RS51497B - w-CARBOXYARYL SUBSTITUTED DIPHENYL CARBAMIDES AS RAF KINASE INHIBITORS - Google Patents

Abstract

The compound selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenyl urea: N- (4-chloro-3- (trifluoroethyl) phenyl) -N '- (3- (2-carbamoyl- 4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) pyridyloxy) phenyl) urea, N- (4-chloro- 3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (2 - (N-methylcarbamoyl) pyridyloxy) phenyl) urea, and N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy) )) phenyl) urea, 4-bromo-3- (trifluoromethyl) phenyl urea: N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4- pyridyloxy) phenyl urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo- 3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N' - ( 2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy) phenyl) urea, and N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro ro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl urea: N- (2-methoxy-4-chloro-5 - (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-Chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl urea, or a pharmaceutically acceptable salt thereof. The application contains 17 more claims.

Description

Field of invention

This invention relates to the use of the aryl urea group in the treatment of raf-mediated diseases, and pharmaceutical compositions for the production of medicaments in such therapy.

State of the art

The p21ras oncogene is a major contributor to the development and progression of human solid cancers and is mutated in 30% of all human cancers (Bolton et al. Ann. Rep. Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 99, 4682-9). In its normal, unmutated form, ras protein is a key element of the signal transduction cascade led by growth factor receptors in almost all tissues (Avruch et al., Trends Biochem. Sci. 19, 279-83). Biochemically, raf is a guanine nucleotide binding protein and its oscillation between the activating GTP-binding and the reactive GDP-binding is tightly controlled by the activity of ras endogenous GTPase activity and other regulatory proteins. In ras mutants in cancer cells, endogenous GTPase activity is facilitated and thus the protein provides constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to cancerous growth of cells carrying these mutants (Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). Inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administering raf kinase-deactivating antibodies or by co-expressing a dominant negative raf kinase or a dominant MEK substrate of raf kinase has been shown to lead to reversion of transformed cells to a normal growth phenotype (see: Daum et al. Trends Biochem. Sci. 1994, 19, 474-80; Fridman et al. J. Biol. Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 426-28) further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation. types of human tumors (Monia et al., Nat. Med. 1996, 2, 668-75).

DESCRIPTION OF THE INVENTION

The present invention provides compounds that are inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector for p21ras, the inhibitors are used in pharmaceutical compositions for human use or veterinary use where inhibition of the kinase pathway is indicated, eg, in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compounds are used in the treatment of solid cancers in humans or animals, e.g., murine cancer, since the progression of these cancers depends on the ras protein as a key element of the signal transduction cascade and thus is responsible for treatment by interrupting the cascade, i.e., inhibiting raf kinase. Accordingly, the compounds of the invention are useful for treating cancers, including solid cancers, such as, for example, cancers (eg, lung, pancreatic, thyroid, gallbladder, or colon), myeloid lesions (eg, myeloid leukemia), or adenomas (eg, villous adenoma of the colon).

The essence of the invention

The present invention therefore provides the use of compounds which are inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector for p21<ras>, the inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, eg, in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compounds are useful in the manufacture of medicaments for the treatment of solid cancers in humans and animals, e.g., mouse cancer, since the progression of these cancers is dependent on the ras protein as a key element of the signal transduction cascade and thus is responsible for treatment by interrupting the cascade, i.e., inhibiting raf kinase. Accordingly, the compounds of the invention are useful for the preparation of medicaments for the treatment of cancers, including solid cancers, such as, for example, cancers (e.g., lung, pancreatic, thyroid, gall bladder, gallbladder, or colon), myeloid disorders (e.g., myeloid leukemia), or adenomas (e.g., villous adenoma of the colon).

The present invention therefore provides compounds generally described as aryl ureas, including both aryl and heteroaryl analogs, which inhibit the raf kinase pathway. Thus, the invention is directed to compounds that inhibit the enzyme raf kinase and also to compounds, compositions and methods for treating cancerous cell growth mediated by raf kinase, wherein the compound of the invention is also acceptable as a salt thereof.

The compounds of the invention are selected from the group consisting of 4-chloro-3-(trifluoromethyl)phenyl urea: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-meth<;>lcarbamoyl)pyridyloxy)phenyl)urea, and N-(4-chloro-3-(trifluoromethyl)phenyl)-N,-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea, 4-bromo-3-(trifluoromethyl)phenyl urea: N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl) urea,

N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, and

N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl urea: N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl urea,

Or a pharmaceutically acceptable salt thereof.

The present invention is also directed to pharmaceutically acceptable salts of the compounds of the invention.

Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include base salts of inorganic and organic acids 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, malic acid, acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. Additionally, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkali metal cations (eg, Li<+>, Na<+>or K<+>), alkaline earth metal cations (eg, Mg<+2>, Ca<+2> or Ba<+2>), ammonium cations, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those derived from protonation or per-alkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

Numerous compounds of formula I possess asymmetric carbons and can exist in racemic and optically active forms. Procedures for separating enantiomeric and diastereomeric mixtures are well known to those skilled in the art. The present invention encompasses any isolated racemic or optically active form for the compounds described in formula I which possess raf inhibitory activity.

GENERAL PREPARATIVE PROCEDURES

The compounds of the invention can be obtained using known chemical reactions and procedures, even from commercially available starting materials. However, general preparative procedures are provided below to assist one skilled in the art in synthesizing these compounds, with more detailed examples set forth in the experimental section that follows.

Substituted anilines can be obtained using standard procedures (March. Advances Organic Chemistrv, 3rd Ed; John Wiley; New York

(1985). Larock Comprehensive Organic Transformations; VCH Publishers; New York (1989)). As shown in Scheme I, aryl amines are usually synthesized by the reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H 2 or a hydride transfer agent, such as formate, cyclohexadiene, or borohydride (Rvlander, Hydrogenation Methods, Academic Press; London, UK (1985)). Nitroaryls can also be directly reduced using a strong hydride source such as LiAlH4

(Seyden-Penne, Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers; New York (1991)), or by using a zero-valent metal such as Fe, Sn or Ca, often in an acidic medium. There are many procedures for the synthesis of nitroaryls (March, Advanced Organic Chemistry, 3rd Ed.; John Wiley, New York (1985). Larock, Comprehensive Organic Transformations; VCH Publishers; New York (1989)).

Nitroaryls are usually formed by electrophilic aromatic nitration using HN03, or an alternative NO2 source. Nitroaryls may be further elaborated prior to reduction. Thus, nitroaryls substituted with potential leaving groups (eg, F, Cl, Br, etc.) can undergo substitution reactions upon treatment with nucleophiles, such as a thiolate (example in Scheme II) or a phenoxide. Nitroaryls can also undergo Ullman-type coupling reactions (Scheme II).

Nitroaryls can also undergo transition metal-mediated cross-coupling reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides, or triflates, undergo palladium-mediated cross-coupling reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reactions, as in the example below), tin aryls (Stille reactions), or zinc aryls (Negishi reaction), to give a biaryl (5). Either nitroaryls or anilines can be converted to the corresponding arenesulfonyl chloride (7) after treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source such as KF then yields the sulfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, such as tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the corresponding trifluoromethylsulfone (9). Alternatively, the sulfonyl chloride 7 can be reduced to the arentiol (10), for example with zinc amalgam. Reaction of thiol 10 with CHCIF 2 in the presence of base gives difluoromethyl mercaptam (11), which can be oxidized to sulfone (12) with any of a variety of oxidants, including CrO3-acetic anhydride (Sedova et al. Zh. Org. Khim. 1970, 6, (568)). As shown in Scheme IV, the formation of an unsymmetrical carbamium can involve the reaction of an aryl isocyanate (14) with an aryl amine (13). A heteroaryl isocyanate can be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl)carbonate (triphosgene), or N,N-carbinyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, acid halide, or anhydride via a Curtius-type displacement. Thus, reaction of acid derivative 16 with an azide source, followed by displacement, gives the isocyanate. The corresponding carboxylic acid (17) can also undergo Curtius-type displacement using diphenylphosphoryl azide (DPPA) or a similar reagent.

Finally, the ureas can be further manipulated using procedures known to those skilled in the art.

The invention also includes pharmaceutical compositions comprising a compound of formula I, and a physiologically acceptable carrier. For use as indicated above.

The compounds can be administered orally, topically, parenterally, by inhalation or spray, or rectally in unit dose formulations. The term "administration by injection" includes intravenous, intramuscular, subcutaneous and parenteral injection, as well as the use of infusion techniques. One or more compounds may be present together with one or more non-toxic pharmaceutically acceptable carriers and, if desired, other active ingredients.

Compositions intended for oral use may be prepared according to any suitable method known to one skilled 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, flavoring agents, coloring agents and preservatives to provide palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for tablet production. These excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating or disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract, thus providing delayed action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds can also be prepared in a solid, rapid-release form.

Formulations for oral use can also be prepared in the form of hard gelatin capsules, where the active ingredient is mixed with an inert solid diluent, such as, for example, calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules, where the active ingredient is mixed with water or oil, such as for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain active materials in admixture with excipients suitable for adjusting aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing agents and wetting agents can be naturally occurring phosphatides, for example lecithin, or condensation products or alkyl oxides with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethylene oxyethanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with with partial esters derived from fatty acids and hexitol anhydride, for example, polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl p-hydroxybenzoate, or one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders and granules suitable for preparing an aqueous suspension may contain water to provide the active ingredient in admixture with the suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are given by way of example and have already been mentioned above. Additional excipients may also be present, for example, sweetening agents, flavoring agents and coloring agents.

The compounds may also be in the form of said liquid formulations, for example, oil suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example in arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. Oil suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents, those mentioned above, can be added to the flavoring agents in order to provide palatable oral preparations. Such compositions may be protected by the addition of antioxidants such as ascorbic acid.

Pharmaceutical compositions according to the invention may also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be natural gums, for example gum acacia or gum tragacanth, natural phosphatides, for example soybean oil, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydride, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening agents and flavoring agents.

Syrups or elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may contain irritants, preservatives, fragrances and coloring agents.

The compounds may also be administered in suppository form for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but solid at rectal temperature and therefore melts in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For all prescribed regimens of use set forth herein for the compounds of formula I, the daily oral dose is preferably from 0.01 to 200 mg/kg of total body weight. The daily dose for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injection, as well as infusion use will preferably be from 0.01 to 200 mg/kg of total body weight. The daily rectal dose is preferably from 0.01 to 200 mg/kg of total body weight. The daily meat dose is preferably from 0.1 to 200 mg/kg given between one and four times a day. The daily inhalation dose is preferably from 0.01 to 10 mg/kg of total body weight.

Those skilled in the art will appreciate that the particular mode of administration will depend on a variety of factors, all of which are taken into account when routinely administering therapeutics. It will also be understood by those skilled in the art that the specific dosage novo in a given patient will depend on various factors, including the specific activity of a given compound, age, body weight, health, sex, time and route of administration, rate of excretion, etc. It will further be appreciated by experts in this field of science that the optimal course of treatment, that is, the method of treatment and the daily number of doses of the compound of formula I or its pharmaceutically acceptable salt given for a defined number of days, will be able to be determined by experts in this field using conventional treatment tests.

However, it is understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination, and severity of the condition being treated.

The compounds may be prepared from known compounds (or from starting materials obtainable from known compounds), for example, by the general preparative procedures set forth below. Raf kinase inhibitory activity of the compounds in question can be routinely assayed, for example, according to the procedures provided below. The following examples are for illustrative purposes only and are not intended or should be construed as limiting the invention in any way.

EXAMPLES

All reactions were performed in flame-dried glass vessels or in an oven under positive pressure of dry argon or dry nitrogen, and mixing was performed with a magnetic stirrer unless otherwise indicated. Sensitive liquids and solutions are transferred by means of a syringe or cannula into reaction vessels through a rubber barrier. Unless otherwise noted, the term "reduced pressure concentration" refers to a Buchi rotary evaporator at about 15-1.332-10<2>Pa (mmHg). Unless otherwise indicated, the term "high vacuum" refers to a vacuum of 0.4-1.0-1.332-102 Pa (mmHg).

All temperatures are reported uncorrected in degrees Celsius (°C). Unless otherwise indicated, all parts and percentages are by weight.

Reagents and solvents of commercial grade were used without further purification. N-cyclohexyl-N'-(methylpolystyrene)carbodiimide was purchased from Calbiochem-Novabiochem Corp. 3-tert-Butyl-aniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-3-(trifluoromethyl)-aniline, 4-chloro-3-(trifluoromethyl)aniline, 2-methoxy-5-(trifluoromethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4-chloro-3-(trifluoromethyl)phenyl isocyanate were purchased and used without further purification. Syntheses of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem. 3, 1995, 129), 4-(3-carbamoylphenoxy)-1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-tert-butylphenyl isocyanate (O. Rohr et al. DE 2,436,108) and 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Zasshi 70, 1967, 491) were previously described.

Thin layer chromatography (TLC) is performed using WWhatman pre-coated silica gel 60A F-254 250 µm glass plates. Plate reading is performed with one or more techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol, after which the plate is heated, (d) immersion of the plate in a solution of cerium sulfate, after which the plate is heated and dried, and/or (e) immersion of the plate in an acid solution of 2,4-dinitrophenylhydrazine and then the plate is heated. Column chromatography ("flash" chromatography) is performed using 230-240 mix EM Science<®>silica gel.

Melting points (m.p.) were determined using a Thomas-Hover melting point apparatus, or on a Metter FP66 automatic melting point apparatus and are uncorrected. Fourier transformed infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton (<1>H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (5 0.00) or residual protonated solvent (CHCl35 7.26, MeOH 8 3.30, DMSO 5 2.49) as standard. Carbon (<13>C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCl38 77.0; MeOD-d38 49.0; DMSO-d68 39.5) as standard. Low-resolution mass spectra (MS) and high-resolution mass spectra (HRMS) were obtained either as electron vibrational (El) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron vibration mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion source was maintained at 250°C. Electron ionization strength is performed with an electron energy of 70 eV with a current trap of 300 [\ A. Liquid-cesium secondary ion mass spectra (FAB-MS), adapted for fast atom bombardment, was obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas (1x10^ torr to 2.5x10"4 torr). A direct insertion desorption chemical ionization (DCI) probe (Vaccumterics, Inc.) was ramped from 0-1.5 amps in 10 seconds and held until decay. sample traces (about 1-2 min). Spectra were scanned from 50-800 amu per scan. HPLC-Electrospray mass spectra (HPLC ES-MS) were obtained using variable ion time in the source. Gas chromatography-ion selective mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 with a silicon column (0.33 mM layer; 25 m x 0.2 mm) and a Hewlett Packard 5971 mass selective detector (ionization energy 70 eV). Elemental analyzes were performed by Robertson Microlit Labs, Madison

His Majesty.

All compounds shown by LRMS NMR spectra and either elemental analysis or HRMS are conformations to specific structures.

List of abbreviations and initials:

AcOH acetic acid

anh anhydrous

atm atmosphere

BOC tert-butoxycarbonyl

CDI 1,1 '-carbonyl diimidazole

conc concentrated

deck analysis

DMAC N,N-dimethylacetamide

DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

DPPA diphenylphosphoryl azide

EDCI 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide EtOAc Ethyl acetate

EtOH ethanol (100%)

Et20 diethyl ether

Et3N triethylamine

h hour(s)

HOBT 1-hydroxybenzotriazole

m-CPBA 3-chloroperoxybenzoic acid MeOH methanol

Friday. ether petroleum ether (boiling range 30-60°C)

temp. temperature

THF tetrahydrofuran

TFA trifluoroAcOH

Tf trifluoromethanesulfonyl

A. General procedures for the synthesis of substituted anilines A1. General procedures for the formation of aryl amines via ether formation

Followed by ester saponification, Curtius displacement and carbamate deprotection. Synthesis of 2-amino-3-methoxynaphthalene

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.) in 200 ml_ DMF was stirred at room temperature for 15 minutes, then treated with iodomethane (3.43 ml_, 55.1 mmol.). The mixture is left to stir at room temperature overnight, then treated with 200 ml of water. The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure (about 0.4 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10.30 g):

<1>H-NMR (DMSO-d6) 5 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (appt, J=8.09Hz, 1H, 7.44 (s, 1H), 7.53 (appt, J=8.09Hz, 1H), 7.84 (d, J=8.09Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).

Step 2. 3-Methoxy-2-naphthalenecarboxylic acid

A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol.) and 10 mL_ water in 100 mL_ MeOH at room temperature was treated with 1 N NaOH solution (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 (MgSO 4 ) and concentrated under reduced pressure. The residue was powdered with hexane, then washed several times with hexane to give 3-methoxy-2-naphthalenecarboxylic acid as a white solid (5.40 g, 92%):<1>H-NMR (DMSO-d6) 5 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.42-7.54 (m, 1H), 7.83 (d, J=8.09Hz, 1H), 8.19 (s, 1H), 12.83 (broad s, 1H).

Step 3. 2-(N-(Carbobenzyloxy)amino-3-methoxynaphthalene).

A solution of 3-methoxy-2-naphthalenecarboxylic acid (3.36 g, 16.6 mmol.) and Et3N (2.59 mL, 18.6 mmol.) in anhydrous toluene (70 mL) was stirred at room temperature for 15 minutes, then treated with a solution of DPPA (5.12 g, 18.6 mmol.) in 10 mL toluene using a pipette. The resulting mixture is heated to 80°C for two hours. After cooling the mixture to room temperature, benzyl alcohol (2.06 mL, 20 mmol.) was added via syringe. The mixture is then heated to 80°C overnight. The resulting mixture was cooled to room temperature, acidified with 10% citric acid solution, and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated NaCl solution, dried over MgSO 4 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 light yellow oil (5.1 g, 100%):

<1>H-NMR (DMSO-d6) δ 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H), 8.76 (s, 1H).

Step 4. 2-Amino-3-methoxynaphthalene

A suspension of 2-(/V-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd/C (0.5 g) in 70 mL of EtOAc was maintained under H2 (balloon) at room temperature overnight. The resulting mixture was filtered through Celite and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder. colors (2.40 g, 85%): <1>H-NMR (DMSO-d6) δ 3.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H); EI-MS m/z 173 (M<+>).

A2. Synthesis of co-carbamyl aniline via carbamylpyridine formation followed by nucleophilic coupling with an aryl amine. Synthesis of 4-(2-N-methylcarbamyl-4-pyridyloxy)aniline

Step 1a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxame via the Menisci reaction

Caution: this is a very dangerous, potentially explosive reaction. To a solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temperature with stirring was added concentrated H 2 SO 4 (3.55 mL) to generate an exotherm. To this mixture was added H 2 O 2 (30% in H 2 O, 17 mL) followed by FeSO 4 7H 2 O (0.56 g) to generate the following exotherm. The resulting mixture was stirred in the dark at room temperature for 1 hour, then gently heated to 45°C for 4 hours. When the bubbling subsides, the reaction mixture is heated to 60°C for 16 hours. The resulting opaque, dark-colored solution is diluted with 700 mL of H2O, then with a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with saturated NaCl solution (2 x 150 mL), then combined, dried (MgSO 4 ) and filtered through a pad of silica gel with EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50% hexanes to 80% EtOAc/20% hexanes). The resulting yellow oil was crystallized at 0°C for 72 hours to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%):

TLC (50% EtOAc/50% hexanes) Rf 0.50;<1>H-NMR (CDCL3) δ 3.04 (d, J=5.1 Hz, 3H), 7.43 (dd, J=5.4 Hz, 1H), 7.96 (broad s, 1H), 8.21 (s, 1H), 8.44 (d, J=5.1 Hz, 1H). 1H); CI-MS m/z 171 ((M+H)<+>).

Step 1b. Synthesis of 4-chloropyridine-2-carbonyl chloride HCl salt via picolinic acid

Anhydrous DMF (6.0 mL) was slowly added to SO 2 Cl 2 (180 mL) at a temperature between 40° and 50°C. The solution was stirred in the range at that temperature for 10 minutes, then picolinic acid (60.0 g, 487 mmol.) was added in portions over 30 minutes. The resulting solution is heated to 72°C (strong evolution of SO2) for 16 hours, and a solid yellow precipitate is formed. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. The addition/concentration procedure is repeated twice. The resulting almost dry residue was filtered and the solids washed with toluene (2 x 200 mL) and dried under high vacuum for 4 hours to give 4-chloropyridine-2-carbonyl chloride as the HCl salt as a yellow-orange solid (92.0 g, 89%).

Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HCl salt

Anhydrous DMF (10.0 mL) was slowly added to SO 2 Cl 2 (180 mL) at a temperature between 40° and 50°C. The solution was stirred at room temperature for 10 minutes, then picolinic acid (100.0 g, 812 mmol) was added over 30 minutes. The resulting solution is heated to 72°C (strong evolution of SO2) for 16 hours, and a yellow solid is formed. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. The addition/concentration procedure is repeated twice. The resulting nearly dry residue was filtered and the solids washed with toluene (50 mL) and dried under high vacuum for 4 h to give 4-chloropyridine-2-carbonyl chloride as the HCl salt as a colorless solid (27.2 g, 16%). Set this material aside.

The red filtrate was added to 200 mL of MeOH at such a rate that the internal temperature was maintained below 55°C. The contents were stirred at room temperature for 45 minutes, cooled to 5°C and treated with Et 2 O (200 mL) dropwise. The obtained solids were filtered, washed with Et2O (200 mL) and dried under reduced pressure at 35°C to give methyl 4-chloropyridine-2-carboxylate as the HCl salt as a white solid (110 g, 65%): m.p. 108-112°C; 1H-NMR (DMSO-d 6 ) δ 3.88 (s, 3H), 7.82 (dd, J=5.5, 2.2 Hz, 1H); 8.08 (d, J=2.2Hz, 1H); 8.68 (d, J=5.5 Hz, 1H); 10.68 (s.s., 1H); HPLC ES-MSm/z172 ((M+H)<+>).

Step 3a: Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carboxylate

A suspension of methyl-4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in MeOH (75 mL) at 0 °C was treated with a 2.0 M solution of methylamine in THF (1 L) at a rate such that the internal temperature was maintained below 5 °C. The resulting mixture was kept at 3°C for 5 hours, then concentrated under reduced pressure. The resulting solids are suspended in EtOAc (1 L) and filtered, and the filtrate is washed with saturated NaCl solution (500 mL), and after drying over Na2SO4, it is concentrated under reduced pressure to give 4-chloro-N-methyl-2-pyridinecarboxamide in the form of bright yellow crystals

(71.2g, 97%): m.p. 41-43°C; 1H-NMR (DMSO-d6) δ 2.81 (s, 3H), 7.74 (dd, J=5.1, 2.2 Hz, 1H), 8.00 (d, J=2.2, 1H), 8.61 (d, J=5.1 Hz, 1H), 8.85 (w.d, 1H); CI-MS/77/Z171 ((M+H)<+>).

Step 3b: Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carbonyl chloride 4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added portionwise to a mixture of a 2.0 M solution of methylamine in 100 mL of THF and MeOH (20 mL) at 0°C. The resulting mixture was kept at 3°C for 4 hours, then concentrated under reduced pressure. The resulting almost dry solid was suspended in EtOAc (100 mL) and filtered. The filtrate was washed with saturated NaCl (2 x 100 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure to give 4-chloro-N-methyl-2-pyridinecarboxamide as a yellow crystalline solid (4.95 g, 88%): m.p. 37-40°C.

Step 4. Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anhydrous DMF (150 mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol) and the reddish-brown mixture was stirred at room temperature for 2 hours. 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 to 80 °C for 8 h. The mixture was cooled to room temperature and partitioned between EtOAc (500 mL) and saturated NaCl (500 mL). The aqueous phase was re-extracted with EtOAc (300 mL). The combined organic layers were washed with saturated NaCl solution (4 x 1000 mL), dried (Na2SO4) and concentrated under reduced pressure at 35°C for 3 hours to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline as a tan solid (17.9 g, 84%): 1H-NMR (DMSO-d6) 5 2.77 (d, J=4.8Hz, 3H), 5.17 (w.s, 2H), 6.64, 6.86 (AA'BB' quartet, J=8.4 Hz, 4H), 7.06 (dd, J=5.5, 2.5 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H), 8.44 (d, J=5.5 Hz, 1H); 8.73 (s.d., 1H); HPLC ES-MSm/z244 ((M+H)<+>).

A3. General procedure for the synthesis of aniline by nucleophilic aromatic addition followed by nitroarene reduction. Synthesis of 5-(4-aminophenoxy)isoindoline-1,3-dione

Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione

To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in concentrated AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture is heated to 120°C for 45 minutes, then the clear, bright yellow mixture is heated to 160°C for 2 hours. The resulting mixture is maintained at 160°C and concentrated to about 15 mL, then cooled to room temperature and pH adjusted to 190 with 1N HCl solution. The resulting precipitate was collected by filtration and dried under reduced pressure to give 5-hydroxyisoindoline-1,3-dione as a light yellow powder product (3.24 g, 72%); <1>H-NMR (DMSO-d6) δ 7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H).

Step 2. Synthesis of 5-(4-nitrophenoxy)isoindoline-1,3-dione

To a stirred suspension of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 °C was added a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The bright yellow-green mixture was allowed to warm to room temperature and stirred for 1 hour, then 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated to 70°C overnight, then cooled to room temperature and diluted slightly with water (150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over (MgSO 4 ) and concentrated under reduced pressure to give 4-(4-nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30%, EtOAc/70% hexanes) R,0.28:<1>H-NMR (DMSO-d6) 8 7.32 (d, J=12Hz, 2H). 7.52-7.57 (m, 2H), 7.89 (d, J=7.8 Hz, 1H), 8.29 (d, J=9 Hz, 2H), 11.43 (w.s, 1H); CI-MSm/ z285 ((M+H)<+>, 100%).

Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-1,3-dione

A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g, 2.11 mmol) in concentrated AcOH (12 mL) and water (0.1 mL) was stirred under a stream of argon while iron powder (0.59 g, 55.9 mmol) was slowly added. The mixture was stirred at room temperature for 72 h, then diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL9. The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure to give 5-(4-aminophenoxy)isoindoline-1,3-dione as a brown solid (0.4 g, 75%): TLC (50% EtOAc/50% hexanes) R, 0.27;<1>H-NMR (DMSO-d6) δ 5.14 (w.s, 2H), 6.62 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 7.03 (d, J=2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J=8.4 Hz, 1H), 11.02 (s, 1H); HPLC ES-MSm/z 255((M+H)<+>, 100%).

A4. General procedure for the synthesis of pyrrolylaniline. Synthesis of 5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline

Step 1. Synthesis of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole

To a stirred solution of 2-nitro-4-tert-butylaniline (0.6 g, 2.57 mmol) in cyclohexane (10 mL), AcOH (0.1 mL) and acetonylacetone (0.299 g, 2.63 mmol) were added via syringe. The reaction mixture is heated to 120°C in the flow

72 hours with azeotropic removal of volatile ingredients. The reaction mixture was cooled to room temperature, diluted with CH 2 Cl 2 (10 mL) and washed sequentially with 1 N brine HCl (15 mL), 1 N NaOH solution (15 mL) and saturated NaCl solution (15 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The resulting orange-brown solid was purified by column chromatography (60g, SiO2; gradient from 6% EtOAc/94% hexanes to 25% EtOAc/75% hexanes) to give 1-(tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole as an orange-yellow solid (0.34g, 49%): TLC (15% EtOAc/85% hexanes) Rf 0.67; <1>H-NMR (CDCl 3 ) δ 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H), 7.62 (dd, 1H), 7.88 (d, J=2.4 Hz, 1H); CI-MSm/ z273 ((M+H)<+>, 50%).

Step 2. Synthesis of 5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline

A suspension of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10%Pd/C (0.056 g) and EtOAc (50 mL) was stirred under H2 (balloon) for 72 h, then filtered through a pad of Celite<®.> The filtrate was concentrated under reduced pressure to give 5- tert -butyl-2-(2,5-dimethylpyrrolyl)aniline as a yellowish solid (0.30 g, 99%); TLC (10% EtOAc/90% hexanes) Rf 0.43; 1H-NMR (CDCl 3 ) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (s.s, 2H), 6.73-6.96 (m, 3H), 7.28 (s.s, 1H).

A5. A general procedure for the synthesis of aniline from aniline using a nucleophilic

aromatic substitutions. Synthesis of 4-(2-(N-methylcarbamoyl)-4-

pyridyloxy)-2-methylaniline HCl salt

A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert -butoxide (10.86 g, 96.77 mmol) and the dark mixture was stirred at room temperature until room temperature was reached in a flask. The contents of the flask are treated with 4-chloro-N-methyl-2-pyridinecarboxamide (procedure A2, step 3b; 7.52 g, 44.2 mmol) and heated to 110°C for 8 hours. The mixture was cooled to room temperature and diluted with water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with saturated NaCl solution (200 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The remaining dark oil was treated with Et 2 O (50 mL) and sonicated. The solution was then treated with HCl (1 M in Et 2 O, 100 mL) and stirred at room temperature for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was filtered off from the solution and stored under aerobic conditions at 0°C before use.<1>H-NMR (DMSO-d6) δ 2.41 (s, 3H), 2.78 (d, J=4.4Hz, 3H), 4.93 (s.s, 2H), 7.19 (dd, J=8.5, 2.6 Hz, 1H), 7.23 (dd, J)5.5,

2.6 Hz, 1H), 7.26 (d, J=2.6Hz, 1H), 7.55 (d, J=2.6Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 8.55 (d, J=5.9 Hz, 1H), 8.99 (q, J=4.8 Hz, 1H).

A6. General procedure for the synthesis of aniline from hydroxyaniline via N-protection, nucleophilic aromatic substitution and deprotection.

Synthesis of 4-(2-N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline

Step 1: Synthesis of 3-Chloro-4-(2,2,2-trifluoroacetylamino)phenol

Iron (3.24 g, 58.00 mmol) was added to TFA (200 mL) with stirring. To this suspension was added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 mL). This colored suspension was stirred at room temperature for 6 hours. The iron is filtered off from the solution and the remaining material is concentrated under reduced pressure. The resulting colored solid was dissolved in water (20 mL). A saturated solution of NaHCO3 (50 mL) is added to the resulting yellow solution. The solid matter precipitated from the solution is separated. The filtrate is gently treated with a solution of sodium bicarbonate until the product is visibly separated from the solution (the determination is made using a small ampoule). The slightly cloudy yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with saturated NaCl solution (125 mL), dried (MgSO4) and concentrated under reduced pressure. <1>H-NMR (DMSO-d6) indicated a 1:1 ratio of nitrophenol starting material to desired product 3-chloro-4-(2,2,2-trifluoroacetylamino)-phenol. The crude material is used in the next step without further purification.

Step 2: Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl-(2,2,2-trifluoro)acetamide A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 mL) was treated with potassium tert-butoxide (5.16 g, 23.46 mmol). 45.98 mmol) and the quenched mixture is stirred at room temperature until reaching room temperature in the flask. The resulting mixture was treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Procedure A2, step 3b; 1.99 g, 11.7 mmol) and heated to 100°C under an argon atmosphere for 4 hours. The dark reaction mixture was cooled to room temperature and then quenched in 100 mL of cold water. The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The remaining grayish brown oil was purified by column chromatography (gradient from 20% EtOAc/petroleum ether to 40% EtOAc/petroleum ether) to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl-(2,2,2-trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol).

Step 3. Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline

A solution of crude 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl-(2,2,2-trifluoro)acetamide (8.59 g, 23.00 mmol) in dry 4-dioxane (20 mL) was treated with 1N NaOH solution (20 mL). This dark colored solution was left to stir for 8 hours. ? To this solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x 40 mL) and the solvent was concentrated to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline as a green oil which solidified on standing (2.86 g, 10.30 mmol): <1>H-NMR (DMSO-d6) 5 2.77 8d, J=4.8 Hz. 3H), 5.51 (s, 2H), 6.60 (dd, J=8.5, 2.6 Hz, 1H), 6.76 (d, J=2.6 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 7.07 (dd, J=5.5, 2.6 Hz, 1H), 7.27 (d, J=2.6 Hz, 1H). 1H), 8.46 (d, J=5.5 Hz, 1H), 8.75 (q, J=4.8, 1H).

A7. General procedure for deprotection of acylated aniline. Synthesis of 4-chloro-2-methoxy-5-(trifluoromethyl)aniline

A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g, 14.95 mmol) in 6M HCl solution (24 mL) was heated to reflux for 1 h. The resulting solution is left to cool to room temperature, during which time it slowly hardens. The resulting mixture is diluted with water (20 mL), then treated with a combination of solid NaOH and a saturated solution of NaHCO3, whereby the solution becomes basic. The organic layer was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure to give 4-chloro-2-methoxy-5-(trifluoromethyl)aniline as a dark oil (3.20 g, 14.2 mmol):<1>H-NMR (DMSO-d6) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

A8. General procedure for the synthesis of 1-Alkoxy-1-carboxyphenyl aniline.

Synthesis of 4-(3-(N-methylcarbamoyl)-4-methoxyphenoxy)aniline.

Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene:

To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene (which was obtained from 2,5-dihydroxybenzoic acid in a manner analogous to that described in procedure A13, step 1.12 mmol) in acetone (50 mL) was added K2CO3 (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated to reflux overnight, then cooled to room temperature and filtered through a pad of Celite<®.>The resulting solution was concentrated under reduced pressure, absorbed on SiO2, and purified by column chromatography (50% EtOAc/50% hexanes) to give 4-(3-rethoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a yellow powder (3 g): m.p. 115-118°C.

Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-1-nitrobenzene:

Do you? 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temperature overnight and then heated to reflux for 4 h. 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 (MgSO 4 ) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (1.04g).

Step 3. 4-(3-(N-Methylcarbamoyl)-4-methoxyphenoxy)-1-nitrobenzene: To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (0.50 g, 1.75 mmol) in CH2Cl2 (12 mL) was added SOCI2 (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 were dissolved in CH2Cl2 (3 mL), then the resulting solution was treated with methylamine solution (2.0 M in THF, 3.5 mL, 7.02 mmol) in portions (CAUTION: gas evolution), and stirred at room temperature for 4 h. The resulting mixture is treated with 1N NaOH solution, then extracted with CH 2 Cl 2 (25 mL).

The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)-4-methoxyphenoxy)-1-nitrobenzene as a yellow solid (0.50 g, 95%).

Step 4. 4-(3-(N-methylcarbamoyl)-4-methoxyphenoxy)aniline:

A suspension of 4-(3-(N-methylcarbamoyl)-4-methoxyphenoxy)-1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under 1 atm H2 pressure (balloon) for 2.5 days, then filtered over a pad of Celite®. The resulting solution was concentrated under reduced pressure to give 4-3-(N-methylcarbamoyl)-4-methoxyphenoxy)aniline as a colorless solid (0.68 g, 96%): TLC (0.1% Et3N/99.9% EtOAc) R, 0.36. A9. General procedure for the preparation of a)-alkylphthalimide-containing aniline. Synthesis of 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione

Step 1. Synthesis of 5-(4-nitrophenoxy)-2-methylisoindoline-1,3-dione: A suspension of 5-(4-nitrophenoxy)isoindoline-1,3-dione (A3 step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temperature for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temperature overnight, then cooled to 0°C and treated with water (10 mL). The resulting solids were collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindoline-1,3-dione as a light yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexanes) Rf 0.61.

Step 2. Synthesis of 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione:

A suspension of 5-(4-nitrophenoxy)-2-methylisoindoline-1,3-dione (0.87 g, 2.78 mmol) and 10% Pd/C (0.10 g) in MeOH was stirred under 1 atm H 2 pressure (balloon) overnight. The resulting mixture is filtered through a layer of Celite<®> and concentrated under reduced pressure. The resulting yellow solid was dissolved in EtOAc (3 mL) and filtered through a pad of SiO2 (60% EtOAc/40% hexanes) to give 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc/60% hexanes) Rf 0.27.A10. General Procedure for Synthesulo-Carbamoylaryl Anilines via Reaction of Cu-Alkoxycarbonylaryl Precursors with Amines. Synthesis of 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline

Step 1. Synthesis of 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine

To a solution of methyl 4-chloropyridine-2-carboxylate as the HCl salt (Procedure A2, step 2, 1.01 g, 4.86 mmol) in 20 mL of THF was added 4-(2-aminoethyl)morpholine (2.55 mL, 19.4 mmol) dropwise and the resulting solution was heated to reflux for 20 h, then cooled to room temperature and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO 4 ) 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) R, 0.50.

Step 2. Synthesis of 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy) aniline.

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert -butoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temperature for 2 h, then treated sequentially with 4-chloro-2-(N-(2-morpholin-4-ylethyl)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 solution (25 mL). The aqueous layer was re-extracted with EtOAc (25 mL). The combined organic layers were washed with saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure. The resulting brown solid was purified by column chromatography (58 g, gradient from 100% EtOAc to 25% MeOH/75% EtOAc) to give 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%: TLC (10% MeOH/90% EtOAc) R, 0.32).

A11. General procedure for the reduction of nitroarenes to arylamines. Synthesis of 4-(3-carboxyphenoxy)aniline.

A suspension of 4-(3-carboxyphenoxy)-1-nitrobenzene (5.38 g, 20.7 mmol) and 105 Pd/C (0.50 g) in MeOH (120 mL) was stirred under H2u 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%). TLC (10% MeOH/90% CH 2 Cl 2 ) R, 0.44 (banded).

A12. General procedure for the synthesis of inozodlinone-containing aniline.

Synthesis of 4-(1-oxoisoindolin-5-yloxy)aniline.

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 zinc powder (47.6 g, 729 mmol) in portions, then the mixture was heated to reflux for 40 min, filtered warm, and concentrated under reduced pressure. The reaction was repeated in the same manner and the combined oily residue was purified by column chromatography (1.1 kg SiO 2 ; gradient from 60% EtOAc/40% hexanes to 25% MeOH/75% EtOAc) to give 5-hydroxyisoindolin-1-one (3.77 g): TLC (100T EtOAc) R, 0.17; HPLC-ES-MS m/z 150 ((M+H)+).

Step 2. Synthesis of 4-(1-isoindolinone-5-yloxy)-1-nitrobenzene

To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 °C was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting suspension was allowed to reach room temperature and stirred for 45 minutes, then 4-fluoro-1-nitrobenzene was added and then the mixture was heated at 70°C for 3 hours. The mixture is cooled to 0°C and treated with water dropwise until a precipitate forms. The resulting solid was collected to give 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf 0.35.

Step 3. Synthesis of 4-(1-oxoisoindolin-5-yloxy)aniline

A suspension of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd/C (0.20 g) in EtOH (50 mL) was stirred under H 2 (balloon) for 4 h, then filtered over a pad of Celite®. The filtrate was concentrated under reduced pressure to give 4-(1-(oxoisoindolin-5-yloxy)aniline as a dark yellow solid. TLC (100% EtOAc) R.0.15.

A13. General procedure for the synthesis of to-carbamoyl aniline via EDCI-

mediated amide formation followed by nitroarene reduction.

Synthesis of 4-(3-/V-Methylcarbamoylphenoxy)aniline.

Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene

A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate (25 g, 150 mmol), and K 2 CO 3 (41 g, 300 mmol) in DMF (125 mL) was heated at reflux overnight, cooled to room temperature, and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed successively with water (3 x 100 mL) and saturated NaCl solution (2 x 100 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc/90% hexane) to give 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).

Step 2. Synthesis of 4-(3-carboxyphenoxy)-1-nitrobenzene

To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene (5.14 g, 17.9 mmol) in 3:1 THF/water (75 mL) was added a solution of LiOH-H 2 O (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated overnight, then cooled to room temperature, concentrated under reduced pressure, and the pH adjusted to 2 with 1 M HCl solution. The light yellow material obtained was collected by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-1-nitrobenzene (4.40 g, 95%).

Step 3. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene

A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72 g, 14.4 mmol), EDCHCl (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 CH 2 Cl 2 (45 mL) was 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 1 M HCl solution (50 mL). The aqueous layer was re-extracted with EtOAc (2 x

50 mL). The combined organic phases were washed with saturated NaCl solution (50 mL), dried (N 2 SO 4 ) and concentrated under reduced pressure to give 4-(3-(N-methyl-carbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g).

Step 4. Synthesis of 4-(3-(N-methylcarbamoyl)phenosky)aniline

A suspension of 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene (1.89 g, 6.95 mmol) and 5% Pd/C (0.24 g) in EtOAc (20 mL) was stirred under H 2 (balloon) overnight. The resulting mixture is filtered through a layer of Celite<®> and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH/95% CH 2 Cl 2 ). The resulting oil solidifies overnight under vacuum to give 4-(3-(N-methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).

A14. General procedure for the synthesis of a)-carbamoyl anilines via EDCI-mediated amide formation followed by nitroarene reduction. Synthesis of 4-3-(5-Methylcarbamoyl)pyridyloxy)aniline

Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene To a suspension of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated to 70 °C overnight, cooled to room temperature and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase is concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g)

Step 2. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline

A suspension of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd/C in MeOH/EtOAc was stirred under H 2 (balloon) for 72 h. The resulting mixture is filtered and concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% EtOAc/90% hexane to 30% EtOAc/70% hexane to 50% EtOAc/50% hexane) to give 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): <1>H NMR (CDCl3) 5 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (d, 1H), 8.51 (d, 1H), 8.87 (d, 1H).

A15. Synthesis of aniline via electrophilic nitration followed by reduction. Synthesis of 4-(3-methylsulfamoylphenoxy)aniline.

Step 1. Synthesis of N-methyl-3-bromobenzenesulfonamide

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 and stirred at 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 2.5 mL). The combined organic phases were washed sequentially with water (2 x 25 mL) and saturated NaCl (25 mL), dried (MgSO 4 ), and concentrated under reduced pressure to give N-methyl-3-bromobenzenesulfonamide as a white solid (2.8 g, 99%).

Step 2. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene

To a slurry containing phenol (1.9 g, 20 mmol), K 2 CO 3 (6.0 g, 40 mmol) and CuJ (4 g, 20 mmol) in DMF (25 mL) was added N-methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol) and the resulting mixture was stirred at reflux overnight, cooled to room temperature and partitioned between EtOAc (50 mL) and 1 N HCl. (50 mL). The aqueous layer was re-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed sequentially with water (2 x 50 mL) and saturated NaCl solution (50 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(N-methylsulfamoyl!)phenyloxy)benzene (0.30 g).

Step 3. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene

To a solution of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10°C was added NaNO 2 (0.097 g, 1.14 mmol) in portions over 5 min. The resulting solution was stirred at -10°C for 1 hour, then allowed to reach room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (10 mL) and water (10 mL). The organic phase was washed sequentially with water (10 mL) and saturated NaCl solution (10 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give 4-(3-(N-methylsulfamoyl)phenyl)-1-nitrobenzene (0.20

g). This material is used in the next step without further purification.

Step 4. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)aniline

A suspension of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.30 g) and 10% Pd/C (0.030 g) in EtOAc (20 mL) was stirred under H 2 (balloon) overnight. The resulting mixture is filtered through a layer of Celite®. The filtrate is concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)aniline (0.070 g).

A16. Modification of w-ketone. Synthesis of 4-(4-(1-(N-methoxy)iminoethyl)

phenoxyaniline HCl salts

To a suspension of 4-(4-acetylphenoxy)aniline HCl salt (obtained analogously to procedure A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0 mL) was added O -methylhydroxylamine HCl salt (0.65 g, 7.78 mmol, 2.0 equiv). The resulting solution is heated at reflux temperature for 30 minutes, cooled to room temperature and concentrated under reduced pressure. The resulting solid was triturated with water (10 mL) and washed with water to give 4-(4-(1-N-methoxy)iminoethyl)phenoxyaniline HCl salt as a yellow solid (0.85 g): TLC (50% EtOAc/50% petroleum ether) Rf 0.78; <1>H NMR (DMSO-d6) 5 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MSm/z257 ((M+H)<+>).

A17. Synthesis of N-(co-silyloxyalkyl)amide. Synthesis of 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline).

Step 1. 4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide

To a solution of 4-chloro-N-(2-hydroxyethyl)pyridine-2-carboxamide (prepared analogously to procedure A2, step 3b; 1.5 g, 7.4 mmol) in anhydrous DMF (7 mL) was added triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv). The resulting yellow solution was stirred for 3 hours at room temperature, then concentrated under reduced pressure. The residue was partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3x10 mL). The combined organic phases were dried (MgSO 4 ), and concentrated under reduced pressure to give 4-chloro-2-(N-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide as an orange oil (2.32 g, 88%). This material is used in the next step without further purification.

Step 2. 4-(4-(2-(N-(2-Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline

To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anhydrous DMF (8 mL) was added potassium tert -butoxide (0.67 g, 6.0 mmol, 1.0 equiv) in one portion causing an exothermic reaction. When this mixture was cooled to room temperature, a solution of 4-chloro-2-(N-(2-trithisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv) in DMF (4 mL) was added followed by K 2 CO 3 (0.42 g, 3.0 mmol, 0.50 equiv). The resulting mixture is heated to 80°C overnight. An additional portion of potassium tert-butoxide (0.34 g, 3 mmol, 0.5 equiv) was then added and the mixture was stirred at 80°C for another 4 hours. The mixture was cooled to 0°C in an ice/water bath, then water (about 1 mL) was slowly added dropwise. The organic layer was extracted with EtOAc (3x10 mL). The combined organic layers were washed with saturated NaCl solution (20 mL), dried (MgSO 4 ), and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (SiO 2 , 30% EtOAc/70% petroleum ether) to give 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline) as a light brown clear oil (0.99 g, 38%).

A18. Synthesis of 2-pyridinecarboxylate ester by oxidation of 2-methylpyridine. Synthesis of 4-(5-(2-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 mL, 91.6 mmol, 1.0 equiv), K 2 CO 3 (25 g, 183 mmol, 2 equiv) in DMF (100 mL) was heated at reflux temperature overnight. The resulting mixture was cooled to room temperature, treated with water (200 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed sequentially with water (2 x 100 mL) and saturated NaCl solution (100 mL), dried (MgSO 4 ) 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)pyridyloxy)-1-nitrobenzene.

A mixture of 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv) in pyridine (20 mL) was heated at reflux for 5 h, then cooled to room temperature. The resulting suspension is filtered, then concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The solution was treated with conc. HCl (7 mL), then heated at reflux for 3 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was partitioned between EtOAc (50 mL) and 1 N NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed sequentially with water (2 x 50 mL) and saturated NaCl solution (50 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 ; 50% EtOAc/50% hexane) to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.70 g).

Step 3. Synthesis of 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline.

A suspension of 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.50 g) and 10% Pd/C (0.050 g) in a mixture of EtOAc (20 mL) and MeOH (5 mL) was exposed to an atmosphere of H 2 (balloon) overnight. The resulting mixture is filtered through a pad of Celite<®>, and the filtrate is concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 ; 70% EtOAc/30% hexane) to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline (0.40 g).

A19. Synthesis of o-sulfonylphenyl aniline. Synthesis of 4-(4-methylsulfonylphenoxy) aniline.

Step 1. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene:

To a solution of 4-(4-methylthiophenoxy)-1-nitrobenzene (2.0 g, 7.7 mmol) in CH 2 Cl 2 (75 mL) at 0 °C was slowly added m-CPBA (57-86%, 4.0 g), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with 1 N NaOH solution (25 mL). The organic layer was washed sequentially with 1 N NaOH (25 mL), water (25 mL), and saturated NaCl (25 mL), dried (MgSO 4 ), and concentrated under reduced pressure to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene as a solid (2.1 g).

Step 2. 4-(4-Methylsulfonylphenoxy)1-aniline: 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene is reduced to aniline in an analogous manner to that described in Procedure A18, Step 3.

B. Synthesis of urea precursors

B1. General procedure for the synthesis of isocyanates from aniline using CDI. Synthesis of 4-Bromo-3-(trifluoromethyl)phenyl isocyanate.

Step 1. Synthesis of 4-bromo-3-(trifluoromethyl)anilineHCIsol

To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et 2 O (500 mL) was added a solution of HCl (1 M in Et 2 O; 300 mL) dropwise and the resulting mixture was stirred at room temperature for 16 h. The resulting pinkish-white precipitate was removed by filtration and washed with Et 2 O (50 mL) to give 4-bromo-3-(trifluoromethyl)aniline HCl salt (73 g, 98%).

Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate

A suspension of 4-bromo-3-(trifluoromethyl)aniline HCl salt (36.8 g, 133 mmol) in toluene (278 mL) was treated with trichloromethyl chloroformate dropwise and the resulting mixture was heated to reflux for 18 hours. The resulting mixture is concentrated under reduced pressure. The residue was treated with toluene (500 mL), then concentrated under reduced pressure. The residue was treated with CH 2 Cl 2 (500 mL), then concentrated under reduced pressure. The CH 2 Cl 2 treatment/concentration protocol was repeated and the resulting amber oil was stored at -20°C for 16 h to give 4-bromo-3-(triluphoromethyl)phenyl isocyanate as a dark brown solid (35.1 g, 86%): GC-MSm/ z265 (M<+>).

C. Urea formation processes

C1a. General procedure for the synthesis of urea by the reaction of isocyanate with aniline. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea

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-(N-methylcarbamoyl)-4-pyridyloxy)aniline (Procedure A2, step 4; 16.0 g, 65.77 mmol) in CH 2 Cl 2 (35 mL) at 0 °C. The resulting mixture was stirred at room temperature for 22 hours. The resulting yellow solid was removed by filtration, then washed with CH2Cl2 (2 x 30 mL) and dried under reduced pressure (1-1.332-102 Pa (mmHg)) to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as a colorless solid (28.5 g, 93%): d.p. 207-209°C; 1H NMR (DMSO-d6) δ 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H), 7.62 (m, 4H), 8.11 (d, J=2.5Hz, 1H), 8.49 (d, J=5.5 Hz, 1H). 8.77 (s.d" 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC-MSm/z465 ((M+H)<+>).

C1b. General procedure for the synthesis of urea by the reaction of isocyanate with aniline. Synthesis of N-(4-Bromo-3-(trifluoromethyl)phenyl-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea

A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (method B1, step 2;

8.0 g, 30.1 mmol) in CH 2 Cl 2 (80 mL) was added dropwise to a solution of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (Procedure A2, Step 3; 7.0 g, 28.8

mmol) in CH2Cl2 (40 mL) at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The resulting yellow solid was removed by filtration, then washed with CH2CI2 (2 x 50 mL) and dried under reduced ... pressure (1-1,332-102 Pa (mmHg)) at 40°C to give N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as a pale yellow solid. (13.2 g, 90%): m.p. 203-205°C; <1>H NMR (DMSO-d6) δ 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H), 7.58 (m, 3H), 7.77 (d, J=8.8 Hz, 1H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (w.d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MSm/z509

((M+H)<+>).

C1c. General procedure for the synthesis of urea by the reaction of isocyanate with aniline. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-methyl-4-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea

A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyricyloxy))aniline (Procedure A5; 0.11 g, 0.45 mmol) in CH 2 Cl 2 (1 mL) was treated with Et 3 N (0.16 mL) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting dark solution was stirred at room temperature for 6 days, then treated with water (5 mL). The aqueous layer was re-extracted with EtOAc (3x5 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea as a dark oil (0.11 g, 0.22 mmol)<1>H NMR (DMSO-d6) 5 2.27 (s, 3H), 2.77 (d, J=4.8 Hz, 3H), 7.03 (dd, J=8.5, 2.6 Hz, 1H), 7.11 (d, J=2.9 Hz, 1H), 7.15 (dd, J=5.5, 2.6 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.62 (d, J=2.6 Hz, 1H) 2H), 7.84 (d, J=8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50 (d, J=5.5 Hz, 1H), 8.78 (q, J=5.2, 1H), 9.52 (s, 1H); HPLC ES-MSm/ z 479 ((M+H)<+>).

C1d. General procedure for the synthesis of urea by reaction of isocyanate with niline. 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) in one portion. The resulting mixture was stirred at room temperature for 1 hour, treated with CH 2 Cl 2 (100 mL), and concentrated under reduced pressure. The resulting pink solid was dissolved in a mixture of EtOAc (110 mL) and MeOH (15 mL), and the clear solution was washed with 0.05 N HCl. The organic layer was concentrated under reduced pressure to give impure N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl)urea (3.3 g): TLC (100% EtOAc) Rf 0.72.

C1e. General procedure for the synthesis of urea by the reaction of isocyanate with aniline. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl)urea

To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH 2 Cl 2 (30 mL) was added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution was stirred at room temperature overnight. The resulting suspension was diluted with CH2Cl2 (50 mL) and filtered to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl)urea as a white solid (5.93 g, 97%): TLC (40% EtOAc/60% hexane) R, 0.44.

C1f. General procedure for the synthesis of urea by the reaction of isocyanate with aniline. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-carboxyphenyl)urea.

To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21 g, 5.46 mmol) in CH 2 Cl 2 (8 mL) was added 4-(3-carboxyphenoxy)aniline (Procedure A11; 0.81 g, 5.76 mmol) and the resulting mixture was stirred at room temperature overnight, then treated with MeOH (8 mL), and stirred for an additional 2 h. The resulting mixture is concentrated under reduced pressure. The resulting brown solid was triturated with 1:1 EtOAc/hexane solution to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-carboxyphenyl)urea as a colorless solid (1.21 g, 76%).

C2a. General procedure for the synthesis of urea by reaction of aniline with N,N'-carbonyl diimidazole followed by addition of another aniline. Synthesis of N-(2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea

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 hour, stirred at room temperature for 16 hours, then 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 H 2 O (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with saturated NaCl solution (100 mL), dried (MgSO 4 ), and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solid was collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil was purified by column chromatography (gradient 33% EcOAc/67% hexane to 50% EtOAc/50% hexane to 100% EtOAc) to give N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea as a tan solid (0.098 g, 30%): TLC (100% EtOAc) R/0.62; 1H NMR (DMSO-d6) δ 2.76 (d, J=4.8Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, J=4.8Hz, 1H), 9.55 (with 1H); FAB-MSm/ z 461 ((M+H)<+>).

C2b. General procedure for the synthesis of urea by reaction of aniline with N,N'-carbonyl diimidazole followed by addition of another aniline. Symmetric ureas as side products of the N,N'-carbonyl diimidazole reaction procedure. Synthesis of Bis(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)venyl)urea

Cdi (0.13 g) was added to a stirred solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH 2 Cl 2 (15 mL) at 0°C. The resulting solution was allowed to warm to room temperature for 1 hour and then stirred at room temperature for 16 hours. 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 (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with saturated NaCl solution (100 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting solid was collected by filtration and washed with EtOAc to give bis(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea (0.081 g, 44%): TLC (100% EtOAc) R, 0.50; <1>H NMR (DMSO-d6) 8 2.76 (d, J=5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J=5.4Hz, 1H), 8.75 (d, J=4.8Hz, 2H), 8.86 (s, 2H); HPLC ES-MSm/z513 ((M+H)<+>).

C2c. General procedure for the synthesis of urea by the reaction of isocyanate with aniline. Synthesis of N-(2-methoxy-5-(trifluoromethyl)phenyl-N'-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl)urea

To a stirring 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-1,3-dione (Procedure A3, Step 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h, then treated with CH 2 Cl 2 (10 mL) and MeOH (5 mL). The resulting mixture was washed sequentially with 1 N HCl (15 mL) and saturated NaCl (15 mL), dried (MgSO 4 ), and concentrated under reduced pressure to give N-(2-methoxy-5-(trifluoromethyl)phenyl-N'-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl)urea as a white solid (0.2 g, 96%): TLC (70%) EtOAc/30% hexane) Rf 0.50;<1>H NMR (DMSO-d6) δ 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3 Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (w.s, 2H), 9.57 (s, 1H), 11.27 (s.s., 1H); HPLC ES-MS 472.0 ((M+H)<+>, 100%).

C2d. General procedure for the synthesis of urea by reaction of aniline with N,N'-carbonyl diimidazole followed by addition of another aniline. Synthesis of N-(5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea

To a stirring solution of CDI (0.21 g, 1.30 mmol) in CH 2 Cl 2 (2 mL) was added 5-(tert-butyl)-2-(2,4-dimethylpyrrolyl)aniline (Procedure A4, Step 2; 0.30 g, 1.24 mmol) in one portion. 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 in one portion. The resulting mixture was heated to 36 °C overnight, then cooled to room temperature and diluted with EtOAc (5 mL). The resulting mixture was washed sequentially with water (15 mL) and 1N HCl solution (15 mL), dried (MgSO 4 ), and filtered through a pad of silica gel (50 g) to give N-(5-(tert-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc/60% hexane) Rf 0.24; <1>H NMR (acetone-d6) δ 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J=4.8 Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J=5.4 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.80 (w.s, 1H); HPLC ES-MS 512 ((M+H)<+>, 100%).

C3. Combination procedure for the synthesis of diphenyl urea using

triphosgene

One of the anilines to be coupled is dissolved in dichloroethane (0.10 M). This solution was added to an 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added bis(trichloromethyl)carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv). The vial is sealed and heated to 80°C for 5 hours, then allowed to cool to room temperature over 10 hours. A second aniline is added (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv). The resulting mixture was heated at 80°C for 4 hours, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture is concentrated under reduced pressure and the product is purified by reverse phase HPLC.

C4. General procedure for the synthesis of urea by the reaction of aniline with phosgene followed by the addition of another aniline. Synthesis of N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea

To a stirred solution was added phosgene (1.9 M in toluene; 2.07 mL, 0.21 g, 1.30 mmol) in CH 2 Cl 2 (20 mL) at 0°C, and anhydrous pyridine (0.32 mL) was added followed by 2-methoxy-5-(trifluoromethyl)aniline (0.75 g). The yellow solution is allowed to warm to room temperature during which time a precipitate forms. The yellow mixture was stirred for 1 hour, then concentrated under reduced pressure. The resulting solids were treated with anhydrous toluene (20 mL) followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (prepared as described in procedure A2; 0.30 g) and the resulting suspension was heated at 80°C for 20 hours and then cooled to room temperature. The resulting mixture was diluted with EtOAc (2 x 250 mL). The organic layers were washed separately with saturated NaCl solution, combined, dried (MgSO 4 ), and concentrated under reduced pressure. The resulting pink-brown residue was dissolved in MeOH and absorbed on SiO2 (100 g). Column chromatography (300 g SiO 2 ; gradient from 1% Et 3 N/33% EtOAc/66% hexane to 1% Et 3 N/99% EtOAc to 1% Et 3 N/20% MeOH/79% EtOAc) followed by concentration under reduced pressure at 45°C afforded a warm, concentrated EtOAc solution, which was treated with hexane (10 mL) to form crystals slightly. N-(2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea (0.44 g): TLC (1% Et 3 N/99% EcOAc) Rf 0.40.

D. Urea interconversion

D1a. Conversion of cj-aminophenyl urea to cj-(aroylamino)phenyl urea. Synthesis of N-(4-(chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methoxycarbonylphrenyl)carboxyaminophenyl)urea)

To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-aminophenyl)urea (Procedure C1d; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 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). EDCI (0.29 g, 1.52 mmol) was added and the resulting mixture was diluted with EtOAc (25 mL) and saturated NaHCO 3 solution (25 mL). The resulting solid was triturated with EtOAc solution (25 mL). is obtained N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)urea (0.27 g, 43%): mp 121-122; TLC (80% EtOAc/20% hexane) R, 0.75.

D1b. Conversion of u-carboxyphenyl urea to u>(arylcarbamoyl)phenyl urea. Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carbamoylphenyl)urea.

To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl)urea (0.14 g, 0.48 mL), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBTH20 (0.14 g, 1.07 mmol) and N-methylmorpholine (0.5 mL, 1.07 mmol) was added. DMF (3 mL) was added to EDCI (0.10 g, 0.53 mmol) and the resulting mixture was allowed to warm to room temperature. The resulting mixture was treated with EtOAc (25 mL). The resulting yellow solid was dissolved in EtOAc (17 g, 70% gradient EtOAc/30% hexane to 10% MeOH/90% EtOAc), to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methiocarbamoylphenyl)carbamoylphenyl)urea as a white solid (0.097 g, 41%): mp 225-229; TLC (100% EtOAc) Pv 0.23.

D1c. A combinatorial approach for the conversion of β-carboxyphenyl urea to β-(arylcarbamoyl)phenyl urea. Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'(4-(N-(3-(N-(3-pyridyl)carbamoyl)phenyl)carbamoyl)phenyl)urea

A mixture of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(3-carboxyphenyl)urea (Procedure C1f; 0.030 g, 0.067 mmol) and N-cyclohexyl-N'-(methylpolystyrene)carbodiimide (55 mg) in 1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CH 2 Cl 2 (1 M; 0.074 mL). (0.074 mmol) (In cases of insolubility, a small amount of DMSO is also added.) The resulting mixture is then treated with THF (1 mL) and the resulting mixture is treated with poly(4-(isocyanatomethyl)styrene) (0.040 g), then cooled to rooms temperature and filter. The resulting solution is filtered through a layer of silica gel (1 g). Concentration under reduced pressure gave N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(N-(3-(N-(3-pyridyl)carbamoyl)phenyl)carbamoyl)phenyl)urea (0.024 g, 59%): TLC (70% EtOAc/30% hexane) Rf 0.12.

D2. Conversion of cj-carboxy urea to uj-carbamoylaryl urea. Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl)urea

To a sample of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-carbomethoxyphenyl)carboxyaminophenyl)urea (0.17 g, 0.34 mmol) was added methylamine (2M in THF; 1 mL, 1.7 mmol) and the resulting mixture was stirred at room temperature overnight, then concentrated under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl)urea as a white solid: mp 247; TLC (100% EtOAc) Pv 0.35.

D3. Conversion of γ-carboalkoxyaryl urea to γ-carboxyaryl urea. Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-carboxyphenyl)urea

To a suspension of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl)urea (Procedure C1e; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added aqueous KOH (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated to reflux for 12 h, cooled to room temperature, and concentrated under reduced pressure. diluted with water (50 mL), then treated with 1 N HCl solution to adjust the pH to 2 to 3. The resulting solid was collected and dried under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-carboxyphenyl)urea as a white solid (5.05 g, 92%).

D4. A general procedure for the conversion of α-alkyl esters to α-alkyl amides. Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl)urea

Step 1. Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-((4-(3-5-carboxypyridyl)oxyphenyl)urea

N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-((4-(3-(5-methoxycarbonylpyridyl)oxyphenyl)urea is synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-(3-(5-methoxycarbonylpyridyl)oxyaniline) (Procedure A14, step 2) in a manner analogous to Procedure C1a. Suspension N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-((4-(3-(5-methoxycarbonylpyridyl)oxyphenyl)urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and stirred at room temperature for 1 hour. The resulting mixture was adjusted to pH 5 with 1 N HCl solution). the precipitate is removed by filtration and washed with water. The resulting solid was dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced pressure. The EtOH/concentration procedure was repeated twice to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-((4-(3-(5-carboxypyridyl)oxyphenyl)urea) (0.18 g, 71%).

Step 2. Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl)urea

A mixture of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-((4-(3-(5-carboxypyridyl)oxyphenyl)urea (0.050 g, 0.011 mmol), N,N-dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N-methylmorpholine (0.035 g, 0.28 mmol) and EDCI (0.032 g, 0.17 mmol) was stirred at room temperature overnight. The resulting solution was washed with water (35 mL), dried (MgSO 4 ), and the residue was treated with Et 2 O dropwise N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl)urea as a white solid (0.48 g, 84%): 1H NMR (DMSO-d6) 8 2.10 (s, 6H), 3.26 (s, 2H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, 1H), 8.43 (s, 1H), 8.69 (s, 1H), 8.90 (s, 1H), 9.14 (s, 1H); HPLC ES-MSm/z522

((M+H)<+>).

D5. General procedure for deprotection of N-(io-silyloxyalkyl)amide. Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-hydroxy) ethylcarbamoyl)pyridyloxyphenyl) urea)

A solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl urea) (prepared analogously to procedure C1a; 0.25 g, 0.37 mmol) in anhydrous THF (2 mL) was treated with tetrabutylammonium fluoride (1.0 M in THF; 2 mL). The mixture was stirred at room temperature. 5 min, then treated with water (10 mL). The combined organic layers were dried (MgSO 4 ) and purified by column chromatography (SiO 2 ; gradient 100% EtOAc/60% hexane). N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).

Below are the compounds listed in the tables below that were synthesized according to the detailed experimental procedures given above. Herein, compounds of Entries 42-45, 49, 85-87, 89, 93, 95 and 96 refer to compounds of the present invention. The remaining compounds refer to the reference compounds.

Synthesis of compounds for the examples listed (see Compound Characterization Tables)

Entry 1: 4-(3-N-Methylcarbamoylphenoxy)aniline is prepared according to procedure A13. According to procedure C3, 3-tert-butylaniline reacts with bis(tichloromethyl)carbonate followed by 4-(3-N-methylcarbamoylphenoxy)aniline and urea is obtained.

Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone are reacted according to procedure A13, step 1 to give 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitrobenzene is reduced according to procedure A13, step 4 to give 4-(4-acetylphenoxy)aniline. According to procedure C3, 3-tert-butylaniline reacts with bis(trichloromethyl)carbonate followed by 4-(4-acetylphenoxy)aniline and urea is obtained.

Input 3: According to procedure C2d, 3-tert-butylaniline is treated with Cdi, followed by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which is prepared according to procedure A8, and urea is obtained.

Entry 4: 5-tert-Butyl-2-methoxyaniline is converted to 5-tert-butyl-2-methoxyphenyl isocyanate according to procedure B1. 4-(3-N-Methylcarbamoylphenoxy) aniline, prepared according to procedure A13, reacts with isocyanate according to procedure C1, and urea is obtained.

Input 5: By procedure C2d, 5-tert-butyl-2-methoxyaniline is reacted with Cdi followed by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which is prepared according to procedure A8, and urea is obtained.

Entry 6: 5-(4-Aminophenoxy)isoindoline-1,3-dione is prepared according to procedure A3. According to procedure 2d, 5-tert-butyl-2-methoxyaniline reacts with CDI followed by 5-(4-aminophenoxy)isoindoline-1,3-dione to give urea.

Entry 7: 4-(1-Oxoisoindolin-5-yloxy)aniline is synthesized according to procedure A12. According to procedure 2d, 5-tert-butyl-2-methoxyaniline reacts with CDI followed by 4-(1-oxoisoindolin-5-yloxy)aniline to give urea.

Entry 8: 4-(3-Methylcarbamoylphenoxy)aniline is synthesized according to procedure A13. According to procedure C2a, 2-methoxy-5-(trifluoromethyl)aniline reacts with CDI followed by 4-(3-N-methylcarbamoylphenoxy)aniline to give urea.

Entry 9: 4-Hydroxyacetophenone reacts with 2-chloro-5-nitropyridine to give 4-(4-acetylphenoxy)-5-nitropyridine according to procedure A3, step 2.

According to procedure A8, step 4, 4-(4-acetylphenoxy)-5-nitropyridine is reduced from 4-(4-acetylphenoxy)-5-aminopyridine. 2-Methoxy-5-(trifluoromethyl)aniline is converted to 2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to procedure B1. The isocyanate reacts with 4-(4-acetylphenoxy)-5-aminopyridine according to

procedure C1a, and urea is obtained.

Entry 10: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone are reacted according to procedure A13, step 1, to give 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitrobenzene is reduced according to procedure A13, step 4, to give 4-(4-acetylphenoxy)aniline. According to procedure C3, 5-(trifluoromethyl)-2-methoxy-butylaniline reacts with bis(trichloromethyl)carbonate followed by 4-(4-acetylphenoxy)aniline, and urea is obtained.

Entry 11: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Procedure A2, Step 3a, was reacted with 3-aminophenol according to Procedure A2, Step 4 using DMAC instead of DMF to give 3-(2-(n-methyl-carbamoyl)-4-pyridyloxy)aniline. According to procedure C4, 2-methoxy-5-(trifluoromethyl)aniline reacts with phosgene followed by 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline, and urea is obtained.

Entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt reacts with ammonia

according to procedure A2, step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide is reacted with 3-aminophenol according to procedure A2, step 4 using DMAC instead of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to procedure C2a, 2-methoxy-5-(trifluoromethyl)aniline reacts with phosgene followed by 3-(2-carbamoyl-4-pyridyloxy)aniline, and urea is obtained.

Entry 13: 4-Chloro-N-methyl-2-pyridinecarboxamide is synthesized according to procedure A2, step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to procedure A2, step 4 using DMAC instead of DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to procedure C2a, 2-methoxy-5-(trifluoromethyl)aniline reacts with CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to give urea.

Entry 14: 4-Chloropyridine-2-carbonyl chloride HCl salt reacts with ammonia according to procedure A2, step 3b to form 4-chloro-2-pyridinecarboxamide.

4-Chloro-2-pyridinecarboxamide is reacted with 4-aminophenol according to procedure A2, step 4, using DMAC instead of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to procedure C4, 2-methoxy-5-(trifluoromethyl)aniline reacts with phosgene followed by 4-(2-carbamoyl-4-pyridyloxy)aniline, and urea is obtained.

Entry 15: According to procedure C2d, 5-(trifluoromethyl)-2-methoxyaniline is reacted with CDI followed by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which is prepared according to procedure A8, to give urea.

Entry 16: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-4-pyridyloxy)-2-methylaniline is synthesized according to procedure A5. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. Isocyanate reacts with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to procedure C1c, and urea is obtained.

Entry 17: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline is synthesized according to procedure A6. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline according to procedure C1, and urea is obtained.

Entry 18: According to procedure A2, step 4, 5-amino-2-methylphenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to procedure A2, step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to procedure C1, and urea is obtained.

Entry 19: 4-Chloropyridine-2-carbonyl chloride is reacted with ethylamine according to procedure A2, step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide reacts with 4-aminophenol according to procedure A2, step 4, and 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline is obtained. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline according to procedure C1a, and urea is obtained.

Entry 2.0: According to procedure A2, step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to procedure A2, step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxy-phenyl isocyanate according to procedure B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according to procedure C1a, and urea is obtained.

Entry 21: 4-(4-Methylthiophenoxy)-1-nitrobenzene is oxidized according to procedure A19, step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. Nitrobenzene is reduced according to procedure A19, step 2 to give 4-(4-methylsulfonylphenoxy)-1-aniline. According to procedure C1a, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 4-(4-methylsulfonylphenoxy)-1-aniline, and urea is obtained.

Entry 22: 4-(3-carbamoylphenoxy)-1-nitrobenzene is reduced to 4-(3-carbamoylphenoxy)aniline according to procedure A15, step 4. According to procedure C1a, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 4-(3-carbamoylphenoxy)aniline to give urea.

Entry 23: 5-(4-Aminophenoxy)isoindoline-1,3-dione is synthesized according to procedure A3. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 5-(4-aminophenoxy)isoindoline-1,3-dione according to procedure C1, and urea is obtained.

Entry 24: 4-Chloropyridine-2-carbonyl chloride is reacted with dimethylamine according to procedure A2, step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide reacts with 4-aminophenol according to procedure A2, step 4, and 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline is obtained. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline according to procedure C1a, and urea is obtained.

Entry 25: 4-(1-Oxoisoindolin-5-yloxy)aniline is synthesized according to procedure A12. 5-(Trifluoromethyl)-2-methoxyaniline is treated with CDI, followed by 4-(1-oxoisoindolin-5-yloxy)aniline according to procedure C2d, and urea is obtained.

Entry 26: 4-Hydroxyacetophenone reacts with 4-fluoronitrobenzene according to procedure A13, step 1 to give 4-(4-acetylphenoxy)nitrobenzene. Nitrobenzene is reduced according to procedure A13, step 4 to give 4-(4-acetylphenoxy)aniline, which is converted to 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt according to procedure A16. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate isocyanate reacts with 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt according to procedure C1a, and urea is obtained.

Entry 27: 4-Chloro-N-methylpyridinecarboxamide is synthesized as described in procedure A2, step 3b. Chloropyridine reacts with 4-aminothiophenol according to procedure A2, step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to procedure C1a, and urea is obtained.

Entry 28: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione is synthesized according to procedure A9. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to procedure C1a, and urea is obtained.

Entry 29: 4-Chloro-N-methylpyridinecarboxamide is synthesized as described in procedure A2, step 3b. Chloropyridine reacts with 3-aminothiophenol according to procedure A2, step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate reacts with with 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to procedure C1a, and urea is obtained. Entry 30: 4-Chloropyridine-2-carbonyl chloride is reacted with isopropylamine according to procedure A2, step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to procedure A2, step 4, and 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline according to procedure C1a, and urea is obtained.

Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline is synthesized according to procedure A14. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to procedure C1a and urea is obtained. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea is saponified according to Procedure D4, Step 1, and the corresponding acid is coupled with 4-(2-amineethyl)morpholine to give the amide according to Procedure D4, Step 2.

Entry 32: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline is synthesized according to procedure A14. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to procedure C1 and urea is obtained. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea is saponified according to Procedure D4, Step 1, and the corresponding acid is coupled with 4-(2-amineethyl)morpholine to give the amide according to Procedure D4, Step 2, to give the amide.

Entry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline is synthesized according to procedure A14. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to procedure C1a and urea is obtained. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea is saponified according to Procedure D4, Step 1, and the corresponding acid is coupled with N,N-dimethylethylenediamine according to Procedure D4, Step 2, to give the amide.

Entry 34: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 4-(3-Carboxy-phenoxy)aniline reacts with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure C1f and N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl)urea is obtained, which is coupled with 3-aminopyridine according to procedure D1c.

Entry 35: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 4-(3-Carboxy-phenoxy)aniline reacts with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure C1f and N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl)urea is obtained, which is coupled with N-(4-fluorophenyl)piperazine according to procedure D1c. Entry 36: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 4-(3-Carboxy-phenoxy)aniline reacts with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure C1f and N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl)urea is obtained, which is coupled with 4-fluoroaniline according to procedure D1c.

Entry 37: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 4-(3-Carboxy-phenoxy)aniline reacts with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure C1f and N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl)urea is obtained, which is coupled with 4-(dimethylamino)aniline according to procedure D1c.

Entry 38: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 4-(3-Carboxy-phenoxy)aniline reacts with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure C1f and N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl)urea is obtained, which is coupled with 5-amino-2-methoxypyridione according to procedure D1c.

Entry 39: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 4-(3-Carboxy-phenoxy)aniline reacts with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure C1f and N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl)urea is obtained, which is coupled with 4-morpholinoaniline according to procedure D1c.

Entry 40: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 5-(Trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure B1. 4-(3-Carboxy-phenoxy)aniline reacts with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to procedure C1f and N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea is obtained, which is coupled with N-(2-pyridyl)piperazine according to procedure D1c.

Entry 41: 4-(3-(N-Methylcarbamoyl)phenoxy)aniline is synthesized according to procedure A13. According to process C3, 4-chloro-3-(trifluoromethyl)aniline is converted to isocyanate, then reacts with 4-(3-(N-methylcarbamoyl)phenoxy)aniline, and urea is obtained.

Entry 42: 4-(2-N-Methylcarbamyl-4-pyridyloxy)aniline is synthesized according to procedure A2. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-N-methylcarbamyl-4-pyridyloxy)aniline according to Method C1a, and urea is obtained.

Entry 43: 4-Chloropyridine-2-carbonyl chloride HCl salt reacts with ammonia according to procedure A2, step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide reacts with 4-aminophenol according to procedure A2, step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-carbamoyl-4-pyridyloxy)aniline, and urea is obtained.

Entry 44: 4-Chloropyridine-2-carbonyl chloride HCl salt reacts with ammonia according to procedure A2, step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide reacts with 3-aminophenol according to procedure A2, step 4, and 3-(2-carbamoyl-4-pyridyloxy)aniline is formed. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 3-(2-(N-methylcarbamoyl-4-pyridyloxy)aniline, and urea is obtained.

Entry 45: 4-Chloro-N-methyl-2-pyridinecarboxamide, which is synthesized according to procedure A2, step 3a, is reacted with 3-aminophenol according to procedure A2, step 4 to form 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline, and urea is obtained.

Entry 46: 5-(4-Aminophenoxy)isoindoline-1,3-dione is synthesized according to procedure A3. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 5-(4-aminophenoxy)isoindoline-1,3-dione, and urea is obtained.

Entry 47: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline is synthesized according to procedure A5. According to procedure C1c, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 5-(4-aminophenoxy)isoindoline-1,3-dione, and urea is obtained.

Entry 48: 4-(3-N-Methylsulfamoyl)phenyloxy)aniline is synthesized according to procedure A15. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-N-methylsulfamoyl)phenyloxy)aniline, and urea is obtained.

Entry 49: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline is synthesized according to procedure A6. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline, and urea is obtained.

Entry 50: According to procedure A2, step 4, 5-amino-2-methylphenyl is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to procedure A2, step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline, and urea is obtained.

Entry 51: 4-Chloropyridine-2-carbonyl chloride is reacted with ethylamine according to procedure A2, step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide reacts with 4-aminophenol according to procedure A2, step 4, and 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline is obtained. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline, and urea is obtained.

Entry 52: According to procedure A2, step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to procedure A2, step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline, and urea is obtained.

Entry 53: 4-(4-Methylthiophenoxy)-1-nitrobenzene is oxidized according to procedure A19, step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. Nitrobenzene is reduced according to procedure A19, step 2 to give 4-(4-methylsulfonylphenoxy)-1-aniline. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(4-methylsulfonylphenoxy)-1-aniline, and urea is obtained.

Entry 54: 4-Bromobenzenesulfonyl chloride is reacted with methylamine according to procedure A15, step 1 to give N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-bromobenzenesulfonamide is coupled with phenol according to procedure A15, step 2 to give 4-(4-(N-methylsulfamoyl)phenoxy)benzene. 4-(4-Methylsulfamoyl)phenoxy)benzene is converted to 4-(4-(N-methylsulfamoyl)phenoxy-1-nitrobenzene according to Procedure A15, step 3. 4-(4-(N-Methylsulfamoyl)phenoxy)-1-nitrobenzene is reduced to 4-(4-N-methylsulfamoyl)phenoxyoxy)aniline according to Procedure A15, step 4. According to Procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-N-methylsuphamoyl)phenyloxy)aniline, and urea is obtained.

Entry 55: 5-Hydroxy-2-methylpyridine is coupled with 1-fluoro-4-nitrobenzene according to procedure A18, step 1, to give 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene. Methylpyridine is oxidized to carboxylic acid, then esterified according to procedure A18, step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene. Nitrobenzene is reduced according to procedure A18, step 3, to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. Aniline reacts with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to procedure C1a, and urea is obtained.

Entry 56: 5-Hydroxy-2-methylpyridine is coupled with 1-fluoro-4-nitrobenzene according to procedure A18, step 1, to give 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene. Methylpyridine is oxidized to carboxylic acid, then esterified according to procedure A18, step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene. Nitrobenzene is reduced according to procedure A18, step 3, to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline. Aniline reacts with 4-chloro-3-

with (trifluoromethyl)phenyl isocyanate according to procedure C1a, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(methoxycarbonyl)-5-pyridyloxy)phenyl urea is obtained. Methyl ester reacts with methylamine according to procedure D2, and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-5-pyridyloxy)phenyl)urea is obtained.

Entry 57: N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea is prepared according to procedure C1d. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea is coupled with mono-methyl isophthalate according to procedure D1a, and urea is obtained.

Entry 58: N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea is prepared according to procedure C1d. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea is coupled with mono-methyl isophthalate according to procedure D1a to give N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea. D2, N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)urea reacts with methylamine to give the corresponding methyl amide.

Entry 59: 4-Chloropyridine-2-carbonyl chloride is reacted with dimethylamine according to procedure A2, step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide reacts with 4-aminophenol according to procedure A2, step 4, and 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline is obtained. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline, and urea is obtained.

Entry 60: 4-Hydroxyacetophenone reacts with 4-fluorobenzene according to procedure A13, step 1 to give 4-(4-acetylphenoxy)nitrobenzene. Nitrobenzene is reduced according to procedure 13, step 4, and 4-(4-acetylphenoxy)aniline is obtained, which is converted to 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt according to procedure A16. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(4-acetylphenoxy)aniline, and urea is obtained.

Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene is synthesized according to

procedure A13, step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene is coupled with 4-(2-aminoethyl)morpholine according to procedure A13, step 3, and 4-(3-(N-(2-morpholineethyl)carbamoyl)phenoxy)-1-nitrobenzene is obtained. According to procedure A13, step 4,4-(3-(N-(2-morpholineethyl)carbamoyl)phenoxy)-1-nitrobenzene is

reduces to 4-(3-(N-(2-morpholineethyl)carbamoyl)phenoxy)aniline. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-(N-(2-morpholineethyl)carbamoyl)phenoxy)aniline, and urea is obtained.

Entry 62: 4-(3-Carboxyphenoxy)-1-nitrobenzene is synthesized according to procedure A13, step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene is coupled with 1-(2-aminoethyl)piperidine according to procedure A13, step 3, to give 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to procedure A13, step 4, 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene is reduced to 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)aniline. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)aniline, and urea is obtained.

Entry 63: 4-(3-Carboxyphenoxy)-1-nitrobenzene is synthesized according to procedure A13, step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene is coupled with tetrahydrofurylamine according to procedure A13, step 3, to give 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to procedure A13, step 4, 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene is reduced to 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline, and urea is obtained.

Entry 64: 4-(3-Carboxyphenoxy)-1-nitrobenzene is synthesized according to procedure A13, step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene is coupled with 2-aminomethyl-1-ethylpyrrolidine according to procedure A13, step 3, to give 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene. According to procedure A13, step 4,4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene is reduced to 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is treated with 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline, and urea is obtained.

Entry 65: 4-Chloro-N-methylpyridinecarboxamide is synthesized as described in procedure A2, step 3b. Chloropyridine reacts with 4-aminothiophenol according to procedure A2, step 4, and 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline is obtained. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline, and urea is obtained.

Entry 66: 4-Chloropyridine-2-carbonyl chloride is reacted with isopropylamine according to procedure A2, step 3b. The obtained 4-chloro-N-isopropyl-2-pyridinecarboxamide reacts with 4-aminophenol according to procedure A2, step 4, and 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline is obtained. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline, and urea is obtained.

Entry 67: N-(4-Chloro-(3-(trifluoromethyl)phenyl-N'-(4-ethoxycarbonylphenyl)urea is synthesized according to procedure C1e. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-ethoxycarbonylphenyl)urea is saponified according to procedure D3 to obtain N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-carboxyphenyl)urea). N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-carboxyphenyl)urea is coupled with 3-methylcarbamoylaniline according to procedure D1b, and N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-methylcarbamoylphenyl)carbamoylphenyl)urea is obtained.

Entry 68: 4-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione is synthesized according to procedure A9. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione, and urea is obtained.

Entry 69: 4-Chloro-N-methylpyridinecarboxamide is synthesized as described in procedure A2, step 3b. Chloropyridine reacts with 3-aminothiophenol according to procedure A2, step 4, and 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline is obtained. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline, and urea is obtained.

Entry 70: 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline is synthesized according to procedure A10. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline, and urea is obtained.

Entry 71: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline is synthesized according to procedure A14. 4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate reacts with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to procedure C1a, and urea is obtained. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea is saponified according to procedure D4, step 1, and the corresponding acid is coupled with 4-(2-aminoethyl)morpholine to give the amide.

Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline is synthesized according to procedure A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate is treated with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to procedure C1a, and urea is obtained. N-(5-(trifluoromethyl)-2-methoxyphenyl-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea is saponified according to procedure D4, step 1, and the corresponding acid is coupled with methylamine according to procedure D4, step 2, to give the amide.

Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline is synthesized according to procedure A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to procedure C1a, and urea is obtained. N-(5-(trifluoromethyl)-2-methoxyphenyl-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea is saponified according to procedure D4, step 1, and the corresponding acid is coupled with N,N-dimethylethylenediamine according to procedure D4, step 2, to give the amide.

Entry 74: 4-Chloropyridine-2-carbonyl chloride HCl salt is reacted with 2-hydroxyethylamine according to procedure A1, step 3b to form 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide is reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to procedure A17 to form 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is treated with 4-(4-(2-(N-(2-triisopropylsulyloxy)ethylcarbamoyl)pyridyloxyaniline, and N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl)urea is obtained).

Entry 75: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to procedure C1f, and urea is obtained, which is coupled with 3-aminopyridine according to procedure D1c.

Entry 76: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-carboxyphenoxy)aniline according to procedure C1f, and urea is obtained, which is coupled with N-(4-acetylphenyl)piperazine according to procedure D1c.

Entry 77: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-carboxyphenoxy)aniline according to procedure C1f, and urea is obtained, which is coupled with 4-fluoroaniline according to procedure D1c.

Entry 78: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-carboxyphenoxy)aniline according to procedure C1f, and urea is obtained, which is coupled with 4-(dimethylamino)aniline according to procedure D1c.

Entry 79: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-carboxyphenoxy)aniline according to procedure C1f, and urea is obtained, which is coupled with N-phenylethylenediamine according to procedure D1c.

Entry 80: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-carboxyphenoxy)aniline according to procedure C1f, and urea is obtained, which is coupled with 2-methoxyethylamine according to procedure D1c.

Entry 81: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-carboxyphenoxy)aniline according to procedure C1f, and urea is obtained, which is coupled with 5-amino-2-methoxypyridine according to procedure D1c.

Entry 82: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-carboxyphenoxy)aniline according to procedure C1f, and urea is obtained, which is coupled with 4-morpholinoaniline according to procedure D1c.

Entry 83: 4-(3-Carboxyphenoxy)aniline is synthesized according to procedure A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(3-carboxyphenoxy)aniline according to procedure C1f, and urea is obtained, which is coupled with N-(2-pyridyl)piperazine according to procedure D1c.

Entry 84: 4-Chloropyridine-2-carbonyl chloride HCl salt is reacted with 2-hydroxyethylamine according to procedure A2, step 3b to form 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide is reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to procedure A17 to form 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to procedure C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline, and N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl)urea is obtained. Urea is deprotected according to procedure D5, and N-(4-chloro-(3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea).

Entry 85: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline is synthesized according to procedure A2. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-methylcarbamoyl)4-pyridyloxy)aniline, and urea is obtained.

Entry 86: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline is synthesized according to procedure A6. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline, and urea is obtained.

Entry 87: According to procedure A2, step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to procedure A2, step 3b, to give 4-(2-(N-methylacrabmoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline, and urea is obtained.

Entry 88: 4-Chloropyridine-2-carbonyl chloride is reacted with ethylamine according to procedure A2, step 3b. The obtained 4-chloro-N-ethyl-2-pyridinecarboxamide reacts with 4-aminophenol according to procedure A2, step 4, and 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline is obtained. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline, and urea is obtained.

Entry 89: 4-Chloro-N-methyl-2-pyridinecarboxamide, which is synthesized according to Procedure A2, Step 3a, is reacted with 3-aminophenol according to Procedure A2, Step 4 to form 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate reacts with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline, and urea is obtained.

Entry 90: According to procedure A2, step 4, 5-amino-2-methylphenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to procedure A2, step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate reacts with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline, and urea is obtained.

Entry 91: 4-Chloropyridine-2-carbonyl chloride is reacted with dimethylamine according to procedure A2, step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide reacts with 4-aminophenol according to procedure A2, step 4, and 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline is obtained. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline, and urea is obtained.

Entry 92: 4-Chloro-N-methylpyridinecarboxamide is synthesized as described in procedure A2, step 3b. Chloropyridine reacts with 4-aminothiophenol according to procedure A2, step 4, to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate is reacted with 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline, and urea is obtained.

Entry 93: 4-Chloro-N-methylpyridinecarboxamide is synthesized as described in procedure A2, step 3b. Chloropyridine reacts with 3-aminothiophenol according to procedure A2, step 4, to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate is reacted with 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline, and urea is obtained.

Entry 94: 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline is synthesized according to procedure A10. 4-Bromo-3-(trifluoromethyl)aniline is converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline, and urea is obtained.

Entry 95: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline is synthesized according to procedure A2. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is synthesized according to procedure A7. 4-Chloro-2-methoxy-4-(trifluoromethyl)aniline is converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline, and urea is obtained.

Entry 96: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline is synthesized according to procedure A6. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is synthesized according to procedure A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline, and urea is obtained.

Entry 97: According to procedure A2, step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to procedure A2, step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is synthesized according to procedure A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline, and urea is obtained.

Entry 98: 4-Chloro-N-methyl-2-pyridinecarboxamide, which is synthesized according to Procedure A2, Step 3a, is reacted with 3-aminophenol according to Procedure A2, Step 4 to form 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate reacts with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline, and urea is obtained.

Entry 99: 4-Chloropyridine-2-carbonyl chloride is reacted with ethylamine according to procedure A2, step 3b. The obtained 4-chloro-N-ethyl-2-pyridinecarboxamide reacts with 4-aminophenol according to procedure A2, step 4, and 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline is obtained. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is synthesized according to procedure A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline, and urea is obtained.

Entry 100: 4-Chloropyridine-2-carbonyl chloride is reacted with dimethylamine according to procedure A2, step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide reacts with 4-aminophenol according to procedure A2, step 4, and 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline is obtained. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is synthesized according to procedure A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline is converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to procedure B1. According to procedure C1a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate reacts with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline, and urea is obtained.

Entry 101: 4-Chloro-N-methyl-2-pyridinecarboxamide, which is synthesized according to Procedure A2, Step 3A, is reacted with 3-aminophenol according to Procedure A2, Step 4 to form 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 2-Amino-3-methoxynaphthalene is synthesized as described in procedure A1. According to procedure C3, 2-amino-3-methoxynaphthalene is reacted with bis(trichloromethyl) carbonate followed by 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to form urea.

Entry 102: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline is synthesized according to procedure A2. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline is synthesized according to procedure A4. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline is reacted with CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline according to procedure C2d to give urea.

Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide is synthesized according to procedure A2, step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide reacts with 4-aminophenol according to procedure A2, step 4 using DMAC to insert DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to procedure C2b, reaction of 3-amino-2-methoxyquinoin with CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline gives bis(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea.

In the Tables that follow are given the only ones that were synthesized according to the detailed experimental procedures described above:

Tables

The compounds listed in Tables 1-6 below are synthesized according to the general procedures shown in the text above, and more detailed exemplary procedures are in the above list of entries and characterization is indicated in the tables.

The preceding examples may be repeated with similar success by substituting the generally or specifically described reactants and/or operating conditions of the present invention for those used in the preceding examples.

Claims (18)

1. A compound selected from the group consisting of 4-chloro-3-(trifluoromethyl)phenyl urea: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea, 4-bromo-3-(trifluoromethyl)phenyl urea: N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, and N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl urea: N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, Or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, characterized in that its pharmaceutically acceptable salt is selected from the group consisting of a) Basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-naphthalene sulfonic acid, 2-naphthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid; and b) Acidic salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, ammonium cations, aliphatically substituted ammonium cations and aromatically substituted ammonium cations. 3. A pharmaceutical composition, characterized in that it consists of compound 1 or its pharmaceutically acceptable salt and a physiologically acceptable carrier. 4. A compound according to claim 1, characterized by being selected from the group consisting of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-N-methylcarbamoyl)(4-pyridyloxy)phenyl)urea, or pharmaceutically acceptable salts thereof. 5. The compound according to claim 4, characterized in that its pharmaceutically acceptable salt is selected from the group consisting of a) Basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid (tosylate salt), 1-naphthalene sulfonic acid, 2-naphthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid; and b) Acidic salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, ammonium cations, aliphatically substituted ammonium cations and aromatically substituted ammonium cations. 6. A pharmaceutical composition, characterized in that it consists of a compound according to claim 4 or its pharmaceutically acceptable salt and a physiologically acceptable carrier. 7. Use of a compound according to claim 1, characterized in that it is selected from the group consisting of 4-chloro-3-(trifluoromethyl)phenyl urea: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea, 4-bromo-3-(trifluoromethyl)phenyl urea: N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, and N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl urea: N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea or their pharmaceutically acceptable salts for the production of medicaments for the treatment of cancer of cell growth mediated by raf kinase. 8. Use of a compound according to claim 1, characterized in that it is selected from the group consisting of 4-chloro-3-(trifluoromethyl)phenyl urea: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea, 4-bromo-3-(trifluoromethyl)phenyl urea: N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, and N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, 2-Methoxy-4-chloro-5-(trifluoromethyl)phenyl urea: N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea urea, or pharmaceutically acceptable salts thereof for the manufacture of medicaments for treatment i) Carcinoma of the lung, pancreas, thyroid, gallbladder, colon, ii) Myeloid leukemia or iii) Villous adenoma of the colon 9. Use of a compound according to claim 1, characterized in that it is selected from the group consisting of 4-chloro-3-(trifluoromethyl)phenyl urea: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea, 4-bromo-3-(trifluoromethyl)phenyl urea: N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbaronoyl)-4-pyridylthio)phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, and N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl urea: N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, or their pharmaceutically acceptable salts for the production of medicaments for the treatment of tumors. 10. Use of the compound according to claim 4, characterized in that it is selected from the group consisting of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-N-methylcarbamoyl)(4-pyridyloxy)phenyl)urea, or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of raf kinase-mediated cancerous cell growth. 11. The use of a compound according to claim 4, characterized in that it is selected from the group consisting of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-N-methylcarbamoyl)(4-pyridyloxy)phenyl)urea, or their pharmaceutically acceptable salts for the production of medicaments for the treatment of i) Carcinoma of the lung, pancreas, thyroid, gall bladder, colon, ii) Myeloid leukemia or iii) Villous adenoma of the colon. 12. Use of a compound according to claim 4, characterized in that it is selected from the group consisting of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-N-methylcarbamoyl)(4-pyridyloxy)phenyl)urea, or their pharmaceutically acceptable salts for the production of medicaments for the treatment of tumors. 13. A compound according to claim 1, characterized in that it is N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl urea). 14. A compound according to claim 1, which is N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea. 15. Pharmaceutical composition, characterized in that it consists of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea or its pharmaceutically acceptable salt and a physiologically acceptable carrier. 16. Pharmaceutical composition, characterized in that it consists of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea or its pharmaceutically acceptable salt and a physiologically acceptable carrier. 17. Use of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of raf kinase-mediated cancerous cell growth. 18. Use of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl-4-pyridyloxy)phenyl) urea or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of raf kinase-mediated cancerous cell growth.