NaHCC>3 solution (2-3 mL). The basic solution was extracted with EtOAc (2 x 250 mL). The organic layers were separately washed with a saturated NaCl solution, combined, dried (MgSO D. Interconversion of Ureas Dla. Conversion of co-Aminophenyl Ureas into co-(Aroylamino)phenyl Ureas. Synthesis of Ar-(4-Chloro-3-((tnfluoromethyI)phenyO-iV,-(4-(3-methoxycarbonylphenyl)carboxyaminopbenyl) Urea CF3 H H To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-jV'-(4-aininophenyl) urea (Method Cld; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 g, 1.38 mmol), HOBT«H20 (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added EDCI HC1 (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp, overnight, diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a saturated NaHC03 solution (25 mL). The organic layer was dried (Na2SC4) and concentratec unde; reduced pressure. The resulting solids were triturated with an EtOAc solution (80% EtOAc/20% hexane) to give A/,-(4-chloro-3-((trifluoromethyl)phenyl)-7v"'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122; TLC (80% EtOAc/20% hexane) R/0.75. Dlb. Conversion of co-Carboxyphenyl Ureas into (o-(Arylcarbamoyl)phenyl Ureas. Synthesis of ;V-(4-Chloro-3-((trifluoromethyl)pbenyI)-iV'-(4-(3-methylcarbamoylphenyl)carbamoylphenyl) Urea CF3 O To a solution of /vr-(4-chloro-3-((trifluoromethyl)phenyl)-Af'-(4-(3-methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBTH20 (0.14 g, 1.07 mmol), and N-methylmorpholine (0.5mL, 1.07 mmol) in DMF (3 mL) at 0 °C was added EDCI-HCl (0.10 g, 0.53 mmol). The resulting mixture was allowed to warm to room temp, and was stirred overnight. The resulting mixture was treated with water (lOmL), and extracted with EtOAc (25 mL). The organic phase was concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane to 10% MeOH/90% EtOAc) to give /V-(4-chloro-3-((trifiuoromethyl)phenyI)-,V'-(4-(3--methylcarbamoylphenyl)carbamoylphenyl) urea as a white solid (0.097 g, 41%): mp 225-229; TLC (100% EtOAc) R/0.23. Die. Combinatorial Approach to the Conversion of ca-Carboxyphenyl Ureas into co-(AryIcarbamoyI)pheny! Ureas. Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyI)-/V'-(4-(N-(3-(N-(3-pyridyI)carbamoyI)phenyl)carbamoyl)phenyl) Urea A mixture of Ar-(4-chloro-3-((trifluoromethyl)phenyl)-/Y'-(3-carboxyphenyl) urea (Method Clf; 0.030 g, 0.067 mmol) and Ar-cyclohexyl-Ar'-(methylpolystyrene)carbodiimide (55 mg) in 1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CH2CI2 (1 M; 0.074 mL, 0.074 mmol). (In cases of insolubility or turbidity, a small amount of DMSO was also added.) The resulting mixture was heated at 36 °C overnight. Turbid reactions were then treated with THF (1 mL) and heating was continued for 18 h. The resulting mixtures were treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting mixture was stirred at 36 °C for 72 h, then cooled to room temp, and filtered. The resulting solution was filtered through a plug of silica gel (1 g). Concentration under reduced pressure afforded JV-(4-chloro-3-((trifluoromethyl)phenyl)-//'-(4-(N-(3-(N-(3- pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70% EtOAc/30% hexane) R/0.12. D2. Conversion of co-Carboalkoxyaryl Ureas into co-Carbamoylaryl Ureas. Synthesis of A/-(4-Chloro-3-((trifluoromethyl)pbenyl)-/V'-(4-(3-methylcarbamovlphenyl)carboxyaminophenyl) Urea To a sample of //-(4-chlorO-3-((trifluoromethyl)phenyl)-Ar'-(4-(3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 mL, \ .7 mmol) ar^d the resultog, rapture, was stared at CQQOI tsm$. civemL^bA, &&& cxx>£, D3. Conversion of w-Carboalkoxyaryl Ureas into co-Carboxyaryl Ureas. Synthesis of Ar-(4'Chloro-3-((trifluoromethyl)phenyl)-7V'-(4-carboxypbenyl) Urea H H To a slurry of /v'-(4-chloro-3-((trifluoromethyl)phenyl)-Ar'-('-ethoxycarbonylphenyl) urea (Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH solution (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated at the reflux temp, for 12 h, cooled to room temp., and concentrated under reduced pressure. The residue was diluted with water (50 mL), then treated with a 1 N HCl solution to adjust the pH to 2 to 3. The resulting solids were collected and dried under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-iV'-(4-carboxyphenyl) urea as a white solid (5.05 g, 92%). D4. General Method for the Conversion of co-AIkoxy Esters into m-Alkyl Amides. Synthesis of/V-(4-Chloro-3-((trifiuoromethyl)pheny!)-A^'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyI)Urea CF3 O ^ D O°tf0H ibtep 1. Synthesis of AH4-Chloro-3-(trifluoromethyl)plienyI)-jV'-((4-(3-(5- carboxypyridyl) oxyphenyl) Urea yV-(4-Chloro-3-(trifluoromethyl)phenyl)-jV'-((4-(3-(5-methoxycarbonylpyridyl)o.xypheny!) urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-(3-(5- methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a manner analogous to Method Cla. A suspension of A/'-(4-chloro-3-(trifluoromethyl)phenyl)-Ar'-((4-(3-(5- methoxycarbonylpyridyl)oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and was stirred at room temp, for 1 h. The resulting mixture was adjusted to pH 5 with a 1 N HC1 solution. The resulting precipitate was removed by filtration and washed with water. The resulting solids were dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced pressure. The EtOH/concentration procedure was repeated twice to give /V-(4-chloro-3- ^nfluoromethyl)phenyl)-Ar'-((4-(3-(5-cirboxypyridyl) oxyphenyl) urea (0.18 Z- 71%). H H Step 2. Synthesis of Ar-(4-chloro-3-(trinuoromethyI)phenyl)-Ar'-((4-(3-(5-(2- dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea A mixture of jV-(4-chloro-3-(trifluoromethyl)phenyl)-/vf'-((4-(3-(5- carboxypyridyl)oxyphenyl) urea (0.050 g, 0.011 mmol), A^A^-dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), W-methylmorpholine (0.035 g, 0.28 mmol), and EDCI'HCl (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room temp, overnight. The resulting solution was separated between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (35 mL), dried (MgSCX) and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CH2G2 (approximately 2 mL). The resulting solution was treated with Et20 dropwise to give yV-(4-chloro-3- (trifluoromethyl)phenyl)-Ar'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea as a white precipitate (0.48 g, 84%: 'H NMR (DMSO-d6) 5 2.10 s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, IH), 8.43 (s, IH), 8.58 (t, IH), 8.69 (s, 1 H). 8.90 (s, IH), 9.14 (s, IH); HPLC ES-MS m/z 522 ((M+H)). General Method for the Deprotection of yV-(©-Silyloxyalkyl)amides. Synthesis of iV-(4-Chloro-3-((trifluoromethyl)phenyl)-Ar'-(4-(4-(2-(JV-(2-bydroxy)ethylcarbamoyl)pyridyloxyphenyl) Urea. CF3 0 H H To a solution of A^-(4-chloro-3-((trifluoromethyl)phenyl)-iV'-(4-(4-(2-(//-(2-triisopropylsilyloxy) ethylcarbamoyl)pyridyloxyphenyl) urea (prepared in a manner analogous to Method CI a; 0.25 g, 0.37 mxnol) in anh THF (2 mL) was tetrabutylammonium fluoride (1.0 M in THF; 2 mL). The mixture was stirred at room temperature for 5 min, then was treated with water (10 mL). The aqueous mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh; gradient from 100% hexane to 40% EtOAc/60% hexane) to give A^(4-chloro-3-((trifluoromethyl)phenyl)-jV'-(4-(4-(2-(yV-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea as a white solid (0.019 g, 10%). Listed below are compounds listed in the Tables below which have been synthesized according to the Detailed Experimental Procedures given above: Syntheses of Exemplified Compounds (see Tables for compound characterization) Entry 1: 4-(3-Af-Methylcarbamoylphenoxy)aniline was prepared according to Method A13. According to Method C3, 3-/ert-butylaniline was reacted with bis(trichloromethyl)carbonate followed by 4-(3-/V-Methylcarbamoylphenoxy)aniline to afford the urea. Entry 2: 4-Fluoro-l-nitrobenzene and /7-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-l-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acelylphenoxy)aniline. According to Method C3, 3-terf-butylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea. [Entry 3: According to Method C2d, 3-ter;-butylaniline was treated with.CDI, followed by 4-(3^V-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea. Entry 4: 5-^rf-Butyl-2-methoxyaniline was converted to 5-/err-butyl-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-yV-Methylcarbamoylphenoxy)aniline, prepared according to Method A13, was reacted with the isocyanate according to Method CI a to afford the urea. Entry 5: According to Method C2d, 5-rerr-butyl-2-methoxyaniline was reacted with CD! followed by 4-(3-Ar-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea. Entry 6: 5-(4-Aminophenoxy)isoindoline-l,3-dione was prepared according to Method A3. According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI followed by 5-(4-aminophenoxy)isoindoline-l,3-dione to afford the urea. Entry 7: 4-(l-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12. According to Method 2d, 5-re/-:-butyl-2-methoxyaniline was reacted with CDI followed by 4-(l-oxoisoindolin-5-yloxy)aniline to afford the urea. Entry 8: 4-(3-Ar-Methylcarbamoylphenoxy)aniline was synthesized according to Method A13. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI followed by 4-(3-/V-methylcarbamoylphenoxy)aniline to afford the urea. Entry 9: 4-Hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine to give 4-(4-acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to Method A8, Step 4, 4-{4-acetylphenoxy)-5-nitropyridine was reduced to 4-(4-acetylphenoxy)o-aminopyridine. 2-Methoxy-5-(trifluoromethyl)aniline was converted to 2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method Bl. The isocyanate was reacted with 4-(4-acetylphenoxy)-5-aminopyridine according to Method Cla to afford the urea. iEntry 10: 4-F\uoro-l-nitrobenzene and />hydToxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-l-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline. According to Method C3, 5-(trifluoromethyl)-2-methoxybutylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea. Entry 11: 4-Chloro-A/-methyl-2-pyridinecarboxarnide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3-(-2-(ALmethylcarbarnoyl)-4-pyridyloxy)aniline. According to Method C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(-2-(//-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 12: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyndinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3-(2-carbamoyl~4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea. Entry 13: 4-Chloro-Ar-methyl-2-pyridinecarbbxamide was synthesized according to Method A2, Step 3b. 4-Chloro-iV-methyl-2-pyridinecarboxamide was reacted with 4-arainophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI followed by 4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 14: 4-Chloropyridine-2-carbonyI chloride HC1 salt was reacted with ammonia according to Method A2, Step 3b to form 4-chioro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenoi according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-carbamoyl-4-pyndyloxy)aniline. According ic Meihod ^HC4, 2-methoxy-5-(trifluoromethyl)ariiline was reacted with phosgene followed by 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea. Entry 15: According to Method C2d, 5-(triflouromethyl)-2-methoxyaniline was reacted with CDI followed by 4-(3-Af-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method AS, to afford the urea. Entry 16: 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized according to Method A5. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. The isocyanate was reacted with 4-(2-(7V-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to Method Clc to afford the urea. Entry 17: 4-(2-(Af-Methylcarbajnoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5- (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5- (Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline according to Method Cla to afford the urea. Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro-Ar-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(Ar-methylcarbamoyI)-4-pyridyloxy)-4-methylaniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluorornethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3-(2-(yV-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to Method C1 a to afford the urea. Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyI)-4- pyridyloxy)aniline. 5-{Trifluoromethyl)-2-methoxyaniline was converted into 5- ([rifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(TrifluoromethyD- gUTiethoxyphenyl isocyanate was reacted with 4-(2-(jV-ethylcarbamoyl)-4-pyndyloxy)aniline according to Method C1 a to afford the urea. Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-M-methyi-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(^-methylcarbamoyI)-4-pyridyloxy)-3-chloroaniline. 5-(Trifluoromethy!)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(TrifIuoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)-3-chIoroaniline according to Method C1 a to afford the urea. Entry 21: 4-(4-Methylthiophenoxy)-l -nitrobenzene was oxidized according to Method A19, Step 1 to give 4-(4-methylsuIfonyiphenoxy)-l-nitrobenzene. The nitrobenzene was reduced according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-l-aniline. According to Method CI a, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-methylsulfonylphenoxy)-l-aniline to afford the urea. Entry 22: 4-(3-carbamoylphenoxy)-l -nitrobenzene was reduced to 4-(3- carbamoylphenoxy)aniline according to Method A15, Step 4. According to Method CI a, 5- (trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3- carbamoylphenoxy)aniline to afford the urea. • Entry 23: 5-(4-Aminophenoxy)isoindoline-l,3-dione was synthesized according to Method A3. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-l,3-dione according to Method C1 a to afford the urea. Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-/V.A'-dimethyl-2-pyridinecarbo.vamide uas reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-l-V\- dimethylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyanilmo \\ as converted into 5-(trifiuoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-. ™(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(/v./V-dimethylcarbamoyl)-4-pyridyloxy)aniline according to Method CI a to afford the urea. £ Entry 25: 4-(l-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12. 5-{Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-(l-oxoisoindolin-5-yloxy)aniline according to Method C2d to afford the urea. Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to i Method A13, Step 1 to give .4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was convened to the 4-(4-(l-(vY-methoxy)iminoethyl)phenoxyaniline HC1 salt according to Method A16. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(tnfluoromethyl)-2-me:hoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-rnethoxyphenyl isocyanate was reacted with 4-(4-(l-(Ar-methoxy)iminoethyl)phenoxyaniline HC1 salt to Method C1 a to afford the urea. Entry 27: 4-Chloro-Ar-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-(2-(Ar-methylcarbamoyl)phenylthio)aniline according to Method Cla to afford the urea. Entry 28: 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-dione was synthesized according to Method A9. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-l,3-dione according to Method CI a to afford the urea. Entry 29: 4-Chloro-/V-methylpyridinecarboxamide was synthesized as described in Meihod A2. Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method -\2, Step 4 to give 3-(4-(2-(Af-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethy!)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3-(4-(2-(Ar-methylcarbamoyl)phenylthio)aniline according to Method CI a to afford the urea Entry 30: 4-Chloropyridine-2-carbonyI chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-yV-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-{A'-isopropylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluorornethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-rnethoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(/V-isopropylcarbamoyl)-4-pyridyloxy)aniline according to Method CI a to afford the urea. Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 5-(Trifiuoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method CI a to afford the urea. Ar-(5-(Trifluoromethyl)-2-methoxyphenyl)-//'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the amide according to Method D4, Step 2. Entry 32: 4-(3-(5-MethoxycarbonyI)pyridyloxy)aniline was synthesized according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. A45-(Trifluoromethyl)-2-methoxyphenyl)-A'-(4-(3-{5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to afford the amide. ffcitry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluorornethyl)-2-methoxyphenyi isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method CI a to afford the urea. M(5-(Trifluoromethyl)-2-methoxyphenyI)-AT-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with ^N-dimethylethylenediamine according to Method D4, Step 2 to afford the amide. Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifiuoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyi)-2-methoxypher.yI isocyanate according to Method Clf to afford .-V-p-(trifluoromethyl)-2-methoxyphenyl)-jV'-(3-carboxyphenyl) urea, which was coupled with 3-aminopyridine according to Method Die. Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(triftuoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-{5-(trifluoromethyO^-methoxyphenyl)-/^'-(3-carboxyphenyl) urea, which was coupled with N-(4-fluorophenyl)piperazine according to Method Die. Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyi isocyanate according to Method Clf to afford /V-(5-(trifluoromethyl)-2-methoxyphenyl)-yV"-(3-carboxyphenyl) urea, which was coupled with 4-fluoroaniline according to Method Die. Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifluoromethyl)-2-methoxyaniline was convened into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-/V'-(3-carboxyphenyI) urea, which was coupled with 4-(dimethylamino)aniline according to Method Die. Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyI)-2-methoxypheny! isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-iV'-(3-carboxyphenyl) urea, which was coupled with 5-amino-2-methoxypyridine according to Method Die. Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All 5-(Trifluorornethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford /v'-(5-(trifluoromethyl)-2-methoxyphenyI)-Af'-(3-carboxyphenyl) urea, which was coupled with 4-morpholmoaniline according to Method Die. Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5-(trifluoromethyO^-methoxyphenyl^'-C^-carboxyphenyl) urea, which was coupled with .V-(2-pyridyl)piperazine according to Method Die Entry 41: 4-(3-{jV-Methylcarbamoyl)phenoxy)aniline was synthesized according to Method A13. According to Method C3, 4-chloro-3-(trifluoromethyl)aniline was converted to the isocyanate, then reacted with 4-(3-(/V-Methylcarbamoyl)phenoxy)aniline to afford the urea. %Entry 42; 4-(2-/V-Methylcarbamyl-4-pyridyloxy)aniline was synthesized according to ethod A2. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-/V-methylcarbamyl-4-pyridyloxy)aniline according to Method Cla to afford the urea. s Entry 43: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea. Entry 44: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(2-carbamoyl-4-pyridyloxy)aniIine. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea. Entry 45: 4-Chloro-Ar-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(Ar-methylcarbamoyl)-4-pyridyloxy)aiiiline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 46: 5-(4-Aminophenoxy)isoindoline-l,3-dione was synthesized according to Method A3. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-l,3-dione to afford the urea. Entry 47: 4-(2-(A^Methylcarbamoyl)-4-pyridyloxy)-2-rnethylaniline was synthesized according to Method A5. According to Method Clc, 4-chIoro~3-(trifiuoromethy!)pheny! isocyanate was reacted with 5-(4-ammophenoxy)isoindoiine-l,3-dione to afford the urea. Aatry 48: 4-(3-j Entry 49: 4-(2-(Ar-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. According to Method CI a, 4-chloro-3-(trifluoromethyl)phenyi isocyanate was reacted with 4-(2-(ALmethylcarbamoyl)-4-pyridyloxy)-2-chloroanihne to afford the urea. Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro-/vr-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(//-methylcarbamoyl)-4-pyridyloxy)-4-methylaniIine. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2^.V-methylcarbamoyl)-4-pyridyIoxy)-4-methylaniline to afford the urea. Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-iV-ethyI-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(Ar-ethylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(.A/-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 52: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-./V-rnethyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(A;-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea. Entry 53: 4-(4-Methylthiophenoxy)-l-nitrobenzene was oxidized according to Method A19, Step 1 to give 4-(4-methylsulfonylphenoxy)-l-nitrobenzene. The nitrobenzene was reduced according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-l -aniline. According to Method Cla, 4-chloro-3-(tnfiuoromethyl)phenyl isocyanate was reacted with 4- ^Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to afford /V-methyl-4-bromobenzenesulfonamide. /V-Methyi-4- bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to afford 4-(4-(Af-methylsulfamoyl)phenoxy)benzene. 4-(4-(/V- Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N-methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3. 4-(4-(Ar-Methylsulfamoyl)phenoxy)-1 -nitrobenzene was reduced to 4-(4-Ar-methylsulfamoyl)phenyloxy)aniline according to Method A15, Step 4. According to Method Cla, 4-chloro-3-(trifluoromethy!)phenyl isocyanate was reacted with 4-(3-Af-methylsulfamoyl)phenyloxy)aniline to afford the urea. Entry 55: 5-Hydroxy-2-methylpyridine was coupled with l-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-l -nitrobenzene. The methylpyridine was oxidized according to the carboxy'ic acid, then esterified according to Method A18, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-nitrobenzene. The nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to Method C1 a to afford the urea. Entry 56: 5-Hydroxy-2-methylpyridine was coupled with l-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-nitrobenzene. The nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2- methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3- (trifluoromethyl)phenyl isocyanate according to Method Cla to give ;V-(4-chloro-3- (trifluoromethyl)phenyl)-A'"-(4-(2-(methoxycarbonyl)-5-pyridyloxy)phenyl) urea. The methyl ester was reacted with methylamine according to Method D2 to afford /vf-(4-chloro-3-(trifluoromethyl)phenyl)-iV'-(4-(2-(iV-methylcarbamoyI)-5-pyridyloxy)phenyl)urea. Entry 57: -V-(4-Chloro-3-(trifluoromethyl)phenyl-/V'-(4-aminophenyl) urea was prepared according to Method Cld. /V-(4-Chloro-3-{tnfluoromethyl)phenyl-/V'-(4-aminophenyl) urea was coupled with wo/jo-methyl isophthalate according to Method Dla to afford the urea. Entry 58: Af-(4-Chloro-3-(trifluoromethyl)phenyI-A'-{4-aminopheny!) urea was prepared according to Method Cld. A^-(4-Chloro-3-(trifluoromethyl)phenyl-/V'-(4-aminophenyl) urea was coupled with mono-methyl isophthalate according to Method Dla to afford yV-(4-chloro- r 3-(trifluoromethyl)phenyl-Ar'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea. According to Method D2, Af-(4-chloro-3-(trifluoromethyl)phenyl-/V-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea was reacted with methylamine to afford the corresponding methyl amide. / Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,Ar-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(Ar,/V-dimethy'carbamoyl)-4-pyridyloxy)anilirie. According to Method Cla. 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(iV,Ar-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was convened to the 4-(4-(l-(//-methoxy)iminoethyI) phenoxyaniline HC1 salt according to Method A16. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-acetylphenoxy)aniline to afford the urea. Entry 61: 4-(3-Carboxyphenoxy)-1 -nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was ■ coupled with 4-(2- aminoethyl)morpholine according to Method A13, Step 3 to give 4-(3-(Ar-(2- morpholinylethyl)carbamoyI)phenoxy)-l -nitrobenzene. According to Method A13 Step 4, 4- (3-{Ar-(2-morpholinylethyl)carbamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(3-(JV-(2- morpholinylethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-3- (tnfluoromethyl)phenyl isocyanate was reacted with 4-(3-(/V-(2- morpholinylethyl)carbamoyl)phenoxy)aniline to afford the urea. Entry 62: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13, btep 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with l-(2-aminoethyl)piperidine according to Method A13, Step 3 to give 4-(3-(AL(2-piperidylethyl)carbamoyl)phenoxy)-l- nitrobenzene. According to Method A13 Step 4, 4-(3-(A'-(2- j piperidylethyl)carbamoyl)phenoxy)-l -nitrobenzene was reduced to 4-(3-(/V-(2- piperidylethyl)carbamoyl)phenoxy)aniline. According to Method CI a, 4-chloro-3- (triiluoromethyl)phenyl isocyanate was reacted with 4-(3-(/V-(2- piperidylethyl)carbamoyl)phenoxy)aniIine to afford the urea. Entry 63: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4-(3-(/V- (tetrahydrofurylmethyl)carbamoyl)phenoxy)-l-nitrobenzene. According to Method A13 Step 4, 4-(3-(//-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(3- (yV-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method CI a, 4-chloro- 3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(/V- (tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford the urea. Entry 64: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with 2-aminomethyl-l-ethylpyrrolidine according to Method. A13, Step 3 to give 4-(3-(/V-((l-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-l-nitrobenzene. According to Method A13 Step 4, 4-(3-(jV-((l-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(3-(Ar-((l-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(iV-((l-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniiine to afford the urea. Entry 65: 4-Chloro-A»r-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Vlethod Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(.V-methylcarbamoyl)phenylthio)aniline to afford the urea. Entry 66: 4-Chloropyridine-2-carbonyI chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-/V-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(iV- isopropylcarbamoyl)-4-pyridyIoxy)aniline. According to Method CI a, 4-chloroo-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(//-isopropylcarbamoyi)-4-pyridyloxy)aniline to afford the urea. Entry 67: Ar-(4-Chloro-3-(trifluoromethyl)phenyl-//'-(4-ethoxycarbonylphenyl) urea was synthesized according to Method Cle. iV-(4-Chloro-3-(trifluorornethyl)phenyl-yV"-(4- ethoxycarbonylphenyl) urea was saponified according to Method D3 to give /V-(4-chloro-3- (trifluoromethyl)phenyl-/V"-(4-carboxyphenyl) urea. Af-(4-Chloro-3-(trifluoromethyl)phenyl- yV'-(4-carboxyphenyl) urea was coupled with 3-methylcarbamoylaniline according to Method Dlb to give Af-(4-chloro-3-(trifluoromethyl)phenyl-Ar'-(4-(3- methylcarbamoylphenyl)carbamoylphenyl) urea. Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-dione was synthesized according to Method A9. According to Method CI a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-l,3-dione to afford the urea. Entry 69: 4-Chloro-/Y-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3-(4-(2-(yV-methylcarbamoyl)phenylthio)aniline. According to Method Cla, 4-chlon>3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(/V-methylcarbamoyl)phenylthio)aniline to afford the urea. Entry 70: 4-(2-(N-(2-MorphoIin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A10. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyI isocyanate was reacted with 4-(2-(/V-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea. 4£ntry 71: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. .V-(4-Chloro-3-(trifluoromethyl)phenyl)-jV'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the amide. Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-Af'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to affo-d the amide. Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. yV-(5-(Trifluoromethyl)-2-methoxyphenyl)-A'"-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with A^jY-dimethylethylenediamine according to Method D4, Step 2 to afford the amide. Entry 74: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with 2- hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-/V-(2- triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-/V-(2- triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(/V-(2- triisopropylsilyloxy)ethyicarbarnoyl)pyridyloxyaniline. According to Method Cla, 4-chloro- 3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(,V-(2- triisopropylsilyloxy)ethylcarbamoyl) pyridyloxyaniline to afford A/-(4-chloro-3-((irifluoromethy!)phenyl)-yV'-(4-(4-(2-(jV-(2-triisopropylsilyloxy) ethylcarbamoyOpyridyloxyphenyl) urea. ^\|ntry 75: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(tnfluorornethyl)phenyl lSocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Clf to afford the urea, which was coupled with 3-aminopyridine according to Method Die. Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N-(4-acetylphenyl)piperazine according to Method Die. Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4-fluoroaniline according to Method Die. Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(tnfluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4-(dimethylamino)aniline according to Method Die. Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N-phenylethylenediamihe according to Method Die. Entry 80: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 2-methoxyethylamine according to Method Die. Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Ch!oro-3-(tririuoromeihyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniIine Recording to Method Clf to afford the urea, which was coupled with 5-amino-2-methoxypyridine according to Method Die. Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-{trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4-morpholinoaniline according to Method Die. Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with /V-(2-pyridyl)piperazine according to Method Die. Entry 84: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with 2- hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-/vr-(2- triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-/V-(2- triisopropyIsilyIoxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(A/-(2- triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method CI a, 4-chloro- 3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(/V-(2- triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to give Ar-(4-chloro-3- ((trifluoromethyl)phenyl)-yV'-(4-(4-(2-(^-(2- triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl) urea. The urea was deprotected according to Method D5 to afford /V-(4-chloro-3-((trifluoromethyl)phenyl)-.'V,-(4-(4-(2-(iV-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea. Entry 85: 4-(2-(/Yr-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Bromo-3-(trifluoromethyl)anilme was converted to 4-bromo-3-(trifiuoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(/V-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. ^"Entry 86: 4-(2-{A-MethyIcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 4-Bromo-3-(trifluoromethyi)aniline was converted into 4-bromo-3- (trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4- bromo-3~(trifiuoromethyl)phenyl isocyanate was reacted with 4-(2-(Ar-methylcarbamoyI)-4- 5 pyridyloxy)-2-chloroaniIine to afford the urea. Entry 87: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-iV-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3-) (trifluoromethyl)aniline was converted into 4-bromo-3-(trifiuoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4-bromo-3-(trifiuoromethyl)phenyl isocyanate was reacted with 4-(2-(jV-methylcarbamoy])-4-pyridyloxy)-3-chloroaniline to afford the urea. i Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-jV-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(Ar-ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo~3-(trifluoromethyl)aniIine was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(Ar-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 89: 4-Chioro-Af-methyl-2-pyridinecarboxaraide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method Cla, 4-bromo-3-(trifluoromethyI)phenyl isocyanate was reacted with 3-(-2-(yV-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 90: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted wiih 4-chloro-/V-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(Af-methylcarbamoyl)-4-pyridyloxy)-4-rnethylanilinc. 4-Bromo3- ^trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(yV-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea. Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-iV,/V-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(yV,/V- dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(.V,Ar-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 92: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(Ar-methylcarbarnoyl)phenylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)pheny! isocyanate according to Method Bl. According to Method Cla, 4-brorno-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(N-methyIcarbarnoyl)phenylthio)aniline to afford the urea. Entry 93: 4-Chloro-Ar-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3-{4-(2-(Ar-methylcarbamoyl)phenyUhio)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(A^rnethylcarbarnoyl)phenylthio)aniline to afford the urea. Entry 94: 4-(2-(Ar-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A10. 4-8romo-3-(trifiuoromethyi)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4- bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(/V-(2-Morpholin-4-^lethyl)carbamoyl)pyridyloxy)aniline to afford the urea. Entry 95: 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Chioro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Ch]oro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(tnfluoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(7V-methylcarbarnoyl)-4-pyridyloxy)aniline to afford the urea. Entry 96: 4-(2-(Ar-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was convened into 4-chloro-2-methoxy-5-(trifluoroir.ethyl)phenyl isocyanate according to Method 3i. According to Method CI a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(Ar-methyIcarbamoyl)-4-pyridyloxy)-2-chloroaniline afford the urea. Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-:hloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-{2-(N-methylcarbarnoyI)-4-pyridyloxy)-3-chloroaniline. 4-Chloro-2-methoxy-5-(trifiuoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifiuoromethyl)aniline was converted into 4-chloro-2-methoxy-5-[trifluoromethyOphenyl isocyanate according to Method Bl. According to Method CI a, 4-;hIoro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(/V-tnethylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea. Entry 98: 4-Chloro-iV-methy[-2-pvridinecarboxamide, which was synthesized according to VIethod A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxyo- \|trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-rnetho\y-> ;trifluoromethy!)aniiine was converted into 4-chloro-2-methoxy-5-(tnfluoromcihyl)phen\ I isocyanate according to Method Bl. According to Method CI a, 4-chloro-2-metho\y-5- V fluoromethyl)phenyl isocyanate as was reacted with 3-{-2-(jV-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-Ar-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(//-ethylcarbamoyl)-4- pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyI isocyanate was reacted with 4-(2-(Ar-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethvlamine according to Method A2, Step 3b. The resulting 4-chloro-MAf-dimethyl~2-pyridinecarboxarnide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-dirnethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifiuoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(AC N-dimethyIcarbamoyl)-4-pyridyIoxy)aniIine to afford the urea. Entry 101: 4-Chloro-//-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(Ar-methylcarbamoyl)-4-pyridyloxy)aniline. 2-Amino-3-methoxynaphthalene was synthesized as described Method Al. According to Method C3, 2-amino-3-methoxynaphthalene was reacted with bis(trichloromethyl) carbonate followed by 3-(-2-(JV-methylcarbamoyl)-4-pyridyloxy)aniline to form the urea. Entry 102: 4-{2-(/V-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 5-rer/-ButyI-2-(2,5-dimethylpyrrolyl)aniline was synthesized according to ^Method A4. 5-rerr-Butyl-2-(2,5-dimethyIpyrroIyl)aniline was reacted with CDI followed by 4-(2-(jV-methylcarbamoyl)-4-pyridyloxy)aniline according to Method C2d to afford the urea. Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-/vr-methyl-2-pyridinecarboxamide was reacted with 4-aminophenot according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b, reaction of 3-amino-2-methoxyquinoline with CDI followed by 4-(2-(N-methylcarbarnoyl)-4-pyridyloxy)aniline afforded bis(4-(2-(Ar-methylcarbamoyl)-4-pyridlyoxy)phenyl)urea. Listed in the Tables below are compounds which have been synthesized according to the Detailed Experimental Procedures given above:Tables The compounds listed in Tables 1 -6 below were synthesized according to the general methods shown above, and the more detailed exemplary procedures are in the entry listings above and characterizations are indicated in the tables. H'lbie 1. 3-ferr-Burylphenyl Ureas «.X.i N H Entry R mp (°C) HPLC (min.) TLC TLC Solvent System Mass Spec. [Source] Synth. Method 1 0 >-NH -o-o Me 0.22 50% EtOAc / 50% hexane 418 (M+H)+ (HPLC ES-MS) A13 C3 2 ^>° (M+H)+ (HPLC ES-MS) A13 C3 3 VNH 133-135 0.68 100% EtOAc 448 (M+H)+ (FAB) A8 C2d Table 2. 5-ter/-Butyl-2-methoxyphenyI Ureas OMe Entry R mp (°C) HPLC (min.) TLC R, TLC Solvent System Mass Spec. [Source] Synth. Method 4 0 V-NH 5.93 448 (M+H)+ (HPLC ES-MS) A13 Bl Cla 5 0 V-NH -O"0"O"°"° 120-122 0.67 100% EtOAc 478 (M+H)+ (FAB) A8 C2d 6 VNH 0 0.40 50% EtOAc / 50% hexane 460 (M-H)-(HPLC ES-MS) A3 C2d «TT -O°-Q^ 0.79 50% EtOAc / 50% hexane 446 (M+H)+ (HPLC ES-MS) A12 C2d Table 3. OMe 5-(Trifluoromethyl)-2-methoxyphenyl Ureas Entrv R mp (°C) HPLC (min.l TLC R. TLC Solvent System Mass Spec. [Source] Synth. Method 8 0 y-NH -o-o * 250 (dec) 460 (M+H)+ (FAB) A13 C2a 9 (M+H)+ (HPLC ES-MS) A3 step 2, A 8 step 4, Bl, Cla 10 -o° (M+H)+ (HPLC ES-MS) A13 C3 11 0.20 2% Et3N/ 98% EtOAc 461 (M+H)+ (HPLC ES-MS) A2 C4 12 —f~\ VNHJ 0.27 1%. Et3N/ 99% EtOAc 447 (M+H)+ (HPLC ES-MS) A2 C4 13 o J-UH 0.62 100% EtOAc 461 (M+H)+ (FAB) A2 C2a 14 0 114-117 0.40 1% EON/ 99% EtOAc 447 (M+H)+ (FAB) A2 C4 .I15 0 V-NH —f V °-\ /"OMe 232-235 0.54 100% EtOAc 490 (M+H)+ (FAB) AS C2d 16 0 Me >~NH 210-213 0.29 5% MeOH / 45% EtOAc / 50% pet ether 475 (M+H)+ (HPLC ES-MS) A5 Bl Clc 17 o CI J—NH -O-^-O1 Me 187-188 0.17 50% EtOAc / 50% pet ether 495 (M+H)+ (HPLC ES-MS) A6 Bl Cla 18 —/ V-Me V-NH2 0.48 100% EtOAc 475 (M+H)+ (HPLC ES-MS) A2 step 4, Bl Cla 19 O V-NH 194- 196 0.31 5% MeOH /45% EtOAc /50% pet ether 475 (M+HK (HPLC ES-MS) A2 Bl Cla 20 0 CI V-NH 214-216 0.25 5% MeOH / 45% EtOAc / 50% pet ether 495 (M+H)+ (HPLC ES-MS) A2 Cla 21 -o°o\: 208-210 0.30 50% EtOAc / 50% hexane 481 (M+H)+ (HPLC ES-MS) Al9C2a 22 o V-NH2 188-190 0.30 70% EtOAc / 50% hexane 447 (M+H)+ (HPLC ES-MS) A15. step 4, Cla 23 VNH 0 0.50 70% EtOAc / 30% hexane 472 (M+H)+ (FAB) A3 Bl Cla 24 0 Me 203-205 0.13 100% EtOAc 479 (M-H)* (HPLC ES-MS) A2 Bl Cla 25 -^>° (M'+H)+ (HPLC ES-MS) A12 C2d 26 MeO -O-CK. 169-171 0.67 50% EtOAc / 50% pet ether 474 (M+H)+ (HPLC ES-MS) A13 step I, A13 step 4, A16, Bl Cla 27 o VNH 218-219 0.40 50% EtOAc / 50% pet ether 477 (M+H)+ (HPLC ES-MS) A2 step 3b, A2 step 4. Bl, Cla 28 V,NMe 0 212-214 0.30 40% EtOAc / 60% hcxane A9 Bl Cla 29 0.33 50% EtOAc / 50% pet ether 474 (M+H,+ (HPLC ES-MS) A2 step 3b, A2 step 4, Bl, Cla JO VNH -O-O Pri 210-211 A2 Bl Cla 31 ov JVNH 210-204 0.43 10% MeOH / CH2C1 2 A14 Bl Cla D4 32 o y-NH 247-249 0.57 10% MeOH / CH2C1 2 AH Bl Cla D4 22 JVNH —(f V-0—4, /) N-M€ W ^-N Me 217-219 0.07 10% MeOH / CH2CI 2 A14 Bl Cla D4 i 34 0 V-NH 0.11 70% EtOAc / 30% hexanc All Bl Clf Die 35 o \_N \=o 0.38 70% EtOAc / 30% hexane All Bl Clf Die 36 F—f V-NH 0.77 70% EtOAc / 30% hexanc All Bl Clf Die 37 N—{' V— NH 0.58 70% EtOAc / 30% hexane All Bl Clf Die 38 MeO-f V-NH W l=o 0.58 70% EtOAc / 30% hexane All Bl Clf Die 39 0 N—f 7—NH W \=/ 1=0 0.17 70% EtOAc / 30% hexanc All Bl Clf Die 40 ^V^NHTVNH \=/ \_y \=/ C=0 0.21 70% EtOAc / 30% hexane All Bl Clf Die Table 4. 3-(Trifluorometbyl)-4-chloroptaenyl Ureas F H H Entry R mp f°C) HPLC (min.) TLC TLC Solvent System Mass Spec. [Source] Synth. Method 41 ov VNH 163-165 0.08 50% EtOAc/ 50% pet ether 464 (M+H)+ (HPLC ES-MS) A13 C3 42 0 >-NH 215 0.06 50% EtOAc/ 50% pet ether 465 (M+H)+ (HPLC ES-MS) A2 Cla 43 o 0.10 50% EtOAc/ 50% pet ether 451 (M+H)+ (HPLC ES-MS) A2 Cla 44 0.25 30% EtOAc/ 70% pet ether 451 (M+H)+ (HPLC ES-MS) A2 Cla 45 0.31 30% EtOAc/ 70% pet ether 465 (M+H)+ (HPLC ES-MS) A2 Cla 46 VNH 0 176-179 0.23 40% EtOAc/ 60% hexane 476 (M+H)+ (FAB) A3 Cla 47 0 Me r~NH 0.29 5% MeOH/ 45% EtOAc/ 50% pet ether 478 (M+H)+ (HPLC ES-MS) A5 Clc 48 ^S-NH 206-209 A15 Cla 49 0 CI >~NH 147-151 0.22 50% EtOAc/ 50% pet ether 499 (M+H)+ (HPLC ES-MS) A6 Cla 50 —P V-Me VNH \= (M-rH)-(HPLC ES-MS) A2 Cla T51 0 V-NH 187- 189 0.33 5% MeOH/ 45% EtOAc/ 50% pet ether 479 (M+H)+ (HPLC ES-MS) A2 Cla 52 0 CI >-NH 219 0.18 5% MeOH/ 45% EtOAc/ 50% pet ether 499 (M+H)+ (HPLC ES-MS) A2 Cla 53 -o°o-k 246-248 0.30 50% EtOAc/ 50% hexane 485 (M+H)+ (HPLC ES-MS) A19, Cla 54 Me 196- 200 0.30 70% EtOAc/ 30% hexane) 502 (M+H)+ (HPLC ES-MS) A15 Cla 55 0 Vo 228-230 0.30 30% EtOAc' 70% CH2C12 466 (M+H)+ (HPLC ES-MS) 56 x=/ N—' NH Me 238-245 57 ^-K-^P* 221-222 0.75 80% EtOAc/ 20% hexane 492 (M+H)+ (FAB) Cld Dla 58 ov VNH 247 0-35 100% EtOAc Cld Dla D2 59 0 Me -o-oMe 198-200 0.09 100% EtOAc 479 (M+H)+ (HPLC ES-MS) A2 Cla 60 MeO -o~cH 158-160 0.64 50% EtOAc/ 50% pet ether 61 ov JVNH \—o 195-197 0.39 10% MeOH/ CH2C1 2 A13 Cla 62 ov JVNH 170-172 0.52 10% MeOH/ CH2C1 2 A13 Cla 63 0 168-171 0.39 10% MeOH/ CH2CA 2 A13 Cla 64 0 Et, V-NH N^ 176- 177 0.35 10% MeOH/ CH2C1 2 A13 Cla 65 ov JVNH -0~s-0 Me i so¬ns 487 (M+H)+ (HPLC ES-MS) A2 Bl Cla 66 ov V-NH 155 A2 Cla 67 ox VNH 225-229 0.23 100% EtOAc Cle D3 Dlb 68 Ny.NMe 0 234-236 0.29 40% EtOAc/ 60% hexane A9 Cla 69 ^=\ /=\ Me 0.48 50% EtOAc/ 50% pet ether 481 (M+H)+ (HPLC ES-MS) 70 0 V—NH \—o 0.46 5% MeOH/ 95% CH2C12 564 (M+H)+ (HPLC ES-MS) A10 Cla 171 0 VNH -Q-°-Q "~M ^0 199-201 0.50 10% MeOH/ CH2C1 2 A14 Cla D4 72 o V-NH 235-237 0.55 10% MeOH/ CH2C1 2 A14 Cla D4 73 o -fV0HO ,N~Me ^^ ^—N Me 200-201 0.21 50% MeOH/ CH2C1 2 A14 Cla D4 74 o -/Vo-O 0Si(PN)3 145- 148 75 (/~VNH 0.12 70% EtOAc/ 30% hexane 527 (M+H)+ (HPLC ES-MS) All Clf Die 76 0 Me—^ Q V=o 0.18 70% EtOAc/ 30% hexane All Clf Die 77 F_fyNH -o-o 0.74 70% EtOAc/ 30% hexane All Clf Die 78 N—f VNH Me \=/ >=0 0.58 70% EtOAc/ 30% hexane All Clf Die Table 5. 3-(Trifluoromethyl)-4-bronioPheny'Ureas FJLF o H H Br Entry R mp TO HPLC (min.) TLC TLC Solvent System Mass Spec. [Source] Synth. Method 85 0. VNH 186- 187 0.13 50% EtOAc/ 50% pet ether 509 (M+H)+ (HPLC ES-MS) A2 Bl Cla 86 0 ci VNH -^y°-c/ Me \50-152 0.31 50% EtOAc/ 50% pet ether 545 (M+H)+ (HPLC ES-MS) A6 Bl Cla 87 o. ci VNH 217-219 0.16 50% EtOAc/ 50% pet ether 545 (M+H>+ (HPLC ES-MS) A2 Bl Cla 88 0. VNH 183-184 0.31 50% EtOAc/ 50% pet ether 525 (M+H)+ (HPLC ES-MS) A2 Bl Cia 89 0.21 50% EtOAc/ 50% pet ether 511 (M+H)+ (HPLC ES-MS) A2 Bl Cla 90 — (M+H)+ (HPLC ES-MS) A2 Bl Cla 91 0V Me W 214-216 0.28 50% EtOAc/ 50% pet ether 522 (M+H)+ (HPLC ES-MS) A2 Bl Cla 92 VNH 0.47 50% EtOAc/ 50% pet ether 527 (M+H)+ (HPLC ES-MS) A2 step 3b. A2 step 4, Bl, Cla 93 _/~A VNH \={ =( Me 0.46 50% EtOAc/ 50% pet ether 527 (M+H)+ (HPLC ES-MS) A2 step 3b. A2 step 4. Bl. Cla 94 145- 0.41 5% AlO 150 MeOH/ 95% CH2C12 Bl Cla Table 6. OMe 5-(TrifluoromethyJ)-4-chloro-2-methoxyphenyl Ureas TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R CQ (min.) Rf System rSource] Method 95 o. 140- 0.29 5% 495 A2 VNH 144 MeOH/ (M+H)+ A7 fi—\ /=\ Me 45% (HPLC Bl -o°-o EtOAc/ ES-MS) Cla 50% pet ether 96 o. 244- 0.39 5% 529 A6 CI V-NH 245 MeOH/ (M+H)+ A7 H /=\ Me 45% (HPLC Bl ^0-°O EtOAc/ ES-MS) Cla 50% pet ether 97 o. 220- 0.25 5% 529 A2 a J—NH 221 MeOH/ (M+H)+ A7 -cS-oMe 45% (HPLC Bl EtOAc/ 50% pet ES-MS) Cla ether 98 -f\ VNH 0.27 5% 495 A2 MeOH/ (M+H)+ A7 \=( /=( Me 45% (HPLC Bl K_/ EtOAc/ 50% pet ether ES-MS) Cla 99 o. 180- 0.52 5% 509 A2 V-NH 181 MeOH/ (M+H)+ A7 -o-oB 45% (HPLC Bl EtOAc/ ES-MS) Cla 50% pet ether 100 0 162-165 A2 A7 Bl Cla Table 7. Additional Ureas Entry R mp (°C) HPLC (mia) TLC TLC Solvent System Mass Spec. [Source] Synth. Method 101 —.., n H OMe 162-165 Al A2 C3 102 I H H 0.10 50% EtOAc/ 50% hexane 442 103 0 I HN NH 0 0 0 0 0 b 0==0 NH-Me Me-NH 125-130 0.24 40% EtOAc/ 60% hexane 512 (M+H)+ (FAB) A2 C2b The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. \C^ WE CLAIM: 1,% A compound selected from the group consisting of the 4-chloro-3-(trifluoromethyl)phenyl ureas: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4- pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl)-4- pyridyloxy) phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl)urea and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-N- methylcarbamoyl)(4-pyridyloxy)phenyl)urea, the 4-bromo-3(trifluoromethyl)phenyl ureas: N-(4-bromo-3-(trifluoromethyl)pheny)-N'-(3-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4- pyridylthio) phenyl)urea, N-(4-bromo-3-(trifiuoromethyl)phenyl)-N'-(2-chloro-4-2-(N- methylcarbamoyl)(4-pyridyloxy))phenyl)urea, and N-(4-bromo-3-(trifluoromethyl))phenyl)-N'-(3-chloro-4-2-(N- methylcarbamoyl)(4-pyridyloxy)phenyl)urea. the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas: N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-2-(N-methylcarbamoyl)-4-pyridylo3cy)phenyl)urea. N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea. or a pharmaceutically acceptable salt thereof. 2. A compound as claimed in claim 1, wherein a pharmaceutically acceptable salt thereof selected from the group consisting of: a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid hydrobromic acid, sulphuric acid, phophoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalne sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic .add, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. 3. A pharmaceutical composition comprising a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier. 4. A compound as claimed in claim 1 selected from the group consisting of: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl-pyridyloxy)phenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4- pyridyloxyjphenyl) urea, '4 N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoy11 (4-pyridyloxy))phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea, N-^-methoj{y-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, or a pharmaceutically acceptable salt thereof. 5. A compound as claimed in claim 4 which is a pharmaceutically acceptable salt thereof selected from the group consisting of: a) basic salts of organic adds and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. 6. A pharmaceutical composition comprising a compound as claimed in claim 4 or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier. 7. A compound as claimed in claim 1 selected from the group consisting of: the 4-chloro-3-(trifiuoromethyl)phenyl ureas: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pj^\|dyloxy)phenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N-(4-(2-carbamoyl-4-pyridyloxyjphenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)4-pyridyloxy) phenyl) urea and N-(4-chloro-3-(trifluoromethyl)phenyl)-N-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea, the 4-bromo-3(trifluoromethyl)phenyl ureas: N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4- pyridyloxy) phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N,-(4-(2-(N-methylcarbamoyl)-4- pyridyloxy) phenyl urea. N-(4-bromo-3-(trrifluoromethyl)phenyl)-N,-(3-(2-(N-methylcarbamoyl)-4- pyridylthio) phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N- methylcarbamoyl)(4-pyridyloxy))phenyl) urea and N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N- methylcarbamoyl)(4-pyridyloxy))phenyl) urea; the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas: N-(2-methoxy-4-chloro-5-(trifluoromethylphenyl)-N'-(4-(2-(N- methylcarbamoyl)-4-pyridyloxy)phenyl) urea, N-(2-methoxy- 4-chloro-5-(trifluoromethyl) phenyl)-N'-(2-chloro-4-(2-(N- methylcarbamoyl) (4-pyridyloxy)) phenyl) urea or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a cancerous cell growth mediated by raf kinase. 8. A compound as claimed in claim 1 selected from the group consisting the 4-chloro-3-(trifluoromethyl)phenyl ureas: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxyjphenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl) (4-pyridyloxy))phenyl) urea, the 4-bromo-3(trifluoromethyl)phenyl ureas: N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)4-pyridyloxy) phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridylthio) phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea and N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea; the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas: N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl) phenyl)-N'-(2-chloro-4-(2-(N- methylcarbamoyl) (4-pyridyloxy)) phenyl) urea or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of: i) carcinoma of the lungs, pancreas, thyroid, bladder, colon, ii) myeloid leukemia or iii) villous colon adenoma. 9. A compound as claimed in claim 1 selected from the group consisting of: the 4-chloro-3-(trifluoromethyl)phonyl ureas: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxyjphenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N,-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea, N-(4-chloro-3-(trifiuoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea, the 4-bromo-3(trifluoromethyl)phenyl ureas: N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)4-pyridyloxy) phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N-(3-(2-(N-methylcarbamoyl)-4-pyridylthio) phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea and N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea; the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas: N-(2-methox^-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N,-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy)phenyl) urea, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of tumors. 10. A compound as claimed in claim 4 selected from the group consisting of: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4 pyridyloxy) phenyl) urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl) -4-pyridyloxy)phenyl) urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl) (4-pyridyloxy))phenyl) urea. or a pharmaceutically acceptable salt hereof for the manufacture of a medicament for the treatment of a cancerous cell growth mediated by raf kinase. 11. A compound as claimed in claim 4 selected from the group consisting °* N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy) phenyl) urea, N-(4-chloro-3-(trifluoromethyl)phanyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl) (4-pyridyloxy))phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4 pyridyloxy)phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea or a pharmaceutically acceptable salt hereof for the manufacture of a medicament for the treatment of: i) carcinoma of the lungs, panaeas, thyroid, bladder, colon, ii) myeloid leukemia or iii) villous colon adenoma. 12. A compound as claimed in claim 4 selected from the group consisting of: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxyjphenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4 pyridyloxy)phenyl)urea, N-\|g-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea or a pharmaceutically acceptable salt hereof for the manufacture of a medicament for the treatment of tumors. 13. A compound as claimed in claim 1 which is N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridylo3^)phenyl) urea. 14. A compound as claimed in claim 1 which is N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbanioyl)-4-pyridyloxy)phenyl) urea 15. A pharmaceutical composition comprising N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridylo3^)phenyl) urea or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier. 16. A pharmaceutical composition comprising N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier. 17. N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy) phenyl) urea, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a cancerous cell growth mediated by raf kinase. 18. N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4"(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl) urea or a pharmaceutical acceptable salt thereof for the manufacture of a medicament for the treatment of a cancerous cell growth m^iated by raf kinase. 19. A pharmaceutically acceptable salt of a compound which is: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy) phenyl) urea of the formula: S o i*!^0Y^TNH: H H or N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl-4-pyridyloxy)phenyl) urea of the formula: 20. A pharmaceutically acceptable salt as claimed in claim 19 which is a basic salt of an organic acid or an inorganic acid which is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, or mandelic acid. 21. A pharmaceutically acceptable salt which is the tosylate salt of: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy) phenyl) urea of the formula: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-N-methylcarbamoyl-4-pyridyloxyjphenyl) urea of the formula: 22. A pharmaceutical composition comprising a pharmaceutically acceptable salt of claim 19, 20 or 21 and pharmaceutically acceptable carrier. Dated this 5th day of July, 2001. [RANJNA MEHTA-DUTT] OF REMFRY 85 SAGAR ATTORNEY FOR THE APPLICANTS)

Full Text

FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"CARBOXYARYL SUBSTITUTED DIPHENYL UREAS"
BAYER CORPORATION, 100 Bayer Road, Pittsburgh, Pennsylvania, 15205, U.S.A.,
The following specification particularly describes the invention and the manner in which it is to be performed:

©"Carboxyarylf substituted diphenyl ureas as raf Joaasc inhibitors
Field of the Invention
This invention relates to the use of a group of carboxvarvl substituted diphenyl ureas pryl ureas-in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.
Background of the Invention
The p21™ oncogene is a major contributor to the development and progression of human
solid caitaers and is mutated in 30% of all human cancers (Bolton et al. Ann. Rep. Med
Chem, 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, unmutated
form, the ras protein is a key element of the signal transduction cascade directed by
growth factor receptors in almost all tissues (Avrucbtit al. Trends Biochem. Sci. 1994,19,
.'&*• 279-83). Biochemically, ras is a guanine nucleotide%nding protein, and cycling between
a GTP-bound activated and a GDP-bound rcs0g form is strictly controlled by ras
, ■ ^*'-W:"
endogenous GTPase activity and other reguIatSry^proteins. In the ras mutants in cancer
cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers
constitutive growth signals to downstream effectors such as the enzyme raf kinase. This
leads to the cancerous growth of the cells which carry these mutants (Magnuson et al,
Semin. Cancer Biol. 1994, 5, 247-53). It has been shown that inhibiting the effect of
active rai- by inhibiting the raf kinase signa/mg pathway by administration of deactivating
antibodies to raf kinase or by co-expression of dominant negative raf kinase or dominant

negative MEK, the substrate of raf kinase, leads to the reversion of transformed cells to the normal growth phenotype (see: Daum et al. Trends Biochem. Set 1994, JP, 474-80; Fridman ut al. J. Biol. Chem, 1994, 269, 30105-S. Kolch et al, (Nature 1991,349, 426-28) have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes. Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., Nat, Med. 1996, 2, 668-75).
Summary of the Invention
The present invention provides compounds which are inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector of p21fM, the inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compounds are useful in the treatment of human or animal solid cancers, e.g., murine cancer, since the progression of these cancers is dependent upon the ras protein signal transduction cascade and therefore susceptible to treatment by interruption of the cascade, i.e., by inhibiting raf kinase. Accordingly, the compounds of the invention are useful in treating cancers, including solid cancers, such as, for example, carcinomas (e.g., of the lungs^pancreas, thyroid, bladder or colon), myeloid disorders (e.g., myeloid leukemia) or adenomas (e.g., villous colon adenoma).
The presont invention therefore provides compounds generally described as aryl ureas, - including both aryl and heteroaryl analogues, which inhibit the raf kinase pathway. -3%* invention also provides a-method for trcating-ft-paf mediated disease state-in humans or mammals. Thus, the invention is directed to compounds which inhibit the enzyme raf kinase and also compounds and compositions ftnd methods for the treatment of cancerous cell growth mediated by raf kinase wherein a compound of the invention Formula I M-administcrcd or can be in the form of a pharmaceutical^ acceptable salt thereof. A compound of the invention is selected from the group consisting of

methvIcarbamovnf4-pyridvIoxv))phenvl') area or a pharmacegticallv acceptable salt thereof
Example's of pharmaecnticallv acceptable salts include those of
N^4-chloro^-ftiif[uoromethvn phe phenyl) orea of the formula;
H H
CI and
N^chloro^-('trifluoromethvnDhenyn"N>^4^-^-methvicarbamovfM-
lyridyloyy) phenylVurea pf the formula:

form of » basic salt described above, such as a tofeylate salt.

-A-D-B

*r

-©

In formula I> D is NH-C(O) NH t
A4s—a-substitutcd moiety of up to 40 carbon atoms of the formula; L (M
*>*-)q » where L fa a 5 or- 6 membered cyclic structure bound directly to P, L* comprises a substituted cyclic-moie^-having at least 5 membcre,-M is a bridging group-having at least-one atom,—q fa-an -integer of from 1 3;-and each cyclic structure of L and-fc* contains 0 4 members of the group consisting ofna-itrogen, oxygen end sulfur, and
S4s a-substitutcd or unsubstitutcdi up-to tricyclic tiryl or hctcrooryl

directly to D containing 0 4 members of the group ooraisting of-nitrogen, oxygen-
M1IU JUJIJUJ)
wlteyem-L* is substituted by at least one gnbotttnont selected from the group
consisting of SOfe C(0)R —-—R^ is hydrogen or a carbon based moiety of up to 21 carbon atoms optionally
: containing octcrontoma selected from N, S-and^Q-and-optionally' halosnbstitated, up
Kv-is hydrogen qr a carbon basod-hioiety of np to 30 carbon atoms optionally containing hctoroatoms selected from N,g and 0 and optionally snbstitutod by hftjogcn, hydroxy and earbqn based, substitnentsof np io-34 carbon atoms, which &fti4&&aHy-eonta»n hetcro atoms >clectftd^iHMfla-Nt-S and 0 and arc optionally
Ej4^ftjre*^RaRb.wherc ^-imd-RbHM'e
-a) HHtefrend^ntfy-hydrogen, ^
-JSP'
— a onrben based moicty-o-f np to-^^arbon atoms optionally containing
hoteroatums selected from N, S and O aj^goptionally snbstitnted by halogen,
hydroxy ftnd-carbon based substitnents o^upUo 24 carboi
. '■. f.t. ~ ■ ■ .
contain Itctcroatoma selected from N» S and O and arc optionally substituted by
halogen, or
_ QSiffi^ where R+ is hydrogen or a carbon based moiety of np to 34
carbon »toms optionally containing hctoroatoms selected from-N, S and Q and optionally substituted by halogen, hydfoxy-and carbon based oubstitnonts of up to
and are optionally substituted by halogen; or
_ ,_&.) Rg-and-Ri, together form a 5-7-mcmbcr heterocyclic strnctnrc of 1 3
hotcrontoms selected from N» S and 0, or a Hofrstifutcd 5 7 member heterocyclic

contain hctcroatoma aclcctcd fromN, S-and 0 and aro optionally substituted by halogen; or
e)-— one of R,- or Rb is C(O), a tVCg divalent alhyleno group or a
substituted G4.-G5 divalent alltylcnc^group bound to -the moiety L to form n cyclic structure with at-least 5 member^ whorein-thc snbstitucnts of the substituted Cf-^s dtvafont-ulhylcnc gronp arc selected from the group consisting of halogon.-hydrojtyi, and—carbon based substituents of up to 24 carbon atoms^ which optionally contain hoteroatoms selected from N» S and 0 and are optionally substituted by halogen;
substituents are selected from the group consisting of hfllogen,-np-to-per halo, and W-n.-where n is 0-3;
jW -— whoroin-oacn-W-is independently selected from the group consisting of CN,
WRy€^Q)ft?, Q Ar, and carbon based moieties of up to-24 carbon atoms, optionally containing heterontoms selected from-N.S and O and optionally substituted by one or more -substituents independently selected frjp the group-consisting of -Cty -
NR?€{0)QR?-6fld-halogcn up to per halo? with'cach R? independently selected from H or a carbon based moiety of up to-24|ffarbon atamst optionally containing heteroafaims selected from N» S and O and optionally substituted by halogen,
wherein Q is O, g» NfflVWm) C(0), CH(OH) > (CHA^O-T-
Ar is n 5 or 6 member-aromatic structure containing 0 3 members selected
from tho group consisting of nitrogen, otygen and-sulfur, which is optionally substittHcd-by halogen, up to per-halo, and optionally substituted by Z^, wherein nl is 0 to 3 and each Z is independently selected-from the group-consisting of CN,
€Q3BV-c(0)fty> C(0)PER*R* NOA> oi£—$&?—3ra^V^»*c(0)ORV-
WR?G(Q)RV-and 0 carbon based moiety of np. to 31 carbon atoms, optfqnaljy

or more tmhstituents selected from t-he-gronp consisting of CN, COUR r-€OR r~
Vvtlivvu tfuuyi;.
In formula I, suitable hctaryl groups include, bat arc not limited to, 5 12
carbon atom aromatic rings or ring systems containing 13 rings, at least one of
which is aromatic^ in which one or morerc-g-.) 1 4 earben-atoms in-one or more of
j tbeHFHigs-efln-bc-rcplaccd by oxygen^ nitrogen or sulfur atoms,—Each ring typically
has3 7 fltems.-F " 3L-, ^r- or 3-pyrrolyl) I I or S.-pyrazolyl, 3,4 or S
oxflzolyl, 3 ,4 or 5 ifloxa^olyl, 3-, 1 or5 tfalqzoh/l)'3 ,'1 or 5 isothhreolyl, 3 ,3 or 4
pyridyli 3V f i 5. .or 6 pyrimidinyl, 1,23 triflfcol 1.% 1 or 5-yl, 1,2,4 triatol 1 t 3
or 5 yl; 1 pr-5-tetrazolyl, 1,2,3 ojoflwzol i or 5 y), 1,3,4 oxadioaol 3 or 5 yl,
1,3,1 thiadipufcol 2 or 5-yl, 1,2,4-psqdiflgol 3 or 5 yl, 1,3,1 tfaiadiojiol 3 -or 5 yl,
1,3,1 thiodiaaol 3 or gyl^ 1,2,3 thlodiflaoM^^r 5 yl, 3, 3-, A t S or 6 2H
thiopyraiiyl, 3-, 3 or 4 1H tbiopyranyl, 3- or jQ|pridagmyl» pyrazinyl, 3-, 3-, 4 , Si
6-or 7-benzofuryl 2 13 , 4,5 ,6 or 7 bonEqjjjipnyl, 1,2 , 3 ,4 »5 > 6 or 7 indolyl,
1 f a ,4 or 5bonzimidagolyl, 1 , 3 , 4 ,5 » ntJ|r 7-benzopyrazobrl, 2 14->-gy6 or 7
bcnzoxoifiOlyl, 3 »4 ,5 6 or 7-bcnzUoxu&oh/la 1,3 -r 4 ,5-, 6- or 7 bongotniazolyl, 2 ,
4-,-5-, 6- or 7 bcnrisothiazolyl, 2,1,5)6 or 7 benz l^oxadiazolM 3 ,3 ,-4-,5 ,6-,
7 -or S-quinolinyl, 1 > 3 ,4,5 ,6,7,8 feoquinolinyl, 1-, 3 ,3 > 4 or 9 carbazolyl) 4-
r^-r3~r4 ,5-^,7,8 or 9 aeridinylt or 2 , 4-, 5,6,7 or 8 quinazolinyl» or
addftiomdly optionally Substituted phenyl 2 or 3 thicnyl, 1,3,4 thiadiazotyl, 3
fyrfyts-3-pyragoIyl, 2 thiazolyl or 5 thiazolyl, etc. For example, B can be 4 methyl
phenyl, 5 methyl 2-tlricnyl> 4 methyl 2 thicnyl, 1 methyl 3 pyi'iyl» 1 methyl 3
pyrazolyl, 5 methyl- 2 thiazolyl op 5 mcthyM,3,4 tbiadiazol 3 yl.
Suitable alkyi groups and alky! portions of groups, cgM. nlltoxy, ate* throughout inehidc-mcthyl, ethyl} propyl, butyl, ete^ including all otratght-choin and branched isomers such as taopropyI> laobutyl,see bf^l,W$butyh cfer

without ftlfayl substituonts such-that,- for example, "(VeyeloalftyjT includes mctbyl substituted cyolopropyl groups—fl& well as cyctobutyl groups.—The term -■cycloalkyr, as used herein also includes saturated heterocyclic groups.
Suitable hflfogfea^gFoups include Fy-GI^ Br, and/or I, from onc-to per substitution (i.e. all H atonw-on-a group replaced-by a halogen atom) being possible nvhiwo an alley! group is subfltitutcd by halogen, mixed.substitution of halogen atom
TF>IO invention also relates to eompound»per sc, of formula I.
The present invention is also directed to pharmaceutically acceptable salts of a compound of the invention formula I. Suitable pharrnaccutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, raethanesalphonic acid, trifluoromethanesulfonji? acid, benzenesutfonic acid, p-toJuenesulfonic acid, I-naphthalenesuJfonic acidvi|flaphthalenesulfonic acid, acetic acid,
trifluoroacetic acid, malic acid, tartaric acid, cMcracid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic aci$/salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li^ Na+ or K*)M alkaline earth cations (e.g., Mg+2 , Ca*2 or Ba+a), the ammonium cation, as well as acid salts of organic Nases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonatibn or peralkylation of triethylamine, A^-diethylamine, AW-dicyclohexylamine, lysine, pyridine, N,N-dimethyhiminopyridine (DMAP), l,4-diazabiclo[2.2.2]octane (DABCO), 1,5-diazabicyc]o[4.3.0]non-5-ene (DBN) and l,8-diazabicycloj;5.4.0]undec-7-ene (DBU).
A number of the compounds of-P&waHtfa-I possess asymmetric carbons and can therefor exist in racemic and optically activeforms. Methods of separation of enantiomeric and

diastereomeric mixtures are well known to one skilled in the art. The present invention encompasses any isolated racemic or optically active form of the compounds of the invention or pfaarmaceuticany acceptable salts thereof dtogoribod" in- Forinnla -I
which possess raf inhibitory activity.
General Preparative Methods
The comjiounds of Formula I the invention may be prepared by the use of known chemical reactions and procedures, some from starting materials which are commercially available. Nevertheless, general preparative methods are provided below to aid one skilled in the art in synthesizing these compounds, with more detailed examples being provided in the Experimental section which follows.
Substituted anilines may be generated using standard methods (March. Advanced Organic Chemistry, 3rd Ed,; John Wiley: New York (1985). Larock. Comprehensive Organic rransformations; VCH Publishers: New Y$rk (1989)). As shown in Scheme I,
aryl amines are commonly synthesized by reduc|im of nitroaiyls using a metal catalyst,
such as INL, Pd, or Pt, and rfe or a hydride transf^sfgen^ such as formate, cyclohexadieue, or a borohydride (Rylander. Hydrogenation^Mjpthods; Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as UAIH4 (Seyden-Penne. Reductions by the Alumina- and BorohydHdes in Organic Synthesis; VCH Publishers: New York (1991)), or using a 2ero valent metal, such as fe, Sn or Cti, often in acidic media. Many methods exist for die synthesis of nitroaryls (March. Advanced Organic Chemistry, 3rd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)).
H2 / catalyst

2
ArNO:

/ (eg. Ni, Pd, Pt) V
EtU »». ArNH2
X M(0)
(eg-Fe,? *

Scheme I Reduction of Nitroaryls to Aiyl Amines
Nitroaryl are commonly formed by electrophilic aromatic nitration using HNO3, or an alternative N HNQ3
Ar-H —*- ArN02
potential leaving groups (e.g. F„ CI, Br, etc.) may undergo substitution reactions on --Mrrealment-Avith-nueleophiles, such^miolate. (exemplified .in Scheme ID or phenoxide. Nitroaryh. may also undergo Uliman-type coupling reactions (Scheme il).

ArSH
02N*
■ jfW ——^
R-^^r^ base ^A

cy~sH
02N
R-"'^=s/ CuO / base
£ Vs-Ar R Br-Ar y^ 2
$$>

m
MP
sal Scheme JI Selected Nucleophilic Aromatic^nbstitwtion using Nitroaryls
'f$r ■".■■■ ■
ft' ■ ••■
Nitroaryl;. may also undergo transition metal mediated cross coupling reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo palladium mediated cross coupling reactions with aryl nocleophiles, such as arylboronic acids (Suzuki reactions,, exemplified below), aryltins (Stille reactions) or aiylzincs (Negishi reaction) to afford the biaryl (5).
02NV^ ArB(0ft')2 OzN
t V-X — *- > VAr
R--W Pd(0) R-^=/
4 5
Either nitroaryls or anilines may be converted Into the corresponding arenesulfonyl chloride (7) on treatment with chlorosalfonic acid, Reaction-ofthe sulfonyJ chloiide with :

a fluoride source, such as KF then affords SUlfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with triniethylsilyl trifluoromethane in the presence of a fluoride source, such as .tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to tbe corresponding trifluoromethyisulfone (9). Alternatively, Sulfonyl chloride 7 may be reduced to the arenethiol (10), for example with zinc amalgum. Reaction of thiol 10 with CHCIF3 in the presence of base gives the difluororriethyl mercaptam (11), which may be oxidized to the sulfone (12) with any of a variety of oxidants, including Cr03-acetic anhydride (Sedovaetal, Zh. Org._Khm- A?70-M5ffi)-

CIS03H
(Me2N)3S Me3SiF2 Me3SiCF3
#

-R

Sp2CI

[0]
S02CHF2

O

12

Scheme QI Selected Methods of Fluorinated Aiyl Sulfone Synthesis
As shown in Scheme IV, non-symmetrical V>rea formation may involve reaction pfanaryl isocyanace (14) .with.an aryl amine.03), The heteroa^l isocyanate may be synthesized

from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichlorpmethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or N,N ^arbonyldiimidazole (CD]). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or ant anhydride by a Curtius-type rearrangement. Thus, reaction of acid derivative 16 withan &ride source, followed by rearrangement affords the isocyanate. The corresponding carboxylk: acid (17) may also be subjected to Curtius-type rearrangements using diphenylphosphory 1 azide pPPA) or a similar reagent.
J
Ar^NHa 13 COCI3
H2N~Ar* 0
Ar^NCO *- ArV. X ;Ar14 H H
'/
15
Ar" "x Ar1' "OH
N3' / \ DPPA
0 O
■ie 17 Mt
?K Scheme IV Selected Methods of Non-Syro$fe:al Urea Formation
Finally, ureas may be further manipulated usi||4nethods familiar to those skilled in the art.
The invention also includes pharmaceutical compositions including a compound of l?eran*la-J, the invention, or a pharmaceuticallv acceptable salt thereof- and a
physiologically acceptable carrier.
The compounds may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term 'administration by injection* includes intravenous, intramuscular, subcutaneous and parenteral injections, as we]] as use of infusion techniques. One or more compounds may be present in association -with

one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.
Compositions intended for oral use may be prepared according to any suitable method * known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations, Tablets contain the active ingredient in admixture with non-toxic pharmaceutical ly acceptable excipients which are suitable for
the^manufacture of tablets. These excipients may be, for example, Inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; .granulating and disintegrating agents, for example, com starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc, the tabletsmay be uncoated or they may be coated by known techniques to delay dismtegration and adsorptioa in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosfearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.
$■' Formulations for oral us* may also be preselpd as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture.with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium c^rboxymethylcellulose, methylcellulose, hydroxypropyl methyJceliuJose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example polyoxy&hytene stearate, or condensation pivdacts of ethylene cokfc w'jfc Jong chain

aliphatic alcohols, for sample heptadecaethylene oxycetanoly or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyeihylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl /7-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose pr saccharin.
| Dispersible powders and granules suitable for preparation of an aqueous suspension by
| the addition of water provide the active ingredient in admixture with a dispersingor
i y/ethng agent, suspending agent arid one or more preservatives. Suitable dispersing or
Byettiiig agents -and suspending agents are, exemplified by those already mentioned above,
lAdditiohaTe^ example, sweetening, flavoring and coloring agents, may also
be present.
The comiJOunds may also be In the form of honjgfueous liquid formulations, e.g., oily suspensions which may be formulated by suspenM| the. active ingredients in a vegetable |f oil, for example arachis oil, olive oil, sesame pf^ peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may $>htain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These ipositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.
come

em
a minera
Pharmaceutical compositions of the invention may also be in the form of oil-in-water ulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate,. and condensation products ~of "the said partial esi^ v^uTe^

polyoxyethylene sorbitan monooleate: The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The compounds may also be administered in the form of suppositories for rectal
^ i administration of the drug. These compositions can be prepared by mixing the drug with
,•; a suitable hon-initating excipient which is solid at ordinary temperatures but liquid at the
; rectal temperature and will therefore melt in the rectum to release the drug. Such
I materials include cocoa better and polyethylene glycols.
■:; For all regimens ofuse disclosed herein for compounds of Formula I the invention or
' pharmaceiiticairv acceptable salts thereof , the ■ daiW-^ml dosage regimen will
preferably be from 0.01 to 200 mg/Kg of total body weight The daily dosage for
administration by injection, including intravenpjy*, intramusculary subcutaneous and
parenteral injections, and use of infusion technio^ will preferably be from 0.01 to 200
r mg/Kg of total body weight. The daily rectal dj|||e. regime will preferably be from 0.01
fif- to 200 mg/Kg of total body weight. The danfe^pical dosage regime will preferably be
from 0,1 to 200 mg administered between one to four times daily. The daily inhalation
dosage regime will preferably be from 0.01 to 10 mg/Kg of total body weight.
It will be appreciated by those skilled in the an that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be appreciated by one skilled in the art that the specific dose level for a given patient depends on a variety of factors, including specific activity of the compound administered, age, body weight, health, sex, diet, time end route of administration, rate of excretion, etc. It will be further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the

pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
It will be anderslood, however, that the specific dose IeVel for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the condition undergoing therapy.
;• The entire enclosure of all applications^ patents and publications cited above and . Hcltm nru-licrcby incorporated by reference, including provisional application Serial ; No. 60/115^877, filed January 13,1909 and non provisional application Serial N-o. 0m$7£L6 filed February 2S, ippo.
The compounds can be produced from known compounds (or from starting materials which, iii rum, can be produced from known compounds), e.g., through- the general preparative methods shown below. The aetivi|wof a given compound to inhibit raf kinase can be routinely assayed, e.g., accordingflo procedures disclosed below. The following examples are for illustrative puipo||??Only and are not intended, nor should they be construed to limit the invention in any|yay.
EXAMPLES
All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mmHg. Unless otherwise stated, the term 'under high vacuum' refers to a vacuum of 0.4- 1.0 mmHg.

All temperatures are-reported uncorrected in degrees Celsius (°C). Unless otherwise f^dicated, all parts and percentages, are by weight.
Commercial grade reagents and solvents were used without further purification. N-
cyclohexyI-//'-(methylpolystyrene)carbodiimide was purchased from Calbiochem-
Novabiochem Corp. 3-ter/-Butylaniline, 5-fert-butyl-2-methoxyaniline, 4-bromo-3-
(trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline 2-methoxyo-
(trifluoromethyl)aniline, 4-/err-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-isocyanatobenzoate, Ar-acetyl-4-chloro-2-medioxy-5-(trifluoromethyl)aiiiline and 4-chloro-3-(trifluoromethyl)phenyl isocyanate were purchased and used without further purification. Syntheses of 3-amino-2-methoxyqumoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem.. 3, 1995, 129), 4- ■'4
Thin-layer chromatography (TLC) was performed using Whitman1' pre-coated glass-backed silica gel 60A F-254 250 urn plates. Visualization of plates1 was effected by one or more of the following techniques: (a) ultraviolet illumination, ^(b*)1 exposure to iodine vapor, (c)

ummersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazme followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science® silica gel.
Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer Proton (*H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (5 0.00) or residual protonated solvent (CHClj 5 7.26; MeOH S 3.30; DMSO 8 2.49) as standard. Carbon (;3C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometi. with solvent (CDC13 5 77.0; MeOD-d3; 5 49.0; DMSO-d6 5 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion source was maintained at 250 °C. Electron impact ionization was performed with electron energy of 70 eV and a trap current of 300 uA. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas (lxl 0"4 torr to 2.5x10"4 torr). The direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared ( -1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospru\ ionization. Spectra were scanned from 120-800 amu using a variable ion time according 10 the number of ions in the source. Gas chromatography - ion selective mass spectra (GC-MS)

^were obtained with a Hewlett Packard 5890 gas chiomatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25 rax 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eV). Elemental analyses are conducted by Robertson Microlit Labs, Madison NJ.
All compounds displayed NMR spectra, LRMS and either elemental analysis or HRMS consistent with assigned structures.
List of Abbreviations and Acronyms:
AcOH acetic acid
anh anhydrous
atm atmosphere(s)
BOC ^r?-butoxycarbony!
CDI l.l'-carbonyl diimidazole
cone concentrated
d day(s)
dec decomposition
DMAC /V,jV-dimethylacetamide
DMPU l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
DMF /V,jV-dimethylformamide
DMSO dimethylsulfoxide
DPPA diphenylphosphoryl azide
EDCI 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide
EtOAc ethyl acetate
EtOH ethanol(100%)
Et20 diethyl ether
EtjN triethylamine
h hour(s)
HOBT 1-hydroxybenzotriazole
w-CPBA 3-chloroperoxybenzoic acid
MeOH methanol
pet. ether petroleum ether (boiling range 30-60 °C)

temp. temperature
^THF tetrahydrofuran
TFA trifluoroAcOH
Tf trifluoromethanesulfonyl
A. General Methods for Synthesis of Substituted Anilines
AI. General Method for Aryl Amine Formation via Ether Formation
Followed by Ester Saponification, Curtius Rearrangement, and Carbamate Deprotection. Synthesis of 2-Amino-3-methoxynaphthaleoe.

C02Me OMe
Step 1. Methyl 3-methoxy-2-naphthoate
A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K2C03 (7.96 g, 57.6
mmol) in DMF (200 mL) was stirred at room temp, for 15 min., then treated with
iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temp.
overnight, then was treated with water (200 mL). The resulting mixture was extracted with
EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated NaCl
solution (100 mL), dried (MgSCU), concentrated under reduced pressure (approximately 0.4
mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10.30 g): 'H-
NMR (DMSO-d6) 5 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, 7=8.09 Hz, 1H), 7.44 (s, 1H), 7.53
(app t, >8.09 Hz, 1H), 7.84 (d, >8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).

Step 2. 3-Metboxy-2-naphthoic acid
A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room temp, was treated with a 1 N NaOH solution (33.4 mL, 33.4 mmol). The mixture was heated at the reflux temp, for 3 h, cooled to room temp., and made acidic with a 10% citric acid solution. The resulting solution was extracted with EtO.Ac (2 \ Inn

mL). The combined organic layers were washed with a saturated NaCl solution, dned K(MgS04) and concentrated under reduced pressure. The residue was triturated with hexane then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): 'H-NMR (DMSO-d6) 6 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d, >8.09 Hz, 1H), 7.91 (d, 7=8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (br s, 1H).

Step 3. 2-(Ar-(Carbobenzyloxy)amino-3-methoxynapbthaIene
A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and EtjN (2.59 mL, 18.6 mmol) in anh toluene (70 mL) was stirred at room temp, for 15 min., then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resulting mixture was heated at 80 °C for 2 h. After cooling the mixture to room temp., benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was then warmed to 80 °C overnight. The resulting mixture was cooled to room temp., quenched with a 10% citric acid solution, and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc/86% hexane) to give 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%): 'H-NMR (DMSO-d6) 8 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H), 8.76 (s,lH).

NH2 OMe
Step 4. 2-Amino-3-methoxynaphthalene
A slurry of 2-(/V-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a H2 atm (balloon) at room temp, overnight. The resulting mixture was filtered through Celite4, and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder (2.40 g.

^5%): 'H-NMR (DMSO-4) 5 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, 7=8.0 Hz, 1H), 7.56 (d, 7=8.0 Hz, 1H); EI-MS m/z 173 (M+).
A2. Synthesis of co-Carbamyl Anilines via Formation of a Carbamylpyridine
Followed by Nucleophilic Coupling with an Aryl Amine. Synthesis of 4-(2-/V-MethylcarbamyI-4-pyridyioxy)aniIine
0
clY^Y^NHMe
Step la. Synthesis of 4-chloro-Ar-methyl-2-pyridinecarboxamide via the Menisci
reaction Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temp, was added cone. H2SO4 (3.55 mL) to generate an exotherm. To this mixture was added H2O2 (30% wt in H20, 17 mL) followed by FeS04*7H20 (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temp, for 1 h, then warmed slowly over 4 h to 45 °C. When bubbling had subsided, the reaction was heated at 60 °C for 16 h. The resulting opaque brown solution was diluted with H20 (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with a saturated NaCl solution (3 x 150 mL), then they were combined, dried (MgS04) and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 4-chloro-W-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) R/0.50; 'H NMR (CDCI3) 5 3.04 (d, 7=5.1 Hz, 3H), 7.43 (dd, 7=5.4, 2.4 Hz, 1H), 7.96 (brs, 1H), 8.21 (s, 1H), 8.44 (d, 7=5.1 Hz, 1 H); CI-MS m/z 171 ((M+H)+).

O Cl.
CI N HCI
Step lb. Synthesis of 4-chloropyridine-2-carbonyl chloride HCI salt via picolinic
acid

i|f Anhydrous DMF (6.0 ml) was slowly added to SOCl2 (180 mL) between 40° and 50 °C. The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g, 487 mmol) was added in portions over 30 min. The resulting solution was heated at 72 °C (vigorous S02 evolution) for 16 h to generate a yellow solid precipitate. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and dried under high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chloride HCl salt as a yellow-orange solid (92.0 g, 89%).
O
CIYV^OMe
I^N HCl
Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HCl salt
Ann DMF (10.0 mL) was slowly added to SOCl2 (300 mL) at 40-48 °C. The solution was stirred at that temp, range for 10 min., then picolinic acid (100 g, 812 mmol) was added over 30 min. The resulting solution was heated at 72 °C (vigorous S02 evolution) for 16 h to generate a yellow solid. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was Filtered, and the solids were washed with toluene (50 mL) and dried under high vacuum for 4 hours to afford 4-chloropyridine-2-carbonyl chloride HCl salt as an off-white solid (27.2 g, 16%). This material was set aside.
The red filtrate was added to MeOH (200 mL) at a rate which kept the internal temperature below 55 °C. The contents were stirred at room temp, for 45 min., cooled to 5 °C and treated with Et20 (200 mL) dropwise. The resulting solids were filtered, washed with Et20 (200 mL) and dried under reduced pressure at 35 °C to provide methyl 4-chloropyndine-2-carboxylate HCl salt as a white solid (110 g, 65%); mp 108-112 °C; 'H-NMR (DMSO-db) 5 3.88 (s, 3H); 7.82 (dd, 7=5.5, 2.2 Hz, 1H); 8.08 (d, 7=2.2 Hz, 1H); 8.68 (d, 7=5.5 Hz, 1 H); 10.68 (br s, 1H); HPLC ES-MS ni/z 172 ((M+Hf).

0
c'Y^Y^NHMe
Step 3a. Synthesis of 4-chloro-/V'-methyl-2-pyridinecarboxamide from methyl 4-
chloropyridine-2-carboxylate
A suspension of methyl 4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in MeOH (75 mL) at 0 °C was treated with a 2.0 M methylamine solution in THF (1 L) at a rate which kept the internal temp, below 5 °C. The resulting mixture was stored at 3 °C for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500 mL), dried (Na2S04) and concentrated under reduced pressure to afford 4-chloro-iV-methyl-2-pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43 °C; 'H-NMR (DMSO-d6) 5 2.81 (s, 3H), 7.74 (dd, 7=5.1,2.2 Hz, 1H), 8.00 (d, 7=2.2, 1H), 8.61 (d, 7=5.1 Hz, 1H), 8.85 (br d, 1H); Cl-MS m/z 171 ((M+Hf).
O
Step 3b. Synthesis of 4-chloro-iY-methyl-2-pyridinecarboxainide from 4-
chloropyridine-2-carbonyl chloride
4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in portions to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0 °C. The resulting mixture was stored at 3 °C for 4 h, then concentrated under reduced pressure. The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate was washed with a saturated NaCl solution (2 x 100 mL), dried (Na2S04) and concentrated under reduced pressure to provide 4-chloro-/vr-methyl-2-pyridinecarboxamide as a yellow, crystalline solid (4.95 g, 88%): mp 37-40 °C.
O

Step 4. Synthesis of 4-(2-(^-methyIcarbamoyl)-4-pyridyloxy)aniline
A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated with potassium re/v-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at

room temp, for 2 h. The contents were treated with 4-chloro-jV-methy]-2-
pyndinecarboxamide (15.0 g, 87.9 mmol) and K2C03 (6.50 g, 47.0 mmol) and then heated at
80 °C for 8 h. The mixture was cooled to room temp, and separated between EtOAc (500
mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with
EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution
(4 x 1000 mL), dried (Na2S04) and concentrated under reduced pressure. The resulting solids
were dried under reduced pressure at 35 °C for 3 h to afford 4-{2-(Ar-methylcarbamoyl)-4-
pyridyloxy)aniIine as a light-brown solid 17.9 g, 84%): 'H-NMR (DMSO-d6) 5 2.77 (d, 7=4.8
Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB* quartet, 7=8.4 Hz, 4H), 7.06 (dd, 7=5.5, 2.5 Hz.
1H), 7.33 (d, 7=2.5 Hz, 1H), 8.44 (d, 7-5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244
((M+H)+).
A3. General Method for the Synthesis of Anilines by Nucleophilic Aromatic
Addition Followed by Nitroarene Reduction. Synthesis of 5-(4-
Aminophenoxy)isoindoline-l,3-dione

O
Step 1. Synthesis of 5-bydroxyisoindoline-l,3-dione
To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in cone. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120 °C for 45 min., then the clear, bright yellow mixture was heated at 160 °C for 2 h. The resulting mixture was maintained at 160 °C and was concentrated to approximately 15 mL, then was cooled to room temp, and adjusted pH 10 with a IN NaOH solution. This mixture was cooled to 0 °C and slowly acidified to pH 5 using a IN HC1 solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-l,3-dione as a pale yellow powder as product (3.24 g, 72%): 'H NMR (DMSO-d6) 8 7.00-7.03 (m, 2H), 7.56 (d, 7=9.3Hz, 1H).

Step 2. Synthesis of 5-(4-nitropbenoxy)isoindoline-l,3-dione
To a stirring slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 °C was added a solution of 5-hydroxyisoindoline-l,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The bright yellow-green mixture was allowed to return to room temp, and was stirred for 1 h, then 1 -fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated at 70 °C overnight, then cooled to room temp, and diluted slowly with water (150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (MgSCu) and concentrated under reduced pressure to give 5-(4-nitrophenoxy)isoindoline-l,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70% hexane) R/0.28; 1H NMR (DMSO-d6) 6 7.32 (d, 7=12 Hz, 2H). 7.52-7.57 (m, 2K), 7.89(d, 7=7.8 Hz, 1H), 8.29 (d, 7=9 Hz, 2H), 11.43 (br s, 1H); CI-MS m/z 285 ((M+H)+, 100%).

H2N' ^ VV°
O
Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-l,3-dione
A solution of 5-(4-nitrophenoxy)isoindoline-l,3-dione (0.6 g, 2.11 mmol) in cone. AcOH (12 mL) and water (0.1 mL) was stirred under stream of argon while iron powder (0.59 g, 55.9 mmol) was added slowly. This mixture stirred at room temp, for 72 h, then was diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgSO.4) and concentrated under reduced pressure to give 5-(4-aminophenoxy)isoindoline-l,3-dione as a brownish solid (0.4 g, 75%): TLC (50% EtOAc/50% hexane) R/0.27; lH NMR (DMSO-d6) 5 5.14 (br s, 2H), 6.62 (d, 7=8.7 Hz, 2H), 6.84 (d, 7=8.7 Hz, 2H), 7.03 (d, 7=2.1 Hz, 1H), 7.23 (dd, IH), 7.75 (d, 7=8.4 Hz, 1H), 11.02 (s, IH); HPLC ES-MS m/z 255 ((M+Hf, 100%).
A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5-tert-
Butyl-2-(2,5-dimethylpyrrolyl)aniline

Step 1. Synthesis of l-(4-terNbutyl-2-nitrophenyI)-2,5-dimethyipyrroIe
To a stirring solution of 2-nitro-4-ferr-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added AcOH (0.1 mL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. The reaction mixture was heated at 120 °C for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temp., diluted with CH2Ch (10 mL) and sequentially washed with a IN HC1 solution (15 mL), a IN NaOH solution (15 mL) and a saturated NaCl solution (15mL), dried ( MgS04) and concentrated under reduced pressure. The resulting orange-brown solids were purified via column chromatography (60 g SiO?; gradient from 6% EtOAc/94% hexane to 25% EtOAc/75% hexane) to give l-(4-rerr-butyl-2-nitrophenyl)-2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85% hexane) Rf 0.67; 'H NMR (CDClj) d 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, IH), 7.62 (dd, IH), 7.88 (d, 7=2.4 Hz, IH); CI-MS m/z 273 ((M+H)+, 50%).

Step 2. Synthesis of 5-terr—Butyl-2-(2,5-dimethy|pyrrolyl)aniIine
A slurry of l-(4-/err-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10%Pd/C (0.056 g) and EtOAc (50 mL) under an H2 atmosphere (balloon) was stirred for 72 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give 5-/err--butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g, 99%): TLC (10% EtOAc/90% hexane) R/0.43; 'H NMR(CDClj) 5 1.28 (s, 9H), 1.87-1.91 (m. 8H). 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, 1H).

General Method for the Synthesis of Anilines from Anilines by Nucleophilic Aromatic Substitution. Synthesis o(4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HC1 Salt
0

i HCI
Me
A solution of 4-ammo-3-methylphenol (5.45 g, 44.25 mmol) in dry dirnethylacetamide (75
mL) was treated with potassium terr-butoxide (10.86 g, 96.77 mmol) and the black mixture
was stirred at room temp, until the flask had reached room temp. The contents were then
treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2
mmol) and heated at 110 °C for 8 h. The mixture was cooled to room temp, and diluted with
water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined
organic layers were washed with a saturated NaCl solution (200 mL), dried (MgSOj) and
concentrated under reduced pressure. The residual black oil was treated with EtiO (50 mL)
and sonicated. The solution was then treated with HCI (1 M in Et20; 100 mL) and stirred at
room temp, for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by
filtration from solution and stored under anaerobic conditions at 0 °C prior to use: !H NMR
(DMSO-d6) 5 2.41 (s, 3H), 2.78 (d, 7=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, 7=8.5, 2.6 Hz.
1H), 7.23 (dd, .7=5.5, 2.6 Hz, 1H), 7.26 (d, 7=2.6 Hz, 1H), 7.55 (d, 7=2.6 Hz, 1H), 7.64 (d,
7=8.8 Hz, 1H), 8.55 (d, 7=5.9 Hz, 1H), 8.99 (q, 7=4.8 Hz, 1H).
A6. General Method for the Synthesis of Anilines from Hydroxyanilines by -V-
Protection, Nucleophilic Aromatric Substitution and Deprotection. Synthesis of4-(2-(A^-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline
CI
Step 1: Synthesis of 3-Chloro-4-(2,2,2-trifluoroacetylamino)phenol
Iron (3.24 g, 58.00 mmol) was added to stirring TFA (200 mL). To this slurry was added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 mL). This urav slurry was stirred at room temp, tor 6 d. The iron was filtered from solution and the

remaining material was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To the resulting yellow solution was added a saturated NaHCOj solution (50 mL). The solid which precipitated from solution was removed. The filtrate was slowly quenched with the sodium bicarbonate solution until the product visibly separated from solution (determined"was using a mini work-up vial). The slightly cloudy yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with a saturated NaCl solution (125 mL), dried (MgSOi) and concentrated under reduced pressure. The 'H NMR (DMSO-d6) indicated a 1:1 ratio of the nitrophenol starting material and the intended product 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol. The crude material was taken on to the next step without further purification.
0
'°W^NHMe
F3cr
H i.
Step 2: Synthesis of 4-(2-(A:-Methylcarbamoyl)-4-pyridyloxy)-2-cblorophenyJ
(222-trifluoro)acetamide
A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 mL) was treated with potassium ferr-butoxide (5.16 g, 45.98 mmol) and the brownish black mixture was stirred at room temp, until the flask had cooled to room temp. The resulting mixture was treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 °C under argon for 4 d. The black reaction mixture was cooled to room temp, and then poured into cold water (100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by column chromatography (gradient from 20% EtOAc/pet. ether to 40% EtOAc/pet. ether) to yield 4-(2-(Ar-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol).
O

,u.
H2N ^ CI
Step 3. Synthesis of 4-(2-(A'-Methylcarbarnoyl)-4-pyridyloxy)-2
MA solution of crude 4-(2-(Ar-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a IN NaOH solution (20 raL). This brown solution was allowed to stir for 8 h. To this solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x 40 mL) and the solvent was concentrated to yield 4-(2-(yV-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline as a green oil that solidified upon standing (2.86 g, 10.30 mmol): 'H NMR (DMSO-d6) 5 2.77 (d, 7=4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, 7=8.5, 2.6 Hz, IH), 6.76 (d, 7=2.6 Hz, IH), 7.03 (d, 7=8.5 Hz, IH), 7.07 (dd, 7=5.5, 2.6, Hz, IH), 7.27 (d, 7=2.6 Hz, IH), 8.46 (d, 7=5.5 Hz, IH), 8.75 (q, 7=4.8, IH).
A7. General Method for the Deprotection of an Acylated Aniline. Synthesis of
4-ChIoro-2-methoxy-5-(trifluoromethyl)aniline
CF3

A suspension of 3-chIoro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g, 14.95 mmol) in a 6M HC1 solution (24 mL) was heated at the reflux temp, for 1 h. The resulting solution was allowed to cool to room temp, during which time it solidified slightly. The resulting mixture was diluted with water (20 mL) then treated with a combination of solid NaOH and a saturated NaHC03 solution until the solution was basic. The organic layer was extracted with CH2CI2 (3 x 50 mL). The combined organics were dried (MgS04) and concentrated under reduced pressure to yield 4-chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g, 14.2 mmol): 'H NMR (DMSO-d6) 5 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).
A8. General Method for Synthesis of co-Alkoxy-o-carboxyphenyl Anilines.
Synthesis of 4-(3-{A/-Metbylcarbamoly)-4-methoxyphenoxy)aniline.
O
rY0TV^oMe
Step 1. 4-(3-Methoxycarbonyl-4-merhoxyphenoxy)-l-nitrobenzene:

»To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-l -nitrobenzene (prepared from 2,5-dihydroxybenzoic acid in a manner analogous to that described in Method A13, Step 1,12 mmol) in acetone (50 mL) was added K2CO3 (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated at the reflux temp, overnight, then cooled to room temp, and filtered through a pad of Celite®. The resulting solution was concentrated under reduced pressure, absorbed onto SiCh, and purified by column chromatography (50% EtOAc / 50% hexane) to give 4-(3~methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene as a yellow powder (3 g): mp 115-118 °C.
O
jfT°I^0H
Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-l-Ditrobenzene:
A mixture of 4-(3-methoxycarbonyI-4-methoxyphenoxy)-l -nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temp, overnight and then heated at the reflux temp, for 4 h. The resulting mixture was cooled to room temp, and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous mixture was made acidic with a IN HC1 solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgS04) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-l-nitrobenzene (1.04 g).
O
Step 3. 4-(3-(Ar-Methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene:
To a solution of 4-(3-carboxy-4-methoxyphenoxy)-l-nitrobenzene (0.50 g, 1.75 mmol) in CH2CI2 (12 mL) was added SOCI2 (0.64 mL, 8.77 mmol) in portions. The resulting solution was heated at the reflux temp, for 18 h, cooled to room temp., and concentrated under reduced pressure. The resulting yellow solids were dissolved in CH2CI2 (3 mL) then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02 mmol) in portions (CAUTION: gas evolution), and stirred at room temp, for 4 h. The resulting mixture was treated with a IN NaOH solution, then extracted with CHjCN (25 mL).

The organic layer was dried (Na2SC>4) and concentrated under reduced pressure to give 4-(3-W(//-methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene as a yellow solid (0.50 g, 95%).
O
'°VY^NHMe
H2N' "*" ^"NjMe
Step 4. 4-(3-(Ar-MethylcarbamoIy)-4-methoxyphenoxy)aniline:
A slurry of 4-(3-(A'-methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene (0.7S g7 2.60 mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under I atm of H2 (balloon) for 2.5 d, then was filtered through a pad of Celite®. The resulting solution was concentrated under reduced pressure to afford 4-(3-(yV-methylcarbamoly)-4-methoxyphenoxy)aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et3N/99.9% EtOAc) R/0.36.
A9. General Method for Preparation of ca-Alkylphthalimide-contaimng
Anilines. Synthesis of 5-(4-Aminophenoxy)-2-metnylisoindoIine-l,3-dione
O
N-Me
O
Step 1. Synthesis of 5-(4~Nitrophenoxy)-2-methylisoindoIine-l,3-dione:
A slurry of 5-(4-nitrophenoxy)isoindoline-l,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp, for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temp, overnight, then was cooled to °C and treated with water (10 mL). The resulting solids were collected and dried under reduced pressure to give 5-{4-nitrophenoxy)-2-methylisoindoline-1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) Kf 0.61.
o

£t.ep 2. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-I,3-dione:
A slurry of nitrophenoxy)-2-methylisoindoline-l,3-dione (0.87 g, 2.78 mmol) and 10% Pd/C (0.10 g) in MeOH was stirred under 1 atm of H? (balloon) overnight. The resulting mixture was filtered through a pad of Celite and concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) and filtered through a plug of SiOi (60% EtOAc/40% hexane) to afford 5-(4-aminophenoxy)-2-methylisoindoline-l,3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc/60% hexane) R/0.27.
A10. General Method for Synthesis of co-Carbamoylaryl Anilines Through
Reaction of ©-Alkoxycarbonylaryl Precursors with Amines. Synthesis of 4-{2-(iV-(2-morpholin-4-ylethyl)carbamoy})pyridyloxy)aniline

o
"IYWG

Step 1. Synthesis of 4-Chloro-2-(jV-(2-morpholin-4-ylethyl)carbamoyl)pyridine
To a solution of methyl 4-chloropyridine-2-carboxylate HC1 salt (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 mmol) dropwise and the resulting solution was heated at the reflux temp, for 20 h, cooled to room temp., and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSCh) and concentrated under reduced pressure to afford 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH/90% EtOAc) Rr0.50.

H,N v ^-^

A^Step 2. Synthesis of 4-(2-( ylethyI)carbamoyl)pyridyioxy)aniline.
A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium terr-butoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temp, for 2 h, then was sequentially treated with 4-chloro-2-(A/-(2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and K.2COj (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 °C overnight, cooled to room temp., and separated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were washed with a saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure. The resulting brown solids were purified by column chromatography (58 g; gradient from 100% EtOAc to 25% MeOH/75% EtOAc) to afford 4-(2-(yV-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC (10% MeOH/90% EtOAc) R/0.32.
All. General Method for the Reduction of Nitroarenes to Arylamines.
Synthesis of 4-(3-Carboxyphenoxy)aniIine.
A slurry of 4-(3-carboxyphenoxy)-l-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd/C (0.50 g) in MeOH (120 mL) was stirred under an H2 atmosphere (balloon) for 2 d. The resulting mixture was filtered through a pad of Celite®, then concentrated under reduced pressure to afford 4-(3-carboxyphenoxy)anihne as a brown solid (2.26 g, 48%): TLC (10% MeOH/90% CH2C12) Rr 0.44 (streaking).
A12. General Method for the Synthesis of Isoindoiinone-Containing Anilines. Synthesis of 4-(l-Oxoisoindolin-5-yloxy)aniHoe.
XJQ
NH

Step 1. Synthesis of 5-hydroxyisoindolin-l-one
io a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the reflux temp, for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 Kg Si02; gradient from 60% EtOAc/40% hexane to 25% MeOH/75% EtOAc) to give 5-hydroxyisoindolin-l-one (3.77 g): TLC (100% EtOAc) R/0.17; HPLC ES-MS m/i 150 ((M+H)+).
O
Step 2. Synthesis of 4-(l-isoindolinon-5-yloxy)-l-nitrobenzene
To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 °C was added 5-hydroxyisoindolin-l-one (2.0 g, 13.4 rr.mol) in portions. The resulting slurry was allowed to warn to room temp and was stirred for 45 min., then 4-fluoro-l-nitrobenzene was added and then mixture was heated at 70 °C for 3 h. The mixture was cooled to 0 °C and treated with water dropwise until a precipitate formed. The resulting solids were collected to give 4-(l-isoindolinon-5-yloxy)-l-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) R/0.35.

NH H,N
O

Step 3. Synthesis of 4-(l-oxoisoindofin-5j-yloxy)aniline
A slurry of 4-(l-isoindolinon-5-yloxy)-l-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd/C (0.20 g) in EtOH (50 mL) was stirred under an H2 atmosphere (balloon) for 4 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford 4-( 1-oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC (100% EtOAc) R/0.15.
A13. General Method for the Synthesis of ©-Carbamoyl Anilines via EDO-
Mediated Amide Formation Followed by Nitroarene Reduction. Synthesis of4-(3-A/-MethyIcarbamoyIphenoxy)aniline.

012

0->N

x^

Step 1. Synthesis of 4-(3-etboxycarbonyiphenoxy)-l-nitrobenzene
A mixture of 4-fluoro-l-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K2CO3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux temp, overnight, cooled to room temp, and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na2S04) and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).

O
OH
0,N'

XT*

Step 2. Synthesis of 4-(3-carboxyphenoxy)-l-nitrobenzene
To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene (5.14 g, 17.9 mmol) in a 3:1 THF/water solution (75 mL).was added a solution LiOH'fyO (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50 °C overnight, then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2 with a 1M HC1 solution. The resulting bright yellow solids were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-l-nitrobenzene (4.40 g, 95%).
O
02N' ^ ^

^Step3. Synthesis of 4-(3-(Ar-methylcarbamoyl)phenoxy)-l-nitrobenzene
A mixture of 4-(3-carboxyphenoxy)-l-nitrobenzene (3.72 g, 14.4 mmol), EDOHC1 (3.63 g, 18.6 mmol), jV-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CH2CI2 (45 mL) was stirred at room temp, for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with a 1M HC1 solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with a saturated NaCl solution (50 mL), dried (T^SClt), and concentrated under reduced pressure to give 4-(3-(/V-methylcarbamoyl)phenoxy)-l-nitrobenzene as an oil (1.89 g).
'NHMe
Step 4. Synthesis of 4-(3-(Ar-metbylcarbamoyI)phenoxy)aniline
A slurry of 4-(3-(yV-methylcarbamoyl)phenoxy)-l-nitrobenzene (1.89 g, 6.95 mmol) and 5% Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an H2 atm (balloon) overnight. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH/95% CH2CI2). The resulting oil solidified under vacuum overnight to give 4-(3-(N-methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).
A14. General Method for the Synthesis of ©-Carbamoyl Anilines via EDO-
Mediated Amide Formation Followed by Nitroarene Reduction. Synthesis of 4-3-(5-MethyIcarbamoyl)pyridyloxy)aniline
O

02N' ^ N
Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-l-nitrobenzene
To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a

^solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated at 70 °C overnight, cooled to room temp., and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g).
O

H2N v N
Step 2, Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline
A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-l-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd/C in MeOH/EtOAc was stirred under an Hz atmosphere (balloon) for 72 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% EtOAc/90% hexane to 30% EtOAc/70% hexane to 50% EtO Ac/50% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): !H NMR (CDC13) 5 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H), 8.87 (d, 1H).

A15, Synthesis of an Aniline via Electropbilic Nitration Followed by Reduction. Synthesis of 4-(3-Methylsulfamoylphenoxy)aniline.
Br-^ ^r^ ^S.
NHMe

Step 1. Synthesis of A^methyl-S-bromobenzenesuIfonamide
To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0 °C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was allowed to warm to room temp, and was stirred at room temp, overnight. The resulting mixture was separated between EtOAc (25 mL) and a 1 M HC1 solution (25 mL). The aqueous phase was back-extracted with EtOAc (2 x 25 mL). The combined organic phases were sequentially washed with water (2 x 25 mL) and a saturated NaCl solution (25 mL), dried (Mg,SQ4 and concentrated under reduced pressure to give M-metbM-1-bromobenzenesuifonamide as a white solid (2.8 g, 99%).

V°YVS

Step 2. Synthesis of 4-(3-(A-methylsuIfamoyl)phenyloxy)benzene
To a slurry of phenol (1.9 g, 20 mmol), K2C03 (6.0 g, 40 mmol), and CuI (4 g, 20 mmol) in
DMF (25 mL) was added Ar-methyl-3-bromobenzenesulfonamide (2.5 g, lOmmol), and the
resulting mixture was stirred at the reflux temp, overnight, cooled to room temp., and
separated between EtOAc (50 mL) and a 1 N.HCl solution (50 mL). The aqueous layer was
back-extracted with EtOAc (2 x 50 mL). The combined organic phases were sequentially
washed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgS04), and
conceicvt.T3.ted under reduced pressure. The residual art was. riurifted ty COVAVJW.
chromatography (30% EtOAc/70% hexane) to give 4-(3-(/V-
methylsulfamoyl)phenyloxy)benzene (0.30 g).

0,N

- Step 3. Synthesis of 4-(3-(ALmethylsu}farnoyl)phenyloxy)-l-nitrobenzene
To a solution of 4-(3-(/V-methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10°C was added NaNO; (0.097 g, 1.14 mmol) in portions over 5 min. The resulting solution was stirred at -10 °C for 1 h, then was allowed to warm to room temp., and was concentrated under reduced pressure. The residue was separated between EtOAc (10 mL) and water (10 mL). The organic phase was sequentially washed with water (10 mL) and a saturated NaCl solution (10 mL), dried (MgS04) and concentrated under reduced pressure to give 4-(3-(A*r-methylsulfamoyl)phenyloxy)-l -nitrobenzene (0.20 g). This material carried on to the next step without further purification.
Step 4. Synthesis of 4-(3-(/V-methylsulfarnoyl)phenyloxy)aniline
A slurry of 4-(3-(A/-methylsulfamoyl)phenyloxy)-l-nitrobenzene (0.30 g) and 10% Pd/C (0.030 g) in EtOAc (20 mL) was stirred under an H2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(Ar-methylsulfamoyl)phenyloxy)aniline (0.070 g).
A16. Modification of ©-ketones. Synthesis of 4-(4-(l-(W-
methoxy)iminoethyl)phenoxyaniline HC1 salt.
HC! *ft
H2N„

O
To a slurry of 4-(4-acetylphenoxy)aniIine HC1 salt (prepared in a manner analogous to Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0 mL) was added 0-methylhydroxylamine HCl salt (0.65 g, 7,78 mmol, 2.0 equiv.). The resulting solution was heated at the reflux temperature for 30 min, cooled to room temperature and concentrated under reduced pressure. The resulting solids were triturated with water (10 mL) and washed with water to give 4-(4-(l -(/V-methoxy)iminoethyl) phenoxyaniline HCl salt as a

fellow solid (0.85 g): TLC (50% EtOAc/50% pet. ether) R/0.78, 'H NMR (DMSO-d6) 5 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257.((M+H)+).
A17. Synthesis of ^-(co-SHyloxyalkyOamides. Synthesis of 4-(4-(2-(A/-(2-
Triisopropylsilyloxy)ethylcarbarnoyl)pyridyloxyaniHne.
-i'r
Step 1. 4-Chloro-Ar-(2-triisopropylsilyloxy)ethyIpyridine-2-carboxamide
To a solution of 4-chloro-Ar-(2-hydroxyethyl)pyridine-2-carboxamide (prepared in a manner analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp, then was concentrated under reduced pressure. The residue was separated between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried (MgSO-t), and concentrated under reduced pressure to afford 4-chloro-2-(N-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide as an orange oil (2.32 g, 88%). This material was used in the next step without further purification.
H;NXJ u « ^r
Step 2. 4-(4-(2-(iV-(2-Triisopropylsilyloxy)ethylcarbamoyI)pyridyloxyaniiine
To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF (8 mL) was added potassium rerr-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) in one portion causing an exotherm. When this mixture had cooled to room temperature, a solution of 4-chloro-2-(jV-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) in DMF (4 mL) was added followed by K2CO3 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was heated at 80 °C overnight. An additional portion of potassium rerr-butoxide (0.34 g, 3 mmol, 0.5 equiv.) was then added and the mixture was stirred at 80 °C an additional 4 h. The mixture v.as cooled to 0 °C with an ice/water bath, then water (approx. \ mL) was slowly added dropwise. The organic layer was extracted with EtOAc (3 x 10 mL). The combined

gjrganic layers were washed with a saturated NaCl solution (20 mL), dried (MgS04) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (Si02; 30% EtOAc/ 70% pet ether) to afford 4-(4-(2-(tf-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown oil (0.99 g, 38%).
A18. Synthesis of 2-PryidinecarboxyIate Esters via Oxidation of 2-
Methylpyridines. Synthesis of 4-(5-(2-
methoxycarbonyl)pyridyloxy)aniline.
Step 1. 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene.
A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), \ fIuorc-4-nitrobenzcne (9.S mL, 91.6 mmol, 1.0 equiv.), K2C03 (25 g, 183 mmol, 2.0 equiv.) in DMF (100 mL) was heated at the reflux temperature overnight. The resulting mixture was cooled to room temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed with water (2 x 100 mL) and a saturated NaCl solution ((100 mL), dried (MgSOt) and concentrated under reduced pressure to give 4-(5-(2-methyl)pyridyloxy)-l-nitrobenzene as a brown solid (12.3 g).

Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)-l-nitrobenzene.
A mixture of 4-(5-(2-methyi)pyridyloxy)-l -nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the reflux temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered , then concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The solution was treated with a cone HC1 solution (7 mL), then heated at the reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was separated between EtOAc (50 mL) and a IN NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were sequentially

gashed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgSOj) and concentrated under reduced pressure. The residue was purified by column chromatography (Si02; 50% EtOAc/50% hexane) to afford 4-(5-(2-methoxycaibonyl)pyridyloxy)-l-nitrobenzene (0.70 g).
O
Step 3. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)auiline.
A slurry of 4-(5-(2-methoxycarbonyI)pyridyloxy)-l-nitrobenzene (0.50 g) and 10% Pd/C (0.050 g) in a mixture of EtOAc (20 mL) and MeOH (5 mL) was placed under a H2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite4', and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCh; 70% EtOAc/30% hexane) to give 4-(5-t,2-methoxycarbonyl)pyridyloxy)aniline (0.40 g).
A19. Synthesis of co-Sulfonylphenyl Anilines. Synthesis of 4-(4-
Methylsulfonylphenyoxy)aniline.

02N v v ,£
O O
Step 1. 4-(4-Methyisulfonylphenoxy)-l-nitrobenzene: To a solution of 4-(4-
methylthiophenoxy)-l-nitrobenzene (2.0 g, 7.7 mmol) in CH2CI2 (75 mL) at 0 °C was slowly
added m-CPBA (57-86%, 4.0 g), and the reaction mixture was stirred at room temperature for
5 h. The reaction mixture was treated with a IN NaOH solution (25 mL). The organic layer
was sequentially washed with a IN NaOH solution (25 mL), water (25 mL) and a saturated
NaCl solution (25 mL), dried (MgS04), and concentrated under reduced pressure to give 4-
(4-methylsuIfonyiphenoxy)-l-nitrobenzene as a solid (2.1 g).
Step 2. 4-(4-MethylsulfonyIphenoxy)-l-aniIine: 4-(4-Methylsulfony!phenoxy)-l-
nitrobenzene was reduced to the aniline in a manner analogous to that described in Method A IS. step 3.

*B, Synthesis of Urea Precursors
Bl_ General Method for the Synthesis of Isocyanates from Anilines Using
CDI. Svnthesis of 4-Bromo-3-(trifluoromethyl)phenyI Isocyanate.

NH2«HCI
Step 1. Synthesis of 4-bromo-3-(trifluoromethyI)aniline HC1 salt
To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et20 (500 mL) was added an HC1 solution (1 M in Et20; 300 mL) dropwise and the resulting mixture was stirred at room temp, for 16 h. The resulting pink-white precipitate was removed by filtration and washed with Et20 (50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline HC1 salt (73 g , 98%).

NCO
Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate
A suspension of 4-bromo-3-(trifluoromethyl)aniline HC1 salt (36.8 g, 133 mmol) in toluene (278 mL) was treated with trichloromethyl chloroformate dropwise and the resulting mixture was heated at the reflux temp, for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mL), then concentrated under reduced pressure. The residue was treated with CH2CI2 (500 mL), then concentrated under reduced pressure. The CH2CI2 treatment/concentration protocol was repeated and resulting amber oil was stored at -20 °C for 16 h, to afford 4-bromo-3-(trifluoromethyl)phenyl isocyanate as a tan solid (35.1 g, 86%): GC-MS m/z 265 (M+).
C. Methods of Urea Formation
Cla. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of A^-(4-Chloro-3-(trifluoromethyl)phenyl)-/V'-(4-(2-(/V-methylcarbamoyl)-4-pyridyloxy)pheoyl) Urea

A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol) in CH2CI2 (35 mL) was added dropwise to a suspension of 4-(2-(/*/-methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH2C12 (35 mL) at 0 °C. The resulting mixture was stirred at room temp, for 22 h. The resulting yellow solids were removed by filtration, then washed with CH2CI2 (2 x 30 mL) and dried under reduced pressure (approximately 1 mmHg) to afford vV-(4-chloro-3-(trifluoromethyl)phenyl)-jV'-(4-(2-(yV-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as an off-white solid (28.5 g, 93%): mp 207-209 °C; 'H-NMR (DMSO-d6) 5 2.77 (d, 7=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, 7=2.5 Hz, 1H), 7.62 (m, 4H), 8.11 (d, 7=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s. 1H), 9.21 (s, 1H); HPLC ES-MS irv'z 465 ((M+H)+).
Clb. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of A^-(4-Bromo-3-(trifluoromethyl)phenyl)-yV-(4-(2-(7V-methylcarbamoyl)-4-pyridyloxy)phenyl)Urea
CF3 O
KK) U
N N H H
A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method Bl, Step 2; 8.0 g, 30.1
mmol) in CH2CI2 (80 mL) was added dropwise to a solution of 4-(2-(7V-methylcarbamoyl)-4-
pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH2C12 (40 mL) at 0 °C. The
resulting mixture was stirred at room temp, for 16 h. The resulting yellow solids were
removed by filtration, then washed with CH2CI2 (2 x 50 mL) and dried under reduced
pressure (approximately 1 mmHg) at 40 °C to afford jV-(4-bromo-3-(trifluoromethyl)pheny 1 )-
/V'-(4-(2-(yV-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-yellow solid (13.2 g.
90%): mp 203-205 °C; 'H-NMR (DMSO-d6) 5 2.77 (d, 7=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d.
7=2.5 Hz, IH), 7.58 (m, 3H), 7.77 (d, 7=8.8 Hz, 1H), 8.11 (d, 7=2.5 Hz, JH). 8.49 (d. 7=5.5
Hz,- lH),8.77(brd, lH),8.99(s, IH), 9.21 (s. IH); HPLC ES-MS m/z 509 ((M-H)').

General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of/V-(4-Chloro-3-(trifluoromethyl)phenyl)-A"-(2-methyl-4-(2-(N-methykarbamoyl)(4-pyridyloxy))phenyl) Urea
CF3 0
O f VJV^T NHMe

A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method A5; 0.11 g, 0.45 mmol) in CH2C12 (1 mL) was treated with Et3N (0.16 mL) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temp, for 6 d, then was treated with water (5 mL). The aqueous layer was back-extracted with EtOAc (3x5 mL). The combined organic layers were dried (MgSCU) and concentrated under reduced pressure to yield Ar-(4-chloro-3-(trifluoromethyl)phenyl)-/Vr'-(2 niethyl-4-(2-(N-mc;:hylcarbamoyl)(4-p^Tidyloxy))phenyi) irea as a brown oil ^0.11 g, 0.22 mmol): 'H NMR (DMSO-d6) 5 2.27 (s, 3H), 2.77 (d, 7=4.8 Hz, 3H), 7.03 (dd, 7=8.5, 2.6 Hz, 1H), 7.11 (d, .7=2.9 Hz, 1H), 7.15 (dd, 7=5.5, 2.6, Hz, 1H), 7.38 (d, 7=2.6 Hz, 1H), 7.62 (app d, 7-2.6 Hz, 2H), 7.84 (d, 7=8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50 (d, 7=5.5 Hz, 1H), 8.78 (q, 7=5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H)+).
Cld. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of /y-(4-Chloro-3-(trifluoromethyr)phenyl)-A"-(4-aminophenyI) Urea
CF3

To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in CH2CI2 (308 mL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The resulting mixture was stirred at room temp, for 1 h, treated with CH2G2 (100 mL), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc (110 mL) and MeOH (15mL), and the clear solution was washed with a 0.05 N HC1 solution. The organic layer was concentrated under reduced pressure to afford impure

%--(4-chloro-3-(trifiuoromethyl)phenyl)-jV'-(4-aniinophenyl) urea (3.3 g): TLC (100% EtOAc) R.y-0.72.
Cle. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of A-(4-Chloro-3-(trifluorornethyl)phenyI)-/V-(4-ethoxycarbonylphenyl) Urea
CF3 0
H H To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH2CI2 (30 mL) was added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution was stirred at room temp, overnight. The resulting slurry was diluted with CH2CI2 (50 mL) and filtered to afford A'-(4-chloro-3-(trifluoromethyl)phenyl)-yV'-(4-ethoxycarbonylphenyl) urea as a white solid (5.93 g, 97%): TLC (40% EtOAc/60% hexane) R/0.44.
Clf. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of A^-Chloro-S-ttrifluoromethyOphenylHV'-(3-carboxyphenyl) Urea
H H To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21g, 5.46 mmol) in CH2CI2 (8 mL) was added 4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76 mmol) and the resulting mixture was stirred at room temp, overnight, then treated with MeOH (8 mL), and stirred an additional 2 h. The resulting mixture was concentrated under reduced pressure. The resulting brown solids were triturated with a 1:1 EtOAc/hexane solution to give /V-(4-chloro-3-(trifluoromethyl)phenyl)-/Y'-(3-carboxyphenyl) urea as an off-white solid (1.21 g, 76%).
C2a. General Method for Urea Synthesis by Reaction of an Aniline with V./V'-
Carbonyl Diimidazole Followed by Addition of a Second Aniline.

Synthesis of/V-(2-Methoxy-5-(trifluoromethyl)pbenyl)-Ar'-(4-(2-(/V-methylcarbamoyl)-4-pyridyloxy)phenyI) Urea
CF3 0
9 ff TJYr NHMe

To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH2C12 (15 mL) at 0 °C
was added CDI (0.13 g). The resulting solution was allowed to warm to room temp, over 1 h,
was stirred at room temp, for 16 h, then was treated with 4-(2-(iV-methylcarbamoyI)-4-
pyridyloxy)aniline (0.18 g). The resulting yellow solution was stirred at room temp, for 72 h,
then was treated with H2O (125 mL). The resulting aqueous mixture was extracted with
EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCl solution
(100 mL), dried (MgS04) and concentrated under reduced pressure. The residue was
triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration
and washed with EtOAc. The fiitrate was concentrated under reduced pressure and the
residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to
50% EtOAc/50% hexane to 100% EtOAc) to give M(2-memoxy-5-(trifluoromethyl)phenyl)-
yV'-(4-(2-(Ar-methylcarbamoyI)-4-pyridyloxy)phenyl) urea as a light tan solid (0.098 g, 30%):
TLC (100% EtOAc) R/0.62; *H NMR (DMSO-d«) 5 2.76 (d, 7=4.8 Hz, 3H), 3.96 (s, 3H),
7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, 7=4.8 Hz, IH), 9.55 (s, 1 H); FAB-MS m/z 461
((M+H)*).

) C2b.

General Method for Urea Synthesis by Reaction of an Aniline with A',/V'-Carbonyl Diimidazole Followed by Addition of a Second Aniline. Symmetrical Urea's as Side Products of a tyA/'-Carbonyl Diimidazole Reaction Procedure. Synthesis of Bis(4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea
o o
MeHN-AY^Y°Y^ o ff"Y°Y'V^NHMe
"V kJWU U
H H

•To a stirring solution of 3-amino-2-methoxyquinoIine (0.14 g) in anhydrous CH2CI2 (15 mL) at 0 C was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over 1 h then was stirred at room temp, for 16 h. The resulting mixture was treated with 4-(2-(/V-methylcarbamoyl)-4-pyridyloxy)anilme (0.18 g). The resulting yellow solution stirred at room temp, for 72 h, then was treated with water (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with a saturated NaCl solution (100 ml), dried (MgSO^j) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis(4-(2-0V-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) R/0.50; lH NMR (DMSO-d6) 6 2.76 (d, J=5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, >5.4 Hz, 1H), 8.75 (d, y-4.8 Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m/r 513 ((M+H)+).
C2c. General Method for the Synthesis of Ureas by Reaction of an Isocyanate
with an Aniline. Synthesis of Ar-(2-Methoxy-5-(trifluoromethyl)phenyWv'-(4-(l,3-dioxoisoindolin-5-yloxy)pheny!) Urea
u H H
O'
To a stirring solution of 2-methoxy-5-(trifluoromethyi)phenyl isocyanate (0.10 g, 0.47 mmol)
in CH2CI2 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-l,3-dione (Method A3, Step
3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h, then was
treated with CH2CI2 (10 mL) and MeOH (5 mL). The resulting mixture was sequentially
washed with a IN HCl solution (15 mL) and a saturated NaCl solution (15 mL), dried
(MgS04) and concentrated under reduced pressure to afford N-(2-methoxy-5-
(trifluoromethyl)phenyl-iV'-(4-(l13-dioxoisoindolm-5-yloxy)phenyl) urea as a white solid (0.2
g, 96%): TLC (70% EtOAc/30% hexane) R/0.50; 'H NMR (DMSO-d6) 5 3.95 (s, 3H), 7.31-
7.10 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H),
[{.27(brs. IH); HPLC ES-MS 472.0 ((M+Hf. 100%).

General Method for Urea Synthesis by Reaction of an Aniline with N,N'-Carbonyl Diimidazole Followed by Addition of a Second Aniline. Synthesis of iV-(5-(rerr-Buryl)-2-(2,5-dimethylpyrrolyl)phenyl)-.'V'-(4-(2-(A^-methylcarb?moyl)-4-pyridyloxy)phenyl) Urea

To a stirring solution of CDI (0.21g, 1.30 mmol) in CH2CI2 (2 mL) was added 5-(/err-butyl)-2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one portion. The resulting mixture was stirred at room temp, for 4 h, then 4-(2-(Ar-methylcarbamoyi)-4-pyridyloxy)aniline (0.065 g, 0>267mnol) was then added in one portion The resulting mixture was heated at 36 °C overnight, then cooled to room temp, and diluted with EtOAc (5 mL). The resulting mixture was sequentially washed with water (15 mL) and a IN HC1 solution (15mL), dried (MgSO-O, and filtered through a pad of silica gel (50 g) to afford ;V-(5-(/e«-butyl)-2-(2,5-dimethylpyrfolyl)phenyl)-A^'-(4-(2-(Af-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc/60% hexane) R/0.24; lH NMR (acetone-dfl) 6 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J=4.8Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, 7=5.4Hz, 1H), 8.57 (d, 7=2.1Hz,■ 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M+H)+, 100%).
C3. Combinatorial Method for the Synthesis of Diphenyl Ureas Using
Triphosgene
One of the anilines to be coupled was dissolved in dichloroethane (0.10 M). This solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a bis(trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The vial was capped and heat at 80 °C for 5 h, then allowed to cool to room temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 mL. 1.0 equiv), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting

Mixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.
C4. General Method for Urea Synthesis by Reaction of an Aniline with Phosgene Followed by Addition of a Second Aniline. Synthesis of yV-(2-Methoxy-5-(trifluoromethyl)pbenyl)-iV'-(4'(2-(N-methykarbamoyl)-4-pyridyioxy)phenyl) tjrea
£
CF3 O
NxNXJ U
H H
To a stirring solution of phosgene (1.9 M in toluene; 2.07 mL0.21g, 1.30 mmol) in CH^Ci: (20 mL) at 0 °C was added anh pyridine (0.32 mL) followed by 2-methoxyo-(tnfluoromethyl)aniline (0.75 g). The yellow solution was allowed to warm to room temp during which a precipitate formed. The yellow mixture was stirred for 1 h, then concentrated under reduced pressure. The resulting solids were treated with anh toluene (20 mL) followed by 4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline (prepared as described in Method A2; 0.30 g) and the resulting suspension was heated at 80 °C for 20 h, then allowed to cool to room temp. The resulting mixture was diluted with water (100 mL), then was made basic with a saturated NaHCC>3 solution (2-3 mL). The basic solution was extracted with EtOAc (2 x 250 mL). The organic layers were separately washed with a saturated NaCl solution, combined, dried (MgSO
D. Interconversion of Ureas
Dla. Conversion of co-Aminophenyl Ureas into co-(Aroylamino)phenyl Ureas.
Synthesis of Ar-(4-Chloro-3-((tnfluoromethyI)phenyO-iV,-(4-(3-methoxycarbonylphenyl)carboxyaminopbenyl) Urea

CF3
H H To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-jV'-(4-aininophenyl) urea (Method Cld; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 g, 1.38 mmol), HOBT«H20 (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added EDCI *HC1 (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp, overnight, diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a saturated NaHC03 solution (25 mL). The organic layer was dried (Na2SC4) and concentratec unde; reduced pressure. The resulting solids were triturated with an EtOAc solution (80% EtOAc/20% hexane) to give A/,-(4-chloro-3-((trifluoromethyl)phenyl)-7v"'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122; TLC (80% EtOAc/20% hexane) R/0.75.
Dlb. Conversion of co-Carboxyphenyl Ureas into (o-(Arylcarbamoyl)phenyl
Ureas. Synthesis of ;V-(4-Chloro-3-((trifluoromethyl)pbenyI)-iV'-(4-(3-methylcarbamoylphenyl)carbamoylphenyl) Urea
CF3 O

To a solution of /vr-(4-chloro-3-((trifluoromethyl)phenyl)-Af'-(4-(3-methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBT*H20 (0.14 g, 1.07 mmol), and N-methylmorpholine (0.5mL, 1.07 mmol) in DMF (3 mL) at 0 °C was added EDCI-HCl (0.10 g, 0.53 mmol). The resulting mixture was allowed to warm to room temp, and was stirred overnight. The resulting mixture was treated with water (lOmL), and extracted with EtOAc (25 mL). The organic phase was concentrated

under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane to 10% MeOH/90% EtOAc) to give /V-(4-chloro-3-((trifiuoromethyl)phenyI)-,V'-(4-(3--methylcarbamoylphenyl)carbamoylphenyl) urea as a white solid (0.097 g, 41%): mp 225-229; TLC (100% EtOAc) R/0.23.
Die. Combinatorial Approach to the Conversion of ca-Carboxyphenyl Ureas
into co-(AryIcarbamoyI)pheny! Ureas. Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyI)-/V'-(4-(N-(3-(N-(3-pyridyI)carbamoyI)phenyl)carbamoyl)phenyl) Urea

A mixture of Ar-(4-chloro-3-((trifluoromethyl)phenyl)-/Y'-(3-carboxyphenyl) urea (Method Clf; 0.030 g, 0.067 mmol) and Ar-cyclohexyl-Ar'-(methylpolystyrene)carbodiimide (55 mg) in 1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CH2CI2 (1 M; 0.074 mL, 0.074 mmol). (In cases of insolubility or turbidity, a small amount of DMSO was also added.) The resulting mixture was heated at 36 °C overnight. Turbid reactions were then treated with THF (1 mL) and heating was continued for 18 h. The resulting mixtures were treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting mixture was stirred at 36 °C for 72 h, then cooled to room temp, and filtered. The resulting solution was filtered through a plug of silica gel (1 g). Concentration under reduced pressure afforded JV-(4-chloro-3-((trifluoromethyl)phenyl)-//'-(4-(N-(3-(N-(3-
pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70% EtOAc/30% hexane) R/0.12.
D2. Conversion of co-Carboalkoxyaryl Ureas into co-Carbamoylaryl Ureas.
Synthesis of A/-(4-Chloro-3-((trifluoromethyl)pbenyl)-/V'-(4-(3-methylcarbamovlphenyl)carboxyaminophenyl) Urea

To a sample of //-(4-chlorO-3-((trifluoromethyl)phenyl)-Ar'-(4-(3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 mL, \ .7 mmol) ar^d the resultog, rapture, was stared at CQQOI tsm$. civemL^bA, *&&& cxx>£, D3. Conversion of w-Carboalkoxyaryl Ureas into co-Carboxyaryl Ureas.
Synthesis of Ar-(4'Chloro-3-((trifluoromethyl)phenyl)-7V'-(4-carboxypbenyl) Urea
H H To a slurry of /v'-(4-chloro-3-((trifluoromethyl)phenyl)-Ar'-('*-ethoxycarbonylphenyl) urea (Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH solution (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated at the reflux temp, for 12 h, cooled to room temp., and concentrated under reduced pressure. The residue was diluted with water (50 mL), then treated with a 1 N HCl solution to adjust the pH to 2 to 3. The resulting solids were collected and dried under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-iV'-(4-carboxyphenyl) urea as a white solid (5.05 g, 92%).
D4. General Method for the Conversion of co-AIkoxy Esters into m-Alkyl Amides. Synthesis of/V-(4-Chloro-3-((trifiuoromethyl)pheny!)-A^'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyI)Urea
CF3 O
^ D O°tf0H

ibtep 1. Synthesis of AH4-Chloro-3-(trifluoromethyl)plienyI)-jV'-((4-(3-(5-
carboxypyridyl) oxyphenyl) Urea
yV-(4-Chloro-3-(trifluoromethyl)phenyl)-jV'-((4-(3-(5-methoxycarbonylpyridyl)o.xypheny!)
urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-(3-(5-
methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a manner analogous to Method
Cla. A suspension of A/'-(4-chloro-3-(trifluoromethyl)phenyl)-Ar'-((4-(3-(5-
methoxycarbonylpyridyl)oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and was stirred at room temp, for
1 h. The resulting mixture was adjusted to pH 5 with a 1 N HC1 solution. The resulting
precipitate was removed by filtration and washed with water. The resulting solids were
dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced
pressure. The EtOH/concentration procedure was repeated twice to give /V-(4-chloro-3-
^nfluoromethyl)phenyl)-Ar'-((4-(3-(5-cirboxypyridyl) oxyphenyl) urea (0.18 Z- 71%).
H H
Step 2. Synthesis of Ar-(4-chloro-3-(trinuoromethyI)phenyl)-Ar'-((4-(3-(5-(2-
dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea
A mixture of jV-(4-chloro-3-(trifluoromethyl)phenyl)-/vf'-((4-(3-(5-
carboxypyridyl)oxyphenyl) urea (0.050 g, 0.011 mmol), A^A^-dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), W-methylmorpholine (0.035 g, 0.28 mmol), and EDCI'HCl (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room temp, overnight. The resulting solution was separated between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (35 mL), dried (MgSCX) and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CH2G2 (approximately
2 mL). The resulting solution was treated with Et20 dropwise to give yV-(4-chloro-3-
(trifluoromethyl)phenyl)-Ar'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl)
urea as a white precipitate (0.48 g, 84%: 'H NMR (DMSO-d6) 5 2.10 s, 6H), 3.26 (s, H), 7.03
(d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, IH), 8.43 (s, IH), 8.58 (t, IH), 8.69 (s, 1 H). 8.90
(s, IH), 9.14 (s, IH); HPLC ES-MS m/z 522 ((M+H)*).

General Method for the Deprotection of yV-(©-Silyloxyalkyl)amides. Synthesis of iV-(4-Chloro-3-((trifluoromethyl)phenyl)-Ar'-(4-(4-(2-(JV-(2-bydroxy)ethylcarbamoyl)pyridyloxyphenyl) Urea.
CF3 0 H H To a solution of A^-(4-chloro-3-((trifluoromethyl)phenyl)-iV'-(4-(4-(2-(//-(2-triisopropylsilyloxy) ethylcarbamoyl)pyridyloxyphenyl) urea (prepared in a manner analogous to Method CI a; 0.25 g, 0.37 mxnol) in anh THF (2 mL) was tetrabutylammonium fluoride (1.0 M in THF; 2 mL). The mixture was stirred at room temperature for 5 min, then was treated with water (10 mL). The aqueous mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh; gradient from 100% hexane to 40% EtOAc/60% hexane) to give A^(4-chloro-3-((trifluoromethyl)phenyl)-jV'-(4-(4-(2-(yV-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).
Listed below are compounds listed in the Tables below which have been synthesized according to the Detailed Experimental Procedures given above:
Syntheses of Exemplified Compounds
(see Tables for compound characterization)
Entry 1: 4-(3-Af-Methylcarbamoylphenoxy)aniline was prepared according to Method A13. According to Method C3, 3-/ert-butylaniline was reacted with bis(trichloromethyl)carbonate followed by 4-(3-/V-Methylcarbamoylphenoxy)aniline to afford the urea.
Entry 2: 4-Fluoro-l-nitrobenzene and /7-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-l-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acelylphenoxy)aniline. According to Method C3, 3-terf-butylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea.

[Entry 3: According to Method C2d, 3-ter;-butylaniline was treated with.CDI, followed by 4-(3^V-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea.
Entry 4: 5-^rf-Butyl-2-methoxyaniline was converted to 5-/err-butyl-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-yV-Methylcarbamoylphenoxy)aniline, prepared according to Method A13, was reacted with the isocyanate according to Method CI a to afford the urea.
Entry 5: According to Method C2d, 5-rerr-butyl-2-methoxyaniline was reacted with CD! followed by 4-(3-Ar-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea.
Entry 6: 5-(4-Aminophenoxy)isoindoline-l,3-dione was prepared according to Method A3. According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI followed by 5-(4-aminophenoxy)isoindoline-l,3-dione to afford the urea.
Entry 7: 4-(l-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12. According to Method 2d, 5-re/-:-butyl-2-methoxyaniline was reacted with CDI followed by 4-(l-oxoisoindolin-5-yloxy)aniline to afford the urea.
Entry 8: 4-(3-Ar-Methylcarbamoylphenoxy)aniline was synthesized according to Method A13. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI followed by 4-(3-/V-methylcarbamoylphenoxy)aniline to afford the urea.
Entry 9: 4-Hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine to give 4-(4-acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to Method A8, Step 4, 4-{4-acetylphenoxy)-5-nitropyridine was reduced to 4-(4-acetylphenoxy)o-aminopyridine. 2-Methoxy-5-(trifluoromethyl)aniline was converted to 2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method Bl. The isocyanate was reacted with 4-(4-acetylphenoxy)-5-aminopyridine according to Method Cla to afford the urea.

iEntry 10: 4-F\uoro-l-nitrobenzene and />hydToxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-l-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline. According to Method C3, 5-(trifluoromethyl)-2-methoxybutylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea.
Entry 11: 4-Chloro-A/-methyl-2-pyridinecarboxarnide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3-(-2-(ALmethylcarbarnoyl)-4-pyridyloxy)aniline. According to Method C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(-2-(//-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 12: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyndinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3-(2-carbamoyl~4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 13: 4-Chloro-Ar-methyl-2-pyridinecarbbxamide was synthesized according to Method A2, Step 3b. 4-Chloro-iV-methyl-2-pyridinecarboxamide was reacted with 4-arainophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI followed by 4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 14: 4-Chloropyridine-2-carbonyI chloride HC1 salt was reacted with ammonia according to Method A2, Step 3b to form 4-chioro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenoi according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-carbamoyl-4-pyndyloxy)aniline. According ic Meihod

^HC4, 2-methoxy-5-(trifluoromethyl)ariiline was reacted with phosgene followed by 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 15: According to Method C2d, 5-(triflouromethyl)-2-methoxyaniline was reacted with CDI followed by 4-(3-Af-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method AS, to afford the urea.
Entry 16: 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized according to Method A5. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. The isocyanate was reacted with 4-(2-(7V-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to Method Clc to afford the urea.
Entry 17: 4-(2-(Af-Methylcarbajnoyl)-4-pyridyloxy)-2-chloroaniline was synthesized
according to Method A6. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-
(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline according to Method Cla to afford the urea.
Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro-Ar-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(Ar-methylcarbamoyI)-4-pyridyloxy)-4-methylaniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluorornethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3-(2-(yV-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to Method C1 a to afford the urea.
Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to
Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted
with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyI)-4-
pyridyloxy)aniline. 5-{Trifluoromethyl)-2-methoxyaniline was converted into 5-
([rifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(TrifluoromethyD-

gUTiethoxyphenyl isocyanate was reacted with 4-(2-(jV-ethylcarbamoyl)-4-pyndyloxy)aniline according to Method C1 a to afford the urea.
Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-M-methyi-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(^-methylcarbamoyI)-4-pyridyloxy)-3-chloroaniline. 5-(Trifluoromethy!)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(TrifIuoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)-3-chIoroaniline according to Method C1 a to afford the urea.
Entry 21: 4-(4-Methylthiophenoxy)-l -nitrobenzene was oxidized according to Method A19, Step 1 to give 4-(4-methylsuIfonyiphenoxy)-l-nitrobenzene. The nitrobenzene was reduced according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-l-aniline. According to Method CI a, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-methylsulfonylphenoxy)-l-aniline to afford the urea.
Entry 22: 4-(3-carbamoylphenoxy)-l -nitrobenzene was reduced to 4-(3-
carbamoylphenoxy)aniline according to Method A15, Step 4. According to Method CI a, 5-
(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-
carbamoylphenoxy)aniline to afford the urea. •
Entry 23: 5-(4-Aminophenoxy)isoindoline-l,3-dione was synthesized according to Method A3. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-l,3-dione according to Method C1 a to afford the urea.
Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according
to Method A2, Step 3b. The resulting 4-chloro-/V.A'-dimethyl-2-pyridinecarbo.vamide uas
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-l-V\-
dimethylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyanilmo \\ as

converted into 5-(trifiuoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-. ™(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(/v./V-dimethylcarbamoyl)-4-pyridyloxy)aniline according to Method CI a to afford the urea.
£ Entry 25: 4-(l-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12. 5-{Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-(l-oxoisoindolin-5-yloxy)aniline according to Method C2d to afford the urea.
Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to i Method A13, Step 1 to give .4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was convened to the 4-(4-(l-(vY-methoxy)iminoethyl)phenoxyaniline HC1 salt according to Method A16. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(tnfluoromethyl)-2-me:hoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-rnethoxyphenyl isocyanate was reacted with 4-(4-(l-(Ar-methoxy)iminoethyl)phenoxyaniline HC1 salt to Method C1 a to afford the urea.
Entry 27: 4-Chloro-Ar-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-(2-(Ar-methylcarbamoyl)phenylthio)aniline according to Method Cla to afford the urea.
Entry 28: 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-dione was synthesized according to Method A9. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-l,3-dione according to Method CI a to afford the urea.
Entry 29: 4-Chloro-/V-methylpyridinecarboxamide was synthesized as described in Meihod A2. Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method

-\2, Step 4 to give 3-(4-(2-(Af-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethy!)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3-(4-(2-(Ar-methylcarbamoyl)phenylthio)aniline according to Method CI a to afford the urea
Entry 30: 4-Chloropyridine-2-carbonyI chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-yV-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-{A'-isopropylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluorornethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-rnethoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(/V-isopropylcarbamoyl)-4-pyridyloxy)aniline according to Method CI a to afford the urea.
Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 5-(Trifiuoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method CI a to afford the urea. Ar-(5-(Trifluoromethyl)-2-methoxyphenyl)-//'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the amide according to Method D4, Step 2.
Entry 32: 4-(3-(5-MethoxycarbonyI)pyridyloxy)aniline was synthesized according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. A45-(Trifluoromethyl)-2-methoxyphenyl)-A'-(4-(3-{5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to afford the amide.

ffcitry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluorornethyl)-2-methoxyphenyi isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method CI a to afford the urea. M(5-(Trifluoromethyl)-2-methoxyphenyI)-AT-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with ^N-dimethylethylenediamine according to Method D4, Step 2 to afford the amide.
Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifiuoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyi)-2-methoxypher.yI isocyanate according to Method Clf to afford .-V-p-(trifluoromethyl)-2-methoxyphenyl)-jV'-(3-carboxyphenyl) urea, which was coupled with 3-aminopyridine according to Method Die.
Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(triftuoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-{5-(trifluoromethyO^-methoxyphenyl)-/^'-(3-carboxyphenyl) urea, which was coupled with N-(4-fluorophenyl)piperazine according to Method Die.
Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyi isocyanate according to Method Clf to afford /V-(5-(trifluoromethyl)-2-methoxyphenyl)-yV"-(3-carboxyphenyl) urea, which was coupled with 4-fluoroaniline according to Method Die.
Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifluoromethyl)-2-methoxyaniline was convened into 5-(trifluoromethyl)-2-methoxyphenyl

isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-/V'-(3-carboxyphenyI) urea, which was coupled with 4-(dimethylamino)aniline according to Method Die.
Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyI)-2-methoxypheny! isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-iV'-(3-carboxyphenyl) urea, which was coupled with 5-amino-2-methoxypyridine according to Method Die.
Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All 5-(Trifluorornethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford /v'-(5-(trifluoromethyl)-2-methoxyphenyI)-Af'-(3-carboxyphenyl) urea, which was coupled with 4-morpholmoaniline according to Method Die.
Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5-(trifluoromethyO^-methoxyphenyl^'-C^-carboxyphenyl) urea, which was coupled with .V-(2-pyridyl)piperazine according to Method Die
Entry 41: 4-(3-{jV-Methylcarbamoyl)phenoxy)aniline was synthesized according to Method A13. According to Method C3, 4-chloro-3-(trifluoromethyl)aniline was converted to the isocyanate, then reacted with 4-(3-(/V-Methylcarbamoyl)phenoxy)aniline to afford the urea.

%Entry 42; 4-(2-/V-Methylcarbamyl-4-pyridyloxy)aniline was synthesized according to ethod A2. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-/V-methylcarbamyl-4-pyridyloxy)aniline according to Method Cla to afford the urea.
s Entry 43: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 44: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(2-carbamoyl-4-pyridyloxy)aniIine. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Entry 45: 4-Chloro-Ar-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(Ar-methylcarbamoyl)-4-pyridyloxy)aiiiline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 46: 5-(4-Aminophenoxy)isoindoline-l,3-dione was synthesized according to Method A3. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-l,3-dione to afford the urea.
Entry 47: 4-(2-(A^Methylcarbamoyl)-4-pyridyloxy)-2-rnethylaniline was synthesized according to Method A5. According to Method Clc, 4-chIoro~3-(trifiuoromethy!)pheny! isocyanate was reacted with 5-(4-ammophenoxy)isoindoiine-l,3-dione to afford the urea.

Aatry 48: 4-(3-j Entry 49: 4-(2-(Ar-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. According to Method CI a, 4-chloro-3-(trifluoromethyl)phenyi isocyanate was reacted with 4-(2-(ALmethylcarbamoyl)-4-pyridyloxy)-2-chloroanihne to afford the urea.
Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro-/vr-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(//-methylcarbamoyl)-4-pyridyloxy)-4-methylaniIine. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2^.V-methylcarbamoyl)-4-pyridyIoxy)-4-methylaniline to afford the urea.
Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-iV-ethyI-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(Ar-ethylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(.A/-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 52: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-./V-rnethyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(A;-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Entry 53: 4-(4-Methylthiophenoxy)-l-nitrobenzene was oxidized according to Method A19, Step 1 to give 4-(4-methylsulfonylphenoxy)-l-nitrobenzene. The nitrobenzene was reduced according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-l -aniline. According to Method Cla, 4-chloro-3-(tnfiuoromethyl)phenyl isocyanate was reacted with 4-
^Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to
Method A15, Step 1 to afford /V-methyl-4-bromobenzenesulfonamide. /V-Methyi-4-
bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to
afford 4-(4-(Af-methylsulfamoyl)phenoxy)benzene. 4-(4-(/V-
Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N-methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3. 4-(4-(Ar-Methylsulfamoyl)phenoxy)-1 -nitrobenzene was reduced to 4-(4-Ar-methylsulfamoyl)phenyloxy)aniline according to Method A15, Step 4. According to Method Cla, 4-chloro-3-(trifluoromethy!)phenyl isocyanate was reacted with 4-(3-Af-methylsulfamoyl)phenyloxy)aniline to afford the urea.
Entry 55: 5-Hydroxy-2-methylpyridine was coupled with l-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-l -nitrobenzene. The methylpyridine was oxidized according to the carboxy'ic acid, then esterified according to Method A18, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-nitrobenzene. The nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to Method C1 a to afford the urea.
Entry 56: 5-Hydroxy-2-methylpyridine was coupled with l-fluoro-4-nitrobenzene according
to Method A18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene. The
methylpyridine was oxidized according to the carboxylic acid, then esterified according to
Method A18, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-nitrobenzene. The
nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-
methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3-
(trifluoromethyl)phenyl isocyanate according to Method Cla to give ;V-(4-chloro-3-
(trifluoromethyl)phenyl)-A'"-(4-(2-(methoxycarbonyl)-5-pyridyloxy)phenyl) urea. The
methyl ester was reacted with methylamine according to Method D2 to afford /vf-(4-chloro-3-(trifluoromethyl)phenyl)-iV'-(4-(2-(iV-methylcarbamoyI)-5-pyridyloxy)phenyl)urea.
Entry 57: -V-(4-Chloro-3-(trifluoromethyl)phenyl-/V'-(4-aminophenyl) urea was prepared according to Method Cld. /V-(4-Chloro-3-{tnfluoromethyl)phenyl-/V'-(4-aminophenyl) urea was coupled with wo/jo-methyl isophthalate according to Method Dla to afford the urea.

Entry 58: Af-(4-Chloro-3-(trifluoromethyl)phenyI-A'-{4-aminopheny!) urea was prepared
according to Method Cld. A^-(4-Chloro-3-(trifluoromethyl)phenyl-/V'-(4-aminophenyl) urea
was coupled with mono-methyl isophthalate according to Method Dla to afford yV-(4-chloro-
r 3-(trifluoromethyl)phenyl-Ar'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea.
According to Method D2, Af-(4-chloro-3-(trifluoromethyl)phenyl-/V-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea was reacted with methylamine to afford the corresponding methyl amide.
/ Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,Ar-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(Ar,/V-dimethy'carbamoyl)-4-pyridyloxy)anilirie. According to Method Cla. 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(iV,Ar-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was convened to the 4-(4-(l-(//-methoxy)iminoethyI) phenoxyaniline HC1 salt according to Method A16. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-acetylphenoxy)aniline to afford the urea.
Entry 61: 4-(3-Carboxyphenoxy)-1 -nitrobenzene was synthesized according to Method A13,
Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was ■ coupled with 4-(2-
aminoethyl)morpholine according to Method A13, Step 3 to give 4-(3-(Ar-(2-
morpholinylethyl)carbamoyI)phenoxy)-l -nitrobenzene. According to Method A13 Step 4, 4-
(3-{Ar-(2-morpholinylethyl)carbamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(3-(JV-(2-
morpholinylethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-3-
(tnfluoromethyl)phenyl isocyanate was reacted with 4-(3-(/V-(2-
morpholinylethyl)carbamoyl)phenoxy)aniline to afford the urea.

Entry 62: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13,
btep 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with l-(2-aminoethyl)piperidine
according to Method A13, Step 3 to give 4-(3-(AL(2-piperidylethyl)carbamoyl)phenoxy)-l-
nitrobenzene. According to Method A13 Step 4, 4-(3-(A'-(2-
j piperidylethyl)carbamoyl)phenoxy)-l -nitrobenzene was reduced to 4-(3-(/V-(2-
piperidylethyl)carbamoyl)phenoxy)aniline. According to Method CI a, 4-chloro-3-
(triiluoromethyl)phenyl isocyanate was reacted with 4-(3-(/V-(2-
piperidylethyl)carbamoyl)phenoxy)aniIine to afford the urea.
Entry 63: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13,
Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with tetrahydrofurfurylamine
according to Method A13, Step 3 to give 4-(3-(/V-
(tetrahydrofurylmethyl)carbamoyl)phenoxy)-l-nitrobenzene. According to Method A13 Step
4, 4-(3-(//-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(3-
(yV-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method CI a, 4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(/V-
(tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford the urea.
Entry 64: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with 2-aminomethyl-l-ethylpyrrolidine according to Method. A13, Step 3 to give 4-(3-(/V-((l-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-l-nitrobenzene. According to Method A13 Step 4, 4-(3-(jV-((l-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(3-(Ar-((l-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(iV-((l-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniiine to afford the urea.
Entry 65: 4-Chloro-A»r-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Vlethod Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(.V-methylcarbamoyl)phenylthio)aniline to afford the urea.

Entry 66: 4-Chloropyridine-2-carbonyI chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-/V-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(iV-* isopropylcarbamoyl)-4-pyridyIoxy)aniline. According to Method CI a, 4-chloroo-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(/*/-isopropylcarbamoyi)-4-pyridyloxy)aniline to afford the urea.
Entry 67: Ar-(4-Chloro-3-(trifluoromethyl)phenyl-//'-(4-ethoxycarbonylphenyl) urea was
synthesized according to Method Cle. iV-(4-Chloro-3-(trifluorornethyl)phenyl-yV"-(4-
ethoxycarbonylphenyl) urea was saponified according to Method D3 to give /V-(4-chloro-3-
(trifluoromethyl)phenyl-/V"-(4-carboxyphenyl) urea. Af-(4-Chloro-3-(trifluoromethyl)phenyl-
yV'-(4-carboxyphenyl) urea was coupled with 3-methylcarbamoylaniline according to Method
Dlb to give Af-(4-chloro-3-(trifluoromethyl)phenyl-Ar'-(4-(3-
methylcarbamoylphenyl)carbamoylphenyl) urea.
Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-dione was synthesized according to Method A9. According to Method CI a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-l,3-dione to afford the urea.
Entry 69: 4-Chloro-/Y-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3-(4-(2-(yV-methylcarbamoyl)phenylthio)aniline. According to Method Cla, 4-chlon>3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(/V-methylcarbamoyl)phenylthio)aniline to afford the urea.
Entry 70: 4-(2-(N-(2-MorphoIin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A10. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyI isocyanate was reacted with 4-(2-(/V-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea.

4£ntry 71: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. .V-(4-Chloro-3-(trifluoromethyl)phenyl)-jV'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the amide.
Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-Af'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to affo-d the amide.
Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. yV-(5-(Trifluoromethyl)-2-methoxyphenyl)-A'"-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with A^jY-dimethylethylenediamine according to Method D4, Step 2 to afford the amide.
Entry 74: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with 2-
hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-/V-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-/V-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride,
followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(/V-(2-
triisopropylsilyloxy)ethyicarbarnoyl)pyridyloxyaniline. According to Method Cla, 4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(,V-(2-
triisopropylsilyloxy)ethylcarbamoyl) pyridyloxyaniline to afford A/-(4-chloro-3-((irifluoromethy!)phenyl)-yV'-(4-(4-(2-(jV-(2-triisopropylsilyloxy) ethylcarbamoyOpyridyloxyphenyl) urea.

^|ntry 75: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(tnfluorornethyl)phenyl lSocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Clf to afford the urea, which was coupled with 3-aminopyridine according to Method Die.
Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N-(4-acetylphenyl)piperazine according to Method Die.
Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4-fluoroaniline according to Method Die.
Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(tnfluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4-(dimethylamino)aniline according to Method Die.
Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N-phenylethylenediamihe according to Method Die.
Entry 80: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 2-methoxyethylamine according to Method Die.
Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Ch!oro-3-(tririuoromeihyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniIine

Recording to Method Clf to afford the urea, which was coupled with 5-amino-2-methoxypyridine according to Method Die.
Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-{trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4-morpholinoaniline according to Method Die.
Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with /V-(2-pyridyl)piperazine according to Method Die.
Entry 84: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with 2-
hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-/vr-(2-
triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-/V-(2-
triisopropyIsilyIoxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride,
followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(A/-(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method CI a, 4-chloro-
3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(/V-(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to give Ar-(4-chloro-3-
((trifluoromethyl)phenyl)-yV'-(4-(4-(2-(^-(2-
triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl) urea. The urea was deprotected according to Method D5 to afford /V-(4-chloro-3-((trifluoromethyl)phenyl)-.'V,-(4-(4-(2-(iV-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea.
Entry 85: 4-(2-(/Yr-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Bromo-3-(trifluoromethyl)anilme was converted to 4-bromo-3-(trifiuoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(/V-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

^"Entry 86: 4-(2-{A-MethyIcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized
according to Method A6. 4-Bromo-3-(trifluoromethyi)aniline was converted into 4-bromo-3-
(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4-
bromo-3~(trifiuoromethyl)phenyl isocyanate was reacted with 4-(2-(Ar-methylcarbamoyI)-4-
5 pyridyloxy)-2-chloroaniIine to afford the urea.
Entry 87: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-iV-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3-) (trifluoromethyl)aniline was converted into 4-bromo-3-(trifiuoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4-bromo-3-(trifiuoromethyl)phenyl isocyanate was reacted with 4-(2-(jV-methylcarbamoy])-4-pyridyloxy)-3-chloroaniline to afford the urea.
i Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-jV-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(Ar-ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo~3-(trifluoromethyl)aniIine was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(Ar-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 89: 4-Chioro-Af-methyl-2-pyridinecarboxaraide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method Cla, 4-bromo-3-(trifluoromethyI)phenyl isocyanate was reacted with 3-(-2-(yV-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 90: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted wiih 4-chloro-/V-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(Af-methylcarbamoyl)-4-pyridyloxy)-4-rnethylanilinc. 4-Bromo*3-

^trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(yV-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.
Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according
to Method A2, Step 3b. The resulting 4-chloro-iV,/V-dimethyl-2-pyridinecarboxamide was
reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(yV,/V-
dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was
converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(.V,Ar-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 92: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(Ar-methylcarbarnoyl)phenylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)pheny! isocyanate according to Method Bl. According to Method Cla, 4-brorno-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(N-methyIcarbarnoyl)phenylthio)aniline to afford the urea.
Entry 93: 4-Chloro-Ar-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3-{4-(2-(Ar-methylcarbamoyl)phenyUhio)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(A^rnethylcarbarnoyl)phenylthio)aniline to afford the urea.
Entry 94: 4-(2-(Ar-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A10. 4-8romo-3-(trifiuoromethyi)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-

bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(/V-(2-Morpholin-4-^lethyl)carbamoyl)pyridyloxy)aniline to afford the urea.
Entry 95: 4-(2-(iV-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Chioro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Ch]oro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(tnfluoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(7V-methylcarbarnoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 96: 4-(2-(Ar-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was convened into 4-chloro-2-methoxy-5-(trifluoroir.ethyl)phenyl isocyanate according to Method 3i. According to Method CI a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(Ar-methyIcarbamoyl)-4-pyridyloxy)-2-chloroaniline afford the urea.
Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-:hloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-{2-(N-methylcarbarnoyI)-4-pyridyloxy)-3-chloroaniline. 4-Chloro-2-methoxy-5-(trifiuoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifiuoromethyl)aniline was converted into 4-chloro-2-methoxy-5-[trifluoromethyOphenyl isocyanate according to Method Bl. According to Method CI a, 4-;hIoro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(/V-tnethylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Entry 98: 4-Chloro-iV-methy[-2-pvridinecarboxamide, which was synthesized according to
VIethod A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to
form 3-(-2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxyo-
|trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-rnetho\y-> ;trifluoromethy!)aniiine was converted into 4-chloro-2-methoxy-5-(tnfluoromcihyl)phen\ I isocyanate according to Method Bl. According to Method CI a, 4-chloro-2-metho\y-5-

V
fluoromethyl)phenyl isocyanate as was reacted with 3-{-2-(jV-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to
Method A2, Step 3b. The resulting 4-chloro-Ar-ethyl-2-pyridinecarboxamide was reacted
with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(//-ethylcarbamoyl)-4-
pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized
according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method CI a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyI isocyanate was reacted with 4-(2-(Ar-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethvlamine according to Method A2, Step 3b. The resulting 4-chloro-MAf-dimethyl~2-pyridinecarboxarnide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-dirnethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifiuoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(AC N-dimethyIcarbamoyl)-4-pyridyIoxy)aniIine to afford the urea.
Entry 101: 4-Chloro-//-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(Ar-methylcarbamoyl)-4-pyridyloxy)aniline. 2-Amino-3-methoxynaphthalene was synthesized as described Method Al. According to Method C3, 2-amino-3-methoxynaphthalene was reacted with bis(trichloromethyl) carbonate followed by 3-(-2-(JV-methylcarbamoyl)-4-pyridyloxy)aniline to form the urea.
Entry 102: 4-{2-(/V-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 5-rer/-ButyI-2-(2,5-dimethylpyrrolyl)aniline was synthesized according to

^Method A4. 5-rerr-Butyl-2-(2,5-dimethyIpyrroIyl)aniline was reacted with CDI followed by 4-(2-(jV-methylcarbamoyl)-4-pyridyloxy)aniline according to Method C2d to afford the urea.
Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-/vr-methyl-2-pyridinecarboxamide was reacted with 4-aminophenot according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b, reaction of 3-amino-2-methoxyquinoline with CDI followed by 4-(2-(N-methylcarbarnoyl)-4-pyridyloxy)aniline afforded bis(4-(2-(Ar-methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.
Listed in the Tables below are compounds which have been synthesized according to the Detailed Experimental Procedures given above:Tables
The compounds listed in Tables 1 -6 below were synthesized according to the general methods shown above, and the more detailed exemplary procedures are in the entry listings above and characterizations are indicated in the tables.

H'lbie 1.

3-ferr-Burylphenyl Ureas

«.X.i
N H

Entry R mp (°C) HPLC (min.) TLC TLC Solvent System Mass
Spec.
[Source] Synth. Method
1 0
>-NH
-o-o Me 0.22 50% EtOAc / 50% hexane 418
(M+H)+ (HPLC ES-MS) A13 C3
2 ^>° (M+H)+ (HPLC ES-MS) A13 C3
3 VNH 133-135 0.68 100% EtOAc 448
(M+H)+
(FAB) A8 C2d

Table 2.

5-ter/-Butyl-2-methoxyphenyI Ureas

OMe

Entry R mp (°C) HPLC (min.) TLC R, TLC Solvent System Mass
Spec.
[Source] Synth. Method
4 0 V-NH 5.93 448
(M+H)+ (HPLC ES-MS) A13
Bl
Cla
5 0 V-NH
-O"0"O"°"° 120-122 0.67 100% EtOAc 478
(M+H)+
(FAB) A8 C2d
6 VNH
0 0.40 50% EtOAc / 50% hexane 460
(M-H)-(HPLC ES-MS) A3 C2d

«TT

-O°-Q^

0.79

50% EtOAc / 50% hexane

446
(M+H)+ (HPLC ES-MS)

A12 C2d

Table 3.

OMe
5-(Trifluoromethyl)-2-methoxyphenyl Ureas

Entrv R mp (°C) HPLC (min.l TLC R. TLC Solvent System Mass
Spec.
[Source] Synth. Method
8 0
y-NH
-o-o * 250 (dec) 460
(M+H)+
(FAB) A13 C2a
9 (M+H)+ (HPLC ES-MS) A3 step
2,
A 8 step
4,
Bl,
Cla
10 -o° (M+H)+ (HPLC ES-MS) A13 C3
11 0.20 2% Et3N/ 98% EtOAc 461
(M+H)+ (HPLC ES-MS) A2 C4
12 —f~\ VNHJ 0.27 1%. Et3N/ 99% EtOAc 447
(M+H)+ (HPLC ES-MS) A2 C4
13 o
J-UH 0.62 100% EtOAc 461
(M+H)+
(FAB) A2 C2a
14 0 114-117 0.40 1% EON/ 99% EtOAc 447
(M+H)+
(FAB) A2 C4

.I15 0 V-NH
—f V °-\ /"OMe 232-235 0.54 100% EtOAc 490
(M+H)+
(FAB) AS C2d
16 0 Me >~NH 210-213 0.29 5%
MeOH
/ 45%
EtOAc
/ 50%
pet
ether 475
(M+H)+ (HPLC ES-MS) A5
Bl Clc
17 o
CI J—NH
-O-^-O1 Me 187-188 0.17 50% EtOAc / 50% pet ether 495
(M+H)+ (HPLC ES-MS) A6
Bl Cla
18 —/ V-Me V-NH2 0.48 100% EtOAc 475
(M+H)+ (HPLC ES-MS) A2 step
4,
Bl Cla
19 O V-NH 194-
196 0.31 5%
MeOH
/45%
EtOAc
/50%
pet
ether 475
(M+HK (HPLC ES-MS) A2
Bl Cla
20 0 CI V-NH 214-216 0.25 5%
MeOH
/ 45%
EtOAc
/ 50%
pet
ether 495
(M+H)+ (HPLC ES-MS) A2 Cla
21 -o°o\: 208-210 0.30 50% EtOAc / 50% hexane 481
(M+H)+ (HPLC ES-MS) Al9C2a
22 o
V-NH2 188-190 0.30 70% EtOAc / 50% hexane 447
(M+H)+ (HPLC ES-MS) A15. step 4, Cla
23 VNH
0 0.50 70% EtOAc / 30% hexane 472
(M+H)+
(FAB) A3
Bl Cla
24 0 Me 203-205 0.13 100% EtOAc 479
(M-H)* (HPLC ES-MS) A2 Bl Cla

25 -^>° (M'+H)+ (HPLC ES-MS) A12 C2d
26 MeO
-O-CK. 169-171 0.67 50% EtOAc / 50% pet ether 474
(M+H)+ (HPLC ES-MS) A13
step I,
A13 step
4,
A16,
Bl
Cla
27 o
VNH 218-219 0.40 50% EtOAc / 50% pet ether 477
(M+H)+ (HPLC ES-MS) A2 step
3b,
A2 step
4.
Bl,
Cla
28 V,NMe 0 212-214 0.30 40% EtOAc / 60% hcxane A9
Bl Cla
29 0.33 50% EtOAc / 50% pet ether 474
(M+H,+ (HPLC ES-MS) A2 step
3b,
A2 step
4,
Bl,
Cla
JO VNH
-O-O Pri 210-211 A2 Bl Cla
31 ov JVNH 210-204 0.43 10%
MeOH
/
CH2C1
2 A14 Bl Cla D4
32 o y-NH 247-249 0.57 10%
MeOH
/
CH2C1
2 AH Bl Cla D4
22 JVNH
—(f V-0—4, /) N-M€ W ^-N Me 217-219 0.07 10% MeOH
/
CH2CI
2 A14 Bl Cla D4

i 34 0
V-NH 0.11 70% EtOAc / 30% hexanc All Bl Clf Die
35 o
\_N
\=o 0.38 70% EtOAc / 30% hexane All Bl Clf Die
36 F—f V-NH 0.77 70% EtOAc / 30% hexanc All Bl Clf Die
37 N—{' V— NH 0.58 70% EtOAc / 30% hexane All Bl Clf Die
38 MeO-f V-NH
W l=o 0.58 70% EtOAc / 30% hexane All Bl Clf Die
39 0 N—f 7—NH W \=/ 1=0 0.17 70% EtOAc / 30% hexanc All Bl Clf Die
40 ^V^NHTVNH \=/ \_y \=/ C=0 0.21 70% EtOAc / 30% hexane All Bl Clf Die
Table 4. 3-(Trifluorometbyl)-4-chloroptaenyl Ureas
F

H H

Entry R mp f°C) HPLC (min.) TLC TLC Solvent System Mass
Spec.
[Source] Synth. Method
41 ov VNH 163-165 0.08 50% EtOAc/ 50% pet ether 464
(M+H)+ (HPLC ES-MS) A13 C3
42 0 >-NH 215 0.06 50% EtOAc/ 50% pet ether 465
(M+H)+ (HPLC ES-MS) A2 Cla
43 o 0.10 50% EtOAc/ 50% pet ether 451
(M+H)+ (HPLC ES-MS) A2 Cla
44 0.25 30% EtOAc/ 70% pet ether 451
(M+H)+ (HPLC ES-MS) A2 Cla
45 0.31 30% EtOAc/ 70% pet ether 465
(M+H)+ (HPLC ES-MS) A2 Cla
46 VNH
0 176-179 0.23 40% EtOAc/ 60% hexane 476
(M+H)+
(FAB) A3 Cla
47 0 Me r~NH 0.29 5%
MeOH/
45%
EtOAc/
50% pet
ether 478
(M+H)+ (HPLC ES-MS) A5 Clc
48 ^S-NH 206-209 A15 Cla
49 0 CI >~NH 147-151 0.22 50% EtOAc/ 50% pet ether 499
(M+H)+ (HPLC ES-MS) A6 Cla
50 —P V-Me VNH \= (M-rH)-(HPLC ES-MS) A2 Cla

T51 0 V-NH 187-
189 0.33 5%
MeOH/
45%
EtOAc/
50% pet
ether 479
(M+H)+ (HPLC ES-MS) A2 Cla
52 0 CI >-NH 219 0.18 5%
MeOH/
45%
EtOAc/
50% pet
ether 499
(M+H)+ (HPLC ES-MS) A2 Cla
53 -o°o-k 246-248 0.30 50% EtOAc/ 50% hexane 485
(M+H)+ (HPLC ES-MS) A19, Cla
54 Me 196-
200 0.30 70% EtOAc/ 30% hexane) 502
(M+H)+ (HPLC ES-MS) A15 Cla
55 0
Vo 228-230 0.30 30% EtOAc' 70% CH2C12 466
(M+H)+ (HPLC ES-MS)
56 x=/ N—' NH Me 238-245
57 ^-K-^P* 221-222 0.75 80% EtOAc/ 20% hexane 492
(M+H)+
(FAB) Cld Dla
58 ov VNH 247 0-35 100% EtOAc Cld Dla D2
59 0 Me
-o-oMe 198-200 0.09 100% EtOAc 479
(M+H)+ (HPLC ES-MS) A2 Cla
60 MeO
-o~cH 158-160 0.64 50% EtOAc/ 50% pet ether
61 ov JVNH
\—o 195-197 0.39 10% MeOH/ CH2C1 2 A13 Cla

62 ov JVNH 170-172 0.52 10% MeOH/ CH2C1 2 A13 Cla
63 0 168-171 0.39 10%
MeOH/
CH2CA
2 A13 Cla
64 0 Et, V-NH N^ 176-
177 0.35 10% MeOH/ CH2C1 2 A13 Cla
65 ov JVNH
-0~s-0 Me i so¬ns 487
(M+H)+ (HPLC ES-MS) A2 Bl Cla
66 ov
V-NH 155 A2
Cla
67 ox VNH 225-229 0.23 100% EtOAc Cle
D3
Dlb
68 Ny.NMe 0 234-236 0.29 40% EtOAc/ 60% hexane A9 Cla
69 ^=\ /=\ Me 0.48 50% EtOAc/ 50% pet ether 481
(M+H)+ (HPLC ES-MS)
70 0 V—NH
\—o 0.46 5%
MeOH/ 95% CH2C12 564
(M+H)+ (HPLC ES-MS) A10 Cla

171 0
VNH
-Q-°-Q "~M
^0 199-201 0.50 10%
MeOH/
CH2C1
2 A14 Cla D4
72 o
V-NH 235-237 0.55 10%
MeOH/
CH2C1
2 A14 Cla D4
73 o
-fV0HO ,N~Me
^^ ^—N Me 200-201 0.21 50% MeOH/ CH2C1 2 A14 Cla D4
74 o
-/Vo-O 0Si(PN)3 145-
148
75 (/~VNH 0.12 70% EtOAc/ 30% hexane 527
(M+H)+ (HPLC ES-MS) All Clf Die
76 0
Me—^
Q
V=o 0.18 70% EtOAc/ 30% hexane All Clf Die
77 F_fyNH
-o-o 0.74 70% EtOAc/ 30% hexane All Clf Die
78 N—f VNH
Me \=/ >=0 0.58 70% EtOAc/ 30% hexane All Clf Die

Table 5.

3-(Trifluoromethyl)-4-bronioPheny'Ureas
FJLF

o
H H

Br

Entry R mp TO HPLC (min.) TLC TLC Solvent System Mass
Spec.
[Source] Synth. Method
85 0.
VNH 186-
187 0.13 50% EtOAc/ 50% pet ether 509
(M+H)+ (HPLC ES-MS) A2 Bl Cla
86 0
ci VNH
-^y°-c/ Me \50-152 0.31 50% EtOAc/ 50% pet ether 545
(M+H)+ (HPLC ES-MS) A6 Bl Cla
87 o. ci VNH 217-219 0.16 50% EtOAc/ 50% pet ether 545
(M+H>+ (HPLC ES-MS) A2 Bl Cla
88 0.
VNH 183-184 0.31 50% EtOAc/ 50% pet ether 525
(M+H)+ (HPLC ES-MS) A2 Bl
Cia
89 0.21 50% EtOAc/ 50% pet
ether 511
(M+H)+ (HPLC ES-MS) A2 Bl Cla
90 — (M+H)+ (HPLC ES-MS) A2 Bl Cla
91 0V Me W 214-216 0.28 50% EtOAc/ 50% pet ether 522
(M+H)+ (HPLC ES-MS) A2 Bl Cla
92 VNH 0.47 50% EtOAc/ 50% pet ether 527
(M+H)+ (HPLC ES-MS) A2 step
3b.
A2 step
4,
Bl,
Cla
93 _/~A VNH \={ =( Me 0.46 50% EtOAc/ 50% pet ether 527
(M+H)+ (HPLC ES-MS) A2 step
3b.
A2 step
4.
Bl.
Cla

94

145- 0.41 5% AlO
150 MeOH/
95%
CH2C12 Bl Cla

Table 6.

OMe
5-(TrifluoromethyJ)-4-chloro-2-methoxyphenyl Ureas

TLC Mass
mp HPLC TLC Solvent Spec. Synth.
Entry R CQ (min.) Rf System rSource] Method
95 o. 140- 0.29 5% 495 A2
VNH 144 MeOH/ (M+H)+ A7
fi—\ /=\ Me 45% (HPLC Bl
-o°-o EtOAc/ ES-MS) Cla

50% pet
ether
96 o. 244- 0.39 5% 529 A6
CI V-NH 245 MeOH/ (M+H)+ A7
H /=\ Me 45% (HPLC Bl
^0-°O EtOAc/ ES-MS) Cla

50% pet
ether
97 o. 220- 0.25 5% 529 A2
a J—NH 221 MeOH/ (M+H)+ A7
-cS-oMe 45% (HPLC Bl

EtOAc/ 50% pet ES-MS) Cla
ether
98 -f\ VNH 0.27 5% 495 A2

MeOH/ (M+H)+ A7
\=( /=( Me 45% (HPLC Bl
K_/ EtOAc/ 50% pet ether ES-MS) Cla
99 o. 180- 0.52 5% 509 A2
V-NH 181 MeOH/ (M+H)+ A7
-o-oB 45% (HPLC Bl

EtOAc/ ES-MS) Cla

50% pet
ether
100 0 162-165 A2 A7 Bl Cla

Table 7. Additional Ureas

Entry R mp (°C) HPLC (mia) TLC TLC Solvent System Mass
Spec.
[Source] Synth. Method
101 —.., n H
OMe 162-165 Al A2 C3
102 I H H 0.10 50% EtOAc/ 50% hexane 442
103 0
I
HN NH
0 0
0 0
0 b
0==0 NH-Me Me-NH 125-130 0.24 40% EtOAc/ 60% hexane 512
(M+H)+
(FAB) A2 C2b
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
\C^

WE CLAIM:
1,% A compound selected from the group consisting of the 4-chloro-3-(trifluoromethyl)phenyl ureas:
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-
pyridyloxy)phenyl)urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl)urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl)-4-
pyridyloxy) phenyl)urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl)urea and
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-N-
methylcarbamoyl)(4-pyridyloxy)phenyl)urea,
the 4-bromo-3(trifluoromethyl)phenyl ureas:
N-(4-bromo-3-(trifluoromethyl)pheny)-N'-(3-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl)urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy)phenyl)urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-
pyridylthio) phenyl)urea,
N-(4-bromo-3-(trifiuoromethyl)phenyl)-N'-(2-chloro-4-2-(N-
methylcarbamoyl)(4-pyridyloxy))phenyl)urea, and
N-(4-bromo-3-(trifluoromethyl))phenyl)-N'-(3-chloro-4-2-(N-
methylcarbamoyl)(4-pyridyloxy)phenyl)urea.
the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas:
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-2-(N-methylcarbamoyl)-4-pyridylo3cy)phenyl)urea.

N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea.
or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1, wherein a pharmaceutically
acceptable salt thereof selected from the group consisting of:
a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid hydrobromic acid, sulphuric acid, phophoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalne sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic .add, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and
b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.

3. A pharmaceutical composition comprising a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier.
4. A compound as claimed in claim 1 selected from the group consisting of:
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl-pyridyloxy)phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-
pyridyloxyjphenyl) urea, '4
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoy11 (4-pyridyloxy))phenyl) urea,

N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea,
N-^-methoj{y-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea,
or a pharmaceutically acceptable salt thereof.
5. A compound as claimed in claim 4 which is a pharmaceutically
acceptable salt thereof selected from the group consisting of:
a) basic salts of organic adds and inorganic acids selected from the
group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid,
phosphoric acid, methanesulphonic acid, trifluorosulphonic acid,
benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene
sulfonic acid, 2-napthalene sulfonic acid, acetic
acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid,
oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic
acid,
phenylacetic acid, and mandelic acid; and
b) acid salts of organic and inorganic bases containing cations selected
from the group consisting of alkaline cations, alkaline earth cations, the
ammonium cation, aliphatic substituted ammonium cations and aromatic
substituted ammonium cations.
6. A pharmaceutical composition comprising a compound as claimed in claim 4 or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier.
7. A compound as claimed in claim 1 selected from the group consisting of:
the 4-chloro-3-(trifiuoromethyl)phenyl ureas:

N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pj^|dyloxy)phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N-(4-(2-carbamoyl-4-pyridyloxyjphenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)4-pyridyloxy) phenyl) urea and
N-(4-chloro-3-(trifluoromethyl)phenyl)-N-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea,
the 4-bromo-3(trifluoromethyl)phenyl ureas:
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-
pyridyloxy) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N,-(4-(2-(N-methylcarbamoyl)-4-
pyridyloxy) phenyl urea.
N-(4-bromo-3-(trrifluoromethyl)phenyl)-N,-(3-(2-(N-methylcarbamoyl)-4-
pyridylthio) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-
methylcarbamoyl)(4-pyridyloxy))phenyl) urea and
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-
methylcarbamoyl)(4-pyridyloxy))phenyl) urea;
the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas:
N-(2-methoxy-4-chloro-5-(trifluoromethylphenyl)-N'-(4-(2-(N-
methylcarbamoyl)-4-pyridyloxy)phenyl) urea,
N-(2-methoxy- 4-chloro-5-(trifluoromethyl) phenyl)-N'-(2-chloro-4-(2-(N-
methylcarbamoyl) (4-pyridyloxy)) phenyl) urea
or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a cancerous cell growth mediated by raf kinase.

8. A compound as claimed in claim 1 selected from the group consisting
the 4-chloro-3-(trifluoromethyl)phenyl ureas:
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxyjphenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea and
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl) (4-pyridyloxy))phenyl) urea,
the 4-bromo-3(trifluoromethyl)phenyl ureas:
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)4-pyridyloxy) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridylthio) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea and N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea;
the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas:
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,

N-(2-methoxy-4-chloro-5-(trifluoromethyl) phenyl)-N'-(2-chloro-4-(2-(N-
methylcarbamoyl) (4-pyridyloxy)) phenyl) urea
or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of:
i) carcinoma of the lungs, pancreas, thyroid, bladder, colon,
ii) myeloid leukemia or
iii) villous colon adenoma.
9. A compound as claimed in claim 1 selected from the group consisting
of:
the 4-chloro-3-(trifluoromethyl)phonyl ureas:
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxyjphenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N,-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea,
N-(4-chloro-3-(trifiuoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea and
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea,
the 4-bromo-3(trifluoromethyl)phenyl ureas:
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)4-pyridyloxy) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N-(3-(2-(N-methylcarbamoyl)-4-pyridylthio) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea and

N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea;
the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas:
N-(2-methox^-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N,-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy)phenyl) urea,
or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of tumors.
10. A compound as claimed in claim 4 selected from the group consisting of:
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4 pyridyloxy) phenyl) urea,
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl) -4-pyridyloxy)phenyl) urea,
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl) (4-pyridyloxy))phenyl) urea.
or a pharmaceutically acceptable salt hereof for the manufacture of a medicament for the treatment of a cancerous cell growth mediated by raf kinase.

11. A compound as claimed in claim 4 selected from the group consisting
°*
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy) phenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phanyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl) (4-pyridyloxy))phenyl) urea,
N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4 pyridyloxy)phenyl)urea,
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea,
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea
or a pharmaceutically acceptable salt hereof for the manufacture of a medicament for the treatment of:
i) carcinoma of the lungs, panaeas, thyroid, bladder, colon, ii) myeloid leukemia or iii) villous colon adenoma.
12. A compound as claimed in claim 4 selected from the group consisting
of:
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxyjphenyl) urea,
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea,

N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4
pyridyloxy)phenyl)urea,
N-|g-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea,
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea
or a pharmaceutically acceptable salt hereof for the manufacture of a medicament for the treatment of tumors.
13. A compound as claimed in claim 1 which is N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridylo3^)phenyl) urea.
14. A compound as claimed in claim 1 which is N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbanioyl)-4-pyridyloxy)phenyl) urea
15. A pharmaceutical composition comprising N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridylo3^)phenyl) urea or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier.
16. A pharmaceutical composition comprising N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier.
17. N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy) phenyl) urea,
or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a cancerous cell growth mediated by raf kinase.
18. N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4"(2-(N-methylcarbamoyl)-4-

pyridyloxy)phenyl) urea or a pharmaceutical acceptable salt thereof for the manufacture of a medicament for the treatment of a cancerous cell growth m^iated by raf kinase.
19. A pharmaceutically acceptable salt of a compound which is:
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy) phenyl) urea of the formula:

S o i*!^0Y^TNH:

H H or
N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl-4-pyridyloxy)phenyl) urea of the formula:

20. A pharmaceutically acceptable salt as claimed in claim 19 which is a basic salt of an organic acid or an inorganic acid which is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, or mandelic acid.
21. A pharmaceutically acceptable salt which is the tosylate salt of:

N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy) phenyl) urea of the formula:

N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-N-methylcarbamoyl-4-pyridyloxyjphenyl) urea of the formula:

22. A pharmaceutical composition comprising a pharmaceutically acceptable salt of claim 19, 20 or 21 and pharmaceutically acceptable carrier.

Dated this 5th day of July, 2001.
[RANJNA MEHTA-DUTT]
OF REMFRY 85 SAGAR
ATTORNEY FOR THE APPLICANTS)

CARBOXYARYL SUBSTITUTED DIPHENYL UREAS

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