BG65158B1 - Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitirs - Google Patents

Abstract

The invention relates to the use of a group of aryl ureas in the production of medicines for treating raf mediated diseases, and to pharmaceutical compositions used in such treatment.

Description

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to the use of a group of arylureas for the manufacture of medicaments for the treatment of raf mediated diseases and to pharmaceutical compositions for use therein treatment. BACKGROUND OF THE INVENTION The p21 ras oncogene is the one that primarily adds to the development and progression of human solid cancers and mutates in 30% of all human cancers (Boltonetal, Ann., Rep. Med Chem., 1994, 29, 165 -74; Bos.Cancer Res., 1989, 49, 4682-9). In its normal, non-mutated form, the ras protein is an element of the signal transduction cascade via growth factor receptors in almost all tissues (Avruch et al., Trends Biochem., 1994, 19, 279-83). From a biochemically 25 point point, ras is a guanine nucleotide binding protein, and the closure of the cycle between GTP-linked in activated form and a GTP-link in the form of more closely controlled by ras endogenous CTRase activity and other regulatory proteins. In the ras mutants in cancer cells, the endogenous ODRase activity is alleviated, and therefore, the protein sends constitutive growth signals such as the raf kinase enzyme to the effector chain. This results in a malignant growth of the cells bearing these mutants (Magnuson et al., Semin., Cancer Biol.1994, 5, 247-53). It has been shown that by inhibiting the effect of active ras by identifying the raf kinase signal pathway by the use of deactivating antibodies on raffinase or by co-expressing a dominant negative raf kinase or dominant non-MEK, the raf kinase substrate leads to a reversal of the normal growth growth of transformed sphenotipe cells (see Daum et al., Trends Biochem Sci 1994, 19, 474-80); Frigmanet al. J. Biol. Chem. 1994,269, 30105-8. Kolch et al. (Nature 1991, 349, 426-28), then showed that inhibition of raf expression by anti-receptor RNA (RNA) blocks cell proliferation in membrane-associated organisms. Similarly, inhibition of the kinase kinase (via anti-receptor oligodeoxynucleotides) was compared in vitro and in vivo with the inhibition of growth of various types of human tumors (Monia et al., Nat.Med.1996, 2, 668-75). SUMMARY OF THE INVENTION The present invention provides compounds that are inhibitors of the raffinase enzyme. Since the enzyme is an effector of the ras p21 chain, the inhibitors are used in human pharmaceutical compositions for veterinary purposes when inhibiting the raf kinase pathway, for example the treatment of tumors and / or malignant growth cells , mediated by raf kinase. In particular, the compounds are used in the treatment of solid cancers in man and in animals, e.g., mouse carcinoma, since the progression of these cancers is dependent on the signal transducing ras protease cascade and is therefore susceptible to leu- by cascade interruption, i.e., ras kinase inhibition. Accordingly, the compounds of the invention are used to treat cancers, including cancerous cancers such as, for example, carcinomas (e.g., lung, pancreas, thyroid, bladder or colon); myeloid diseases (e.g., myeloma leukemia) or adenomas (e.g., fibrous adenoma of the colon). The present invention provides compounds that are generally described as aryl ureas, including both analogs, and aryl and heteroaryls that inhibit the raf kinase pathway. Thus, the invention is directed to compounds that inhibit the raf kinase enzyme, and also to compounds, compositions and methods for the treatment of carcinoma cell growth mediated by raf kinase, wherein a compound of the invention is an acceptable salt thereof. A compound of the invention is selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenylurea: N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (3- ) phenylurea, 50 65158 N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N -methylcarbamoyl) -4- pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) - N '- (4-pyrimidyl) (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl urea and N- (4-chloro- 3- (trifluoromethyl) phenyl) -N- (2- chloro- 4- ) -4-pyridyloxy) phenyl) urea 4-Bromo-3- (trifluoromethyl) phen N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- [3- [2- (N-methylpiperazinyl) -4- (phenylmethyl) (4-bromo-3- (trifluoromethyl) phenyl) - N '- (4-fluorophenyl) (4-bromo-3- (trifluoromethyl) phenyl) -N- (2-chloro-4- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- -diyloxy) phenyl) urea. 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) urea: N- (4- -4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2- ) -4-pyridyloxy) phenyl) urea or pharmaceutically acceptable salts thereof The present invention is also directed to a pharmaceutically acceptable salt of a compound of the invention Suitable pharmaceutically acceptable salts are well known to those skilled in the art include basic salts of non-organic and organic k such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and almond and the acid-acid. In addition, pharmaceutically acceptable salts include acidic salts of inorganic bases such as salts containing alkali metal cations (e.g., Li +, Na + or Kv, alkaline earths 10 cations (e.g., Mg + 2, Ca + 2 or Ba + 2) such as the acid salts of organic bases including aliphatic and aromatic ammonium and quaternary ammonium cations such as those derived from the protonation, the alkylation of triethylamine, N, N-diethylamine, N, N-dicyclohexylamine, lysine, pyridine, N, N-dimethylaminopyridine (DMMP), 1,4-diazabicyclo [2.2.2] octane BCO), 1,5-diazabicyclo [4.3.0] non-5-ene 20 (DBN), and 1,8- diazabicyclo [5.4.0] undec-7en (DBU) The present invention encompasses any isolated racemic or optically active form of the compounds described in < RTI ID = 0.0 > a < / RTI > which have inhibitory activity. General Methods of Preparation The compounds of formula I can be prepared using known chemical reactions and procedures, some of the commercially available starting materials. However, the general preparation methods shown below to give assisted by those skilled in the art in the synthesis of these compounds, with more detailed examples being shown in the experimental part which follows. Substituted anilines can be generated using standard methods (March, 45 Advanced Organic Chemistry, 3rd Ed., John Wiley: New York (1985), Comprehensive Organic Transformation, VCH Publishers: New York, 1989). is shown in Scheme I, aryl amines are usually synthesized by reducing nitro-aryls using metal catalysts such as 65158 such as Ni, Pd, or Pt, and H2 or a hydride-transferring agent such as formate , cyclohexadiene or borohydride (Rylander.Hydrogenation Methods, Academic Press: London, UK (1985)). Nitroaryls can also be directly reduced using a strong hydride source such as LiAlH4 (Seyden-Penne, Reducing by the Alumino and Borohydrides in Organic Synthesis, VCH Publisher: New York (1991)), or using metal c zero valence, such as Fe, Sn or Ca, in acidic medium. There are many methods for the synthesis of nitroaryls (March, Advanced Organic Chemistry, 3rd Ed., John Wiley: New York (1985) .Larock Comprehensive Organic Transformation, 15VCH Publishers: New York (1989)). H2 (catalyst) (e.g., N, Pd, Pt) [Hl

Scheme II Selected Nucleophilic Aromatic Substitution Using Nitroaryls Nitroaryls may also be referred to as cross-linked transverse metal-mediated reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo palladium-mediated cross-coupling reactions with aryl nucleophiles such as arylboronic acids (Suzuki reactions, below), arylalkylates (Stille reactions), or arylzinc (Negishi reaction) to yield the biaryl (5).

4 S

ArNO2

ArNH " 20 M (O) (e.g., FeSn.Ca)

Scheme I Reduction of Nitroaryls to Arr. Nitroaryls are generally obtained by electrophoretic aromatic nitration, e.g., NO3 or an alternative source. Nitroaryls may also be present before reduction. Thus, nitroarillins with laminae 25 are expressed using NO2-. substituting 30 Ar-HNO3,

ArNO, potential leaving groups (e.g., F, Cl, Br, etc.) may undergo substitution reactions by treating them with nucleophiles such as thiolate (exemplified in Scheme II) or phenoxide. Nitroaryls may also be subjected to coupling reactions (Scheme II). Nitroaryl and aniline can also be converted to the corresponding arylsulfonyl chloride (7) by reaction with a chlorosulfonic acid. Reaction of a sulfonyl chloride with a fluoride source such as KF then leads to the formation of a sulfonyl fluoride (8). The reaction of the sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride extractor such as tris (dimethylamino ) sulfonium difluorotrimethylsilconate (TASF) affords the corresponding trifluoromethylsulfone (9). Alternatively, the sulfonyl chloride 7 can be reduced to arethiol (10), for example, with zinc amalgam. Reaction of thiol 10 with CHClF2 in the presence of base gives the difluoromethyl mercaptan (11) which can be oxidized to sulfone (12) with any of the various oxidants, including C203-acetic anhydride (Sedova et al., Zh Org Khim, 1970, 6, (568)

AlSi3H2O2Br-Ar2C10H6OH

O2N 65158

SOp

10 chcif2 osnova (Me ^ NJijS MegSiljMegSiCij

T

SpF CF

[0] SO £ HF2

Scheme III Selected Methods for Syntheses of Fluorinated Thiol Sulfone As shown in Scheme IV, the urethane formation of urea may comprise reacting an aryl isocyanate (14) with an aryl amine (13). The heteroaryl isocyanate may be synthesized from a heteroaryl amine by treating it with phosgene or a phosgene equivalent such as trichloromethyl chloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene) or N, N'-carbonyl diimidazole (CDI). The isocyanate can also be 4Ar- separated from a heterocyclic derivative carboxylic acid, such as an ester, an acid halide, or an anhydride, by a recirculating rearrangement reaction. Thus, reacting the acid derivative 16 with an acidic source, followed by rearrangement, results in the formation of an isocyanate. The corresponding carboxylic acid (17) can also be subjected to Kurziusian rearrangement reactions using diphenylphosphoryl azide (DPPA) or a similar reagent. NH2 13COCl,

Ar1-NCO14

HjN-AG

DPPA Ar1 < / RTI >

Ark X Xn 15 16 65158

Scheme IV Selected methods for asymmetric urea formation Finally, ureas can also be processed using methods familiar to those skilled in the art. The invention also includes pharmaceutical compositions comprising a compound of the formula I, and a physiologically acceptable carrier. The compounds can be administered orally, 10-fold, parenterally, by inhalation, or by sprays or rectally, as dosage forms for single-dose administration. The term " injection by injection " includes intravenous, intramuscular, subcutaneous and parenteral injections as well as the use of infusion techniques. One or more compounds may be present in combination with one or more non-toxic pharmaceutically acceptable carriers and, optionally, other active 20 parts. Compositions intended for oral use may be prepared according to any suitable method known in 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, flavor enhancers, coloring agents and preserving agents in order to provide 30 tasty compositions. The tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the preparation of tablets. These excipients may be, for example, 35 inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; and binders, for example, magnesium stearate, stearic acid, or talc. The tablets may be coated or they may be coated by known techniques to delay the development and adsorption in the gastrointestinal tract and thereby provide delay for a longer period of time. For example, delayed action products such as glyceryl monostearate or glyceryl distearate may be used. These compounds can also be obtained as solid, fast release forms. Formulations for oral administration may also be presented as solid gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is a mixed aqueous or oil medium, for example, peanut oil, liquid paraffin or olive oil. The aqueous suspensions contain the active products mixed with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia resin, dispersing, or wetting agents may be naturally-occurring phosphatides, for example, lecithin or condensation products, or alkylene oxide with fatty acids, for example, polyoxyethylene stearate or cone ethylene oxide enhancing products with long chain aliphatic alcohols, for example, heptadeca-ethylene oxycetanol or condensation products of ethylene oxide with partial esters of fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with particulate esters, fatty acid derivatives and hexetol anhydride, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavor enhancers and one or more sweetening agents such as such as sucrose or saccharin. Dispersion powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those directly referred to above. Additional excipients, for example, sweetening, more tasteful, and coloring agents, may be present. The compounds may also be the non-aqueous liquid dosage form, for example, oil suspensions which can be prepared by suspending the active ingredients in vegetable oil, for example peanut oil, olive oil, sesame oil or peanut oil or mineral oil, such as liquid paraffin. Oily suspensions may contain thickening agents, for example, beeswax, hard paraffin or cetyl alcohol. Sub-cures, such as those mentioned above, and flavor enhancers can be added to provide delicious oral compositions. These compositions can be preserved by adding a thiooxidant such as ascorbic acid. The pharmaceutical compositions of the invention may also be in the form of oil-water emulsions. The oil phase may be a vegetable oil, for example, olive oil or peanut oil, or a mineral oil, for example, liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be natural gums, for example, gum acacia or gum tragacanth, natural phosphatides, e.g., soybean, lecithin, and esters, or fatty acid esters derived from fatty acids and hexetol anhydrides, e.g., sorbitan mono oleate and condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be prepared with sweetening agents, for example, glycerol, propylene glycol, sorbitol, or sucrose. Some drug formulations may also contain irritant-reducing agents, preservatives, and flavor enhancers. The compounds can also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the carrier with a suitable non-irritating excipient which is solid at ordinary temperature but is liquid at the rectal temperature, thereby melting in the rectum to separate the material. Such products include coconut oil and polyethylene glycols. For all of the areas of use described herein, for the compounds of formula I, the daily oral dosage regimen is preferably from 0.01 to 200 mg / kg body weight. Daily dosage for injection, including intravenous , intramuscular, subcutaneous and parenteral injection, and use of infusion techniques, is preferably from 10 0.01 to 200 mg / kg total body weight. Dental malformation for rectal administration is preferably from 0.01 to 200 mg / kg total body weight. The daily dose for topical administration is preferably from 0.1 to 200 mg, administered once, up to 15 times four times a day. The daily inhalation dose is preferably from 0.01 to 10 mg / kg of total body weight. It will be appreciated by those skilled in the art that the specific administration method 20 depends on various factors, all of which are taken into account by the routine physician. It will also be appreciated by those skilled in the art that the specific dosage level for a given patient depends on various factors including the specific activity of the compound administered, age, body weight, health status, (la, diet, time and route of administration, rate of excretion, and 30 etc.) It should also be noted by those skilled in the art that the optimal course of treatment, i. e. , the mode of treatment, the number of doses of the compound of formula I, or a pharmacist thereof orally acceptable salt, for a number of days, may be determined by one of ordinary skill in the art using conventional medical tests, but it is to be understood that the specific dosage for each individual patient for 40 days. the age, body weight, general health status, sex, diet, time of administration, route of administration, and rate of excretion 45, combination of medicaments and how hard it is with the condition that is being treated. The full inclusion of all the applications, patents and publications cited above and below 50 is provided herein, including 65158 provisional application Serial No. 60 / 115,877 filedJanuary 13,1999 and non-provisional application SerialNo. Compounds may yield compounds (or from the starting compounds, in turn, compounds may be prepared), for example, by means of methods for preparation, shown in a given compound to inhibit : The invention may be routinely studied, for example, the following methodical examples are for illustrative purposes only, and are not intended to be construed as limiting the invention to any of the claims. The activation rafKH-imer is the same as the two, and they are not restricted. EXAMPLES 15 All reactions are carried out in glass-dried or oven-dried glass vessels at positive pressure from dry argon or dry nitrogen and agitated with magnetic stirrers, except when is stated otherwise. The exact liquids and solutions are transferred by means of a syringe or cannula and are transferred to the reaction vessels through a rubber barrier. Excluding cases where otherwise termed " reduced pressure concentration " means the use of a Buchi rotary evaporator at approximately 15 mm Ng. Excluding cases where the term "high vacuum" refers to vacuum, the order of 0-14 mm Hg. All temperatures are uncoated in degrees Celsius (° C). Unless otherwise stated, all hours and percentages are by weight. Reagents and commercial grade solvents are used without further purification. N-cyclohexyl-N '- (methylpolystyrene) carbodiimide is purchased from Calbiochem-Novabiochem Corp. 4-chloro-3- (trifluoromethyl) aniline, 2-methoxy-5- (trifluoromethyl) aniline , 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-isocyanatobenzoate, N -acetyl-4chloro-2methoxy-5- (trifluoromethyl) - (trifluoromethyl) phenyl isocyanate are purchased and used without further purification. The syntheses of 3-amino-2-methoxy-quinoline (E. Cho et al., WO 1998/04040, A.Cordi et al., EP 542,609, IBID Bioorg, Med Chem. 1995, 129), 4- (3-Carboxyphenoxy) -1-nitrobenzene (K.Ikawa Yakugaku Zasshi 79, 1959, 560, Chem. O. Rohr et al., DE 2,436,108) [2- [e] & ll-5- (trifluoromethyl) phenyl isocyanate (K.Inukai et al, JP 42,025,067; IBID Kogyo KagakuZasshi 70,1967,491). Thin layer chromatography (TLC) was performed using Whatman® factory-made silica gel plates on a glass-core 60A F-254 250 μm. Plate observation is performed by one or more of the following techniques: (a) ultraviolet light, (b) iodine vapor exposure, (c) immersing the tray in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersing the tray in a solution of cesium sulphate followed by heating; and / or (f) immersing the tray in an acidic ethanolic solution of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science® silica gel. Melting points are determined using a Thomas-Hoover melting point apparatus or Mettler FP66 automatic melting point apparatus and are uncorrected. Infrared red spectrum with Fourier transformation was obtained using a Mattson 4020 Galaxy Series spectrophotometer. The proton (1 H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer or with Me4Si (delta 0.00) or a colloidal protonated solution (CHCl3 delta 7.26; 3.30; DMSO delta 2.49) as standard. Low resolution (MS) spectra and high resolution spectra (HRMS) are obtained either as electron impact mass spectra (EI) or as fast atom bombardment (FAB) mass spectrometry mass spectra. Electron Spectrum mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a VacumetricsDescription Chemical Ionization Probe for an imported sample. The ion source is maintained at 25 ° C. The electronic impact is carried out with the power of the electron 70 eV and a trap with a power of 300 microA. Secondary liquid phase cesium mass spectrometry (FAB - MS), modern, rapid - atom bombardment is obtained using a Kratos Concept 1 - H spectrometer. Mass spectra of chemical ionisation (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989 A) with methane or c ammonia as a gaseous reactant (1 x 10-4 torr to 2.5 x 10-4 torr). The DCI desorption probe (Vaccumetrics, Inc.) ranges from 0-1.5 amps in 10 s and resists at 10 amps while all traces of the sample disappear (~ 1 - 2 min) . The spectra were scanned at 50-800 μm in 2 s. On scan. HPLC (HPLC) mass spectroscopy (HPLC ES-MS) were obtained using a Hewlett Packard 1100HPLC equipped with a quaternary pump, a variable wavelength detector, a C-1518 cluster, and an electrospray ionizer mass spectrometer with trap of FinninganLCQ ions. The spectra were scanned from 120-800 amu using a varying ion time as the number of ions in the source. GC-MS are obtained with a Hewlett Packard 5890 gas chromatograph equipped with HP-1 methyl silicone colloid (0.33 mM coating, 25 m or 0.2 mm) and Hewlett Packard 5971 Mass selective detector (ionisation energy 70 eV). Elemental analysis was performed by Robertson Microlit Labs, Madison NJ. All the NMR spectra, LRMS and / or elemental analysis, orHRMS, are consistent with certain structures. 30 List of abbreviations and acronyms: AcOH acetic acid

Anh anhydrous

Atmosphere (s) BOC tert-butoxycarbonyl 35 GDI 1,1'-carbonyldiimidazole

Cone Concentrated Oden (Days)

Dec DecarationDMAC N, N-dimethylacetamideDMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone DMF N, N -dimethylformamideDMSO dimethylsulfoxideDPPA diphenylphosphoryl azide EDCI 1- (3 -dimethylaminopropyl) -3- ethylcarbodiimide

EtOAc ethyl acetate 40 45 EtOH

Et2O ethanol (100%) diethyl ether

Et3N triethylamine hour (s) HOBT 1-hydroxybenzotriazole-CPBA 3-chloroperoxybenzoic acid MeOH methanol

Pet. EA ether tether (ether range 30-60 ° C)

Temp, THF Temperature Tetrahydrofuran TEA Trifluoride

Tf Trifluoromethanesulfonyl A. Basic Methods for Synthesis of Substituted Anilines A1. Basic methods for the formation of arylamine by formation of ether, followed by ester introduction, rearrangement of Curtius, and removal of carbamate protection. Synthesis of 2-amino-3-methoxynaphthalene

OMe Step 1. Methyl 3-methoxy-2-naphthoate A suspension of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K 2 CO 3 (7.96 g, 57.6 mmol) ) was stirred at room temperature for 15 min, then treated with iodomethane (3.43 ml, 55.1 mmol). The mixture was stirred at room temperature overnight, then treated with water (200 ml). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organics were washed with saturated NaCl solution (100 ml), dried (MgSO4), concentrated under reduced pressure (approximately 0.4 mm Hg overnight) to give methyl 3-methoxy-2-naphthoate (10.3 g): 1 H NMR (DMSO-d 6)? 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J = 8 , 7.94 (s, 1H), 7.54 (app t, J = 8.09 Hz, 1H), 7.84 (d, J = , 90 (s, 1 H), 8.21 (s, 1 H). 50 65158

OMe 10 Step 2.3-Methoxy-2-naphthoic acid To a solution of 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH of 15NaOH (33.4 mL, 33.4 mmol). The mixture was heated to reflux for 3 hours, cooled to room temperature, and acidified with 10% citric acid solution. The resulting solution was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated under reduced pressure. The residue was triturated with hexane, then washed several times with 25 hexanes to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): 1H NMR (DMSO-d6) delta 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, d, J = 8.09 Hz, 1H), 8.1 (s, 1H), 3012.83 (br s, 1H). 35

Step 3. 2- (N- (carbobenzyloxy) imino-3-methoxynaphthalene A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et 3 N mmol) in anhydrous toluene (70 mL) was stirred at room temperature for 15 min then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via a pipette. The resulting mixture was was heated at 80 DEG C. for 2 hours. After cooling the mixture to room temperature, benzylic alcohol (2.06 ml, 20 mmol) was added via syringe, then the mixture was heated at 80 ° C for one hour The resulting mixture was cooled to room temperature , quenched with 10% citric acid solution, and extracted with EtOAc (2 x 100 ml ).The combined organic layers were washed with saturated NaCl solution, dried (MgSO4) 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% DMSO-d6) δ 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 , 20 (s, 1 H), 8.76 (s, 1 H).

Step A: A suspension of 2- (N- (carbobenzyloxy) -amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 105 Pd / C (0.5 g) ml) was kept at room temperature overnight. The resulting mixture was filtered through Celite® and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a white solid (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 3H) 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0Hz, 1H), EI-MS m / z 173 -carbamyl-anilines by forming a carbamylpyridine followed by a nucleus Amino-4-pyridyloxy) -aniline Synthesis of 4- (2-N-methylcarbamyl-4-pyridyloxy) -aniline 10 65158

Me Stage la. Synthesis of 4-Chloro-N-methyl-2-pyridinecarboxamide by Menisci reaction Warning: This is an extremely hazardous potentially explosive reaction To a stirred solution of 4-chloropyridine (10.0 g) in N-methylformamide ml) at room temperature was added concentrated H 2 SO 4 (3.55 mL) to generate an exotherm. To this mixture was added H 2 O 2 (30% w / v H 2 O, 17 mL), and then FeSO 4 .7H 2 C ) to generate another exotherm.The resulting mixture was stirred in the dark at room temperature for 1 h, then slowly warmed for 4 h to 45 ° C. the reaction was heated at 60 ° C for 16 h. The resulting opaque brown solution was diluted with H 2 O (700 mL), then with a 10% NaOH solution (250 mL), and the resulting mixture was extracted with EtOAc The organic phases were washed with saturated NaCl solution (3x150 ml), then combined, dried (MgSO4), and filtered through a pad of silica gel using EtOAc. The resulting brown oil was purified by column chromatography (gradient of 50% EtOAc / 50% hexane to 80% EtOAc / 20% hexane). 4-chloro-5,3%): 1H-NMR? (Dd, J (s, 1H), m + H) +). yellow oil was crystallized at 0 ° C for 72 h to afford 1-methyl-2-pyridinecarboxamide (0.61 TLC 50% EtOAc / 50% hexane) Rf 0.50 (CDCl3) delta 3.04 d, J = 5.1 Hz, 3H), 7.24 (s, 1H), 8.28-4.4 (d, J = 5.1 Hz, , 1H); Cl-MS m / z 171 (

HCl Step lb. Synthesis of 4-chloropyridine-2-carbonyl chloride HCl salt by picolinic acid Anhydrous DMF (6.0 ml) was slowly added to SOCl 2 (180 ml) in the range of 40 ° C to 50 ° C. The solution was stirred at these temperature ranges for 10 min, then picolinic acid (60.0 g, 5.487 mmol) was added in portions over 30 min. The resulting solution was heated at 72 [deg.] C. of SO2) for 16 hours to generate a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 ml. The toluene addition / concentration procedure was repeated twice. The resulting near-dry residue was filtered and the solid was washed with toluene (2 x 200 ml) and dried at high vacuum for 4 hours to give 4-chloropyridine-2-carbonyl chloride HCl salt as a yellow-orange solid product (92.0 g, 89%).

25 Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HCl salt Anhydrous DMF (10.0 ml) was slowly added to SOCl 2 (300 ml) at 40-48 ° C. The solution was stirred at these temperature ranges for 30 min, then picolinic acid (100 g, 812 mmol) was added over a period of 30 min. The resulting solution was heated at 72 ° C (vigorous evolution of SO 2) over a period of 16 h to generate a yellow solid. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 ml. The recrystallized toluene / concentration was repeated twice. The resulting almost dry residue was filtered and the solid was washed with toluene (50 mL) and dried under high vacuum for 4 h to give 4-chloropyridin-2- carbonyl chloride HCl salt, as an off-white solid (27.2 g, 16%). This product is retained. The red filtrate was added to MeOH (200 ml) at a rate that kept the internal temperature below 55 ° C. The contents were stirred at room temperature for 50 min, cooled to 5 ° C and treated with 11 65158

Et 2 O (200 mL) dropwise. The resulting solids were filtered, washed with Et 2 and dried under reduced pressure to give methyl 4-chloropyridoxylate HCl salt as a white solid (110 g, 65%): mp 108-112 ° C; (D, J = 2.2 Hz, 1H), 85.5 Hz, 1H), 10.68 (s, 3H), 7.82 (br s, 1 H); HPLC ES @ 172 ((M + H) +), 0.05, (200 ml), 35 ° C, in-2-caro pro-1 H-NMR, , J = - MS m / z (dd;

Me (7.0 g, 32.95 mmol) was added portionwise to a mixture of a 2.0 M solution of methylamine in THF (100 mL) and MeOH (20 mL) at 0 ° C. The resulting mixture was stored at 3 ° C for 4 hours, then concentrated under reduced pressure. The obtained nearly dry solids are suspended in EtOAc (100 ml) and filtered. The filtrate is washed with saturated NaCl solution (2 x 100 ml), dried (Na2SO4) and concentrated under reduced pressure, 4-chloro-N-methyl-2-pyridinecarboxamide as a yellow crystalline solid (4.95 g, 88%): mp 37-40 ° C; 15 Stage For. Synthesis of 4-chloro-2-pyridinecarboxamide from methyl 4-chloropyridine-2-carboxylate To a suspension of 4-chloropyridine-2-carboxylate HCl salt (89 g, 428 mmol) in MeOH 2.0 M solution of methylamine in THF (1 L) at a rate that maintains the internal temperature below 5 ° C. The resulting mixture was stored at 3 ° C for 5 h, after 25 h, concentrated under reduced pressure. The obtained solids were suspended in EtOAc (11) and filtered. The filtrate was washed with N-methyl-

dried with 30% N-methyl chloropyridine with saturated NaCl solution (500 ml) (Na2SO4) and concentrated in vacuo to give 4-methyl-2-pyridinecarboxamide from methyl rdidine-2-carboxylate, the form of yellowish crystals (71.2 g, 97%): mp 41-43 ° C; 1 H NMR (DMSO-d6) δ 2.81 (s, 3H), 7.15 (t, J = 2.2 Hz, = 5.1 Hz, 1H), 8.85 (brd, 1H), Cl-MS m / z 171 (M + H) +, 74 (dd, J 351H) 4. Synthesis of 4- (2- (14-methylcarbamoyl) -4-pyridyloxy) aniline A solution of 4-aminophenol (9.60 g, 88.0mmol) in anhydrous DMF (150ml) butoxide (10.29 g, 91.7 mmol), and the red-brown brown mixture was stirred at room temperature for 2 h. The contents were treated with 4-chloro-N-methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and K 2 CO 3 (6.50 g, 47.0 mmol) and then heated at 80 ° C for 8 h. The mixture was cooled to room temperature and separated The combined organic layers were washed with sat. NaCl solution (4 x 1000 mL), dried (Na2SO4), and extracted with EtOAc (500 mL) and saturated NaCl solution (500 mL). The resulting solids were slurried under reduced pressure at 35 ° C for 3 hours to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline, the substrate of (17.9 g, 84%): 1 H NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J = , 5 Hz, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m / z 244 ((M + H) +). Basic method of synthesizing anilines by nucleophilic aromatic addition, followed by reduction of nitroarine. Synthesis of 5- (4-aminophenoxy) iso-Step 3b. Synthesis of 4-chloro- N -methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carboxylate 4-chloropyridine-2-carbonyl chloride HCl salt 50 12 65158

Step 1. Synthesis of 5-Hydrolidin-1,3-dione To a mixture of ammonium carbonate (54.9 mmol) in conc. The resulting mixture was heated at 120 ° for 45 minutes, then the clear yellow mixture was heated at 160 ° C in pyridine (5.28 g, was added at -45 mmol) in a prolonged flash over 2 h. The resulting mixture was kept at 160 ° C, 1 mL then was added, and the mixture was concentrated to ca. cooled to room temperature to pH 10 with 1N NaOH solution cooled to 0 ° C and slowly acidified to pH 5 using 1N HCl solution.The resulting slurry was collected by filtration and dried at reduced pressure to give 5-hydroxyisoindoline-1,3-dione as a pale yellow powder (324 g, 72%): 1 H NMR (DMSO- d6) δ 7.00-7.03 (m, d, J = 9.3

Hz, 1H). 30

35 Step 2. Synthesis of 5- (4-nitrophenoxy) isoindoline-1,3-dione To a suspension of NaH (1.1 g, 44 in DMF (40 ml) at 0 ° C was added a solution of 5-hydroxyisoindoline- 1,3-diol 19.6 mmol) in DMF (40 mL). The resulting mixture was allowed to warm to room temperature and stirred continuously, then a syringe was added to the syringe. The mixture was heated at 70 < 0 > C overnight, then (3.2 g., m.p.), stirred at room temperature for 40 minutes, diluted slowly with water (150 ml), and extracted with EtOAc (2 x 100 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 5- (4-nitrophenoxy) isoindoline-1,3-dione as a yellow solid (3.3 g, 62.5): TLC (30% EtOAc / 70% hexane) Rf 0.28; 1 H NMR (DMSO-d6) δ 7.32 (d, J = 12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J = 7.8Hz, , 8.29 (d, J = 9 Hz, 2 H), 11.43 (brs, 1 H); CI-MS m / z 285 ((M + H) +), Ia%

Step 3 Synthesis of 5- (4-aminophenoxy) isoindoline-1,3-dione A solution of 5- (4-nitrophenoxy) isoindoline-1,3- dione (0.6 g, in concentrated NaOH (12 ml) and water (0.1 ml) was stirred under argon while at once iron powder (0.59 g, 55.9 mmol) was added. This mixture was stirred at room temperature for 72 h, then diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgSO4), and concentrated under reduced pressure to give 5- (4-aminophenoxy) isoindoline-1,3-dione as a tan solid (04 g, 75%): TLC (50% EtOAc / 50% , 27; 1 H NMR (DMSO-d6) δ 5.14 (br s, 2H), 6.62 (d, J = 8.7 Hz, ), 7.03 (d, J = 2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 ); HPLC ES-MS m / z 255 ((M + H) +, 100%). A4. Basic synthesis method for pyrrolylanilines. Synthesis of 5-tert-butyl-2- (2,5-dimethylpyrrolyl) -aniline N0; Step 1: Synthesis of 1- (4-tert-Butyl-2-nitrophenyl) -2,5-dimethylpyrrole To a stirred solution of 2-nitrobenzylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added AcOH (0.1 mL) and acetonitrile (0.29 g, 2.63 mmol) via syringe. The reaction mixture was heated at 120 ° C for 72 h with azeotropic removal volatile products. The resulting mixture was cooled to room temperature, diluted with H 2 Cl 2 10 (10 mL) and immediately washed with 1 N HCl solution (15 mL), 1 N NaOH solution (15 mL), and a saturated solution of NaCl (15 ml), dried (MgSO4), and concentrated under reduced pressure. The resulting orange-brown solids were purified by column chromatography (60 g of SiO2, gradient of 6% EtOAc / 94% hexanes to 25% EtOAc / 75% hexanes) to give 1- (4- nitrophenyl) -2,5-dimethylpyrrole, as an orange-yellow solid (0.34 g, 49%): TLC (85% hexanes) Rf 0.67; (M, 1H), 7.62 (dd, 1H), 7.88 (s, 6H), 5.84 d, J = 2.4 Hz, 1 H); Cl-MS m / z 273 ((M + H) + 50%). 25 A5. Basic method for synthesizing anilines from anilines by nucleophilic aromatic substitution. Synthesis of 4- (2- (L-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline HCl salt

Y \ h N. i

Step 2 Synthesis of 5- tert -butyl-2- (2,5-dimethylpyrrolyl) -aniline A suspension of 1- (4-tert-butyl-2-phenylethyl) ) -2,5-dimethylpyrrole (0.341 g, 1.25 mmol) in EtOAc (50 ml) in H2 O (balloon) was stirred and then filtered through a pad of filtrate concentrated under reduced pressure to give 5-tert-butyldimethylpyrrolyl) -aniline, with a strong solid (0.30 g, 99%).

EtOAc / 90% hexane) Rf 0.43; 1 H NMR δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 52H), 6.73-6.96 (m, 3H), 7.28 (br s, nitropherol), 10% overnight at 72 hours,

(5.45 g, 44.4 mmol) was added to a solution of 4-amino-3-methylphenol (5.0 g, 25 mmol) in dry dimethylacetamide (75 ml) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol), and the mixture was stirred at room temperature until the flask was at room temperature. 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b, 7.52 g, 44.2 mmol) and heat at 110 ° C for 8 h. The organic layer was extracted with EtOAc (5 x 100 mL), the combined organic layers (200 mL), dried (MgSO4), and concentrated under reduced pressure.The residual black oil was treated with Et2O (50 mL) and sonicated, and then the solution was treated with HCl (1M in Et2O, 100 mL) and stirred at room temperature for 5 min The residual dark pink solid (7.04 g, 24.1 mmol) was removed by filtration from the solution and stored (s, 3H), 2.78 (d, J = 4.4 Hz, 3H), 4.93 (br s, 1H) 2H), 7.19 (dd, J = 8.5, 2.6 Hz, 1H), 7.23 (dd, J = 5.5, 2.6 Hz, = 2.6 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H) (d, J = 8.8 Hz, 1H), 8.55 (d, J = 5.9 Hz, 1H), 8.99 (q, J = 4.8 Hz, 1H). A6. Basic method for synthesizing anions of hydroxyanilines by N-protection, nucleophilic aromatic substitution and deprotection. Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline 50 14

I 65158

Step 1. Synthesis of 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol Iron (3.24 g, 58.00 mmol) was added to stirred TFA (200 mL). To this suspension was added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 mL). This gentle slurry was stirred at room temperature for 6 days. Iron is filtered off the solution, and the remaining! product is concentrated under reduced pressure. The semi-gray solid was dissolved in water (20 ml). To the resulting yellow solution was added a saturated solution of NaHCO3 (50 ml). The solid product which precipitates in the solution is removed. The filtrate is slowly quenched with sodium bicarbonate until the product is visibly separated from the solution (using a small laboratory vessel). The light yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers are washed with a saturated solution of HaNaCl (125 ml), dried (MgSO4), and concentrated under reduced pressure. 1 H-NMR (DMSO-d 6) shows a 1: 1 ratio of the starting product nitrophenol and the expected product 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol. The crude product is taken for the next step without further purification with 4-chloro-14-methyl-2-pyridinecarboxamide (Method A2, step 3b, 1.99 g, 11.7 mmol) and heated at 100 ° The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated to a solution of < RTI ID = 0.0 > under reduced pressure. The residual brown oil was purified by column chromatography (gradient from 20% EtOAc / petroleum ether to 40% EtOAc / petroleum ether), whereby yielding 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -2-chlorophenyl (222-trifluoro) -acetamide as a yellow solid 15 product (8.59 g, 23.0 mmol).

NH2e Step 2. Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl (222-trifluoro) acetamide To a solution of crude 3-chloro- 4- 2-trifluoroacetylamino) phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 ml) was treated with tert-butoxide (5.16 g, 45.98 mmoles) Step 3. Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline To a solution of crude 4- (2- (N -methylcarbamoyl) -pyridinyloxy) -2-chlorophenyl (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a 1N NaOH solution (20 mL) The solution was extracted with EtOAc (3 x 40 ml) and the solvent was concentrated to give 4- (2- ( N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline as a green oil which solidified upon standing (2.86 g, 10.30 mmol): 1 H NMR (DMSO- J = 8.5Hz, 1H), 6.76 (d, J = 5.5Hz, 3H) J = 8.5 Hz, 1H), 7.07 (dd, J = 5.5, 2.6 Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.75 (q, J = 4, 4.8 Hz, 1H). A7. A general method of deprotection of acylated aniline. Synthesis of 4-chloro-2-methoxy-5- (trifluoromethyl) -aniline (45%) with potassium hydroxide

(1505 mmol): 3H), 5.30 A suspension of 3-chloro-6- (N - (trifluoromethyl) phenoxyacetamidobenzaldehyde, ) -anisole (4.00 g, 14.956M HCl solution (24 ml) was refluxed for 1 h. The resulting solution was cooled to room temperature and gently solidified and diluted with water (20 ml ), after work up with a combination of solid NaOHpa3TBopaNaHCO3, while being solubilized.The organic layer was dried (MgSO4), and the combined organic layer was dried (MgSO4) (3.20 g, 14, 1 H-NMR (DMSO-d6) δ 3.84 (s, (s, 2H), 7.01 (s, 2H) A8 Basic synthesis of omega-alkoxy-omega-carboxyphenyl anilines 20 Synthesis of 4- (3- (L -methylcarbamoyl) -4methoxyphenoxy) aniline ex op; op

25-30 Step 1.4- (3-Methoxycarbonyl-4-methoxy-phenoxy) -1-nitrobenzene To a solution of 4- (3-carboxy- 4 -hydroxyphenoxy) -1- nitrobenzene (prepared from 2,5- (50 ml) was added K 2 CO 3 (5 g) and dimethylsulfate (3.5 ml). The resulting mixture was heated at reflux for overnight, then cooled to a sufficient temperature, and filtered through a Celite® cartridge. The resulting solution was concentrated under reduced pressure, taken up in SiO2, and purified by column chromatography (50% EtOAc / 50% hexane) to give 4- (3-methoxycarbonyl-4methoxyphenoxy) nitrobenzene, in the form of a yellow powder (3 g). TT 115-118 ° C. 40 О

Step 2. 4- (3-Carboxy-4-methoxy-phenoxy) -1-nitrobenzene: A mixture of 4- (3-methoxycarbonyl-4- , 33 g) and water (5 ml) in MeOH (45 ml) was stirred at room temperature overnight and then heated at reflux for 4 hours. The resulting mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in water (50 ml), and the aqueous mixture was acidified with 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 4- (3-carboxy-4-methoxy-phenoxy) -1-nitrobenzene (1.04 g).

Step 3. To a solution of 4- (3-carboxy-4-methoxy-phenoxy) -1-nitrobenzene (0.50 g, 1, 75 mmol) in CH2Cl2 (12 ml) was added SOCl2 (0.64 ml, 8.77 mmol) in portions. The resulting solution was heated to reflux for 18 hours, cooled to room temperature, and concentrated under reduced pressure. The resulting yellow solids are dissolved in CH 2 Cl 2 (3 ml), then the solution is treated with a solution of methylamine (2.0 M in THF, 3.5 ml, 7.02 mmol) in portions (CAUTION: gas), and stirred overnight at room temperature for 4 h. The resulting mixture was treated with 1N NaOH solution, then extracted with CH2Cl2 (25 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give 4- (3- (N-501665158 methylcarbamoyl) -4-methoxyphenoxy) -4-nitrobenzene as a yellow solid product (0.50gp 95%).

NHMe Step 4. 4- (3- (4-Methylcarbamoyl) -4-methoxyphenoxy) aniline: A suspension of 4- (3- (N -methylcarbamoyl) -4methoxyphenoxy) -1- nitrobenzene (0.78 g, 60 mmol) and 10% Pd / C (0.20 g) in EtOH (55 mL) was stirred at 1 for H2 (bubble) for 2.5 days, then filtered through a Celite The resulting solution was concentrated under reduced pressure to give the product. 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et3N / 99.9% EtOAc) Rf 0.36 A9. A general method for the preparation of omega-alkylphthalimide containing anilines. Synthesis of 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione

Step 2. Synthesis of 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione: A suspension of nitrophenoxy) -2-methylisoindoline-1,3- dione (0.87 g, , 78 mmol) and 10% Pd / C (0.10 g) in MeOH was stirred at 1 at H 2 (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 SiO2 (60% EtOAc / 40% hexane) to give 5- (4-amino- phenoxy) -2- methylisoindoline-1,3- dione , under a yellow solid (0.67 g, 86%): TLC (40% EtOAc / 60% hexane) Rf 0.27. A10. A general method for the preparation of omega-carbamoyl anilines by the interaction of omega-alkoxycarbonyl precursors with 2-amines. Synthesis of 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxyaniline

N-Me

Step 1. Synthesis of Nanotrophenoxy) -2-methylisoindoline-1,3,5-dione: A suspension of 5- (4-nitrophenoxy) isoindoline-1,3- 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temperature for 1 h, then treated with methyl iodide (0.3 mL, The resulting mixture was stirred at room temperature overnight, then cooled to 0 ° C and treated in the arc (15 mL), and the resulting solids were collected and dried under reduced pressure, there is thus obtained 5- (4-nitrophenoxy) -2-methylisoindoline-1,3-dione, in the form of Step 1: Synthesis of 4-Chloro-2- (N- (2-morpholin-4-ylethyl) - carbamoyl) pyridine To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, step 2, (1.01 g, 4.86 mmol) in THF (20 mL) (2.55 ml, 19.4 mmol) was added and the resulting solution was heated at reflux temperature for 20 hours, cooled to room temperature, treated with water (50 ml) . The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 4-chloro-2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH / 90% EtOAc) Rf 0.50. 50 17 65158

Synthesis of 4- (1-oxoisoindolin-5-yloxy) aniline Step 2. Synthesis of 4- (2- (N- (2-Morpholin-4-ylethyl) -carbamoyl) pyridyloxy) aniline. A solution of 4-aminophenol (0.49 g, 52.5 mmol) and potassium tert-butoxide (0.53 g, 4.75 mmol) in DMF (8 ml) was stirred at room temperature over 2 h, then sequentially acted with 4-chloro-2- (N- (2-morpholin-4-yl-ethyl) -carbamoyl) pyridine (1.22 g, 4.52 mmol) and K 2 CO 3 (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 ° C overnight, cooled to room temperature, and partitioned between EtOAc (25 mL) and saturated NaCl (25 mL). The aqueous layer was extracted with EtOAc (25 mL). The combined organics were washed with saturated NaCl solution (3 x 25 mL) and concentrated in vacuo to give the brown brown solids obtained by column chromatography (58 g, gradient from 100% EtOAc to 25% MeOH / 75% EtOAc) to give 4- (2- (14- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy (1.0 g, 65%): TLC (10% MeOH / 90%

All. Basic Method for Reducing Nitrates to Arylamines Synthesis of 4- (3-carboxyphenoxy) -aniline

10 15 pressure. Purification 20 (a) Aniline c) Rf 0.32; 25 Step 1. Synthesis of 5-hydroxyisoindolin-1-one To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 ml) was slowly added portions of zinc powder (47.6 g, mmol), then the mixture is heated to reflux for 40 minutes, filtered hot and concentrated under reduced pressure. The reaction was repeated using the same scheme, and the combined oil residue was purified by column chromatography (1.1 Kg SiO2, gradient of 60% EtOAc / 40% hexane to 25% MeOH / 75% EtOAc) to give 5- hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) Rf 0.17; HPLC ES-MS m / z 250 ((M + H) +);

30

A suspension of 4- (3-carboxyphenoxy) -1-norbenzene (5.38 g, 20.7 mmol) and 10% Pd / C (0.05 g) in MeOH (120 mL) was stirred under 40N H2 ) for 2 days. The resulting mixture was filtered through a pad of Celite®, then concentrated under reduced pressure to give 4- (3-carboxyphenoxy) aniline as a brown solid (2.26 g, 48%): 45TLC (10% MeOH / 90% CH2Cl2) Rf 0.44 (Nails). A12. Basic method for synthesizing naisoindolinone-containing anilines. Step 2. Synthesis of 4- (1-isoindolinon-5-yloxy) -1-nitrobenzene To a suspension of NaH (0.39 g, 16.1 mmol) in DMF at 0 ° C was added 5-hydroxyiso- 1-one (2 g, 13.4 mmol) in portions. The slurry was allowed to warm to room temperature and stirred for 45 min, then 4-fluoro-1-nitrobenzene was added, and then the mixture was heated to 70 ° C for 3 h. The mixture was cooled to 0 ° C and treated dropwise with water until a precipitate was obtained. The resulting solids were collected to give 4- (1-isoindolinon-5-yloxy) -1-nitrobenzene as a tan solid (3.23 g, 89%): TLC (100 EtOAc) , 35. 18 65158

Step 3 Synthesis of 4- (1-oxoisoindolin-5-yloxy) aniline A suspension of 4- (1-isoindolinone) -1 -nitrobenzene (2.12 g, g) in EtOH (50 ml) was stirred at room temperature for 4 hours, filtered through a Celite® cartridge. Concentration under reduced pressure gave 4- (1-oxoisoindoline-5-aniline as a dark yellow: IRIS (100% EtOAc) Rf 0.15, A13. Basic method for the synthesis of carbamoyl anilines by the form of Cl- amide followed by reduction of nitroarine Synthesis of 4- (3-N-methylcarbamoyl-phenoxy) aniline: -5-yl-Pd / Catosulfate after this co-yloxy) Step 2 Synthesis of 4- (3-Carboxy-phenoxy) -1-nitrobenzene To a vigorously stirred mixture of 4- (3-ethoxycarbonylethoxy) -1-1nitrobenzene (5.14 g, 17.9 mmol ) in a 3: 1 THF / aqueous solution (75 mL) ml) was added a solution of LiOH. H2O (150 g, 35.8 mmol) in water (36 mL). The resulting mixture was warmed to 50 ° C overnight, then cooled to room temperature, concentrated under reduced pressure and brought to pH 2 with a 1M solution of HCl. The resulting brown-yellow solids were collected by filtration and washed with hexane to give 4- (3-carboxyphenoxy) -1-nitrobenzene (4.40 g, 95%).

/ V

Step 1: Synthesis of 4- (3-carbonylethoxy) -1 -nitrobenzene A mixture of 4-fluoro-1-nitrobenzene (150 mmol), ethyl 3-hydroxybenzoate (25 g) and K2CO3 (41 g, 300 mmol) The resulting mixture was extracted with EtOAc (3 x 150 mL) and the combined phases were washed successively with 100 mL) and saturated solution (Na2 SO4), concentrated under reduced pressure, and the residue was purified by column chromatography (10% EtOhexane) to give 4- (3-carbonylethoxy) -1 -nitrobenzene, (38 g), ethoxycarboxaldehyde (125 mg, 25 mmol)

NHMe Step 3. Synthesis of 4- (3- (L -methylcarbamoyl) phenoxy) -1-nitrobenzene A mixture of 4- (3-carboxyphenoxy) -1nitrobenzene (3.72 g, ), EDC1. HCl (3.63 g, 18.6 mmol), N-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF, 8 mL, 16 mmol) in CH2Cl2 stirred at room temperature for 3 days, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 ml) and the resulting mixture was extracted with 1M HCl solution (50 ml). The aqueous layer was extracted again with EtOAc (2 x 50 ml). The combined organic phases are washed with saturated NaCl solution (50 ml), dried (Na2SO4), and concentrated under reduced pressure to give 4- (3- (N-methylcarbamoyl) phenoxy) nitrobenzene, the oil form (1.89 g). (16 ml, 150 mmol) (35 ml) was refluxed with 40 ml of water (3 x 100 ml), under reduced pressure (45 ° C), 90% ethoxy

NHMe

Step 4. Synthesis of 4- (3- (N-methylcarbamoyl) phenoxy) -aniline A suspension of 4- (3- (N -methylcarbamoyl) phenoxy) -1nitrobenzene (1.89 g, , 95 mmol) in 5% Pd / C (0.24 g) in EtOAc (20 ml) was stirred under an H2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The residue was purified by 15 column chromatography (5% MeOH / 95% CH 2 Cl 2). The resulting oil solidified overnight to give 4- (3- (N-methylcarbamoyl) phenoxy) -aniline as a yellow solid (0.5 g, 2056%). A14. A general method for synthesizing omega-carbamoyl anilines by formation of EDCI-mediated amide followed by reduction of nitrobenzene. Synthesis of 4-3- (5-methylcarbamoyl) pyridyloxy) -aniline Step 2. Synthesis of 4-3- (5-methylcarbamoyl- ) pyridyloxy) -aniline A suspension of 4-3- (5-methylcarbamoyl) -pyridyloxy) -1 -nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd / C in MeOH / EtOAc was stirred in an atmosphere of H2 (balloon) for 72 hours. The resulting mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (gradient of 10% EtOAc / 90% hexane to 30% EtOAc / 70% hexane to 50% EtOAc / 50% hexane) to give 4-3- (5-methylcarbamoyl) pyridyloxy) 1 H NMR (CDCl 3)? 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, , 1H), 8.51 (d, 1H), 8.87 (d, 1H). A15. Synthesis of aniline by electrophilic nitration, followed by reduction. Synthesis of 4- (3-N-methylcarbamoyl-phenoxy) aniline

Step 1. Synthesis of 4-3- (5- (benzoyl) pyridyloxy) -1-nitrobenzene To a suspension of NaH (0.63 g, 26 in DMF (20 ml) , 1 mmol) in DMF The resulting solution was added to a solution of 4-fluorobenzene (1.4 mL, 13.1 mmol) in DMF, the resulting mixture was heated to 70 ° C overnight, cooled to room temperature and The reaction mixture was treated with MeOH (5 mL), water (5 mL), and the resulting mixture was extracted with EtOAc (100 mL), the organic layer was dried under reduced pressure and the residue was purified by column chromatography (EtOAc / 70% hexanes) methyl-carbamoyl) pyridyloxy) -1-ene (0.60 g). (10 ml) was added and this solution was concentrated in vacuo (30% yielded 4-3-nitrobenzaldehyde 20

Step 1. Synthesis of N-methyl-3-bromo-benzenesulfonamide 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 temperature overnight. The resulting mixture was partitioned between EtOAc (25 mL) and 1 M HCl solution (25 mL). The aqueous phase was re-extracted with EtOAc (2 x 25 mL). The combined organic phases are sequentially washed with water (2 x 25 mL), saturated NaCl solution (25 mL), dried (MgSO4), and concentrated under reduced pressure to give N-methyl-3-bromobenzenesulfonamide (2, 8 g, 99%). 65158

NHMe Step 2. Synthesis of 4- (3- (N-methylsulfamoyl) phenyloxy) -benzene To a suspension of phenol (1.9 g, 20 mmol), K2CO3 (6.0 g, 40 mmol) (4 g, 20 mmol) in THF (25 mL) was added N-methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol) overnight, cooled to room temperature, partitioned between EtOAc (50 mL) and 1N HCl (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). Combine the combined phases with a sequencer (2 x 50 mL), and with a saturated NaCl solution, dry (MgSO4), and concentrate under reduced pressure. The residual oil was purified by column chromatography on silica gel (70% hexane) to give 3- (N-methylsulfamoyl) phenoxy) benzene 10

(50 ml), washed with water (30%) to give 4- (0.30 g) at 15-20 DEG C. Step 4. Synthesis of 4- (3- (N (0.30 g) and 10% Pd / C (0.030 ml) in EtOAc (20 ml) was added dropwise to a solution of 4- (3- (N- The mixture was filtered through a pad of Celit®, the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography (30% EtOAc / 70% hexane) to give 4- (3- (L-methylsulfamoyl) phenoxy) aniline (0.070 g) A16 Modifiers nd omega-ketones. Synthesis of 4- (4- (1- (1h-methoxy) imino-aminoethyl) phenoxyaniline HC1 salt.

Step 3 Synthesis of 4- (3- (Methylsulfamoyl) phenoxy) -1-nitrobenzene To a solution of 34- (3- (N-methylsulfamoyl) phenoxy) benzene (0.30 g, 14 mmol) in TEA (6 mL) at -10 ° C / hrpH6aBaNaNO2 (0.097g, 1.14mmol) was added portionwise over 5 minutes. The resulting solution was stirred at -10 ° C for 1 h, then allowed to warm to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (10 mL) and water (10 mL). The organic phase was washed successively with water (10 ml), saturated NaCl solution (10 ml), dried (MgSO4), and concentrated under reduced pressure to give 4- (3- (N-methylsulfamoyl) -phenoxy) -1-nitrobenzene (0.20 g). This product was stored for the next step without further purification. To a suspension of 4- (4-acetylphenoxy) -aniline HCl salt (prepared in a manner analogous to Method A13, Step 4, 1.0 g, 3.89 mmol) in EtOH (10 mL) and pyridine ml) was added O-methylhydroxylamine HCl (0.65 g, 7.78 mmol, 2.0 eq.). The resulting solution was heated to reflux for 30 minutes, 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- (1- (L-methoxy) iminoethyl) phenoxyaniline HCl salt as a yellow solid (0.85 g): ILC (50% EtOAc / 50% petroleum ether) Rf 0.78 1 H-NMR (DMSO-d6) δ 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m / z 257 (M + H) +). Synthesis of N- (o-meryloxyalkyl) amides. Synthesis of 4- (4- (2- [4- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline 21 65158

Step 1: 4-Chloro-14- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide To a solution of 4-chloro- N- (2 -ethyl) pyridine-2carboxamide (prepared analogously to Method A2, Step 3b; (1.59 g, 8.2 mmol, imidazole (1.12 g, 16.4 mmol, 2.2 eq.), 5 g., In anhydrous DMF (7 ml), was added triethylsilyl chloride The residue was partitioned between water (10 mL) and EtOAc (10 mL), extracted with EtOAc, the dried organic layers were dried and concentrated under reduced pressure to give 4-chloro -N- (2-triiso-silyloxy) -ethylpyridine-2-carboxylic acid The orange oil solution (2.32 g, 88% product was used in the next step further purification, hydroxypropyl chloroformate (7.4 mmol) and isopro-1.1 eq.) was added to the 3 h coc- 20gSO4), in the case of co-propyl amide, below 25%).

30 Step 2. 4- (4- (2-N- (2-tritylpropyloxy) ethylcarbamoyl) pyridyloxylates To a solution of 4-hydroxyaniline (6.0mmol) in DMF (8ml) , 0 mmol, 1.0 eq.) To give an exothermic reaction. When this mixture is cooled to room temperature, a solution of 4-chloro-triisopropylsilyloxy) -ethyl) -pyridineamide (2.32 g, 1 eq.) In DMF then K 2 CO 3 (0.42 g, 3.0 mmol). The resulting mixture was heated at 80 ° overnight, then an additional portion of potassium tert-butoxide: 3 mmol, 0.5 eq. ), and the mixture was stirred for another 4 h. The mixture was stirred at 0 ° C in an ice / water bath, then water was added slowly (approximately 1 ml of the extraction layer was extracted with EtOAc / 3 x HSS (0.70 g of a reaction mixture, -2-N- (2-carboxamide-40 (4 ml), and 50 eq.) Was added (0.34 g, 45 at 80 ° C drops, ) The combined organic layers were washed with a saturated solution of NaCl (20 mL), dried (MgSO4), and concentrated under reduced pressure.The brown residual oil was purified by column chromatography (SiO2, 30% EtOAc / 70% petroleum ether) to give 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarb amyl) pyridyloxyaniline as a clear, light brown oil (0.99 g, 38%) A18 Synthesis of 2-pyridinecarboxylate esters by oxidation of 2-methylpyridines Synthesis of 4- (5- -methoxycarbonyl) pyridyloxy) -aniline

Step 1. 4- (5- (2-Methyl) pyridyloxy) -1-nitrobenzene. A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-nitrobenzene (9.8 g, 91.6 mmol), K 2 CO 3 (25 g, 0 eq.) In DMF (100 mL) was heated to reflux 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 successively washed with water (2 x 100 mL) and sat. NaCl (100 mL), dried (MgSO4), and concentrated under reduced pressure to give 4 - (5- (2-methyl) pyridyloxy) -1-nitrobenzene as a brown solid (12.3 g).

Step 2. Synthesis of 4- (5- (2-methoxycarbonyl) pyridoxy) -1-nitrobenzene. A mixture of 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene (1.70 g, 7.39 mmol) and triiodide dioxide (2.50 g, 22.2 mmol, 3 eq.) In pyridine, (20 ml) was heated at reflux for 5 h, then cooled to room temperature. The slurry was filtered, then concentrated under reduced pressure, dissolved in MeOH (100 mL). A solution of HCl is then added to the solution and the mixture is heated to reflux temperature for 3 h, brought to room temperature and concentrated under reduced pressure. The residue is partitioned between EtOAc (50 ml) and 1N NaOH solution The combined organic layers were washed with water (2 x 50 mL) and brine (50 mL), dried (MgSO4 concentrated under reduced pressure, purified by column chromatography (SiO2, 50% EtOAc / 50% , 4- (5- (2-methoxycarbonyloxy) -1-nitrobenzene (0.70 g) was obtained, the residue was cooled, (50 mL), x 50 mL), washed with sat. (4 mL), and the isopropylmagnesium chloride

OMe Step 3. Synthesis of 4- (5- (2-methoxy-carbonyl) -pyridoxy) aniline. A suspension of 4- (5- (2-methoxycarbonyl) -pyridoxy) -1 -nitrobenzene (0.50g) and 10% Pd / C (0.050ml) in a mixture of EtOAc (20ml) and MeOH placed in an atmosphere of H2 (balloon) overnight. The resulting mixture was filtered through a pad of Celite®, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 70% EtOAc / 30% hexane) to give 4- (5- (2-methoxycarbonyl) pyridoxy) -aniline (0.40 g). A19. Synthesis of omega-sulfonylphenylanilines. Synthesis of 4- (4-methylsulfonyl-phenoxy) aniline. 1-nitrobenzene (2.0 g, 7.7 mmol) in CH 2 Cl 2 (75 mL) at 0 ° C was added m-CPBA (57%, 4.0 g) slowly and the reaction mixture was stirred at room temperature 5 h. The reaction mixture was treated with 1N NaOH solution (25 mL). The organic layers are then washed with 1 N NaOH solution (25 ml), the addition (25 ml) and saturated NaCl solution (25 ml), dried (MgSO4), and concentrated at reduced pressure , to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene, the solid form solid (2.1 g). Step 2. 4- (4-Methylsulfonylphenoxy) -aniline: 15 4- (4-methylsulfonylphenoxy) -1-nitrobenzene is reduced to the aniline in a manner analogous to that described in Method A18, Step 3. B. Synthesis of urea B1 precursors. Basic method for synthesizing isocyanates from anilines using CDI. Synthesis of 4-bromo-3- (trifluoromethyl) phenylisocyanate. 25

Step 1 Synthesis of 4-bromo-3- (trifluoromethyl) aniline HCl salt To a solution of 4-bromo-3- (trifluoromethyl) aniline (64g, 267mmol) in Et2O (500ml) solution of HCl (1M in Et2O, 300 mL), and the resulting mixture was stirred at room temperature for 16 h. The resulting pink-white precipitate was filtered off and washed with Et 2 O (50 mL), to give 4-bromo-3- (trifluoromethyl) -aniline HCl salt (73 g, 98% ).

45

Step 1: 4- (4-Methylsulfonylphenoxy) -1-nitrobenzene: To a solution of 4- (4-methylthiophenoxy) -Etapa 2. Synthesis of 4-Bromo- 3- (trifluoromethyl) phenylisocyanate 23 65158 To a slurry of the 4-bromo-3- (trifluoromethyl) aniline HCl salt (36.8 g, 133 mmol) in toluene (278 ml) was treated dropwise with trichloromethylchloroformate and the resulting mixture heated at reflux temperature over 18 hours. The resulting mixture was concentrated under reduced pressure. The residue is treated with toluene (500 ml), then concentrated under reduced pressure. The residue was treated with CHCl3 (500ml), then concentrated under reduced pressure. The CH 2 Cl 2 / concentration under reduced pressure procedure was repeated, and the resulting amber oil was kept at -20 ° C for 16 h to give 4-bromo-3- (trifluoromethyl) phenylisocyanate as reddish -black solid (35.1 g, 86%): GC-MS m / z 265 (M +). C. Methods for urea Cl formation a. (4-chloro-3- (trifluoromethyl) phenyl) -N4 '- (4- (2- (N -methylcarbamoyl) -4- pyridyloxy) phenyl) urea 25

NHMe A solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (14.60 g, 65.90 mmol) in CH 2 Cl 2 (35 mL) was added dropwise to a suspension of 4- (2- (Method A2, Step 4, 16.0 g, 65.77 mmol) in CH 2 Cl 2 (35 mL) at 0 ° C, and the resulting mixture was stirred at ambient temperature for 22 h. The resulting yellow solids were collected by filtration, then washed with CH2Cl2 (2 x 30 mL), and dried under reduced pressure (approximately 1 mm Hg) to give N- (4-chloro-3 (trifluoromethyl) phenyl) -N '- (4- (2- (14-methylcarbamoyl) -4-pyridyloxy) phenyl) urea but an off-white solid (28.5 g, 93%): mp 207-209 ° C; 1 H-NMR (DMSO- d6) δ 2.77 (d, J = 4.8 Hz, , 16 (m, 3H), 7.37 (d, J = 2.5 Hz, 1H), 7.62 (m, 4H) , 49 (d, J = 5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 465 ((M + H) < + >);

Clb. Basic Method for Synthesis of 50 Ureas by Isocyanate Sanylin Reaction. Synthesis of N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-

A solution of 4-bromo-3- (trifluoromethyl) phenyl isocyanate (Method B1, Step 2, 8.0 g, 30.1 mmol) in CH2Cl2 (80 mL) was added dropwise to a solution of 4- (Method A2, Step 4, 7.0 g, 28.8 mmol) in CH 2 Cl 2 (40 mL) at 0 ° C, the resulting mixture was stirred at room temperature in The resulting yellow solids were collected by filtration, then washed with CH 2 Cl 2 (2 x 50 mL), and dried at reduced pressure (approximately 1 mm Hg) at 40 ° C to give N- (4-6-methoxy-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N- as a pale yellow solid (13.2 g, 90%): mp 203-205 ° C; 1 H-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, , 16 (m, 3H), 7.37 (d, J = 2.5 Hz, 1H), 7.58 (m, 3H) , 11 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.77 (br d, 9.21 (s, 1H); HPLC ES-MS m / z 509 ((M + H) +);

Clc. Basic synthesis method is achieved by reaction of isocyanate-sanitiline. Synthesis of N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (2-methyl- 4- (2- (N -methylcarbamoyl) (4-pyridyloxy)

To a solution of 2-methyl-4- (2- (N -methylcarbamoyl) (4-pyridyloxy) aniline isocyanate (Method A5, 0.11g, 0.45mmol) in CH2Cl2 (1ml) 0.16 ml) and 4-chloro-3- (trifluoromethyl) phenyl) isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at ambient temperature for 6 h. water (5 ml). The aqueous layer was extracted again with EtOAc (3 x 5 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give N - (4-chloro-3- (trifluoromethyl) phenyl) -4- (2- N-methylcarbamoyl) (4-pyridyloxy) -phenyl) urea as a brown oil (0.11 g, 0.22 mmol): 1 H NMR (DMSO- d 6)? 2.27 2.77 (d, J = 4.8 Hz, 3H), 7.03 (dd, J = 8.5, 2.6 Hz, 1H) ), 7.15 (dd, J = 5.5, 2.6 Hz, 1H), 7.38 (d, J = 2.6 Hz, (D, J = 8.8 Hz, 1H), 8.17 (s, 1H), 8.50 (d, J = 5.5 Hz, (q, J = 5.2 Hz, 1 H), 9.52 (s, 1 H); HPLC ES-MS m / z 479 ((M + H) +).

Cld. Basic synthesis method is achieved by reaction of isocyanate-sanitiline. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4-aminophenyl) urea

To a solution of 4-chloro-3- (trifluoromethyl) phenyl) isocyanate (2.27 g, 10.3 mmol) in CH 2 Cl 2 (308 mL) was added p-phenylenediamine (3.32 g , 30.7 mmol). The resulting mixture was stirred at room temperature for 1 h, then treated with CH 2 Cl 2 (100 mL), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc (3 x 5 mL). The aqueous layer was extracted again with EtOAc (110 mL) and MeOH (15 mL), and the clear solution was washed with 0.05 N HCl solution. The organic layer was concentrated under reduced pressure to give impure N- (4-chloro-3- (trifluoromethyl) phenyl) -14 '- (4-aminophenyl) urea (3.3 g) (100% EtOAc) Rf 0.72.

Cle. Basic method for synthesizing ureas by isocyanate reaction with aniline. Synthesis of 14- (4-chloro-3- (trifluoromethyl) phenyl) -14 '- (4-ethoxycarbonylphenyl) urea

(4-chloro-3- (trifluoromethyl) aniline (3.21 g, 16.4 mmol) was added to a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH 2 Cl 2 ) and the solution was stirred at room temperature overnight. The suspension was diluted with CH2Cl2 (50 mL) and filtered to give N- (4-chloro-3- (trifluoromethyl) phenyl) (4-ethoxycarbonylphenyl) urea as a white solid (5.93 g, 97%): TLC (40% EtOAc / 60% hexane) Rf 0.44. of ureas by reacting isocyanate with aniline Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- boksilfenil) urea 20

To a solution of 4-chloro-3- (trifluoromethyl) phenyl) isocyanate (1.21g, 5.46mmol) in CH 2 Cl 2 (8ml) was added 4- (3-carboxyphenoxy) (Method A11, 0.81 g, 5.76 mmol), the resulting mixture was stirred at room temperature overnight, then treated with MeOH (8 mL), and stirred overnight at 2 h. The resulting brown solids were triturated with 1: 1 EtOAc / hexane to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- carboxylphenyl) urea as an off-white solid (1.21 g, 76%). C2a. A general method for urea synthesis by an aniline reaction with N, N'-carbonyl diimidazole followed by a second secondary aniline. Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2- (L- methylcarbamoyl) -4- pyridyloxy) phenyl) urea 45

To a solution of 2-methoxy-5- (trifluoromethyl) aniline (0.15 g) in anhydrous CH 2 Cl 2 (15 ml) at 0 ° C was added CDI (0.13 g). The resulting solution was allowed to warm to room temperature over 1 h, stirred at ambient temperature for 16 h, then treated with 4- (2- (4-methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 5 hours at 72 hours, then treated with H2O (125 ml). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organics were washed with saturated NaCl solution (100 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was saponified (90% EtOAc / 10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residual oil was purified by column chromatography (gradient of 33% EtOAc / 67% hexane, 50% EtOAc / 50% hexane to 100% EtOAc) to give N- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.098 g, 30%), light reddish solid: ILC (100% EtOAc) Rf 0.62; 1 H NMR (DMSO-d6) δ 2.76 (d, J = 4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 m, 1 H), 8.75 (d, J = 4.8 Hz, 1 H), 259.55 (s, 1 H); FAB-MS m / z 461 ((M + H) < + >). C2b. A general method for urea synthesis by an aniline reaction with N, N'-carbonyl diimidazole followed by a second secondary aniline. Symmetric ureas as byproducts in the reaction procedure of N, N'-carbonyl diimidazole. Synthesis of bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea 35

To a stirred solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH 2 Cl 2 (15 ml) at 0 ° C was added CDI (0.13 g). The resulting solution was allowed to warm to room temperature over 1 h, then stirred at room temperature for 16 h. The resulting mixture was treated with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 72 hours, then treated with water ml). The resulting aqueous 50% mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with a saturated solution of NaCl (100 mL), dried (MgSO4), 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- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.081 g, 44% 100% EtOAc) Rf 0.50; 1 H NMR (DMSO-d6) δ 2.76 (d, J = 5.1 Hz, 6H), 3.96 (s, 3H), 7.1-7.6 (m, 12H) (d, J = 5.4 Hz, 1H), 8.75 (d, J = 4.8 Hz, 2H), 8.86 (s, 2H), 9.55 (s, 1H); HPLC ES-MS m / z 513 ((M + H) +). C2c. Basic synthesis method is achieved by reaction of isocyanate-sanitiline. Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (1,3-dioxoisoindolin-5- yloxy)

To a stirred solution of 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.47 mmol) in CH 2 Cl 2 (1.5 mL) was added 5- (4 aminophenoxy) isoindoline- -dione (Method A3, Step 3, 0.12 g, 0.47 mmol). The resulting mixture was stirred for 12 h, then treated with CH 2 Cl 2 (10 mL) and MeOH (5 mL) and further stirred for 2 h. The resulting mixture was successively washed with 1N HCl solution (15 mL) and brine saturated NaCl solution (15 ml), dried (MgSO4), and concentrated under reduced pressure to give (2-methoxy-5- (trifluoromethyl) phenyl) -NX4- (1,3- 5-yloxy) phenyl) urea as a white solid (0.2 g, 96%): TLC (70% EtOAc / 30% hexane) Rf 0.50; [delta] 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J = 9.3 Hz, Hz, 1 H), 8.53 (brs, 2H), 9.57 (s, 1H), 11.27 (brs, 1H); HPLC ES-MS m / z 472.0 ((M + H) +, 100%). C2d. Basic method for synthesizing urea by reacting aniline with N, N'-65158 carbonyl diimidazole followed by addition of a second aniline. Synthesis of N- (5-tert-butyl) -2- (2,5-dimethyl-pyrrolyl) -enyl) -N- (2- (N-

NHMe 10 To a stirred solution of CDI (0.21 g, 1.30 mmol) in CH2Cl2 (2 mL) was added 5- (tert-butyl) -2- (2,5-dimethylpyrrolyl) aniline 2, 0.30 g, 1.24 mmol). The resulting mixture was stirred at room temperature for 4 h then 4- (2- (N-methylcarbamoyl) -4-pyridyloxy aniline (0.065 g, 0.267 mmol) was added once. The resulting mixture was heated at 36 ° C overnight, then cooled to room temperature and diluted with EtOAc (5 mL). The resulting mixture was successively washed with water (15 ml) and 1N HCl solution (15 ml), dried (MgSO4), and filtered through a pad of silica gel (50 ml) to give N- (5- -butyl) -2- (2,5-dimethylpyrrolyl) phenyl) -N4 '- (4- (2- (N -methylcarbamoyl) -4- (pyridyloxy) phenyl) urea, a yellowish solid (0.033 g, 24%): TLC (40% EtOAc / 60% hexane) Rf 0.24; 1 H NMR (acetone-d6) , 89 (d, J = 4.8 Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (D, J = 5.4 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.80 (br s, ES-MS m / z 515 ((M + H +, 100%) C33 Combined method for synthesizing diphenyl ureas using triphosgene Ed of the anilines to be combined were dissolved in dichloroethane (0.10 M), and this solution was added to a 8 ml vial (0.5 ml) containing dichloroethane (1 ml), to which was added a solution of bis (trichloromethyl) carbonate (0.12 M in dichloroethane, 0.2 mL, 0.4 eq.), then diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 eq.). The vial was sealed and heated at 80 ° C for 5 hours, then allowed to cool to room temperature over approximately 10 hours. Diisopropylethylamine (0.35 M in dichloroethane, 0.2 ml, 1.2 eq.) Was then added dropwise. 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 reversed phase HPLC. C4. Basic method for the synthesis of urea by aniline and phosgene reaction, followed by the addition of a second aniline. Synthesis of 14- (2-methoxy-5- (trifluoromethyl) phenyl) -N- (4- (2- (N- 0.10 M in dichloroethane, 0.5 mL 1.0 eq.), 27

To a stirred solution of phosgene (1.9 M toluene, 2.07 g, 1.30 mmol) in CH2Cl2 (20 mL) at 0 was added anhydrous pyridine (0.32 mL) and then 2-methoxy -5- (trifluoromethyl) -aniline (0.75 g). The yellow solution was allowed to warm to room temperature, with a precipitate formed over time. The yellow mixture was stirred for 1 h, then concentrated under reduced pressure. The resulting products were treated with anhydrous toluene (20 ml), then with 4- (2- (L-methylcarbamoyl) -4-pyridyloxy) aniline (prepared according to method A2, 0.30 g) is heated at 80 ° for 20 h, then allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL), then made alkaline with a saturated solution of NaHCO3 (2-3 mL). The alkaline solution was extracted with EtOAc (2 x 250 mL). The organic layers were washed separately with saturated NaCl solution, combined, dried (MgSO4), and concentrated under reduced pressure. The resultant pink-brown residue is dissolved in MeOH and absorbed in SiO2 (100 g). After purification by column chromatography (300 g SiO2 gradient from 1% Et3N / 33% EtOAc / 66% hexanes to 1% Et3N / 99 EtOAc to 1% Et 3 N / 20% MeOH / 79% EtOAc) followed by concentration under reduced pressure at 45 ° C yields a hot concentrated solution in EtOAc, treated with sulfene (10 ml) Crystallization 50 65158 N- (2-Methoxy-5- (trifluoromethyl) phenyl) -N- (4- (2- (N -methylcarbamoyl) -4- (pyridyl) oxyphenyl) urea (0.44g), TLC (1% Et3N / 99% EtOAc) Rf0.40 D. Mutual Conversion of Ureas DI a.Converted (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4- (3-methoxycarbonylphenyl) -carbonylaminophenyl) ) urea 10

To a solution of 14- (4-chloro-3 - ((difluoromethyl) phenyl) -N- (4-aminophenyl) urea (Method Cld, 0.050 g, 1.52 mmol), monomethylphosphonate , 25 g, 1.38 mmol), HOBT.H 2 O (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added EDC1.HCl (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (25 mL) and successively washed with water (25 mL) and saturated NaHCO3 The organic layer was dried (Na2SO4) and concentrated under reduced pressure, and the resulting solids were triturated with EtOAc (80% EtOAc / 20% hexanes) to give (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea (0.27 g, 43% 121-122; TLC (80% EtOAc / 20% hexane) Rf 0.75;

Dlb. Conversion of omega-carooxyphenyl ureas to omega- (arylcarbamoyl) phenyl ureas. Synthesis of N 4 -chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea 20

NHMe 40 To a solution of T4- (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4- (3methylcarbamoylphenyl) -carbonylaminophenyl) urea (0.14 g, 0.48 mmol) (0.080 g, 0.53 mmol), HOBT.H 2 O (0.14 g, 1.07 mmol) and N-methylmorpholine (0.5 mL, 1.07 mmol) in DMF (3 mL) 0 ° C was added EDCI.HCl (0.10 g, 0.53 mmol). The resulting mixture was allowed to warm to room temperature and stirred overnight to give the resulting mixture (10 ml) , 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 (17 g, gradient of 70% EtOAc / 30% hexane to 10% MeOH / 90% EtOAc) to give N- (4-chloro-3 - ((trifluoromethyl) N- (4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea as a white solid (0.097 g, 41%): mp 225-229 °; TLC (100% EtOAc) Rf 0.23;

Die. Combination of converting omega-carboxyphenyl ureas into omega- (arylcarbamoyl) phenyl ureas. Synthesis of N 4-Chloro-3 - ((trifluoromethyl) phenyl) -N- (4- (N -pyridyl) carbamoyl) phenyl) carbamoyl)

To a mixture of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (3-carboxyphenyl) urea (Method Clf (0.030 g, 0.67 mmol) and N -oxo- - (methylpolystyrene) carbodiimide (55mg) in 1,2-dichloroethane (1ml) was treated with a solution of 3-aminopyridineCH2Cl2 (1M, 0.074ml, 0.074mmol) (In case of insolubility or turbidity, The resulting mixture was heated at 36 ° C overnight, then treated with THF (1 mL) and the heating continued for 18 h. The resulting mixture was treated with a mixture of (4-isocyanatomethyl) styrene (0.040 g) and the resulting mixture was stirred at 36 ° C. The solution was filtered through a plug of silica gel (1 g). After concentrating under reduced pressure, N- (4-chloro-3- ( (trifluoromethyl) phenyl) -N '- (4- (N- (3-pyridyl) carbamoyl) phenyl) carbamoylphenyl) urea (0.024 g, 59%): TLC (70% EtOAc / 30% Rf0.12, D2 Conversion of omega-carboalkoxyalkyl ureas to omega-carbamoyl ureas. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- [4- (3 -methylcarbamoylphenyl)

To a sample of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) (1 M in THF, 1 mL, 1.7 mL) and the resulting mixture was stirred at room temperature overnight then concentrated under reduced pressure to give 14- (4- chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3 -methylcarbamoylphenyl) -carboxyaminophenyl) urea as a white solid, mp 247; TLC (100% , 35. D3 Conversion of Omega-Carboalkoxyaryl Ureas to Omega-Carboxyaryl Ureas Synthesis of l 4- (4-Chloro-3 - ((Tr fluoro-methyl) phenyl) -N '- (4-carboxyphenyl) urea 10 15

(4-chloro-3- (trifluoromethyl) phenyl) -N - ((4- (3- (5-carboxy- ) of urea Synthesis of 4-chloro-3- (trifluoromethyl) phenyl) -N - ((4- (3- (5methoxycarbonylpyridyl) oxyphenyl) urea from 4- trifluoromethyl) phenyl isocyanate and 4- (3- (5-methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) was prepared in analogy to Method Cl To a slurry of N- (4 -chloro- 3- (trifluoromethyl) ) Of N - ((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) 5 mmol) in water (1 mL), and stirred at room temperature The resulting mixture was brought to pH 5 with 1N HCl solution, the resulting precipitate was filtered off and washed with water, and the resulting solids were dissolved in EtOH (10 mL) The resulting solution in EtOH / concentration was repeated twice to give N- (4-chloro-3- (trifluoromethyl) phenyl) -14 '- ((4- - (3- (5-carboxypyridyl) oxyphenyl) urea (0.18 g, 71%). (Method J1, 5.93 g, 15.3 mmol) in MeOH (75 mL) was added aqueous KOH (3 mL) 2.5 N, 10 mL, 23 mmol). The resulting mixture was heated to reflux for 12 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water (50 ml), then treated with 1N HCl solution to pH 2 to 3. The resulting solids were collected and dried under reduced pressure to give N- (4- chloro-3 - ((trifluoromethyl) phenyl) -N- (4-carboxyphenyl) urea, white solid form (5.05 g, 92%) D4. Synthesis of N- (4-Chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- [3- (5- (2-dimethylaminoethyl) carbamoyl) phenyl) urea

30 35 40 45

Step 2 Synthesis of N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- [3- (5- (2-dimethylaminoethyl) carbamoyl) from N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- [3- (5-carboxypyridyl) oxyphenyl] urea (0.050 g, 0.011 mmol) (0.028 g, 0.17 mmol) and N-methylmorpholine (0.035 mL, 0.28 mmol) and EDCI.HCl (0.10 g, 0.17 mmol) , 0.53 mmol) in DMF (2.5 mL) was stirred at room temperature overnight.The solution was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (35 ml), dried (MgSO4), and concentrated under reduced pressure.The residue (4-chloro-3- (trifluoromethyl) phenyl) -14 - ((4- (3- (S) - (2-dimethylaminoethyl) carbamoyl) -pyridyl) oxyphenyl) urea (0.48 g, 84% 1 HNMR (DMSOd6) delta 2.10 (s, 6H) (M, 3H), 8.05 (s, 1H), 8.43 (s, 1H), 50.29 (s, 1H) 58 (t, 1H), 8.69 (s, 1H), 8.90 (s, 1H); 9.14 (s, 1H); HPLC ES-MS m / z 522 ((M + H) +). D5. Basic Method for Conversion HaN-

I (omega-silyloxyalkyl) amides. Synthesis of N- (4-Chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- [4- (2- (N- (2hydroxyethylcarbamoyl) pyridyloxyphenyl)

chs'

(2 mL) was added to a solution of sodium hydroxide (1.0 mL)

To a solution of 14- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4-4- (2- (N- (2- triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea In a manner analogous to Method Cl, 0.25 g, 0.37 mmol), in anhydrous THF was added tetrabutylammonium fluoride THF (2 ml).  The mixture was stirred at room temperature for 5 min, followed by water (10 ml).  The aqueous mixture was extracted with EtOAc (3 x 10 mL).  The combined organics were dried (MgSO4), and serried under reduced pressure.  The residue was purified by column chromatography (SiO2 gradient from 100% hexane to 40% EtOAc / 60% hexane) to give N- (4-chloro-3 - ((trifluoromethyl) 4- (2- (N- (2-hydroxyethylcarbamoyl) pyridyloxyphenyl) urea the white solid (0.019 g, 10%).  Below are the compounds listed in the tables below which are synthesized according to the detailed experimental procedures given below: Synthesis of exemplified compounds (see compound characterization tables) Description 1: 4- (3-M methylcarbamoylphenoxy) aniline was prepared according to method A13. According to method C3, 3-tert-butylaniline interacts with bis (trichloromethyl) carbonate, followed by 4- (3-N-methylcarbamoylphenoxy) aniline to give the urea.  Description 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone are reacted according to Method A13, step 1, to give 4- (4-acetyl-phenoxy) -1 -nitrobenzene.  4- (4-acetylphenoxy) -1-nitrobenzene was reduced according to Method A13, Step 4, to give 4- (4-acetylphenoxy) -aniline.  According to method C3, 3-tert-butaniline is reacted with bis (trichloromethyl) carbonate followed by 4- (4-acetylphenoxy) aniline to give urea.  Description 3: According to Method C2d, 3-tert-butylaniline is reacted with CDI, followed by 4- (3-N-methylcarbamoyl) -4-methoxyphenoxy) -aniline, obtained according to Method A8, to yield urea.  Description 4: 5-tert-Butyl-2-methoxyaniline was converted to 5-tert-butyl-2-methoxyphenyl isocyanate according to process BI.  4- (3-N-methylcarbamoylphenoxy) aniline prepared according to Method A13 is reacted with an isocyanate according to Method C1a to yield urea.  Description 5: According to method C2d, 5-tert-butyl-2-methoxyaniline is reacted with CDI, followed by 4- (3- N -methylcarbamoyl) -4- methoxyphenoxy) aniline urea is obtained.  Description 6: 5- (4-aminophenoxy) isoindoline-1,3-dione was prepared according to method A3. According to method 26.5-tert-butyl-2-methoxyaniline is reacted with CDI followed by 5- (4-aminophenoxy) isoindoline-1,3-dione to give urea.  Description 7: 4- (1-oxoisoindolin-5-yloxy) aniline was synthesized according to Method A12. According to Method 2d, 5-tert-butyl-2-methoxyaniline is reacted with CDI followed by 4- (1-oxoisoindolin-5-yloxy) aniline to yield urea.  Description 8: 4- (3-N-methylcarbamoyl-phenoxy) aniline was synthesized according to method A13.  According to Method C2a, 2-methoxy-5- (trifluoromethyl) aniline is reacted with GDI followed by 4- (3-N-methylcarbamoylphenoxy) -aniline to give the urea.  Description 9: 4-Hydroxyacetophenone is 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 is reduced to 4- (4-acetylphenoxy) -5-aminopyridine.  2-methoxy-5- (trifluoromethyl) -aniline is converted to 2-methoxy-5- (trifluoromethyl) phenylisocyanate according to Method B1.  The isocyanate is reacted with 4- (4-acetylphenoxy) -5-amino-pyridine according to Method C1a to provide the desired product.  Description 10: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1, to give 4- (4-acetylphenoxy) -1-nitrobenzene.  4- (4-Acetyl-phenoxy) -1-nitrobenzene is reduced according to Method A13, Step 4, to give 4- (4-acetylphenoxy) aniline.  According to method C3, 5- (trifluoromethyl) -2-methoxybutylaniline interacts with bis (trichloromethyl) carbonate followed by 4- (4-acetylphenoxy) aniline to give the urea.  Description 11: 4-Chloro-N-methyl-2-pyridinecarboxamide synthesized according to the method A2 step 3a was reacted with 3-aminophenol according to method A2 step 4 using DMAC instead of DMF to give 3 - (- 2- (N-methylcarbamoyl) -4-pyridyloxy) aniline.  According to the method, C4,2-methoxy-5- (trifluoromethyl) -aniline is reacted with phosgene, then twice with 3 - (- 2- (L -methylcarbamoyl) -4pyridylsulphaniline) .  Description 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3A, to give 4-chloro-2-pyridinecarboxamide.  4-chloro-2-pyridinecarboxamide is reacted with 3-amino-phenol according to method A2 step 4 using DMAC instead of DMF to give 3- (2-carbamoyl-4-pyridyloxy) aniline.  According to C2a, 2-methoxy-5- (trifluoromethyl) aniline is reacted with phosgene, followed by 3- (2-carbamoyl) -4-pyridyloxy) -aniline, to give the urea.  Description 13: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to method A2, step 3b.  4-chloro-N-methyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to the procedure A2 step 4 using DMAC instead of DMF to give 4- (2- (N -methylcarbamoyl) -4- pyridyloxy ) -aniline.  According to the C2a method, 2-methoxy-5- (trifluoromethyl) -aniline is reacted with CDI, followed by 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline, to give the urea.  Description 14: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to method A2, step 3b to give 4-chloro-2-pyridinecarboxamide.  4-chloro-2-pyridinecarboxamide is reacted with 4-amino-phenol according to method A2 step 4 using DMAC instead of DMF to give 4- (2-carbamoyl-4-pyridyloxy) aniline.  According to the method, C4,2-methoxy-5- (trifluoromethyl) aniline is reacted with phosgene, followed by 4- (2-carbamoyl) -4-pyridyloxy) aniline, to give the urea.  Description 15: According to process C2d, 5- (trifluoromethyl) 2-methoxyaniline is reacted with CDI followed by 4- (3-methylcarbamoyl) -4-methoxyphenoxy) aniline A8, until the gain.  10 Description 16: 4- (2- (L-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was synthesized according to method A5. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1.  The isocyanate is reacted with 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -2-methylaniline according to Method C1 to give the urea.  Description 17: 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to method A6.  5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1.  5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline according to Method C1a to give the urea.  Description 18: According to Method A2, Step 4, 5-amino-2-methylphenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide which is synthesized according to Method A2, Step 3b 3- (2- (L-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline is obtained.  5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1.  35 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 3- (2- (L-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline according to Method C1a to give the urea.  Description 19: 4-Chloropyridine-2-carbonyl chloride 40 is reacted with ethylamine according to the method A2, step 3b.  The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide is reacted with 4-amino-phenol according to Method A2 step 4 to give 4- (2- (N -ethylcarbamoyl) -4-pyridyl-45oxyl) aniline.  5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1.  5- (Trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridin-50-yloxy) aniline according to Method C1a to give the urea.  Description 20: According to Method A2, step 4,4-Amino-2-chlorophenol is reacted with 4-chloro-14-methyl-2-pyridinecarboxamide, synthesized according to Method A2, Step 3b, (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline.  5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1.  5- (Trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (2- (14-methylcarbamoyl) amino) -3-chloroaniline according to Method Cf 1a to give the urea.  Description 21: 4- (4-methylthiophenoxy) -1-nitrobenzene was oxidized according to Method A19, Step 1, to give 4- (4-methylsulfonylphenoxy) -1 -nitrobenzene.  The nitrobenzene was sequenced according to Method A19, Step 1, to give 4- (4-methylsulfonylphenoxy) -1-aniline.  According to Method Cl, 5- (trifluoromethyl) -2O-methoxyphenyl isocyanate is reacted with 4- (4-methylsulfonylphenoxy) -1-aniline until the urea is obtained.  Description 22: 4- (3-Carbamoylphenoxy) -1-nitrobenzene is reduced to 4- (3-carbamoyl-25phenoxy) aniline according to Method A15, Step 4. According to Method C1, 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (3-carbamoylphenoxy) aniline to give the urea.  Description 23: 5- (4-aminophenoxy) isoindole-3-one-1,3-dione was synthesized according to method A3.  5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 5- (4- (3-aminophenoxy) isoindoline-1,3-dione according to the method of Cla, to give the urea.  Description 24: 4-Chloropyridine-2-carbonyl chloride is reacted with dimethylamine, according to A2, step 3b.  The resulting 4-chloro-N, N-di-methyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2 step 4 to give 4- [2- (14,14- dimethylcarbamoyl) pyridyloxy) aniline.  5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -4S-methoxyphenyl isocyanate according to Method B1.  5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline according to Method C1a to give the urea.  Description 25: 4- (1-oxoisoindolin-5-yloxy) aniline was synthesized according to Method A12.  5- (Trifluoromethyl) -2-methoxyaniline is treated with CDI followed by 4- (1-oxo-isoindolin-5-yloxy) aniline according to Method C2d to give the urea.  Description 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene, according to Method A13, Step 1, to give 4- (4-acetylphenoxy) nitrobenzene.  The nitrobenzene was sequenced according to Method A13, Step 4, to give 4- (4-acetylphenoxy) aniline, which was converted to 4- (4- (1- (N -methoxy) iminoethylphenoxyaniline HCl salt according to Method A16. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1.  5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt according to Method C1 to give urea.  Description 27: 4-Chloro-14-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b.  Chlorpyridine interacts with 4-aminothiophenol according to Method A2 step 4 to give 4- (4- (2- (14-methyl-carbamoyl) -phenylthio) aniline.  5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline, according to Method C1, to give the urea.  Description 28: 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione was synthesized according to Method A9. 5- (trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxy-phenyl isocyanate according to Method B1.  5- (Trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione according to Method C1 to give the urea.  Description 29: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, step 3b.  Chlorpyridine interacts with 3-aminothiophenol according to Method A2 step 4 to give 3- (4- (2- (N-methyl-carbamoyl) phenylthio) aniline.  5- (trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate, 32 65158 according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline according to method C1 to give the urea.  Description 30: 2-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to method A2, step 3b.  The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide is reacted with Method A2, Step 4 to give 4- (2- (4-isopropylcarbamoyl) -4-pyridyloxy) -10aniline.  5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (2- (14-isopropylcarbamoyl) -4- (15-pyridyloxy) aniline according to Method C1 to yield urea.  Description 31: 4- (3- (5-Methoxycarbonyl) -pyridinyloxy) aniline was synthesized according to Method A14. 5- (trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1 to give the urea.  N- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified in step D4 step 1 and the corresponding acid portion in the coupling reaction 4- (2-aminoethyl) -morpholine, to give the amide according to method D4, step 2.  Description 32: 4- (3- (5-Methoxycarbonyl) -pyridinyloxy) aniline was synthesized according to the method A14.  5- (trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to give the urea.  N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (4- (3- (5 -methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4 step 1 and the corresponding acid is reacted in a coupling reaction with methylamine, 45 to obtain the amide according to Method D4, Step 2, to give the amide.  Description 33: 4- (3- (5-Methoxycarbonyl) -pyridyloxy) aniline was synthesized according to the method A14.  5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to give the urea.  N- (5- (trifluoromethyl) -2-methoxyphenyl) -N'-4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, acid was coupled with N, N-dimethylethylenediamine according to Method D4, Step 2, to give the amide.  Description 34: 4- (3-carboxyphenoxy) aniline was synthesized according to method All.  5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1.  4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method Clf to give 14- (5- (trifluoromethyl) -2- 3-carboxyphenyl) urea, which is reacted with 3-aminopyridine according to Method Die.  Description 35: 4- (3-carboxyphenoxy) aniline was synthesized according to method All.  5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1.  4- (3-Carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method Clf to give L- (5- (trifluoromethyl) -2methoxyphenyl) 3-carboxyphenyl) urea, which participated in the coupling reaction with N- (4-fluorophenyl) piperazine, according to Method Die.  Description 36: 4- (3-carboxyphenoxy) aniline was synthesized according to the All method.  5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1.  4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method Clf to yield 4- [5- (trifluoromethyl) -2- 3-carboxyphenyl) urea, which participates in the coupling reaction with 4-fluoroaniline according to Method Die.  Description 37: 4- (3-Carboxyphenoxy) aniline was synthesized according to the All method.  5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1.  4- (3-Carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method Clf to give N- (5- (trifluoromethyl) N '- (3-carboxyphenyl) urea, which is present in the coupling reaction with 4- (dimethylamino) aniline according to Method Die.  Description 38: 4- (3-carboxyphenoxy) aniline was synthesized according to the All method.  5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1.  4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method Clf to give N- (5- (trifluoromethyl) -2- (3-carboxyphenyl) urea, which is present in the coupling reaction with 5-amino-2-methoxypyridine according to Method Die.  Description 39: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A1 5- (Trifluoromethyl) -2-methoxyaniline was converted to 205- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1.  4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method Clf to give N- (5- (trifluoroacetyl) -2- Apos; - (3-carboxyphenyl) urea, which is coupled with 4-morpholinoaniline, according to Method Die.  Description 40: 4- (3-Carboxyphenoxy) aniline was synthesized according to method Al.  5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1.  4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method Clf to give 14- (5- (trifluoromethyl) -2- ] -N '- (3-carboxyphenyl) urea, which was coupled with N- (2-pyridyl) piperazine according to Method D 1c.  Description 41: 4- (3- (N-methylcarbamoyl) phenoxy) aniline was synthesized according to method A13. According to method C3, 4-chloro-3- (trifluoromethyl) aniline is converted to the isocyanate and then reacted with 4- (3-carboxyphenoxy) anilines with 4- (3- (N -methylcarbamoyl) -phenoxy) the urea is obtained.  Description 42: 4- (2-N-methylcarbamyl-4-pyridyloxy) aniline was synthesized according to method A2. 4-Chloro-3- (trifluoromethyl) phenylisocyanates are reacted with 4- (2-N-methylcarboxyl-4- (5-pyridyloxy) aniline according to Method C1a to give the urea.  Description 43: The 4-chloropyridine-2-carbonyl chloride HCl salt is reacted with ammonia according to method A2, step 3b to give 4-chloro-2-pyridinecarboxamide.  4-Chloro-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4, to give 4- (2-carbamoyl) -4-pyridyloxy) aniline.  According to Method C1, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2-carbamoyl) -4-pyridyloxy) -aniline to yield the urea.  Description 44: The 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to method A2, step 3b to give 4-chloro-2-pyridinecarboxamide.  4-chloro-2-pyridinecarboxamide is reacted with 3-aminothiophenol according to method A2 step 4 to give 3- (2-carbamoyl-4-pyridyloxy) aniline.  According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2-carbamoyl-4-pyridyloxy) aniline to give urea.  Description 45: 4-Chloro-14-methyl-2-pyridinecarboxamide synthesized according to Method A2, Step 3a is reacted with 3-aminothiophenol according to Method A2 step 4 to give 3- (4-methylcarbamoyl) -4-pyridyloxy) aniline.  According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (4-methylcarbamoyl) -4-pyridyloxy) -aniline to yield urea.  Description 46: 5- (4-aminophenoxy) isoindoline-1,3-dione was synthesized according to method A3. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to give urea.  Description 47: 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was synthesized as described in Method A5, according to Method C1c, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to give the urea.  Description 48: 4- (3-N-methylsulfamoyl) phenyloxy) aniline was synthesized as described in Method A15.  According to Method Cl, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-N-methylsulfamoyl) phenyloxy) aniline, 34 65158 to yield urea.  Description 49: 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to the method described in Method A6.  According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2chloroaniline to yield urea.  Description 50: According to Method A2, Step 4, 5-amino-2-methylphenol is reacted with 4-chloro-N-2-pyridinecarboxamide synthesized according to Method A2, Step 3B to give 3- - (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline.  According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4- methylaniline to give urea.  Description 51: 4-Chloropyridine-2-carbonyl chloride is reacted with ethylamine according to the method A2, step 3B.  The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide is reacted with 4-amino-phenol according to method A2 step 4 to give 4- (2- (Lethylcarbamoyl) -4-pyridyloxy) aniline.  According to Method C1a, 44chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) -aniline to yield urea.  Description 52: According to method A2, step 4,4-amino-2-chlorophenol is reacted with 4-chloro-N-2-pyridinecarboxamide synthesized according to method A2 step 3B to give 4- (2- (14-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline.  According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (14-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to yield urea.  Description 53: 4- (4-methylthiophenoxy) -1-nitrobenzene was oxidized according to Method A19, Step 1, to give 4- (4-methylsulfonylphenoxy) -1 -nitrobenzene.  The nitrobenzene was sequenced according to Method A19, Step 2, to give 4- (4-methylsulfonylphenoxy) -1-aniline.  According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4-methylsulfonylphenoxy) -1-aniline to yield urea.  Description 54: 4-bromobenzenesulfonyl chloride is reacted with methylamine according to the method A15 step 1 to yield N-methyl-4-bromobenzenesulfonamide.  N-methyl-4-bromobenzenesulfonamide is reacted with phenol according to Method A15 step 2, 5 to give 4- (4- (N-methylsulfamoyl) phenoxy) benzene.  4- (4- (14-Methylsulfamoyl) phenoxy) benzene was converted to 4- (4- (N-methylsulfamoyl) phenoxy) -1 -nitrobenzene according to Method A15, Step 3.  4- (4- (L-methylsulfamoyl) -10-phenoxy) -1-nitrobenzene is reduced to 4- (4-N-methylsulfamoyl) phenoxy) aniline, A15, step 4.  According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate interacts with 4- (4- (1-methylsulfamoyl) phenoxy) -15-aniline to yield urea.  Description 55: 5-Hydroxy-2-methylpyridine was coupled to 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4- (5- -1-nitrobenzene.  The methylpyridine is oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2, to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene.  The nitrobenzene 25 was reduced according to Method A18, Step 3, to give 4- (5- (2-methoxycarbonyl) -pyridinyloxy) aniline.  The aniline is reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method C1a to yield urea.  Description 56: 5-Hydroxy-2-methylpyridine was coupled to 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4- (5- oxy) -1-nitrobenzene.  The methylpyridine is oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2, to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene.  The nitrobenzene is reduced according to Method A18, Step 3, at 40 to give 4- (5- (2-methoxycarbonyl) -pyridinyloxy) aniline.  The aniline is reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method C1a to give N- (4-chloro-3- (trifluoromethyl) phenyl) -5-pyridyloxy) phenyl) urea. The methyl ester is reacted with methylaniline according to Method D2 to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N -methylcarbamoyl) -5- pyridyloxy) urea.  Description 57: N- (4-Chloro-3- (trifluoromethyl) phenyl) -3- (trifluoromethyl) phenyl) -N &apos;-( 4-aminophenyl) urea was coupled with mono-methyl isophthalate according to Method D1a to give 5-urea.  Description 58: 14- (4-Chloro-3- (trifluoromethyl) phenyl-14 '- (4-aminophenyl) urea was prepared according to method Cld.  N- (4-Chloro-3- (trifluoromethyl) phenyl) -N- (4-aminophenyl) urea was coupled with mono-methyl isophthalate according to Method D1a to give N- -3- (trifluoromethyl) phenyl-14 '- (4- (3-methoxycarbonylphenyl) -carbonylaminophenyl) urea.  According to Method D2, N- (4-chloro-3- (trifluoromethyl) phenyl-N- (4- (3-methoxycarbonylphenyl) -carbonylaminophenyl urea is reacted with methylamine to give the corresponding methyl amide.  Description 59: 4-Chloropyridin-2- <RTIgt; carbonyl chloride </ RTI> is reacted with diethylamine, according to A2, step 3B. The resulting 4-chloro-N, N-1 H -ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2 step 4 to give 4- (2- (N, -2-pyridyloxy) aniline. According to Method Q1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N, N-diethylcarbamoyl) -4-pyridyloxy) aniline to yield urea. Description 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13 Step 1 to give 4- (4-acetyl-phenoxy) nitrobenzene. The nitrobenzene was reduced according to Method A13 step 4 to give 4- (4-acetylphenoxy) aniline which was converted to 4- (4- (1- (L-methoxy) iminoethyl) phenoxyaniline HCl salt , according to Method A16. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4-acetylphenoxy) aniline to give the urea 40 Description 61: 4- carboxyphenoxy) -1-nitrobenzene was synthesized according to method A13 step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was added in a coupling reaction with 4- (2-aminoethyl) morpholine according to Method A13, step 453. receive and 4- (3-N- (2-morpholinyl-ethyl) carbamoyl) phenoxy) -1-nitrobenzene. According to Method A13, step 4,4- (3-N- (2-morpholinylethyl) carbamoyl) phenoxy) -1 -nitrobenzene was reduced to 4- (3 N- (2morpholinylethyl) carbamoyl) phenoxy) aniline. According to Method C1, 4-chloro-3- (trifluoromethyl) phenyl) isocyanate is reacted with 4- (3-14- (2-morpholinylethyl) carbamoyl) phenoxy) -aniline to give the urea. Description 62: 4- (3-Carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1- nitrobenzene was used in the coupling reaction with 1- (2aminoethyl) piperidine according to Method A13 , step 3, to give 4- (3 - (1- (2-piperidyl-ethyl) carbamoyl) phenoxy) -1-nitrobenzene. According to Method A13, step 4,4- (3- (N- (2-piperidyl-ethyl) carbamoyl) phenoxy) -1- nitrobenzene is reduced to 4- (3- carbamoyl) phenoxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl) isocyanate is reacted with 4- (3- (N- (2-piperidylethyl) carbamoyl) phenoxy) aniline to yield urea. Description 63: 4- (3-Carboxyphenoxy) -1-nitrobenzene was synthesized according to method A43 step 2. 4- (3-Carboxyphenoxy) -1- nitrobenzene was used in the coupling reaction with tetrahydrofurfurylamine according to Method A13, step 3, there is obtained 4- (3- (N1- (tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene. According to Method A13, Step 4, 4- (3- (N- (Tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- [N- (tetrahydrofurylmethyl) carbamoyl) phenoxy) -aniline. Method Cia, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (N- (tetrahydrofurylmethyl) -carbamoyl) phenoxy) -aniline to yield urea. Description 64: 4- (3-Carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1 -nitrobenzene was coupled with 2-aminomethyl- according to Method A13, Step 3, to give 4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1 -nitrobenzene. According to Method A13, step 4,4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1- nitrobenzene was reduced 4- (3- ) carbamoyl) -phenoxy)) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate interacts with 4- (3- (14 - ((1 -methylpyrrolidinyl) methyl) carbamoyl) phenoxy)) aniline. gets urea. Description 65: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3B. Chloropyridine is reacted with 4-aminophenol according to Method A2 step 4 to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) -aniline According to Method C1a, 4-chloro-3- - (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- (4-methylcarbamoyl) phenylthio) aniline to give urea Description 66: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine Method A2, step 3B The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2 step 4 to give 4- (2- (14-isopropylcarbamoyl- ) -4-pyridyloxy) anions In accordance with Cla, 4-chloro-3- (trifluoromethyl) phenylisocyanate is reacted with 4- (2- (N-isopropylcarbamoyl) -4pyridyloxy) aniline to give urea Description 67: chloro-3- (trifluoromethyl) phenyl-N '- (4-ethoxycarbonylphenyl) urea is synthesized according to the method of Cle. N- (4-Chloro-3- (trifluoromethyl) (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4-carboxylphenyl) urea N- (4- (4-Carboxyphenyl) urea was added to 3-methylcarbam ilanilin, saglasnometod Dlb, yielding Ν- (4-χπορο-3- (trifluoromethyl) phenyl-№- (4- (3-methyl-carbamoylphenyl) carbamoylphenyl urea. Description 68: 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione was synthesized according to the method of Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- aminophenoxy) -2-methylisoindoline-1,3-dione was obtained, yielding urea. Description 69: 4-Chloro-methyl-pyridinecarboxamide was synthesized according to the method described in Method A2, Step 3B. Chloropyridine is reacted with 3-aminophenol according to Method A2 step 4 to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) -aniline According to Method C1a, 4-chloro-3- - (trifluoromethyl) phenyl isocyanate is reacted with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline to give urea Description 70: 4- [2- (14- (2- 4-ylethyl) carbamoyl) -pyridinyloxy) aniline is reacted with 4- (2- (N- (2-methoxyphenyl) Morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to give urea Description 71: 4- (3- (5-Methoxycarbonyl) pyridyloxy) -aniline was synthesized according to Method A14, 4-chloro- 3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4-chloro-3- (trifluoromethyl) phenyl) -N- (4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to give urea. -pyridyl) oxy) phenyl urea was saponified according to Method D4, Step 1, and the corresponding acid participated in a coupling reaction with 4- (2-aminoethyl) morpholine to give the amide. Description 72: 4- (3- (5-Methoxycarbonyl) -pyridinyloxy) aniline was synthesized according to the procedure of 4- (3- (5-methoxycarbonyl- methoxycarbonyl) -pyridinyloxy) aniline according to Method C1a to yield urea. N- (5- (tert -fluoromethyl) -2-methoxyphenyl) -N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl urea seosaponica according to Method D4, step 1 and the corresponding acid was coupled to the methylamine addition reaction according to Method D4 step 2 to give amide 30 Description 73: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14.4 chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) -pyridinyloxy) aniline according to Method 35Cl to give urea N- (5- -2-methoxyphenyl) -N '- (4- (3- (5-methoxycarbonyl- pyridyl) oxy) phenyl urea was sequestered according to method D4 step 1 and the corresponding acid was added to the reaction mixture with N, N-dimethylethylenediamine according to the method D4 step 2 to give the amide. 74: 4-chloropyridine-2-carbonyl chloride The HCl salt was reacted with 2-hydroxyethylamine according to Method A2, step 3B, yielding 4-chloro-N- (2- triisopropylsilyloxy) ethylpyridin-2 -carboxamide. 4-chloro-4- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide is reacted with triisopropylsilyl chloride, followed by 4-aminophenol, 50 according to Method A17, N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline According to Method Cl, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (4- ) pyridyloxyphenyl) urea Description 75: 4- (3-Carboxy 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl-pyridyloxy) -aniline according to Method Clf, urea which participates in the coupling reaction with 3-aminopyridine according to the method of Method 7. Description 76: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) anilyl, according to method Clf, to yield urea, which shows coupling with N- (4-acetylphenyl) piperazine azine according to Method Die. Description 77: 4- (3-Carboxyphenoxy) aniline was synthesized according to the All method. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method Clf to yield urea, which is present in the coupling reaction with 4-fluoroaniline according to Method Die. Description 78: 4- (3-carboxyphenoxy) aniline was synthesized according to method AP. 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method Clf to give urea, which is present in the coupling reaction with 4- (dimethylamino) method Die. Description 79: 4- (3-Carboxyphenoxy) aniline was synthesized according to the All method. 4-Chloro-403- (trifluoromethyl) phenyl Isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method Clf to yield urea, which is coupled with N-phenylethylenediamine according to Method Die. 45 Description 80: 4- (3-Carboxyphenoxy) aniline was synthesized according to the All method. The 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline, according to Method Clf to give urea, which is reacted with 2-methoxyethylamine, according to method Die. Description 81: 4- (3-carboxyphenoxy) aniline was synthesized according to method All. 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to method Clf to yield urea, which is reacted with 5-amino- methoxypyridine according to Method Die. Description 82: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11.4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline, to give the urea, which participates in the coupling reaction with 4-morpholinoaniline, according to Method Die. Description 83: 4- (3-carboxyphenoxy) aniline was synthesized according to method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method Clf to yield urea, which participates in the coupling reaction with 14- (2pyridyl) , according to Method Die. Description 84: 4-Chloropyridine-2-carbonyl chloride The HCl salt is reacted with 2-hydroxyethylamine according to Method A2, Step 3B, to give 4-chloro-14- (2triisopropylsilyloxy) -2-carboxamide. The 4-chloro- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide is reacted with triisopropylsilyl chloride followed by 4-aminophenol according to Method A17 to give 4- (4- (2-triisopropylsilyloxy) ethylcarbamoylpyridinyloxyaniline According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (14- (2triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline, to give N- (4-bromo-3 - ((trifluoromethyl) phenyl) -14 '- (4- co (4-chloro-3 - ((trifluoromethyl) phenyl) -14 '- (4- Description 85: 4- (2- (14-Methylcarbamoyl) -4-pyridyloxy) -aniline was synthesized according to Method A2.4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo- 3- (trifluoromethyl) phenyl isocyanate according to method B. According to method 38 65158 isocyanate, C1a, 4-bromo-3- (trifluoromethyl) phenylalanate is reacted with 4- (2- (N -bomoyl) aniline, in the presence of urea. Description 86: 4- (2- (14-methylcarbodi-pyridyloxy) -2-chloroaniline was synthesized by Method A6.4-Bromo-3- (trifluoromethyl) Example 87: According to the method 4-amino-2-chlorophenol is reacted with N - (2-carbamoyl) -4-pyridyloxy) aniline, methyl-2-pyridinecarboxamide, synthesized according to method A2, step 3B, to give 4- (2- (N -methylcarbamoyl) -4-oxy) -3- chloraniline 4-Bromo- 3- in 4-bromo-3-methylphenyl) isocyanate, cf. asno m <According to Method C1a, 4-bromo-3- (trifluoromethyl) isocyanate is reacted with methylcarbamoyl) -4-pyridyloxy) -3-lin to give the urea. Description 88: 4-Chloropyridine-2-chloride is reacted with ethylamine, Method A2, Step 3B. The resulting 4-chloro-2-pyridinecarboxamide is reacted with 4-bromo-3- (trifluoromethyl) aniline to 4-bromo-3- phenyl isocyanate according to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with ethylcarbamoyl) -4-pyridyloxy) aniline to yield urea. Description 89: 4-Chloro-N-methyl-2-carboxamide synthesized according to Step A2, step 3 is reacted with 3-amine method A2, step 4, where 3- (2- (N -methylcarbamoyl) 4-bromo-3- (trifluoromethyl) phenylnanoate is reacted with 3- (2-trifluoromethylphenyl) -4-bromo-3- (trifluoromethyl) (L-methyl) -4-pyridyloxy) -aniline to give urea (ammoyl) -4-cephem-ethyl) anilyl) Step 4 4-Chloro-is syn-pyridinium- (trifluoromethyl) -fluoro-4- (2- (N -chloro-carbonyl) 4-bromo-4- (2- (N-methylpyridin-2-yl) phenoxy) -pyridoyl) Description 90: According to Method A2, step 4,5-amino-2-chlorophenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, synthesized according to Method A2, to give 3- (2- (14-methylcarbamoyl) -4-pyridyloxy) -3-methylaniline 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo- 3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylsulfonate according to Method B1. 4-chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to method A2, step 3B, to give the desired urea. pyridinecarboxamide was reacted with 4-aminophenol according to method A2 step 4 to give 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline 4-bromo-20 3- ) aniline was converted to 4-bromo-3- (trifluoromethyl) l) phenyl isocyanate according to Method B1-but. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (R) -dimethylcarbamoyl) -4-pyridyloxy) aniline to yield urea. Description 92: 4-Chloro-N-methylpyridinecarboxamide was synthesized according to Method A2, Step 3B. Chloropyridine is reacted with 3-aminophenol according to Method A2, step 304 to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) -aniline, 4-bromo-3- ) -aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- N-methylcarbamoyl) phenylthio) -aniline to give urea Description 93: 4-Chloro-N-methylpyridinecarboxamide was synthesized according to the procedure described in Method A2, Step 3.B Chloropyridine was reacted with 3-aminophenol according to Method A2 , et 4-bromo-3- (trifluoromethyl) -aniline was converted to 4-bromo-3- (4-chloro- tri-4-fluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (4- [2- (N- Example 94: 4- (2- (T4-2-Morpholin-4-yl) ethyl) carbamoyl) pyridyloxy) aniline was synthesized according to Method A10.4-Bromo- trifluoromethylphenyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to the method of B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-2-morpholin-4-ylethyl) carbamoylpyridoxy) -aniline to yield urea. Description 95: 4- (2- (L-methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to Method A2. 4-chloro-2-methoxy-5- (trifluoromethyl) -aniline was synthesized according to method K1. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -aniline to yield urea. Description 96: 4- (2- (L-methylcarbamoyl) -4- (2-pyridyloxy) aniline was synthesized according to method A6. 4-Chloro-2-methoxy-5- (trifluoromethyl) -aniline was synthesized according to Method 2, Process Method C1a, 4-Chloro-2-methoxy-5-methylphenyl) isocyanate is 4- [2- (N -methylcarbamoyl) -4-pyridinylchloroaniline to give urea: Description 97: -2-chlorophenol is reacted with N-methyl-2-pyridinecarboxamide according to Method A2, step 3B, to give 4- (2- (L -methylcarbamoyl) aniline is synthesized according to the present invention A7. 4-Chloro-2-methoxy-5- (trifluoro) aniline is converted to 4-chloro-2- (trifluoromethyl) phenyl isocyanate according to Method C1a, 4-chloroisobutyl-5- - (2- (L-methylcarbamoyl) dloxy) -2-chloroaniline, in which the title compound is synthesized according to method A2, step 3a, with 3-amino-phenol according to method A2, step 4, to give 3- (2- (N-methylcarbamoyl) -4-pyridyl-5,4,4-chloro- - (trifluoromethylsulfonyloxy) -2-oxazolidinone (30.2 g, step 4,4-chloro) -pyridine-35: 5- (4-chloro-2-methoxy-5- (4-pyridyl) -4-pyridyl) trifluoromethyl) -aniline was converted to 4-chloro-3-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1 . According to Method C1a, 4-chloro-3-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (N -methylcarbamoyl) -4- pyridyloxy) aniline to yield urea . Description 99: 4-Chloropyridine-2-carbonyl chloride is reacted with ethylamine according to A2, step 3B. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (14-ethylcarbamoyl) -4-pyridyloxy) aniline. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to the procedure A7.4-Chloro-2methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro- 2- methoxy- 5- ) phenyl isocyanate, according to the method B1. According to Method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (L-ethylcarbamoyl) -4-pyridyloxy) aniline to yield urea. Description 100: 4-Chloropyridine-2-carbonyl chloride is reacted with dimethylamine according to method A2, step 3B. The resulting 4-chloro-14,14-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2 step 4 to give 4- (2- (N, N- pyridyloxy) -aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenylisocyanate is reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline to yield urea. Description 101: 4-Chloro-N-methyl-2-pyridinecarboxamide synthesized according to Method A2 step 3 is reacted with 3-amino-phenol according to Method A2 step 4 to give 3- (2-amino-3-methoxynaphthalene) is synthesized according to the method described in Method A1. (102) 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to the procedure A2.5-tert- 2- (2,5-dimethylpyrrolyl) -aniline was synthesized according to method A4.5-tert-butyl-2- (2,5-dimethylpyrrolyl) aniline was reacted with GDI followed by 4- (N-methyl-carbamoyl) -4-pyridyloxy) aniline According to the procedure of Example 2, there is obtained urea Description 103: 4-Chloro-L1 -methyl-2pyridinecarboxamide, -chloro-N-methyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to the procedure A2 step 4 using DMAC instead of DMF to give 4- (2- (N -methyl-Table 1.3- tert -butylphenylurea carbamoyl) -4-pyridyloxy) aniline. In accordance with C2b, the reaction of 3-amino-2-methoxyquinoline with CDI followed by 4- (2- (N-methylcarbamoyl) -4pyridyloxy) aniline results in the preparation of 4- (2- -methyl-carbamoyl) -4-pyridyloxy) phenyl urea. Listed below are the compounds synthesized according to the detailed experimental procedures given in Table 10 above: Tables The compounds listed in Tables 1 - 6 below are synthesized according to the basic methods outlined above, and more detailed 15-mer procedures are in the descriptions listed above and the characteristics are shown in the tables.

Inventory. we R T.p. (° C) HPLC (min.) TLC Rf TLC System Resolution Mass Spectrum. (source) Synth. (M + H) + (HPLC ES-MS) A13 C3 41 65158 2) 0.58 50% EtOAc / 50% hexane 403 (M + H) + (FAB) A8 C2d Table 2. 5-tert-Butylphenyl urea

Inventory Rt. (° C) HPLC (min.) TLC Rf TLC System Resolution Mac Spectrum. (source) Synth. Method 4 0 NH Me 5,93 448 (M + H) + (HPLC ES-MS) A13 B1 C1a 5O-Nt -O-O-Leu 120-122 0,67 100% EtOAc 478 + H) + (FAB) A8 C2d 42 65158 6 NH 0.40 50% EtOAc / 50% hexane 460 (M-H) + (HPLC ES-MS) hexane 446 (M + H) + (HPLC ES-MS) A12 C2d Table 3. 5- (Trifluoromethyl) -2-methoxyphenyl urea

Inventory Rt. (° C) HPLC (min.) TLC Rf TLC System Resolution Mac Spec. (source) Synth. Method 8 0 -NH Me 250 (dec) 460 (M + H) + (FAB) A13 C2a 9m <206-208 0.54 10% MeOH / 90% CH2Cl2 446 (M + H) A3 step 2, A8 step 4 B1, 43 65158 C1a 10 0.33 50% EtOAc / 50% petroleum ether 445 (M + H) + (HPLC ES-MS A13 C3) H 2 O / 0.27% 2 H 2 O / 2% Et 3 N / 98% EtOAc 461 (M + H) + (HPLC ES- + H) + (HPLC ES-MS A2 C4 H3 N2 O2 O2 H2 O 0.62 100% EtOAc 461 (M + H) + (FAB) A2 C2a14. , 40% 1 Et3 N / 99% EtOAc 447 (M + H) + (FAB) A2 C4 15 V-NH2 O2 -SCl3 m is 232-235 0.54 100% EtOAc 447 + H) + (FAB) A8 C2d 44 65158 16 0 MeV NH3 210-213 0.29 5% MeOH / 45% EtOAc / 50% pet ether 475 (M + H) + (HPLC ES-MS A5 B1 Clc 17 -13% -NH Me 187-188 0.17 50% EtOAc / 50% petroleum ether 495 (M + H) + (HPLC ES-MS A6 B1 Cl 18 / (M + H) + (HPLC ES-MS A2 step 4, B1, C19a NH3 194-196 0.31 5% MeOH / 45% EtOAc / 50% Et3 O 472 (M + H) @ + (HPLC ES-MS A2 B1, Cl2 20 NH2 Me 214-216 0.25-Sap, -MS A2 Cl 2 21 y 4 Me 208-210 0.30 50% EtOAc / 50% hexane 481 (M + H) + (HPLC ES-MS) A19 C2a 22 0 NH2 188-190 0.30 70% EtOAc / 50 % Hexane 447 (M + H) + (HPLC ES-MS) A15 Stage 4 C1a 45 65158 23-0-0 0.50 70% EtOAc / 30% hexane 472 (M + H) + (FAB) (HPLC) ES-MS A2 B1 Cl2 25 -O-C SC JH 0.09 75% EtOAc / 25% EtOAc / hexane 4458 (M + H) + (HPLC ES-MS A12 C2d 26 Me-Q-O Me 169-171 0.67 50% EtOAc / 50% ether 474 (M + H) + (HPLC ES-MS A13 step 1, A13 step4A16, B1, Cl2 27.0 and 0.27) .NH Me 218-219 0.40 50% EtOAc / 50% ) + (HPLC ES-MS A9 B1, Cl 2 28% NMe 212-214 0.30 40% EtOAc / 60% Hexane A 2 C 29 29% O-NH 3 0.33 50% EtOAc / 50% ether 474 (M + H) + (HPLC ES-MS A2 step 3b, A2 step4B1, C11a 46 65158 30 0 in NH2 Pr-i 210-211 A2 B1 Cl2 31- % MeOH / CH 2 Cl 2 A 14 B1 Cl 2 d 4 32 2N 4 M (247-249 0.57 10% MeOH / CH 2 Cl 2 A 14 B 1 Cl d d 4 33 0 y-NH CH 2 Cl 2 = , 07 10% MeOH / CH 2 Cl 2 A 14 B 1 Cl 2 d 4 34 0 NH-0 → 0 → 0.11 70% EtOAc / 30% hexane A11 B1 Clf D1 C35 N10 C 0.38 70% EtOAc / 30 % Hexane A11 B1 Clf D1c 47 65158 36 F-yy NH = 0 0.77 70% EtOAc / 30% hexane A11 B1 C1f D1c 37 "WA-NH Mb / - 0.58 70% EtOAc / 30% hexane A11 B1 Clf D1c 38 Me ° - 0.58 70% EtOAc / 30% hexane A11 B1 C1f D1 C39- C / 70% EtOAc / 30% Hexane A11 B1 Clf D1c 40 1 0.21 70% EtOAc / 30% hexane A11 B1 C1f D1c Table 4 3- (Trifluoromethyl) -4-chlorophenyl ureas

48 65158 Description R T.p. (° C) HPLC (min.) TLG Rf TLC System Resolution Mass Spectrum. (source) Synth. Method 41 0 Y-NH 163-165 0.08 50% EtOAc / 50% pet. ether 464 (M + H) + (HPLC ES-MS A13 C32 42 V-NH2S 0.06 50% EtOAc / 50% 0.02% EtOAc / 70% petroleum ether 451 (M + H) + (HPLC ES-MS A2 Clal 44- M + H) + (HPLC ES-MS A2 Clal 45 1L 0.31 30% EtOAc / 70% petroleum ether 465 (M + H) + (HPLC ES-MS A2 Clal 46 # 0.23 40% EtOAc / 60% hexane 476 (M + H) + (FAB) A3 Clal 49 65158 47 Me 0 MgNH 0.29 5% MeOH / 45% EtOAc / 50% + (HPLC ES-MS A5 ClC1 MeMe 48 vJ -NH2 Me 206-209 A15 Cl4 49 ClO10 -NH Me 147-151 0.22 50% EtOAc / 50% petroleum ether 499 (M + H) + (HPLC ES-MS A2 Cl, 50%): MH + = 0.54 100% EtOAc / 479 (M + H) + (HPLC ES- 189 0.33 c% MeOH / 45% EtOAc / 50% pet ether 479 (M + H) + (HPLC ES-MS A2 Cl2 52 Cl -0.90% EtOAc / 50% hexane 485 (M + H) + (HPLC ES-MS A19 Cl 53 HCl 3 nk ° XMe 246-248 0.30 50% EtOAc / 50% hexane 485 (M + H) + (HPLC ES-MS A19 Cla 50 65158 54- 50% EtOAc / 50% Hexane 502 (M + H) + (HPLC ES-MS A15 Oa 55 0 He 228-230 0.30 30% EtOAc / 70% CH2Cl2 466 (HPLC) ES-MS Cld D1a 58 1H Me 247 0.35 100% EtOAc C1 d D1a D2 59 v m.p. = 198-100 0.09 100% EtOAc 479 (M + H) + (HPLC ES-MS A2 Cl2 60 Me Me Me 158-160 0.64 50% EtOAc / 50% ether 61 0-NH 195- 197 0.39 10% MeOH / CH 2 Cl 2 A 13 Cl 51 51 65158

62 170-172 0.52 10% MeOH / CH 2 Cl 2 A 13 Cl 6 63 168-171 0.39 10% MeOH / CH 2 Cl 2 A 13 Cl 6 64 E-NH -O-Q Et 176-177 0.35 10% MeOH / CH 2 Cl 2 A13 C1a 65 ° C -NH Me ISO- 133 487 (M + H) + (HPLC ES-MS A2 B1 C1a 66 0 -NH Pr-155 A2 Cla 67 NIH Me 225-229 0.23 100% EtOAc Cl D3 D1b 68 010 NMe 234-236 0.29 40% EtOAc / 60% hexane A9 Cl-69-OV-NH- (0.4 mM NaCl 0.48 50% EtOAc / 50% petroleum ether 481 (M + H) &lt; + &gt; (HPLC ES-MS A10 &lt; RTI ID = 0.0 & , 50 10% MeOH / CH 2 Cl 2 A 14 C 1 a D 4 72 0 V-Nb E 235-237 0.55 10% MeOH / CH 2 Cl 2 A 14 C 1 a D 4 73 0 V -NH 2 = 50% MeOH / CH 2 Cl 2 A14 Cl 2 D 4 74 V-NH-O-Q 1 (Pr-i), 145-148 75 2 0.12 70% EtOAc / 30% hexane 527 (M + MS A11 Clf D1c 53 65158 76 N-nitric acid 0.18 70% EtOAc / 30% hexane A11 C1f D1c 77 F- hexane A11 C1f D1c 78 'VpuH k / L = L -0-0 = c 0.58 70% EtOAc / 30% hexane A11 Clf D1c 79 C-NH-C-0 C18 HCl 0.47 70% EtOAc / 30% hexane 569 (M + H) + (HPLC ES-MS A11 Clf D1c 80.0) Me 0.18 70% EtOAc / 30% hexane 557 (M + H) + (HPLC ES-MS A11 Clf D1c 81 MeO- C 0.58 70% EtOAc / 30% hexane 557 (M + H) + (HPLC ES-MS A11 Clf D1c 54 65158

(HPLC) ES-MS A11 Clf D1c 83 0.01-0.77 70% EtOAc / 30% hexane 611 (M + H) hexane A11 Clf D1c V 84 X-NH2 179-183 A2 A17 C1a D5 Table 5 3- (Trifluoromethyl) -4-bromophenyl ureas

Description R T.t. (° C) HPLC (min.) TLC Rf TLC System Resolution Mac Spectrum. (source) Synth. Method 85 0-8-8-8-8- 0.17 50% EtOAc / 50% petroleum ether. ether 509 (M + H) + (HPLC ES-MS A2 B1 Clal 55 65158 86 Cl 0, -NH Me 150-152 0.31 50% EtOAc / 50% ES-MS A6 B1 Cla 87 Clc -NH Me 217-219 0.16 50% EtOAc / 50% petroleum ether 545 (M + H) + (HPLC ES-MS A2 B1 C1a88 -QcO- NH 3 - 184 0.31 50% EtOAc / 50% petroleum ether 525 (M + H) + (HPLC ES-MS A2 B1 Cl and 89% (M + H) + 515 (M + H) + (HPLC ES-MS A2 B1 Cla 90 -Me 0) -NH- (M Gn) 0.28 50% EtOAc / 50% (HPLC ES-MS A2 B1 C1a91-cP Leu 214-216 0.28 50% EtOAc / 50% petroleum ether 522 (M + H) + (HPLC ES-MS A2 B1 Cl and 92% MeOH 0.47 50% EtOAc / 50% petroleum ether 527 (M + H) + (HPLC ES-MS A2 step 3b, A2 step 4, B1 56 65158 C18H25NO4 0.47 50% EtOAc / 50% petrolether 527 (M + H) + (HPLC ES-MS A2 Stage, A2 Stage 4, B1 Clal 94 C-NH-145-150 0.41 5% MeOH / 95% CH2Cl2A10B1Cl Table 6. 5- ( ifluormetil) -4-chloro-2-methoxyphenyl ureas

F

Inventory Rt. (° C) HPLC (min.) TLC Rf TLC System Resolution Mass Spectrum. (source) Synth. Method 95 in NH3 Me 140-144 0.29 5% MeOH / 45% EtOAc / 50% pet. ether 495 (M + H) + (HPLC ES-MS A2A7B1C1a96 -NH Me 244-245 0.39 5% MeOH / 45% EtOAc / 50% petroleum ether 529 (M + H) + (HPLC ES-MS A2 A7 B1): MS (ESI) m / z (HPLC) ES-MS A2A7B1C1a 990 V-O-CH2 -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH HCl Et 180- 181 0.52 E% MeOH / 45% EtOAc / 50% petroleum ether 509 (M + H) + (HPLC ES-MS A2A7B1C1a 100 0 VN d3r-162- 165A2 A7 B1 Clal Table 7 Affiliated Ureas Description R (° C) HPLC (min) TLC Rf TLC System Mac Spectrum (source) Synthetic Method 101 xxxxAu · T. H OMe NH - 165 A1 A2 C3 58

Claims (12)

(ES + MS) A2 A4 C2d103 HN NH 125-130 0.24 40% EtOAc / 60% Hexane 512 (M + H) + (FAB A2 C2b Jq) NH-Me Me-NF = Omega-carboxylaryl substitutents selected from the group consisting of sero-3- (trifluoromethyl) phenyl ureas: N- (4-chloro-3- (trifluoromethyl) N- (4-chloro-3- (trifluoromethyl) -N &apos;-( 3- (2- (N -methylcarbamoyl) -4-pyridyl) (4- (2-carbamoyl-4-pyridyloxy) phenoxy) -N- (4-chloro-3- (trifluoromethyl) ) of 4-bromo-3- (trifluoromethyl) phenyl, N - (4-bromo-3- -bromo-3- (trifluoromethyl) -N '- (3- (2- (14-carbamoyl) -4- pyridyl) urea, 4- (2- (N-methylcarbamoyl) -4-pyridyl) urea N- (4-bromo-3- (trifluoromethyl) (2-chloro-4- (2- (1-methylcarbamoylpyridinyloxy) phenyl) urea, N-methylcarbamoyl) -4- (4-bromo-3- (trifluoromethyl) phenyl) -N- [3-chloro-4- [2- (N -methylcarbamoyl) -4pyridyloxyphenyl] urea 2-Methoxy- 4-Chloro-5- (trifluoromethyl) phenyl) urea: 14- (2-Methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N ' ) -N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2- ) -4-pyridyloxy) phenyl) urea or pharmaceutically acceptable salts thereof. A compound according to claim 1, characterized in that it is a pharmaceutically acceptable salt thereof selected from the group consisting of: a) basic salts of organic acids of mineral acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoro-sulphonic acid, benzenesulfonic acid, p-toluenesulfonic acid (tosate salt), 1-naphthalenesulfonic acid, 2- naphthalenesulfonic acid, acid, trifluoroacetic acid , maleic acid, tartaric acid, citric acid, lactic acid, oxalic acid, yantarnakiselina, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid; and salts of organic and mineral-containing cations selected from the group consisting of alkaline cations, earth cations, ammonium cations, aliphatic ammonium cations and aromatic ammonium cations. A pharmaceutical composition comprising a compound of formula I or a pharmaceutical salt thereof and a physiologically acceptable carrier 4. A compound according to claim 1, wherein: T4- (4-chloro-3- (trifluoromethyl) 14 &apos;-( 4- [2- (N- methylcarbamoyl) phenyl) urea N- (4-Chloro-3- (trifluoromethyl) -N '- (4- (2- (4-bromo-3- (trifluoromethyl) -N '- (4- (2- (N -methylcarbamoyl) -4- phenyl) urea N - (2-Methoxy-4-chloro-5-methyl) phenyl) -N ' (trimethyl) phenyl) -LP- (2-chloro-4- (2- (N-mesoyl) -4-pyridyloxy) phenyl) urea or a pharmacist thereof inflowing Pryiemka 5. A compound according to claim 1, wherein said pharmaceutically acceptable salt is selected from the group consisting of: (a) basic salts of organic carboxylic acids selected from the group consisting of hydrochloric acid, hydrogen chloride, sulfuric acid, methanesulfonic acid, fluorosulphonic acid, benzenesulphonic acid, p-toluenesulfonic acid salt), 1-naphthalenesulfonic acid sulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, citric acid, oxalic acid, succinic acid, maleic acid), zinc acid, salicylic acid, citric acid and mandelic acid; and from a group of alkali metal substituents which may be substituted. (phenyl) -diyloxy) -15-phenyl) -yl) urea, phenyl) -1,4-dichloro-phenyl) -dichloro-2-methyl) -4-fluorocarbamate. , 4-non-racterite, sulfonate, c-bromo-phosphoric acid, trifluoromethosilate-a, 2-naphthalene acid, ) acidic salts of organic and mineral bases containing cations selected from the group consisting of alkali cations, alkaline cations, ammonium cation, aliphatic, substituted ammonium cations and aromatic substituted ammonium cations. A pharmaceutical composition comprising a compound according to claim 4, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. Use of a compound of claim 1 selected from the group consisting of: 4-chloro-3- (trifluoromethyl) phenyl ureas 14- (4-Chloro-3- (trifluoromethyl) phenyl) -NX3- (2- 4-pyridyloxy) phenyl urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N ' (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4-pyridyloxy) 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl urea and T4- (4-chloro- 3- (trifluoromethyl) phenyl) -N ' N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea 4-Bromo-3 (triflou phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) (4-bromo-3- (trifluoromethyl) phenyl) -N- (2-chloro-4- 2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea and N- (4-bromo-3- (trifluoromethyl) phenyl) -N ' methylcarbamoyl) -4-pyridyloxy) phenyl) urea. 2-Methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N- (4- (2- (2-chloro-4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea 14- (2-Methoxy- 4- chloro- 5- (trifluoromethyl) phenyl) -N ' 4-pyridyloxy) phenyl) urea, 60 65158 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer mediated cancer cell growth. The use of a compound of claim 1 is selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenylurea: 4- (4-chloro-3- (trifluoromethyl) (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (4-chloro-3- (trifluoromethyl) phenyl) -N- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- - (trifluoromethyl) phenyl) -N- (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea and 14- (4-chloro- 3- (trifluoromethyl) (2-chloro- (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea 4-Bromo- fluoromethyl) phenyl urea: N- (4-bromo-3- (trifluoromethyl) phenyl) -N ' (4-bromo-3- (trifluoromethyl) phenyl) -4- (trifluoromethyl) phenyl) (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4-pyridylthio) (3- (4-bromo-3- (trifluoromethyl) phenyl) -N- (3-chloro- methylcarbamoyl) -4-pyridyloxy) phenyl) urea. 2-Methoxy-4-chloro-5- (trifluoromethyl) phenyl) urea 14- (2-Methoxy- 4- chloro- 5- (trifluoromethyl) phenyl) (2-Methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N- (2- ) -4-pyridyloxy) phenyl) urea or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of: 45 I) carcinoma of the lungs, pancreas, thyroid, bladder, colon; II) myelogenous leukemia, or III) fibrous colon adenoma 5θ 10 15 20 25 30 35 Use of a compound of claim 1 selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenyl ureas: 14- (4-chloro-3- (trifluoromethyl) phenyl) 4-pyridyloxy) phenylurea, 14- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- - (4-Chloro-3- (trifluoromethyl) phenyl) -N- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea and N- [4-chloro-3- (trifluoromethyl) phenyl] - (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea 4-Bromo-3- (trifluoromethyl) (4-bromo-3- (trifluoromethyl) phenyl) -N &apos;-( 3- (2- (N -methylcarbamoyl) -4pyridinyloxy) phenyl) urea, N- bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- - (4-methylcarbamoyl) -4-pyridyloxy) phenyl) urea and N- (4-bromo-3- (trifluoromethyl) phenyl) -N4- (3- ) -4-pyridyloxy) phenyl) urea. 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) urea N- (2-Methoxy-4-chloro- 5- (trifluoromethyl) phenyl) -N ' 4-chloro-4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea N- (2-methoxy- -yl) -4-pyridyloxy) phenyl) urea, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of tumors. Use of a compound of claim 4 selected from the group consisting of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- [2- (4-methylcarbamoyl) phenyl) urea N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- ) phenyl) -N '- (2-chloro- (4- (2- (L -methylcarbamoyl) -4-pyridyl) ) phenyl) urea, N- (4-6-bromo-3- (trifluoromethyl) phenyl) -N1- (4-chloro-3- (trifluoromethyl) phenyl) -N ' 4-pyridyloxy) -N '- (2-chloro- (4- (2- (N -methylcarbamoyl) -4- phenyl) urea pyridyl (4-bromo-3- (trifluoromethyl) phenyl) methyl) phenyl) -N '- (4-chlorophenyl) (2- (N-methylcarbamoyl) -4- N '- (4- (2- (N -methylcarbamoyl) -4- pyridyloxy) pyridyloxy) phenyl) urea, phenyl) urea N- (2- chloro-5- (trifluoro-14- (2-methoxy-4- chloro- 5- (trifluoromethyl) phenyl) -N- (2- chloro- 4- (2- (14- methylcarbamethyl) ) -N- [4- (2- (N-methylcarbamoyl) -4-methyl) -4-pyridyloxy) phenyl) urea. 10-pyridyloxy) phenyl) urea or a pharmaceutically acceptable salt thereof, 14- (2-methoxy-4-chloro-5- (trifluoroacetic acid for methyl) phenyl) -N ' -4- (2- (14-methylcarbamate for the growth of cancer cells, methyl) -4-pyridyloxy) phenyl) urea. derived from raf kinase. or a pharmaceutically acceptable co- Use of a compound according to claim 15 for the manufacture of a medicament for claim 4 selected from the group consisting of: treatment of tumors. N- (4-chloro-3- (trifluoromethyl) phenyl) - 13. A compound according to claim 1, N- (4- (2- (N- chloro-3- (trifluoromethyl) phenyl) phenyl) urea] 4 '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea; The compound of claim 1, N- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, 20 which is N - [ (4-chloro-3- (trifluoromethyl) phenyl) -N- (4-chloro-3- (trifluoromethyl) phenyl) -N ' - [4-bromo-3- (2-chloro- (4- (4-chloro-3- (tri- [N- (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) ) -N '- (4- (2-carbamoyl-4-phenyl) urea pyridyloxy) phenyl) urea or a pharmacist thereof - 14- (2-methoxy-4-chloro-5- (trifluoroacetally acceptable salt and physiologically acceptable) phenyl) -N '- (4- [2- (14- methylcarbamoyl) 16. A pharmaceutical composition comprising 14- (2-methoxy-4-chloro-5- (trifluoromethyl) -N- (4-chloro-3- (2-chloro-4- (2- (N-methylcarbamoylmethyl) phenyl) -14 ' pyridyloxy) phenyl) urea. 4-pyridyloxy) phenyl) urea, or a pharmaceutically acceptable salt thereof, [LIVI is a pharmaceutically acceptable salt and physiols for the manufacture of a medicament for a pharmaceutically acceptable carrier. treatment of: 35 17. Use of the N- (4-chloro-3- (tri-I) carcinoma of the lungs, the lymphocyte, fluoromethyl) phenyl) -N'- , bladder, thick pyridyloxy) phenyl) urea, or a pharmaceutical gut; (II) myelogenous leukemia or carcinoma for the treatment of growth III) fibrin adenoma of raffin kinase-mediated cancer cell wall 40. Use of N- (4-chloro-3- (4- (4-methylphenyl) -N '- (4- (2-carbamoyl- (4-chloro-3- (trifluoromethyl) phenyl) pyridyloxy) phenyl) urea or a pharmacologically active N- (4- acceptable salt for the production of a phenyl urea agent for the treatment of raffin kinase-mediated cancer cell 14- (4-chloro-3- (trifluoromethyl) phenyl) -45. Issue of the Patronal Office of the Republic of Bulgaria 1797 Co (52 Maria B.Br., "G.M. Dimitrov Blvd.") Expert: B. Shikalanova Editor: R. Georgieva No. 63602 62 Printing: 40 YU