NO321059B1 - omega-carboxyaryl-substituted diphenylurea compounds such as rafkinase inhibitors, pharmaceutical preparations for the treatment of cancer and the use of the compounds in the manufacture of the drugs. - Google Patents

Description

Field of the invention

This invention relates to a group of arylurea compounds, pharmaceutical preparations for the treatment of cancer and the use of the compounds in the manufacture of the drugs for inhibiting a cancer cell growth mediated by raf-kinase.

The background of the invention

The p21<ras->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, 49, 4682-9). In its normal, unmutated form, the ras protein is a key element in the signal transduction cascade controlled by growth factor receptors in almost all tissues (Avruch et al., Trends Biochem.

Sei., 1994, 19, 279-83). Biochemically, ras is a guanine nucleotide-binding protein, and cycling between a GTP-bound, activated and a GDP-bound, resting form is carefully controlled by the endogenous GTPase activity of ras and other regulator proteins. In the ras mutants in cancer cells, the endogenous GTPase activity is suppressed, and the protein therefore emits constitutive growth signals to downstream effectors, such as the enzyme raf-kinase. This leads to the cancerous growth of the cells carrying these mutants (Magnuson et al., Semin. Cancer Biol., 1994, 5, 247-53). It has been shown that inhibition of the effect of active ras by inhibiting the signaling pathway for raf-kinase by administration of deactivating antibodies to raf-kinase or by co-expression of dominant negative raf-kinase or dominant-negative MEK, the substrate for raf-kinase, leads to the reversion of transformed cells to the normal growth phenotype (see: Daum et al., Trends Biochem. Sei., 1994, 19, 474-80; Fridman et al., J. Biol. Chem., 1994, 269, 30105-8. Kolch et al. (Nature, 1991, 349, 426-28) have further indicated that inhibition of raf expression by means of antisense RNA blocks cell proliferation in membrane bound oncogenes. Similarly, inhibition of raf kinase (by of antisense oligodeoxynucleotides) have been correlated in vitro and in vivo with inhibition of the growth of many different human tumor types (Monia et al., Nat. Med., 1996, 2, 668-75).

Summary of the invention

The present invention provides compounds which are inhibitors of the enzyme raf-kinase. As the enzyme is a downstream effector of p21<ras>, the inhibitors can be used in pharmaceutical preparations for human or veterinary use where inhibition of the raf-kinase reaction pathway is indicated, e.g. in the treatment of tumors and/or cancer cell growth mediated by raf-kinase. The compounds are particularly useful in the treatment of fixed human or animal cancers, e.g. murine cancers, as the progression of these cancers is dependent on the ras protein signal transduction cascade and therefore amenable to treatment by disruption of the cascade, i.e. by inhibition of raf kinase. Consequently, the compounds according to the invention can be used in the treatment of cancers, including solid cancers, such as e.g. carcinomas (eg of the lung, pancreas, thyroid, bladder or colon), myeloid disorders (eg myeloid leukaemia) or adenomas (eg woolly colon adenoma).

The present invention therefore provides compounds generally described as aryl urea compounds, including both aryl and heteroaryl analogs, which inhibit the raf kinase reaction pathway. The compounds can be used in a method for treating a raf-mediated disease state in humans or mammals. The invention is thus directed to compounds that inhibit the enzyme raf-kinase, and also compounds and preparations for the treatment of cancer cell growth mediated by raf-kinase, where a compound of formula I is administered, or a pharmaceutically acceptable salt thereof. The compounds are characterized by the fact that they are chosen from:

or a pharmaceutically acceptable salt thereof, wherein D is -NH-C(O)-NH-,

A is a substituted residue with the formula:

where

L is phenyl, optionally substituted with substituents selected from the group consisting of halogen and C 1 -C 10 alkyl;

L<1> is pyridinyl substituted with the substituent -C(O)Rx;

M is one or more bridging groups selected from the group consisting of -0- and -S-,

where Rx is NRaRb and Ra and Rb independently of each other are:

a) hydrogen,

b) C 1 -C 10 alkyl and

c) C 1 -C 10 alkyl substituted with hydroxy, C 3 -C 12 cycloalkyl having 1-3 heteroatoms selected from 0, N and S, or

-OSi(R f ) 3 , where R f is C 1 -C 10 alkyl; and

B is an unsubstituted phenyl group or a phenyl group substituted with substituents selected from the group consisting of halogen up to per-halo and Wn, where n is 0-3, and each W is independently selected from the group consisting of:

a) C 1 -C 10 alkyl,

b) C 1 -C 10 -Alkoxy,

c) halo-substituted C 1 -C 10 alkyl and

d) C3-C12 heteroaryl with 1-3 heteroatoms selected from 0, N and

S, optionally substituted with C 1 -C 10 alkyl,

B) N-(5-(trifluoromethyl)-2-methoxy-phenyl)-N'-(4-(2-(N-(2-dimethylamine)ethylcarbamoyl)-4-pyridyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof, and C) N-(3-(trifluoromethyl)-4-chlorophenyl)-N'-(4-(2-(N-(2-dimethylamine)ethylcarbamoyl)-4-pyridyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof.

Suitable alkyl groups and alkyl parts of groups, e.g. alkoxy etc, always includes methyl, ethyl, propyl, butyl etc, including all straight chain and branched isomers, such as isopropyl, isobutyl, sec-butyl, tert-butyl etc.

The term "cycloalkyl". refers, as used here, to cyclic structures with or without alkyl substituents, so that e.g. "4-cycloalkyl" includes methyl-substituted cyclopropyl groups as well as cyclobutyl groups. The term "cycloalkyl" as used herein also includes saturated heterocyclic groups.

Suitable halogen groups include F, Cl, Br and/or I, with from single to per substitution (that is, all H atoms on a group replaced with a halogen atom) possible when an alkyl group is substituted with halogen, where mixed substitution of halo -genome types are also possible on a specific residue.

The invention also relates to compounds per se, of formula I.

The present invention is also directed to pharmaceutically acceptable salts of formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic 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. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g. Li<+>, Na<+> or K+), alkaline earth cations (e.g. Mg<+2>, Ca< +2> or Ba<+2>), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary iron anonium cations, such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diaza-bicyclo[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).

A number of the compounds of formula I have asymmetric carbon atoms and can therefore exist in racemic and optically active forms. Methods for the separation of enantiomeric and diastereomer mixtures are well known to those skilled in the art. The present invention encompasses any isolated racemic or optically active form of compounds described in formula I, which have raf inhibitor activity.

General manufacturing procedures

The compounds of formula I can be prepared using known chemical reactions and methods, some from starting materials that are commercially available. Nevertheless, general preparation procedures are provided below to assist those skilled in the art in synthesizing these compounds, more detailed examples being provided in the experimental section that follows.

Substituted anilines can be prepared using standard procedures (March. Advanced Organic Chemistry,

3rd ed., John Wiley: New York (1985). Larock, Comprehensive Organic Transformations, VCH Publishers: New York (1989)). As

shown in Reaction Scheme I, arylamines 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 a borohydride (Rylander, Hydrogenation Methods, Academic Press: London, UK

(1985)). Nitroaryls can also be reduced directly by 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 methods 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)).

H2/catalyst

(e.g. Fe, Sn, Ca)

Reaction scheme I Reduction of nitroaryls to arylamines

Nitroaryls are usually formed by electrophilic aromatic nitration using HNO3, or an alternative N02" source. Nitroaryls can be further processed before reduction. Nitroaryls substituted with potential leaving groups (e.g. F, Cl, Br etc.) can thus undergo substitution reactions when treated with nucleophiles, such as thiolate (exemplified in reaction scheme II) or phenoxide.

Nitroaryls can also undergo Ullman-type coupling reactions (reaction scheme II).

Reaction scheme II Selected nucleophilic aromatic substitution using nitroaryls

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, exemplified below), aryltin compounds (Stille reactions) or arylzinc compounds (Negishireaction), whereby the biaryl (5) is obtained.

Nitroaryls or anilines can be converted to the corresponding arenesulfonyl chloride (7) by treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source, such as KF, then gives sulfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with trimethylsilyltrifluoromethane in the presence of a fluoride source, such as tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF), leads to the corresponding trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 can be reduced to the arenthiole (10), e.g. with zinc amalgam. Reaction of thiol 10 with CHC1F2 in the presence of base gives the difluoromethyl mercaptam (11), which can be oxidized to the sulfone (12) with any of many different oxidants, including CrO3 acetic anhydride (Sedova et al., Zh. Org. Khim ., 1970, 6 (568) .

Reaction scheme III Selected methods for fluorinated arylsulfone synthesis

As shown in Reaction Scheme IV, non-symmetric urea formation may involve the reaction of an aryl isocyanate (14) with an arylamine (13). The heteroarylisocyanate can be synthesized from a heteroarylamine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis-(trichloromethyl)carbonate (triphosgene), or N,N'-carbonyldiimidazole (CDI). The isocyanate can also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by means of a Curtius-type rearrangement. Reaction of acid derivative 16 with an azide source, followed by rearrangement, thus gives the isocyanate. The corresponding carboxylic acid (17) can also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent.

Reaction scheme IV Selected methods for non-symmetrical urea formation

Finally, urea compounds can be further manipulated using methods well known to those skilled in the art.

The invention also encompasses pharmaceutical preparations, including a compound of formula I, and a physiologically acceptable carrier.

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

Preparations intended for oral use can be prepared according to any suitable method known in the art for the preparation of pharmaceutical preparations. Such preparations may contain one or more agents selected from the group consisting of diluents, sweeteners, flavoring agents, coloring agents and preservatives to provide appealing preparations. Tablets contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can e.g. be inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate;

granulating and disintegrating agents, e.g. corn starch, or alginic acid; and binders, e.g. magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated using known techniques to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, such a time-delaying material as glyceryl monostearate or glyceryl distearate can be used. These compounds can also be produced in solid, fast-release form.

Formulations for oral use can also be presented as hard gelatin capsules where the active ingredient is mixed with an inert, solid diluent, e.g. calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, e.g. peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, e.g. sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally occurring phosphatide, e.g. lecithin, or condensation products or an alkylene oxide with fatty acids, e.g. polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain aliphatic alcohols, e.g. hepta-decaethyleneoxycetanol, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides, e.g. polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, e.g. ethyl, or n-propyl-p-hydroxybenzoate, 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 producing an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, e.g. sweetening, flavoring and coloring agents may also be present.

The compounds can also be in the form of non-aqueous, liquid formulations, e.g. oil suspensions which can be formulated by suspending the active ingredients in a vegetable oil, e.g. arachis oil, olive oil, sesame oil or peanut oil, or such a mineral oil as liquid paraffin. The oil suspensions may contain a thickener, e.g. beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those indicated above, and flavoring agents may be added to provide palatable oral preparations. These preparations can be preserved by the addition of such an antioxidant as ascorbic acid.

Pharmaceutical preparations according to the invention can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil, e.g. olive oil or arachis oil, or a mineral oil, e.g. liquid paraffin, or mixtures thereof. Suitable emulsifiers can be naturally occurring gums, e.g. gum acacia or gum tragacanth, naturally occurring phosphatides, e.g. soybean, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, e.g. sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, e.g. polyoxyethylene sorbitan monooleate. The emulsions may also contain sweeteners and flavourings.

Syrups and elixirs can be formulated with sweeteners, e.g. glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a soothing agent, a preservative and flavoring and coloring agents.

The compounds can also be administered in the form of suppositories for rectal administration of the drug. These preparations can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at normal temperatures, but liquid at the rectal temperature, and will therefore melt in the rectum, so that the drug is released. Such materials include cocoa butter and polyethylene glycols.

For all regimens of use described herein for compounds of formula I, the daily oral dosage regimen will preferably be from 0.01 to 200 mg/kg total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injection, and using injection techniques, will preferably be from 0.01 to 200 mg/kg total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one and four times daily. The daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/kg total body weight.

It will be understood by those skilled in the art that the particular method of administration will depend on many different factors, all of which are considered routine when administering therapeutics. It will also be understood by those skilled in the art that the particular dose level for a particular patient depends on many different factors, including specific activity of the compound being administered, age, body weight, health, sex, diet, time of administration and

-the route, the rate of excretion, etc. It will further be understood by those skilled in the art that the optimal course of treatment, i.e. the method of treatment and the daily number of doses of a compound of formula I, or a pharmaceutically acceptable salt

thereof, given for a certain number of days can be determined by those skilled in the art using standard processing tests.

However, it will be understood that the particular dose level for any particular patient will depend on many different factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combination and the severity of the condition undergoing therapy.

The compounds can be prepared from known compounds (or from starting materials which in turn can be prepared from known compounds), e.g. through the general manufacturing methods shown below. The activity of a particular compound in inhibiting raf-kinase can be assayed routinely, e.g. according to procedures described below.

Examples

All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen and were magnetically stirred, unless otherwise noted. Sensitive liquids and solutions were transferred via syringe or needle and introduced into reaction containers through rubber caps. Unless otherwise stated, the term "concentration under reduced pressure" refers to the use of a Buchirotation evaporator at approximately 15 mmHg. Unless otherwise stated, the term "under high vacuum" refers to a vacuum of 0.4-1.0 mmHg.

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

Commercial grade reagents and solvents were used without further purification. N-cyclohexyl-N1 -

(methylpolystyrene)carbodiimide was purchased from Calbiochem-Nova-biochem Corp. 3-tert-butylaniline, 5-tert-butyl-2-methoxy-aniline, 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 was purchased and used without further purification Synthesis 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 Kagaku Zasshi, 70, 1967, 491) has previously been described.

Thin layer chromatography (TLC) was performed using "Whatman" precoated silica gel 60A F-254 glass-backed 250 µm size plates. Visualization of plates was performed using one or more of the following techniques:

(a) ultraviolet irradiation, (b) exposure to iodine vapor,

(c) immersing the plate in a 10% solution of phosphomolybdic acid in ethanol, followed by heating, (d) immersing the plate in a cerium sulfate solution, followed by heating, and/or (e) immersing the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine, followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh "EM Science" silica gel.

Melting points (m.p.) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus, and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton^<H>) nuclear magnetic resonance spectra (NMR spectra) were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer, either with Me4Si (8 0.00) or residual protonated solvent (CHC13, 8 7.26 ; MeOH 8 3.30; DMSO 8 2.49) as standard. Carbon(<13>C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC13 8 77.0; MeOD-d3; 8 49.0; DMSO-d6 8 3.95) as standard. Low-resolution mass spectra (MS) and high-resolution mass spectra (HRMS) were obtained either as electron impact (El) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EIMS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion source was maintained at 250 °C. Electron deionization was performed with an electron energy of 70 eV and a trap current of 300 uA. Liquid cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment, were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CIMS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas (1 x 10"<*> torr to 2.5 x 10"<4> torr). The direct injection desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was "ramped" from 0 to 1.5 amps for 10 seconds and held at 10 amps until all traces of the sample disappeared (approximately 1-2 minutes). Spectra were scanned from 50 to 800 amu at 2 seconds per scanning. HPLC-electrospray mass spectra (HPLC-ES-MS) were obtained using a Hewlett Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionizer -ing. Spectra were scanned from 120 to 800 amu using a variable ion time according to the number of ions 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-methyl-silicon column (0.33 mM coating, 25 m x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eV). Elemental analyzes are performed by Robertson Microlit Labs, Madison, ;NJ. ;All compounds exhibited NMR spectra, LRMS and either elemental analysis or HRMS consistent with assigned structures. ;List of abbreviations and acronyms ;AcOH acetic acid ;atm. atmosphere(s) ;BOC tert.-butoxycarbonyl ;CDI 1,1'-carbonyldiimidazole ;dec. decomposition ;DMAC N,N-dimethylacetamide ;DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-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 ;HOBT 1-hydroxybenzotriazole ;m-CPBA 3-chloroperoxybenzoic acid ;MeOH methanol ;pet.ether petroleum ether (boiling range 30-60 °C) temp. temperature ;THF tetrahydrofuran ;TFA trifluoroacetic acid ;Tf trifluoromethanesulfonyl. A. General procedures for the synthesis of substituted ;anilines ;Al. General procedure for arylamine formation via ether formation, followed by ester saponification, Curtius rearrangement and carbamate deprotection. Synthesis of 2-amino-3-methoxynaphthalene ;;Step 1: methyl-3-methoxy-2-naphthoate ;A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K2CO3 ( 7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temperature for 15 min and then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temperature overnight and was then treated with water (200 ml). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO 4 ) and concentrated under reduced pressure (ca. 0.4 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10.30 g) . ^-NMR (DMSO-d6) 6 2.70 (s, 3 H), 2.85 (s, 3 H), 7.38 (ca. t, J = 8.09 Hz, 1 H), 7, 44 (s, ;1 H), 7.53 (approx. t, J = 8.09 Hz, 1 H), 7.84 (d, J = 8.09 Hz, 1 H), 7.90 (s , 1H), 8.21 (s, 1H). ;Step 2: 3-Methoxy-2-naphthoic acid ;A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room temperature was treated with a 1 N NaOH solution (33.4 mL, 33.4 mmol). The mixture was heated at reflux temperature for 3 hours, cooled to room temperature and acidified with a 10% citric acid solution. The resulting solution was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO 4 ) and concentrated under reduced pressure. The residue was triturated with hexane and then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%). """H-NMR (DMSO-d6) δ 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d, J = 8.09 Hz, 1 H), 7.91 (d, J = 8.09 Hz, 1 H), 8.19 (s, 1 H), 12.83 (br s , 1 H). ;Step 3: 2-( N -( carbobenzyloxy) amino- 3- methoxynaphthalene ; A solution of 3-methoxy-2-naphthoic 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 min and then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette . The resulting mixture was heated at 80 °C for 2 hours. After cooling the mixture to room temperature, benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was then heated to 80 °C overnight. The the resulting mixture was cooled to room temperature, the reaction quenched with a 10% citric acid solution and the reaction mixture extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO 4 ) and concentrated under reduced pressure. The residue p was purified by column chromatography (14% EtOAc/86% hexane) to give 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene) as a pale yellow oil (5.1 g, 100%). 1H-NMR (DMS0-d6) δ 3.89 (s, 3H) , 5.17 (s, ;2H) , 7.27-7.44 (m, 8H) , 7.72-7, 75 (m, 2 H) , 8.20 (s# 1 H) , 8.76 (S, 1 H) . ;Step 4: 2-amino-3-methoxynaphthalene ;A slurry of 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd/C (0.5 g ) in EtOAc (70 mL) was kept under a H2 atmosphere (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 light pink powder ( 2.40 g, 85%). , 2 H) , 7.43 (d, J = 8.0 Hz, 1 H) , 7.56 (d, J = 8.0 Hz, 1 H) ; EIMS m/z 173 (M+) ; A2 .Synthesis of co-carbamylanilines via formation of a carba-mylpyridine, followed by nucleophilic coupling with an arylamine.Synthesis of 4-(2-N-methylcarbamyl-4-pyridyloxy)aniline;Step la;Synthesis of 4-chloro-N- methyl-2- pyridinecarboxamide via Meni sc i-reaction Warning: this is a very dangerous, potentially explosive reaction To a stirred solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temperature r was added concentrated H 2 SO 4 (3.55 mL) to produce an exotherm. To this mixture was added H 2 O 2 (30 wt% in H 2 O, 17 mL), followed by FeSO 4 -7 H 2 O (0.56 g) to produce another exotherm. The resulting mixture was stirred in the dark at room temperature for 1 hour and then slowly warmed to 45 °C over 4 hours. When bubbling had stopped, the reaction mixture was heated at 60 °C for 16 hours. The resulting opaque brown solution was diluted with H 2 O (700 mL), followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with a saturated NaCl solution (3 x 150 mL) and then combined, dried (MgSO 4 ) and filtered through a pad of silica gel using EtOAc. The resulting yellow oil was purified by column chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%); TLC (50% EtOAc/50% hexane), Rf 0.50. 3-NMR (CDCl 3 ); 8 3.04 (d, J = 5.1 Hz, 3 H), 7.43 (dd, J = 5.4, 2.4 Hz, 1 H), 7.96 (br s, ;1 H) , 8.21 (s, 1 H), 8.44 (d, J = 5.1 Hz, 1 H); CIMS 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 SOCl 2 (180 mL) at 40-50 °C. The solution was stirred at that temperature range for 10 minutes, and then picolinic acid (60.0 g, 487 mmol) was added in portions over 30 minutes. The resulting solution was heated at 72°C (vigorous evolution of SO 2 ) for 16 hours, producing a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. The process of toluene addition and concentration was repeated twice. The resulting almost dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and dried under high vacuum for 4 h to give 4-chloropyridine-2-carbonyl chloride 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 SOCl2 (300 mL) at 40-48 °C. The solution was stirred at that temperature range for 10 minutes, and then picolinic acid (100 g, 812 mmol) was added over 30 minutes. The resulting solution was heated at 72 °C (vigorous evolution of SO 2 ) for 16 h to afford a yellow solid. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. The process of toluene addition and concentration was repeated twice. The resulting almost dry residue was filtered, and the solids were washed with toluene (50 mL) and dried under high vacuum for 4 h to give 4-chloropyridine-2-carbonyl chloride HCl salt as an off-white solid (27 .2 g, 16%). This material was set aside. ;The red filtrate was added to MeOH (200 mL) at a rate that kept the internal temperature below 55 °C. The contents were stirred at room temperature for 45 minutes, cooled to 5 °C and treated dropwise with Et 2 O (200 ml). The resulting solids were filtered, washed with Et 2 O (200 mL) and dried under reduced pressure at 35 °C to give methyl 4-chloropyridine-2-carboxylate HCl salt as a white solid (110 g, 65%); m.p. 108-112 °C. ^-NMR (DMS0-d6) 3.88 (s, 3 H), 7.82 (dd, J = 5.5, 2.2 Hz, 1 H), 8.08 (d, J = 2.2 Hz, 1 H), 8.68 (d, J = 5.5 Hz, 1 H), 10.68 (br s, 1 H); HPLC ES-MS m/z 172 ((M + ;H)+). ;;Step 3a: Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from methyl-4-chloropyridine-2-carboxylate ;A suspension of methyl-4-chloropyridine-2-carboxylate HCl salt (89.0 g , 428 mmol) in MeOH (75 mL) at 0 °C was treated with a 2.0 M methylamine solution in THF (1 L) at a rate that kept the internal temperature below 5 °C. The resulting mixture was stored at 3°C for 5 hours and then concentrated under reduced pressure. The resulting solids were slurried in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure to give 4-chloro-N-methyl-2-pyridinecarboxamide as pale yellow crystals (71.2 g, 97 %); m.p. 41-43 °C. ^-NMR (DMS0-d6) δ 2.81 (s, 3 H), 7.74 (dd, J = 5.1, 2.2 Hz, 1 H), 8.00 (d, J = 2, 2, 1 H), 8.61 (d, J = 5.1 Hz, 1 H), 8.85 (br d, 1 H); CIMS m/z 171 ((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 2.0 M methylamine solution in THF (100 mL) at 0 °C. The resulting mixture was stored at 3°C for 4 hours and then concentrated under reduced pressure. The resulting almost dry solids were slurried in EtOAc (100 mL) and filtered. The filtrate was washed with a saturated NaCl solution (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 h. The contents were treated with 4-chloro-N-methyl-2-pyridinecarboxamide (15.0 g, 87 .9 mmol) and K 2 CO 3 (6.50 g, 47.0 mmol) and then heated at 80 °C for 8 h. The mixture was cooled to room temperature and partitioned between EtOAc (500 mL) and a saturated NaCl solution (500 The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution (4 x 1000 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 °C for 3 h to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline as a light brown solid (17.9 g, 84%). <1>H -NMR (DMSO-d6) 6 2.77 (d, J = 4.8 Hz, 3 H), 5.17 (br s, 2 H), 6.64, 6.86 (AA< *>BB<1> quartet, J = 8.4 Hz, 4 H), 7.06 (dd, J = 5.5, 2.5 Hz, 1 H), 7.33 (d, J = 2.5 Hz, 1 H), 8.44 (d, J = 5.5 Hz, 1 H), 8.73 (br d, 1 H); HPLC ES-MS m/z 244 ((M + H)+). A3. General procedure for the synthesis of anilines 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 was heated at 120°C for 45 minutes, and then the clear pale yellow mixture was heated at 160°C for 2 hours. The resulting mixture was maintained at 160°C and was concentrated to approx. 15 ml, then it was cooled to room temperature and adjusted to pH 10 with a 1 N NaOH solution. This mixture was cooled to 0 °C and slowly acidified to pH 5 using a 1 N HCl solution. The resulting precipitate was collected by filtration and dried under reduced pressure to give 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as the product (3.24 g, 72%). """H-NMR (DMSO-d 6 ) δ 7.00-7.03 (m, 2 H), 7.56 (d, J = 9.3 Hz, 1 H).

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

To a slurry of NaH (1.1 g, 44.9 mmol) in DMF

(40 ml) at 0 °C with stirring, a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 ml) was added dropwise. The light yellow-green mixture was allowed to return to room temperature and stirred for 1 hour, and then 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated at 70 °C overnight and then cooled to room temperature and slowly diluted with water (150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure to give 5-(4-nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, 62%); TLC (30% EtOAc/70% hexane), Rf 0.28. <1>H-NMR (DMSO-d6) 8 7.32 (d, J = 12 Hz, 2 H) , 7.52-7.57 (m, 2 H), 7.89 (d, J = 7 .8 Hz, 1 H), 8.29 (d, J =

9 Hz, 2 H), 11.43 (br s, 1 H); CIMS m/z 285 ((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 argon flow while iron powder ( 0.59 g, 55.9 mmol) was slowly added. This mixture was stirred at room temperature for 72 h and was then diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure to give 5-(4-aminophenoxy)isoindoline-1,3-dione as a tan solid (0.4 g, 75%); TLC (50% EtOAc/50% hexane), Rf 0.27. <X>H-NMR (DMSO-de) δ 5.14 (br s, 2 H), 6.62 (d, J = 8.7 Hz, 2 H), 6.84 (d, J = 8, 7 Hz, 2 H), 7.03 (d, J = 2.1 Hz, 1 H), 7.23 (dd, 1 H), 7.75 (d, J = 8.4 Hz, 1 H) , 11.02 (s, 1 H); HPLC ES-MS m/z 255 ((M+H)\100%).

A4. General procedure for the synthesis of pyrrolylanilines.

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

Step 1: Synthesis of 1-(4-tert.-butyl-2-nitrophenyl)-2,5-dimethyl-pyrro1

To a solution of 2-nitro-4-tert-butylaniline

(0.5 g, 2.57 mmol) in cyclohexane (10 mL) with stirring, AcOH (0.1 mL) and acetonylacetone (0.299 g, 2.63 mmol) were added via syringe. The reaction mixture was heated at 120 °C for 72 hours with azeotropic removal of volatiles. The reaction mixture was cooled to room temperature, diluted with CH 2 Cl 2 (10 mL) and sequentially washed with a 1 N HCl solution (15 mL), a 1 N NaOH solution (15 mL) and a saturated NaCl solution (15 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting orange-brown solids were purified via column chromatography (60 g SiO 2 ; gradient from 6% EtOAc/94% hexane to 25% EtOAc/75% hexane) to give 1-(4-tert-butyl-2-nitrophenyl )-2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%); TLC (15% EtOAc/85% hexane), Rf 0.67. <1>H-NMR (CDCl 3 ) δ 1.34 (s, 9 H), 1.89 (s, 6 H), 5.84 (s, 2 H), 7.19-7.24

(m, 1 H), 7.62 (dd, 1 H), 7.88 (d, J = 2.4 Hz, 1 H); CIMS m/z 273 ((M + H)<+>, 50%) .

Step 2: Synthesis of 5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline A slurry 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) under H 2 atmosphere (balloon) was stirred for 72 h and 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 yellowish solids (0.30 g, 99%); TLC (10% EtOAc/90% hexane), Rf 0.43. 3-NMR (CDCl 3 ) 1.28 (s, 9 H), 1.87-1.91 (m, 8 H), 5.85 (br s, 2 H), 6.73-6.96 (m , 3 H), 7.28 (br s, 1 H). A5. General procedure for the synthesis of anilines from anilines by means of nucleophilic aromatic substitution. 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 black mixture was stirred at room temperature until the flask had reached room temperature. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Procedure A2, step 3b; 7.52 g,

44.2 mmol) and heated at 110 °C for 8 h. 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 combi-

Third organic layers were washed with a saturated NaCl solution (200 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The remaining black 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 minutes. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration from solution and stored under anaerobic conditions

at 0 °C before use. <1>H-NMR (DMSO-d6) δ 2.41 (s, 3 H), 2.78 (d, J = 4.4 Hz, 3 H), 4.93 (br s, 2 H), 7.19 (dd, J = 8.5, 2.6 Hz, 1 H), 7.23 (dd, J = 5.5, 2.6 Hz, 1 H), 7.26 (d, J = 2.6 Hz, 1 H), 7.55 (d, J = 2.6 Hz, 1 H), 7.64 (d, J = 8.8 Hz, 1 H), 8.55 (d, J = 5.9 Hz, 1 H), 8.99 (q, J = 4.8 Hz, 1 H).

A6. General procedure for the synthesis of anilines from hydroxyanilines by means of N-protection, nucleophile, 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 slurry was added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 mL ).This gray slurry was stirred at room temperature for 6 days. The iron was filtered from the solution, and the remaining material was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To the resulting yellow solution, saturated NaHCO 3 solution (50 mL) was added. The solid that precipitated from the solution was removed. Sodium bicarbonate solution was slowly added to the filtrate until the product visibly separated from the solution (determined by using a small work-up bottle). The slightly cloudy, yellow solution was extracted with EtOAc

(3 x 125 ml). The combined organic layers were washed with a saturated NaCl solution (125 mL), dried (MgSO 4 ) and concentrated under reduced pressure. 3-NMR (DMS0-d6) indicated a ratio of

1:1 between the nitrophenol starting material and the intended product 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol. The crude material was taken up 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 impure 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, 45.98 mmol) and the tan-black mixture was stirred at room temperature until the flask had cooled to room temperature. The resulting mixture was treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Procedure A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 °C under argon for 4 days. The black reaction mixture was cooled to room temperature and then poured into cold water (100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The remaining brown oil was purified by column chromatography (gradient from 20% EtOAc/pet.ether to 40% EtOAc/pet.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,

23.0 mmol) in dry 4-dixane (20 mL) was treated with a 1 N NaOH solution (20 mL). This brown solution was allowed to stand with stirring 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 after have stood (2.86 g, 10.30 mmol). ^-NMR

(DMSO-de) 6 2.77 (d, J = 4.8 Hz, 3 H), 5.51 (s, 2 H), 6.60 (dd, J = 8.5, 2.6 Hz, 1 H), 6.76 (d, J = 2.6 Hz, 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.07 (dd, J = 5.5, 2.6, Hz, 1 H), 7.27 (d, J = 2.6 Hz, 1 H), 8.46 (d, J = 5.5 Hz, 1 H), 8.75 (q, J = 4.8, 1H).

A7. General procedure for deprotection of an 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 a 6 M HCl solution (24 mL) was heated at reflux temperature in 1 hour. The resulting solution was allowed to cool to room temperature, below which it solidified slightly. The resulting mixture was diluted with water (20 mL) and then treated with a combination of solid NaOH and a saturated NaHCO 3 solution until the solution became basic. The organic layer was extracted with CH 2 Cl 2 (3 x 50 mL). The combined organics were dried (MgSO 4 ) and concentrated under reduced pressure to give 4-chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g, 14.2 mmol). 3-NMR (DMSO-d 6 ) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

A8. General procedure for the synthesis of co- alkoxy- co-carboxyphenylanilines. 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 (prepared from 2,5-dihydroxybenzoic acid in an analogous manner to that described in Method A13; step 1, 12 mmol) in acetone (50 ml) K 2 CO 3 (5 g) and dimethylsulphate (3.5 ml) were added. The resulting mixture was heated at reflux temperature overnight and then cooled to room temperature and filtered through a pad of celite. The resulting solution was concentrated under reduced pressure, absorbed onto SiO 2 , and purified by column chromatography (50% EtOAc/50% hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a yellow powder (3 g); m.p. 115-118 °C.

Step 2. 4-( 3- carboxy- 4- methoxyphenoxy)- 1- nitrobenzene

A mixture of 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 at reflux temperature for 4 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50 mL) and the aqueous mixture was acidified with a 1 N 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 (1.04 g).

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 CH 2 Cl 2 (12 mL) was added SOCl 2 (0.64 mL, 8.77 mmol) in portions. The resulting solution was heated at reflux temperature for 18 hours, cooled to room temperature and concentrated under reduced pressure. The resulting yellow solid was dissolved in CH 2 Cl 2 (3 mL), and then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02 mmol) in portions (WARNING: gas evolution ) and stirred at room temperature for 4 hours. The resulting mixture was treated with a 1 N NaOH solution and then extracted with CH 2 Cl 2 (25 mL). The organic layer was dried (Na 2 SO 4 ) 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 slurry 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 (balloon) for 2.5 days and then filtered through a pad of celite. The resulting solution was concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)-4-methoxyphenoxy)aniline as an off-white solid (0.68 g, 96%). TLC (0.1% Et 3 N/99.9% EtOAc), Rf 0.36.

A9. General procedure for the production of co-alkyl-phthalimide-containing anilines. Synthesis of 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione

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

A slurry 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 and then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temperature overnight and 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 pale yellow solid (0.87 g, 83%). TLC (35% EtOAc/65% hexane), Rf 0.61.

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

A slurry of 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. H2 (balloon) overnight. The resulting mixture was filtered through a pad of celite and concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) and filtered through a plug of SiO 2 (60% EtOAc/40% hexane) to give 5-(4-aminophenoxy)-2-methylisoindoline-1,3- dione as a yellow solid (0.67 g, 86%). TLC (40% EtOAc/60% hexane), Rf 0.27.

A10. General procedure for the synthesis of oo-carbamoyl-arylanilines through the reaction of co-alkoxycarbonyl-aryl 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 HCl salt (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added 4-(2-aminoethyl) morpholine (2.55 ml,

19.4 mmol) dropwise, and the resulting solution was heated at reflux temperature for 20 h, 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), Rf 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 and was then sequentially treated 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 a saturated NaCl solution (25 mL). The aqueous layer was back-extracted with EtOAc (25 mL). The combined organic layers were washed with a saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure. The resulting brown solids were purified by column chromatography (58 g, gradient from 100% EtOAc to 25% MeOH/75% EtOAc) to give 4-(2-N-(2-morpholin-4-ylethyl) -carbamoyl)pyridyloxy)aniline (1.0 g, 65%). TLC (10% MeOH/90% EtOAc), Rf 0.32. Everything. General procedure for the reduction of nitroarenes to arylamines'

A slurry of 4-(3-carboxyphenoxy)-1-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd/C (0.50 g) in MeOH (120 mL) was stirred under an H 2 atmosphere (balloon) for 2 days. The resulting mixture was filtered through a pad of celite and 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 ), Rf 0.44 ("streaking").

A12. General procedure for the synthesis of isoindolinone-containing anilines

Step 1: Synthesis of 5-hydroxyisoindolin-l-one

To a solution of 5-hydroxyphthalimide (19.8 g,

121 mmol) in AcOH (500 mL) was slowly added portionwise zinc dust (47.6 g, 729 mmol) and then the mixture was heated at reflux for 40 min, filtered hot and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oil residue was purified by column chromatography (1.1 kg SiO 2 ; gradient from 60% EtOAc/40% hexane to 25% MeOH/75% EtOAc) to give 5-hydroxyisoindoline -l-one (3.77 g). TLC (100% EtOAc), Rf 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 1 portions. The resulting slurry was allowed to warm to room temperature and stirred for 45 minutes, and then 4-fluoro-1-nitrobenzene was added and the mixture was then heated at 70°C for 3 hours. The mixture was cooled to 0 °C and treated with water dropwise until a precipitate formed. The resulting solids were 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 slurry 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 an H2 atmosphere (balloon) for 4 hours and then filtered through 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 f . 0.15.

A13. General procedure for the synthesis of co-carbamoylanilines via EDCI-mediated amide formation, followed by nitroarene reduction. Synthesis of 4-(3-N-methylcarbamoyl-phenoxy) 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 phases were washed sequentially with water (3 x 100 mL) and a 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 a solution (75 mL) of THF and water in the ratio 3:1 was added a solution LiOH»H 2 O (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50 °C overnight and then cooled to room temperature, concentrated under reduced pressure and adjusted to pH 2 with a 1 M HCl solution. The resulting pale yellow solids were removed 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>1-nitrobenzene (3.72 g, 14.4 mmol), EDCI "HCl (3.63 g, 18.6 mmol), N-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF, 8 mL, 16 mmol) in CH 2 Cl 2 (45 mL) was stirred at room temperature for 3 days and then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with a 1 M HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with a saturated NaCl solution (50 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil. (1.89g).

Step 4: Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)aniline

A slurry 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 an H2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH/95% CH 2 Cl 2 ). The resulting oil solidified under vacuum overnight to give 4-(3-(N-methylcarbamoyl)phenoxy)aniline as a yellow solid

(0.95 g, 56%) .

A14. General procedure for the synthesis of co-carbamoylanilines via EDC 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 slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 ml). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL), and the resulting mixture was heated at 70 °C overnight, cooled to room temperature, and treated with MeOH (5 mL), followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g).

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

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

A15. Synthesis of an aniline via electrophilic nitration, followed by reduction. Synthesis of 4-(3- methylsulfamoyl-phenoxy) 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 was stirred at room temperature overnight. The resulting mixture was partitioned between EtOAc (25 mL) and a 1 M HCl solution (25 mL). The aqueous phase was back-extracted with EtOAc (2 x 25 mL). The combined organic phases were washed sequentially with water (2 x 25 mL) and a saturated NaCl solution (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 of phenol (1.9 g, 20 mmol), K 2 CO 3 (6.0 g, 40 mmol) and Cl (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 a 1 N HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were sequentially washed with water (2 x 50 ml) and a saturated NaCl solution (50 ml), dried (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 (0.30g).

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 within 5 minutes. The resulting solution was stirred at -10 °C for 1 hour and then allowed to warm to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (10 mL) and water (10 mL). The organic phase was washed sequentially with water (10 mL) and a saturated NaCl solution (10 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give 4-(3-(N-methylsulfamoyl)-phenyloxy)- 1-nitrobenzene (0.20 g). This material was carried on to the next step without further purification.

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

A slurry 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 an H2 atmosphere ( balloon) overnight. The resulting mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(N -methylsulfamoyl)phenyloxy)aniline (0.070 g).

A16. Modification of eo-ketones. Synthesis 4-( 4-( 1-( N- methoxy) -

iminoethyl) phenoxyaniline HCl salt

To a slurry of 4-(4-acetylphenoxy)aniline HCl salt) (prepared analogously to Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0 mL) was added O-methylhydroxylamine-HCl salt (0.65 g, 7.78 mmol, 2.0 eq.). The resulting solution was heated at reflux temperature for 30 minutes, cooled to room temperature and concentrated under reduced pressure. The resulting solids were triturated with water (10 mL) and washed with water to give 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt as a yellow solid (0.85 g ).TLC (50% EtOAc/50% pet.ether), Rf 0.78; H1-NMR (DMSO-d6) δ 3.90 (s, 3H) , 5.70 (s, 3H); HPLC -MS m/z 257 ( (M + H) +) . A17. Synthesis of N-( co-silyloxyalkyl) amides. Synthesis of 4-( 4-( 2-( N-( 2- triisopropylsilyloxy) ethylcarbamoyl) pyridyl- oxyaniline

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 Method A2, Step 3b; 1.5 g, 7.4 mmol) in anhydrous DMF (7 mL) triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 eq.) and imidazole (1.12 g, 16.4 mmol, 2.2 eq.) were added. The resulting yellow solution was stirred for 3 hours at room temperature and then concentrated under reduced pressure. The residue was partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried (MgSO 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 was 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 exotherm. When this mixture was cooled to room temperature, a solution of 4-chloro-2-(N-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv) in DMF (4 mL) was added , followed by K2CO3 (0.42 g, 3.0 mmol,

0.50 eq.). The resulting mixture was heated at 80 °C overnight. A further portion of potassium tert-butoxide

(0.34 g, 3 mmol, 0.5 eq.) was then added and the mixture was stirred at 80 °C for an additional 4 h. The mixture was cooled to 0 °C with an ice-water bath, and then water (ca. 1 mL) was slowly added dropwise. The organic layers were extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with a saturated NaCl solution (20 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The brown oil residue was purified by column chromatography (SiO 2 ; 30% EtOAc/70% pet ether) to give 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)-pyridyloxyaniline as a clear, light brown oil (0.99 g, 38%).

A18. Synthesis of 2-pyridine carboxylate esters via oxidation of 2-methylpyridines. 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, 2.0 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 (3 x 100 mL). The combined organic layers were washed sequentially with water (2 x 100 mL) and a 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) were heated at reflux for 5 h and then cooled to room temperature. The resulting slurry was filtered and then concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The solution was treated with a concentrated HCl solution (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 a 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 a 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 slurry 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 placed under an H2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 ; 70% EtOAc/30% hexane) to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline (0.40 g).

A19. Synthesis of co-sulfonylphenylanilines. 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 hours. The reaction mixture was treated with a 1 N NaOH solution (25 mL). The organic layer was washed sequentially with a 1 N NaOH solution (25 mL), water (25 mL) and a saturated NaCl solution (25 mL), dried (MgSO 4 and concentrated under reduced pressure to give 4-(4 -methyl-sulfonyl-enoxy)-1-nitrobenzene as a solid (2.1 g).

Step 2: 4-(4-methylsulfonylphenoxy)-1-aniline

4-(4-Methylsulfonylphenoxy)-1-nitrobenzene was reduced to the aniline in an analogous manner to that described in Method A18, Step 3.

B. Synthesis of urea precursors

Bl. General procedure for the synthesis of isocyanates from anilines using CDI. Synthesis of 4-bromo-3-(trifluoromethyl)phenylisocyanate

Step 1: Synthesis of 4-bromo-3-(trifluoromethyl)aniline HCl salt

To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et 2 O (500 mL) was added an HCl solution (1 M in Et 2 O; 300 mL) dropwise, and the the resulting mixture was stirred at room temperature for 16 hours. The resulting pink-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 dropwise with trichloromethyl chloroformate and the resulting mixture was heated at reflux temperature for 18 h . The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mL) and then concentrated under reduced pressure. The residue was treated with CH 2 Cl 2 (500 mL) and then concentrated under reduced pressure. The CH 2 Cl 2 treatment/concentration procedure was repeated and the resulting amber oil was stored at -20 °C for 16 h to give 4-bromo-3-(trifluoromethyl)phenyl isocyanate as a tan solid (35.1 g , 86%) . GC-MS m/z 265 (M+).

C. Processes for Urea Formation

Cia. General method for the synthesis of urea compounds by reacting an isocyanate with an 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 (Method 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 solids were removed by filtration, then washed with CH 2 Cl 2 (2 x 30 mL) and dried under reduced pressure (ca. 1 mmHg) to give N-(4-chloro-3-(trifluoromethyl)phenyl) -N1-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-phenyl)urea as an off-white solid (28.5 g, 93%); mp 207-209 °C; """H-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, 3 H) , 7.16 (m, 3 H), 7.37 (d, J = 2.5 Hz, 1 H), 7.62 (m, 4 H), 8.11 (d, J = 2.5 Hz, 1 H), 8.49 (d, J = 5.5 Hz, 1 H), 8.77 (br d, 1 H), 8.99 (s, 1 H), 9.21 (s, 1 H); HPLC ES-MS m/z 465 ((M + H)+ ).Clb. General procedure for the synthesis of urea compounds by reacting an isocyanate with an aniline. Synthesis of N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea

To a solution of 4-(2-(N -methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH 2 Cl 2 (40 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 hours. The resulting yellow solids were removed by filtration and then washed with CH 2 Cl 2 (2 x 50 mL) and dried under reduced pressure (ca. 1 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; H1-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, 3 H), 7.16 (m, 3 H), 7.37 (d, J = 2.5 Hz, 1 H), 7.58 (m, 3 H), 7.77 (d, J = 8.8 Hz, 1 H), 8.11 (d, J = 2.5 Hz, 1 H), 8.49 (d, J = 5.5 Hz, 1 H), 8.77 (br d, 1 H), 8.99 (s, 1 H), 9.21 (s, 1 H); HPLC ES-MS m/z 509 ((M+H)+). Clc. General procedure for the synthesis of urea compounds by reacting an isocyanate with an aniline. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea

A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method 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 brown solution was stirred at room temperature for 6 days and then treated with water (5 mL). The aqueous layer was back-extracted with EtOAc (3 x 5 mL). The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-methyl-4-(2-(N-methylcarbamoyl) ) (4-pyridyloxy))phenyl)urea as a brown oil (0.11 g,

0.22 mmol). <X>H-NMR (DMS0-d6) 8 2.27 (s, 3 H) , 2.77 (d, J =

4.8 Hz, 3 H), 7.03 (dd, J = 8.5, 2.6 Hz, 1 H), 7.11 (d, J =

2.9 Hz, 1 H), 7.15 (dd, J = 5.5, 2.6 Hz, 1 H), 7.38 (d, J =

2.6 Hz, 1 H), 7.62 (approx. d, J = 2.6 Hz, 2 H), 7.84 (d, J =

8.8 Hz, 1 H), 8.12 (s, 1 H), 8.17 (s, 1 H), 8.50 (d, J = 5.5 Hz,

1H), 8.78 (q, J = 5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479

((M + H)<+>) .

Cld. General method for the synthesis of urea compounds by reacting an isocyanate with an aniline. 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 share. 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 solids were dissolved in a mixture of EtOAc (110 mL) and MeOH (15 mL) and the clear solution was washed with a 0.05 N HCl solution. 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.

Cle. General method for the synthesis of urea compounds by reacting an isocyanate with an aniline. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N1-(4-ethoxycarbonyl-phenyl)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-(trifluoro-■ methylDaniline (3.21 g, 16.4 mmol) ), and the solution was stirred at room temperature overnight. The resulting slurry was diluted with CH 2 Cl 2 (50 mL) and filtered to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N<1->(4 -ethoxycarbonylphenyl)urea as a white solid (5.93 g, 97%) TLC (40% EtOAc/60% hexane), Rf 0.44.

Cif. General method for the synthesis of urea compounds by reacting an isocyanate with an 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 (Method All; 0.81 g , 5.76 mmol), and the resulting mixture was stirred at room temperature overnight and then treated with MeOH (8 mL) and stirred for an additional 2 h. The resulting mixture was concentrated under reduced pressure. The resulting brown solids were triturated with a 1:1 solution of EtOAc and hexane to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-carboxyphenyl)-urea as an off-white solid (1.21 g, 76%).

C2a. General procedure for urea compound synthesis by reaction of an aniline with N,N'-carbonyldiimidazole, followed by addition of a second aniline. Synthesis of N-(2-methoxy-5-(trifluoromethyl)phenyl)-N1-(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 and then treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 72 h and then treated with H 2 O (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCl solution (100 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The remainder was triturated (90%

EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil was purified by column chromatography (gradient from 33% EtOAc/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 light tan solid (0.098 g, 30%). TLC (100% EtOAc), Rf 0.62; """H-NMR (DMSO-d6)

8 2.76 (d, J = 4.8 Hz, 3 H), 3.96 (s, 3 H), 7.1-7.6 and 8.4-8.6 (m, 11 H), 8.75 (d, J = 4.8 Hz, 1 H), 9.55 (s, 1 H); FAB-MS m/z 461 ((M + H) +). C2b. General procedure for urea compound reynthesis by reaction of an aniline with N,N'-carbonyldiimidazole, followed by addition of a second aniline. Symmetric urea compounds as byproducts of an N,N'-carbonyldiimidazole reaction procedure. Synthesis of bis( 4-( 2-( N- methylcarbamoyl)- 4- pyridyloxy) phenylurea

To a stirred solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH 2 Cl 2 (15 mL) at 0 °C was added CDI (0.13 g). The resulting solution was allowed to warm to room temperature over 1 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 and 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 a saturated NaCl solution (100 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea (0.081 g, 44%). TLC (100% EtOAc), Rf 0.50; H1-NMR (DMSO-ds) δ 2.76 (d, J = 5.1 Hz, 6 H) , 7.1-7.6 (m, 12 H) , 8.48 (d, J = 5, 4 Hz, 1 H), 8.75 (d, J = 4.8 Hz, 2 H), 8.86 (s,

2H); HPLC ES-MS m/z 513 ((M + H)+).

C2c. General method for the synthesis of urea compounds by reacting an isocyanate with an aniline. Synthesis of N-(2-methoxy-5-(trifluoromethyl)phenyl-N'-(4-(1,3-dixo-soindolin-5-yloxy)phenyl)urea

To a stirred solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol) in CH 2 Cl 2 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-1,3 -dione (Method A3, Step 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h and then treated with CH 2 Cl 2 (10 mL) and MeOH (5 mL). The resulting mixture was washed sequentially with a 1 N HCl solution (15 mL) and a saturated NaCl solution (15 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give N-(2-methoxy-5- (trifluoromethyl)-phenyl-N<1->(4-(1,3-dioxoisoindolin-5-yloxy)phenyl)urea as a white solid (0.2 g, 96%) TLC (70% EtOAc/ 30% hexane), Rf 0.50; <X>H-NMR (DMS0-d6) δ 3.95 (s, 3 H) , 7.31-7.10 (m, 6 H) , 7.57 ( d, J = 9.3 Hz, 2 H), 7.80 (d, J = 8.7 Hz, 1 H), 8.53 (br s, 2 H), 9.57 (s, 1 H) , 11.27 (br s, 1 H); HPLC ES-MS 472.0 ( (M + H)\ 100%) . C2d. General procedure for urea compound synthesis by reacting an aniline with N, N'-carbonyldiimidazole, followed by of addition of a second aniline Synthesis of N-( 5-( tert-butyl)- 2-( 2, 5- dimethylpyrrolyl) phenyl)- N'-( 4-( 2-( N- methylcarbamoyl)- 4- pyridyloxy) phenyl) urea To a stirred solution of CDI (0.2 lg, 1.30 mmol) in CH 2 Cl 2 (2 mL) was added 5-(tert-butyl)-2-(2,5-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, and then 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-aniline (0.065 g, 0.267 mmol) was added in one portion. The resulting mixture was heated at 36 °C overnight and then cooled to room temperature and diluted with EtOAc (5 mL). The resulting mixture was washed sequentially with water (15 mL) and a 1 N 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)phenylurea as a yellowish solid (0.033 g, 24% ).TLC (40% EtOAc/60% hexane), Rf 0.24; H1-NMR-acetone-ds) 6 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J = 4.8 Hz, 3 H), 5.83 (s, 2 H), 6.87-7.20 (m, 6 H), 7.17 (dd, 1 H), 7, 51-7.58 (m, 3 H), 8.43 (d, J = 5.4 Hz, 1 H), 8.57 (d, J = 2.1 Hz, 1 H), 8.80 ( br S, 1 H) ; HPLC ES-MS 5 2 ( (M + H) \ 100 %) .

C3. Combinatorial method for the synthesis of diphenylurea compounds using triphosgene

One of the anilines to be coupled was 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 a bis(trichloromethyl)carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv), followed by diisopropylethylamine

(0.35 M in dichloroethane, 0.2 ml, 1.2 equiv). The bottle was closed and heated at 80 °C for 5 hours and then allowed to cool to room temperature for approx. 10 hours. The second aniline was added (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv). The resulting mixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.

C4. General procedure for the synthesis of urea compounds by reacting an aniline with phosgene, followed by the addition of a second aniline. Synthesis of N-(2-methoxy-5-(trifluoromethyl)phenyl)-N1-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea

To a stirred solution of 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 was added anhydrous pyridine (0.32 mL) , followed by 2-methoxy-5-(trifluoromethyl)aniline (0.75 g). The yellow solution was allowed to warm to room temperature, below which a precipitate formed. The yellow mixture was stirred for 1 hour and 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 Method A2; 0.30 g), and the resulting suspension was heated at 80 °C for 20 hours and then allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL) and then basified with a saturated NaHCO 3 solution (2-3 mL). The basic solution was extracted with EtOAc (2 x 250 mL). The organic layers were washed separately with a saturated NaCl solution, combined, dried (MgSO 4 ) and concentrated under reduced pressure. The resulting rose-brown residue was dissolved in MeOH and absorbed on SiO 2 (100 g). Column chromatography (300 g SiO2; gradient from 1% Et3N/33% EtOAc/66% hexane to 1% Et3N/99% EtOAc to 1% Et3N/20% MeOH/79% EtOAc) followed by concentration under reduced pressure at 45 °C gave a hot, concentrated EtOAc solution which was treated with hexane (10 mL) to slowly form crystals of N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N- methylcarbamoyl)-4-pyridyloxy)phenyl)urea (0.44 g). TLC (1% Et 3 N/99% EtOAc), Rf 0.40.

D. Inter-formation of urea compounds

Dia. Conversion of co-aminophenylurea compounds to co-(aroylamino)phenylurea compounds. Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)urea

To a solution of N-(4-chloro-3-((trifluoromethyl)-phenyl)-N<1->(4-aminophenyl)urea (Procedure Cld; 0.050 g, 1.52 mmol), monomethyl 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 mmol) was added EDCl»HCl (0, 29 g, 1.52 mmol). The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (25 mL) and washed sequentially with water (25 mL) and a saturated NaHCO 3 solution (25 mL). The organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure.The resulting solids were triturated with an EtOAc solution (80% EtOAc/20% hexane) to give N-4-chloro-3-((trifluoromethyl)phenyl)-N '-(4-(3-Methoxycarbonylphenyl)carboxyamino-phenylDurea (0.27 g, 43%); mp 121-122 °C; TLC (80% EtOAc/20% hexane), Rf 0.75). Dlb. Conversion of co-carboxyphenyl urea compounds to oo-(arylcarbamoyl)phenylurea compounds Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoyl)-phenyl) l) carbamoylphenyl) urea

To a solution of N-(4-chloro-3-((trifluoromethyl)-phenyl)-N'-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl)urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g,

0.53 mmol), HOBT»H 2 O (0.14 g, 1.07 mmol) and N-methylmorpholine (0.5 ml, 1.07 mmol) in DMF (3 ml) at 0 °C was added EDCI» HCl (0.10 g, 0.53 mmol). The resulting mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was treated with water (10 mL) and extracted with EtOAc (25 mL). The organic phase was concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) and then filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane to 10% MeOH/90% EtOAc) to give N- (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carbamoylphenyl)urea as a white solid (0.097 g, 41%); mp 225-229 °C; TLC (100% EtOAc), Rf 0.23.

Dlc. Combinatorial method for the conversion of co-carboxy enylurea compounds into co-(arylcarbamoyl)-phenylurea compounds. 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 (Method Cif; 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 or turbidity, a small amount of DMSO was also added .) The resulting mixture was heated at 36 °C overnight. Turbid reaction mixtures were then treated with THF (1 mL), and heating was continued for 18 h. The resulting mixtures were treated with poly(4-(isocyanatomethyl)styrene) (0.040 g), and the resulting mixture was stirred at 36 °C for 72 h, then cooled to room temperature and filtered. The resulting solution was filtered through a plug of silica gel (1 g). Concentration under reduced pressure gave N-(4 -chloro-3-((trifluoromethyl)phenyl)-N1-(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 oo-carboalkoxyaryl urea compounds to di-carbamoylurea compounds. 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 (2 M in THF; 1 ml,

1.7 mmol), and the resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N<1->(4- (3-Methylcarbamoylphenyl)carboxyaminophenyl)urea as a white solid, mp 247 °C, TLC (100% EtOAc), Rf 0.35.

D3. Conversion of co-carboxyarylurea compounds to co-carboxyarylurea compounds. Synthesis of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-carboxyphenyl)urea

To a slurry of N-(4-chloro-3-((trifluoromethyl)-phenyl)-N<1->(4-ethoxycarbonylphenyl)urea (Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 ml) was added an aqueous KOH solution (2.5 N, 10 ml, 23 mmol). The resulting mixture was heated at reflux temperature for 12 h, cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water ( 50 mL) and then treated with a 1 N HCl solution to adjust the pH to 2-3. The resulting solids were collected and dried under reduced pressure to give N-(4-chloro-3-((trifluoromethyl )phenyl)-N<1->(4-carboxy-phenyl)urea as a white solid (5.05 g, 92%). D4. General procedure for the conversion of co-alkyl esters to co-alkyl amides. Synthesis of N-( 4- chloro- 3-(( trifluoromethyl) phenyl)- N'-(( 4-( 3-( 5-( 2- dimethylamino-ethyl) 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-methoxy-carbonylpyridyl)oxyphenyl)urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4 -(3-(5-methoxycarbonylpyridyl)oxyaniline (Method A14, Step 2) in an analogous manner to Method Cia. A suspension of 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 was stirred at room temperature for 1 hour. The resulting mixture was adjusted to pH 5 with a 1 N HCl solution. The resulting precipitate was removed by filtration and washed with water. The resulting solids were dissolved in EtOH (10 mL), and the resulting solution was concentrated under reduced pressure. The EtOH/concentration procedure was repeated twice to give 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 EDCl·HCl (0.032 g, 0.17 mmol) in DMF ( 2.5 mL) was stirred at room temperature overnight. The resulting solution was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (35 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CH 2 Cl 2 (ca. 2 mL). The resulting solution was treated dropwise with Et 2 O to give N-(4-chloro-3-(trifluoromethyl)phenyl)-N 1 -((4- (3-(5-(2-Dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl)urea as a white precipitate (0.48 g, 84%). H1-NMR (DMSO-d6) 8 2.10 (s, 6 H) , 3.26 (s, H), 7.03 (d, 2 H), 7.52 (d, 2 H), 7.60 (m, 3 H), 8.05 (s, 1 H ), 8.43 (s, 1 H), 8.58 (t, 1 H), 8.69 (s, 1 H), 8.90 (s,

1 H) , 9.14 (s, 1 H) ; HPLC ES-MS m/z 522 ((M + H)+).

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

To a solution of N-(4-chloro-3-((trifluoromethyl)-phenyl)-N'-(4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)-pyridyloxyphenyl)urea (prepared on analogously to method Cia; 0.25 g, 0.37 mmol) in anhydrous THF (2 mL) was added tetrabutylammonium fluoride (1.0 M in THF; 2 mL). The mixture was stirred at room temperature for 5 min, and then it was treated with water (10 mL). The aqueous mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 ; gradient from 100% hexane to 40% EtOAc/60% hexane) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2- hydroxy)ethylcarbamoyl)pyridyloxyphenyl)urea as a white solid (0.019 g, 10%).

Listed below are compounds set forth in the tables below that have been synthesized according to the detailed experimental procedures set forth above:

Syntheses of exemplified compounds

(see tables for compound characterization)

No. 1: 4-(3-N-methylcarbamoylphenoxy)aniline was prepared according to method A13. According to method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl)carbonate, followed by 4-(3-N-methylcarbamoylphenoxy)aniline, whereby the urea compound was obtained.

No. 2: 4-fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to method A13, step 1, whereby 4-(4-acetylphenoxy)-1-nitrobenzene was obtained. 4-(4-acetylphenoxy)-1-nitrobenzene was reduced according to method A13, step 4, whereby 4-(4-acetylphenoxy)aniline was obtained. According to method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl)carbonate, followed by 4-(4-acetylphenoxy)aniline, whereby the urea compound was obtained.

No. 3: According to method C2d, 3-tert-butylaniline was treated with CDI, followed by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to method A8, whereby the urea compound was obtained.

No. 4: 5-tert-butyl-2-methoxyaniline was converted to 5-tert-butyl-2-methoxyphenyl isocyanate according to method B1. 4-(3-N-methylcarbamoylphenoxy)aniline), prepared according to method A13, was reacted with the isocyanate according to method Cia, whereby the urea compound was obtained.

No. 5: According to method C2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI, followed by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to method A8, whereby one obtained the urea compound.

No. 6: 5-(4-aminophenoxy)isoindoline-1,3-dione was prepared according to method A3. According to method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI, followed by 5-(4-aminophenoxy)isoindoline-1,3-dione, whereby the urea compound was obtained.

No. 7: 4-(1-oxoisoindolin-5-yloxy)aniline was synthesized according to method A12. According to method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI, followed by 4-(1-oxoisoindolin-5-yloxy)aniline, whereby the urea compound was obtained.

No. 8: 4-(3-N-methylcarbamoylphenoxy)aniline was synthesized according to method A13. According to method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI, followed by 4-(3-N-methylcarbamoylphenoxy)aniline, whereby the urea compound was obtained.

No. 9: 4-hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine, whereby 4-(4-acetylphenoxy)-5-nitropyridine was obtained according to method A3, step 2. According to method A8, step 4, 4-( 4-acetylphenoxy)-5-nitropyridine reduced to 4-(4-acetylphenoxy)-5-aminopyridine. 2-Methoxy-5-(trifluoromethyl)-aniline was converted to 2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to method B1. The isocyanate was reacted with 4-(4-acetylphenoxy)-5-aminopyridine according to method Cia, whereby the urea compound was obtained.

No. 10: 4-fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to method A13, step 1, whereby 4-(4-acetylphenoxy)-1-nitrobenzene was obtained. 4-(4-acetylphenoxy)-1-nitrobenzene was reduced according to method A13, step 4, whereby 4-(4-acetylphenoxy)aniline was obtained. According to method C3, 5-(trifluoromethyl)-2-methoxybutylaniline was reacted with bis-(trichloromethyl)carbonate, followed by 4-(4-acetylphenoxy)aniline, whereby the urea compound was obtained.

No. 11: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4, using DMAC instead of DMF, to give 3 -(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to method C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene, followed by 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 12: 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to method A2, step 3b, whereby 4-chloro-2-pyridinecarboxamide was obtained. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to method A2, step 4, using DMAC instead of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene, followed by 3-(2-carbamoyl-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 13: 4-chloro-N-methyl-2-pyridinecarboxamide was synthesized according to method A2, step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, using DMAC instead of DMF, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy )aniline. According to method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI, followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-aniline, whereby the urea compound was obtained.

No. 14: 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to method A2, step 3b, whereby 4-chloro-2-pyridinecarboxamide was obtained. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, using DMAC instead of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to method C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene, followed by 4-(2-carbamoyl-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 15: According to method C2d, 5-(trifluoromethyl)-2-methoxyaniline was reacted with CDI, followed by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to method A8, whereby the urea compound was obtained .

No. 16: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized according to method A5. 5-(trifluoromethyl)-2-methoxycyanine was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to method Clc, whereby the urea compound was obtained.

No. 17: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloro-aniline was synthesized according to method A6. 5-(trifluoromethyl)-2-methoxycyanine was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline according to method Cia, whereby the urea compound was obtained.

No. 18: According to method A2, step 4, 5-amino-2-methylphenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide which had been synthesized according to method A2, step 3b, whereby 3-(2-( N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline.

5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxy enyl isocyanate according to method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to method Cia, whereby the urea compound was obtained.

No. 19: 4-chloropyridine-2-carbonyl chloride was reacted with ethylamine according to method A2, step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, whereby 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline was obtained. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method B1. 5-(Trifluoromethyl)-2-methoxy-phenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy) aniline according to method Cia, whereby the urea compound was obtained.

No. 20: According to method A2, step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to method A2, step 3b, whereby 4-(2- (N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methyl oxyphenyl isocyanate according to method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according to method Cia, whereby the urea compound was obtained.

No. 21: 4-(4-methylthiophenoxy)-1-nitrobenzene was oxidized according to method A19, step 1, whereby 4-(4-methylsulfonylphenoxy)-1-nitrobenzene was obtained. The nitrobenzene was reduced according to method A19, step 2, whereby 4-(4-methyl-sulfonylphenoxy)-1-aniline was obtained. According to method Cia, 5-(trifluoromethyl)-2-methoxyphenylisocyanate was reacted with 4-(4-methylsulfonylphenoxy)-1-aniline, whereby the urea compound was obtained.

No. 22: 4-(3-carbamoylphenoxy)-1-nitrobenzene was reduced to 4-(3-carbamoylphenoxy)aniline according to method A15, step 4. According to method Cia, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3 -carbamoylphenoxy)aniline, whereby the urea compound was obtained.

No. 23: 5-(4-aminophenoxy)isoindoline-1,3-dione was synthesized according to method A3. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxy-phenyl isocyanate according to method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione according to method Cia, whereby the urea compound was obtained.

No. 24: 4-chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to method A2, step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, whereby 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline was obtained. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxy-phenyl isocyanate according to method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline according to method Cia, whereby the urea compound was obtained.

No. 25: 4-(1-oxoisoindolin-5-yloxy)aniline was synthesized according to method A12. 5-(Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-(1-oxoisoindolin-5-yloxy)aniline according to method C2d, whereby the urea compound was obtained.

No. 26: 4-hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to method A13, step 1, whereby 4-(4-acetylphenoxy)nitrobenzene was obtained. The nitrobenzene was reduced according to method A13, step 4, whereby 4-(4-acetyl-phenoxy)aniline was obtained, which was converted to 4-(4-(1-(N-methoxy)imino-ethyl)phenoxyaniline-HCl- salt according to method A16. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method B1. 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-(l -(N-methoxy)iminoethyl)phenoxyaniline HCl salt according to method Cia, whereby the urea compound was obtained.

No. 27: 4-chloro-N-methylpyridinecarboxamide was synthesized as described in method A2, step 3b. The chloropyridine was reacted with 4-aminophenol according to method A2, step 4, whereby 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline was obtained. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl )-2-methoxy enyl isocyanate according to method B1. 5-(trifluoromethyl)-2-methoxy enyl isocyanate was reacted with 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to method Cia, whereby the urea compound was obtained.

No. 28: 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to method A9. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method B1. 5-(Trifluoromethyl)-2-methoxy-phenyl isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione according to method Cia, whereby the urea compound was obtained.

No. 29: 4-chloro-N-methylpyridinecarboxamide was synthesized as described in method A2, step 3b. The chloropyridine was reacted with 3-aminothiophenol according to method A2, step 4, whereby 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline was obtained. 5-(trifluoromethyl)-2-methoxyaniline) was converted to 5-( trifluoromethyl)-2-methoxyphenyl isocyanate according to method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to method Cia, whereby the urea compound was obtained.

No. 30: 4-chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to method A2, step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, whereby 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline was obtained. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method B1. 5-(Trifluoromethyl)-2-methoxy enyl isocyanate was reacted with 4-(2-(N-isopropyl-carbamoyl)-4-pyridyloxy) aniline according to method Cl, whereby the urea compound was obtained.

No. 31: 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline was synthesized according to method A14. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method B1. 5-(Trifluoromethyl)-2-methoxy-phenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy) aniline according to method Cia, whereby the urea compound was obtained. N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea was saponified according to method D4, step 1, and the corresponding acid was coupled with 4 -(2-aminoethyl)morpholine, whereby the amide was obtained according to method D4, step 2.

No. 32: 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline was synthesized according to method A14. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method B1. 5-(Trifluoromethyl)-2-methoxy-phenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy) aniline according to method Cia, whereby the urea compound was obtained. N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea was saponified according to method D4, step 1, and the corresponding acid was coupled with methylamine according to method D4, step 2, whereby the amide was obtained.

No. 33: 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline was synthesized according to method A14. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method B1. 5-(Trifluoromethyl)-2-methoxy-phenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy) aniline according to method Cia, whereby the urea compound was obtained. N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea was saponified according to method D4, step 1, and the corresponding acid was coupled with N ,N-dimethylethylenediamine according to method D4, step 2, whereby the amide was obtained.

No. 34: 4-(3-(carboxyphenoxy)aniline was synthesized according to method All. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method Bl. 4-(3-(carboxyphenoxy) aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method Cif, whereby N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl)urea was obtained, which was coupled with 3- aminopyridine according to method Dlc.

No. 35: 4-(3-(carboxyphenoxy)aniline was synthesized according to method All. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method Bl. 4-(3-(carboxyphenoxy) aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method Cif, whereby N-(5-(trifluoromethyl)-2-methoxyphenyl)-N<1->

(3-carboxyphenyl)urea, which was coupled with N-(4-fluorophenyl)piperazine according to method Dlc.

No. 36: 4-(3-(carboxyphenoxy)aniline was synthesized according to method All. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method Bl. 4-(3-(carboxyphenoxy) aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method Cif, whereby N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl)urea was obtained, which was coupled with 4- fluoroaniline according to method Dlc.

No. 37: 4-(3-(carboxyphenoxy)aniline was synthesized according to method All. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method Bl. 4-(3-(carboxyphenoxy) aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method Cif, whereby N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-

(3-carboxyphenyl)urea, which was coupled with 4-(dimethylamino)aniline according to method Dlc.

No. 38: 4-(3-(carboxyphenoxy)aniline was synthesized according to method All. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method Bl. 4-(3-(carboxyphenoxy) aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method Cif, whereby N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl)urea was obtained, which was coupled with 5- amino-2-methoxy-pyridine according to method Dlc.

No. 39: 4-(3-(carboxyphenoxy)aniline was synthesized according to method All. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method Bl. 4-(3-(carboxyphenoxy) aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method Cif, whereby N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl)urea was obtained, which was coupled with 4- morpholinoaniline according to method Dlc.

No. 40: 4-(3-(carboxyphenoxy)aniline was synthesized according to method All. 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method Bl. 4-(3-(carboxyphenoxy) aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to method Cif, whereby N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl)urea was obtained, which was coupled with N- (2-pyridyl)piperazine according to method Dlc.

No. 41: 4-(3-(N-methylcarbamoyl)phenoxy)aniline was synthesized according to method A13. According to method C3, 4-chloro-3-(trifluoromethyl)aniline was converted to the isocyanate, which was then reacted with 4-(3-(N-methylcarbamoyl)phenoxy)aniline, whereby the urea compound was obtained.

No. 42: 4-(2-(N-methylcarbamyl-4-pyridyloxy)aniline was synthesized according to method A2. 4-chloro-3-(trifluoromethyl)-phenylisocyanate was reacted with 4-(2-N-methylcarbamyl-4-pyridyloxy) aniline according to method Cia, whereby the urea compound was obtained.

No. 43: 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to method A2, step 3b, whereby 4-chloro-2-pyridinecarboxamide was formed. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, whereby 4-(2-carbamoyl-4-pyridyloxy)-aniline was formed. According to method Cia, 4-chloro-3-(trifluoromethyl)-phenylisocyanate was reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 44: 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to method A2, step 3b, whereby 4-chloro-2-pyridinecarboxamide was formed. 4-chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to method A2, step 4, whereby 3-(2-carbamoyl-4-pyridyloxy)-aniline was formed. According to method Cia, 4-chloro-3-(trifluoromethyl)-phenylisocyanate was reacted with 3-(2-carbamoyl-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 45: 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to method A2, step 3a, was reacted with 3-aminophenol according to method A2, step 4, whereby 3-(2-(N-methylcarbamoyl)-4 -pyridyloxy)aniline was formed. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 46: 5-(4-aminophenoxy)isoindoline-1,3-dione was synthesized according to method A3. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione, whereby the urea compound was obtained.

No. 47: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized according to method A5. According to method Clc, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione, whereby the urea compound was obtained.

No. 48: 4-(3-(N-methylsulfamoyl)phenyloxy)aniline was synthesized according to method A15. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-(N-methylsulfamoyl)phenyloxy)aniline, whereby the urea compound was obtained.

No. 49: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to method A6. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline, whereby the urea compound was obtained.

No. 50: According to method A2, step 4, 5-amino-2-methylphenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to method A2, step 3b, whereby 3-(2- (N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline, whereby the urea compound was obtained.

No. 51: 4-chloropyridine-2-carbonyl chloride was reacted with ethylamine according to method A2, step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, whereby 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline was obtained. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 52: According to method A2, step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to method A2, step 3b, whereby 4-(2- (N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline, whereby the urea compound was obtained.

No. 53: 4-(4-methylthiophenoxy)-1-nitrobenzene was oxidized according to method A19, step 1, whereby 4-(4-methylsulfonylphenoxy)-1-nitrobenzene was obtained. The nitrobenzene was reduced according to method A19, step 2, whereby 4-(4-methyl-sulfonylphenoxy)-1-aniline was obtained. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(4-methylsulfonyl-phenoxy)-1-aniline, whereby the urea compound was obtained.

No. 54: 4-bromobenzenesulfonyl chloride was reacted with

methylamine according to method A15, step 1, whereby N-methyl-4-bromobenzenesulfonamide was obtained. N-methyl-4-bromobenzenesulfonamide was coupled with phenol according to method A15, step 2, whereby 4-(4-(N-methylsulfamoyl)phenoxy)benzene was obtained. 4-(4-(N-methylsulfamoyl)phenoxy)benzene was converted to 4-(4-(N-methylsulfamoyl)-phenoxy)-1-nitrobenzene according to method A15, step 3. 4-(4-(N-methylsulfamoyl) phenoxy)-1-nitrobenzene was reduced to 4-(4-

(N-methylsulfamoyl)phenyloxy)aniline according to method A15, step 4. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline, whereby the urea compound was obtained .

No. 55: 5-hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to method A18, step 1, whereby 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene was obtained. The methylpyridine was oxidized according to the carboxylic acid and then esterified according to method A18, step 2, whereby 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene was obtained. The nitrobenzene was reduced according to method A18, step 3, whereby 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline was obtained. The aniline was reacted with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to method Cia, whereby the urea compound was obtained.

No. 56: 5-hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to method A18, step 1, whereby 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene was obtained. The methylpyridine was oxidized according to the carboxylic acid and then esterified according to method A18, step 2, whereby 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene was obtained. The nitrobenzene was reduced according to method A18, step 3, whereby 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline was obtained. The aniline was reacted with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to method Cia, whereby N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(methoxycarbonyl)-5 -pyridyloxy)phenyl)urea. The methyl ester was reacted with methylamine according to method D2, whereby N-(4-chloro-3-(trifluoromethyl)phenyl)-N<1->(4-(2-(N-methylcarbamoyl)-5-pyridyloxy)phenyl) urea.

No. 57: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl)urea was prepared according to method Cld. N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl)urea was coupled with monomethyl isophthalate according to method Dia, whereby the urea compound was obtained.

No. 58: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl)urea was prepared according to method Cld. N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl)urea was coupled with monomethyl isophthalate according to method Dia, whereby N-(4-chloro-3-(trifluoromethyl)phenyl)-N '-(4-(3-methoxycarbonylphenyl)-carboxyaminophenyl)urea. According to procedure D2, N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl)urea reacted with methylamine, whereby the corresponding methylamide was obtained.

No. 59: 4-chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to method A2, step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, whereby 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline was obtained. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 60: 4-hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to method A13, step 1, whereby 4-(4-acetylphenoxy)nitrobenzene was obtained. The nitrobenzene was reduced according to method A13, step 4, whereby 4-(4-acetyl-phenoxy)aniline was obtained, which was converted to 4-(4-(1-(N-methoxy)imino-ethyl)phenoxyaniline-HCl- salt according to method A16 According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(4-acetylphenoxy)aniline, whereby the urea compound was obtained.

No. 61: 4-(3-carboxyphenoxy)-1-nitrobenzene was synthesized according to method A13, step 2. 4-(3-carboxyphenoxy)-1-nitrobenzene was coupled with 4-(2-aminoethyl)morpholine according to method A13, step 3 , whereby 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene was obtained. According to procedure A13, step 4, 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2-morpholinylethyl)carbamoyl)-phenoxy)aniline . According to method Cia, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline, whereby the urea compound was obtained.

No. 62: 4-(3-carboxyphenoxy)-1-nitrobenzene was synthesized according to method A13, step 2. 4-(3-carboxyphenoxy)-1-nitrobenzene was coupled with 1-(2-aminoethyl)piperidine according to method A13, step 3 , whereby 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene was obtained. According to procedure A13, step 4, 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2-piperidylethyl)carbamoyl)-phenoxy)aniline . According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)aniline, whereby the urea compound was obtained.

No. 63: 4-(3-carboxyphenoxy)-1-nitrobenzene was synthesized according to method A13, step 2. 4-(3-carboxyphenoxy)-1-nitrobenzene was coupled with tetrahydrofurfurylamine according to method A13, step 3, whereby 4-( 3-(N-(tetrahydrofurfurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to method A13, step 4, 4-(3-(N-(tetrahydrofurfurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(tetrahydrofurfurylmethyl)carbamoyl)phenoxy)aniline. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-(N-(tetrahydrofurfurylmethyl)carbamoyl)phenoxy)aniline, whereby the urea compound was obtained.

No. 64: 4-(3-carboxyphenoxy)-1-nitrobenzene was synthesized according to method A13, step 2. 4-(3-carboxyphenoxy)-1-nitrobenzene was coupled with 2-aminomethyl-1-ethylpyrrolidine according to method A13, step 3, whereby 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene was obtained. According to method A13, step 4, 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-((1-methylpyrrolidinyl)methyl) )carbamoyl)phenoxy)aniline. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline, whereby the urea compound was obtained.

No. 65: 4-chloro-N-methylpyridinecarboxamide was synthesized as described in method A2, step 3b. The chloropyridine was reacted with 4-aminothiophenol according to method A2, step 4, whereby 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline was obtained. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline, whereby the urea compound was obtained.

No. 66: 4-chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to method A2, step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, whereby 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline was obtained. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 67: N-(4-chloro-3-(trifluoromethyl)phenyl)-N<1->(4-ethoxy-carbonylphenyl)urea was synthesized according to method Cle. N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl)urea was saponified according to procedure D3, whereby N-(4-chloro-3-(trifluoromethyl)phenyl)-N' -(4-carboxyphenyl)urea. N-(4-chloro-3-(trifluoromethyl)phenyl)-N<1->(4-carboxyphenyl)urea was coupled with 3-methylcarbamoylaniline according to method Dlb, whereby N-(4-chloro-3-(trifluoromethyl) )phenyl)-N'-(4-(3-methylcarbamoyl-phenyl)carbamoylphenylurea.

No. 68: 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to method A9. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione, whereby the urea compound was obtained.

No. 69: 4-chloro-N-methylpyridinecarboxamide was synthesized as described in method A2, step 3b. The chloropyridine was reacted with 3-aminophenol according to method A2, step 4, whereby 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline was obtained. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline, whereby the urea compound was obtained.

No. 70: 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to method A10. According to method Cia, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline, whereby the urea compound was obtained.

No. 71: 4-3-(5-methoxycarbonyl)pyridyloxy)aniline was synthesized according to method A14. 4-chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-3-(5-methoxycarbonyl)-pyridyloxy)aniline according to method Cal, whereby the urea compound was obtained. N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxyphenyl)urea was saponified according to method D4, step 1, and the corresponding acid was coupled with 4- (2-aminoethyl)morpholine, whereby the amide was obtained.

No. 72: 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline was synthesized according to method A14. 4-Chloro-3-(trifluoromethyl)-phenylisocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to method Cia, whereby the urea compound was obtained. N-(5-(trifluoromethyl)-2-methoxyphenyl)-N1 -(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea was saponified according to method D4, step 1, and the corresponding acid was coupled with methylamine according to procedure D4, step 2, which gave the amide.

No. 73: 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline was synthesized according to method A14. 4-Chloro-3-(trifluoromethyl)-phenylisocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to method Cia, whereby the urea compound was obtained. N-(5-(trifluoromethyl)-2-methoxyphenyl)-N<1->(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea was saponified according to method D4, step 1, and the corresponding acid was coupled with N,N-dimethylethylenediamine according to method D4, step 2, whereby the amide was obtained.

No. 74: 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-hydroxyethylamine according to method A2, step 3b, whereby 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide was formed. 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to procedure A17, whereby 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline was formed. According to method Cia, 4-chloro-3-(trifluoromethyl)-phenylisocyanate was reacted with 4-(4-(2-(N-(2-triisopropylsilyloxy)-ethylcarbamoyl)pyridyloxyaniline, whereby N-(4-chloro -3-((trifluoromethyl)phenyl)-N<1->(4-(4-(2-(N-(2-triisopropylsilyloxy)-ethylcarbamoyl)pyridyloxyphenyl)urea.

No. 75: 4-(3-carboxyphenoxy)aniline was synthesized according to method All. 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to method Cif, whereby the urea compound was obtained, which was coupled with 3-aminopyridine according to method Dlc.

No. 76: 4-(3-carboxyphenoxy)aniline was synthesized

according to procedure All. 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(carboxyphenoxy)aniline according to method Cif, whereby the urea compound was obtained, which was coupled with N-(4-acetylphenyl)piperazine according to method Dlc.

No. 77: 4-(3-carboxyphenoxy)aniline was synthesized according to method All. 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-(carboxyphenoxy)aniline according to method Cif, whereby the urea compound was obtained, which was coupled with 4-fluoroaniline according to method Dlc.

No. 78: 4-(3-carboxyphenoxy)aniline was synthesized according to method All. 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-(carboxyphenoxy)aniline according to method Cif, whereby the urea compound was obtained, which was coupled with 4-(dimethylamino)aniline according to method Dlc.

No. 79: 4-(3-carboxyphenoxy)aniline was synthesized according to method All. 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-(carboxyphenoxy)aniline according to method Cif, whereby the urea compound was obtained, which was coupled with N-phenylethylenediamine according to method Dlc.

No. 80: 4-(3-carboxyphenoxy)aniline was synthesized according to method All. 4-Chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-(carboxyphenoxy)aniline according to method Cif, whereby the urea compound was obtained, which was coupled with 2-methoxyethylamine according to method Dlc.

No. 81: 4-(3-carboxyphenoxy)aniline was synthesized according to method All. 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-(carboxyphenoxy)aniline according to method Cif, whereby the urea compound was obtained, which was coupled with 5-amino-2-methoxypyridine according to method Dlc.

No. 82: 4-(3-carboxyphenoxy)aniline was synthesized according to method All. 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-(carboxyphenoxy)aniline according to method Cif, whereby the urea compound was obtained, which was coupled with 4-morpholinoaniline according to method Dlc.

No. 83: 4-(3-carboxyphenoxy)aniline was synthesized

according to procedure All. 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-(carboxyphenoxy)aniline according to method Cif, whereby the urea compound was obtained, which was coupled with N-(2-pyridyl)piperazine according to method Dlc.

No. 84: 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-hydroxyethylamine according to method A2, step 3b, whereby 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide was formed. 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to procedure A17, whereby 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline was formed. According to method Cia, 4-chloro-3-(trifluoromethyl)-phenylisocyanate was reacted with 4-(4-(2-(N-(2-triisopropylsilyloxy)-ethylcarbamoyl)pyridyloxyaniline, whereby N-(4-chloro -3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-triisopropylsilyloxy)-ethylcarbamoyl)pyridyloxyphenyl)urea. The urea compound was deprotected according to procedure D5, whereby N -(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl)urea.

No. 85: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to method A2. 4-bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to method B1. According to method Cia, 4-bromo-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 86: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to method A6. 4-bromo-3-(trifluoromethyl) aniline was converted to 4-bromo-3-(trifluoromethyl)-phenyl isocyanate according to method B1. According to method Cia, 4-bromo-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline, whereby the urea compound was obtained.

No. 87: According to method A2, step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to method A2, step 3b, whereby 4-(2- (N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to method B1. According to method Cia, 4-bromo-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline, whereby the urea compound was obtained.

No. 88: 4-chloropyridine-2-carbonyl chloride was reacted with ethylamine according to method A2, step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, whereby 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline was obtained. 4-bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to method B1. According to method Cia, 4-bromo-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 89: 4-chloro-N-methyl-2-pyridinecarboxamide which was synthesized according to method A2, step 3a, was reacted with 3-aminophenol according to method A2, step 4, whereby 3-(2-(N-methylcarbamoyl)-4- pyridyloxy)aniline was formed. 4-bromo-3-(trifluoromethyl) aniline was converted to 4-bromo-3-(trifluoromethyl)-phenyl isocyanate according to method B1. According to method Cia, 4-bromo-3-(trifluoromethyl)phenylisocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 90: According to method A2, step 4, 5-amino-2-methylphenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to method A2, step 3b, whereby 3-(2- (N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. 4-bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to method B1. According to method Cia, 4-bromo-3-(trifluoromethyl)phenylisocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline, whereby the urea compound was obtained.

No. 91: 4-chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to method A2, step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, whereby 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline was obtained. 4-bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to method B1. According to method Cia, 4-bromo-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(NjN-dimethylcarbamoyl)-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 92: 4-chloro-N-methylpyridinecarboxamide was synthesized as described in method A2, step 3b. The chloropyridine was reacted with 4-aminophenol according to method A2, step 4, whereby 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline was obtained. 4-bromo-3-(trifluoromethyl)aniline was converted to 4-bromo -3-(trifluoromethyl)phenylisocyanate according to method Bl. According to method Cia, 4-bromo-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline, whereby the urea compound was obtained.

No. 93: 4-chloro-N-methylpyridinecarboxamide was synthesized as described in method A2, step 3b. The chloropyridine was reacted with 3-aminophenol according to method A2, step 4, whereby 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline was obtained. 4-bromo-3-(trifluoromethyl)aniline was converted to 4-bromo -3-(trifluoromethyl)phenylisocyanate according to method Bl. According to method Cia, 4-bromo-3-(trifluoromethyl)phenylisocyanate was reacted with 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline, whereby the urea compound was obtained.

No. 94: 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to method A10. 4-bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3-(trifluoromethyl)-phenyl isocyanate according to method B1. According to method Cia, 4-bromo-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline, whereby the urea compound was obtained.

No. 95: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to method A2. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to method A7. 4-chloro-2-methoxy-5-(trifluoromethyl)aniline was converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to method Bl. According to method Cia, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 96: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to method A6. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to method A7. 4-chloro-2-methoxy-5-(trifluoromethyl)aniline was converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to method Bl. According to method Cia, 4-chloro-2-methoxy-5-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline, whereby the urea compound was obtained.

No. 97: According to method A2, step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to method A2, step 3b, whereby 4-(2- (N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to method A7. 4-chloro-2-methoxy-5-(trifluoromethyl)aniline was converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to method Bl. According to method Cia, 4-chloro-2-methoxy-5-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline, whereby the urea compound was obtained.

No. 98: 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to method A2, step 3a, was reacted with 3-aminophenol according to method A2, step 4, whereby 3-(2-(N-methylcarbamoyl)-4 -pyridyloxy)aniline was formed. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to method A7. 4-chloro-2-methoxy-5-(trifluoromethyl)aniline was converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to method Bl. According to method Cia, 4-chloro-2-methoxy-5-(trifluoromethyl)phenylisocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 99: 4-chloropyridine-2-carbonyl chloride was reacted with ethylamine according to method A2, step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, whereby 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline was obtained. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to method A7. 4-chloro-2-methoxy-5-(trifluoromethyl)aniline was converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to method Bl. According to method Cia, 4-chloro-2-methoxy-5-(trifluoromethyl)-phenylisocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)-aniline, whereby the urea compound was obtained.

No. 100: 4-chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to method A2, step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, whereby 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline was obtained. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to method A7. 4-chloro-2-methoxy-5-(trifluoromethyl)aniline was converted to 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to method Bl. According to method Cia, 4-chloro-2-methoxy-5-(trifluoromethyl)phenylisocyanate was reacted with 4-(2-(N-dimethylcarbamoyl)-4-pyridyloxy)aniline, whereby the urea compound was obtained.

No. 101: 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to method A2, step 3a, was reacted with 3-aminophenol according to method A2, step 4, whereby 3-(2-(N-methylcarbamoyl)-4 -pyridyloxy)aniline was formed. 2-amino-3-methoxynaphthalene was synthesized as described in method A1. According to method C3, 2-amino-3-methoxynaphthalene was reacted with bis(trichloromethyl)carbonate, followed by 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline, whereby the urea compound was formed.

No. 102: 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline

was synthesized according to method A2. 5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized according to method A4. 5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline was reacted with CDI, followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline according to method C2d, whereby the urea compound was obtained.

No. 103: 4-chloro-N-methyl-2-pyridinecarboxamide was synthesized according to method A2, step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, using DMAC instead of DMF, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy )aniline. According to procedure C2b, reaction of 3-amino-2-methoxyquinoline with CDI, followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy) aniline, gave bis(4-(2-(N-methylcarbamoyl)- 4-pyridyloxy)-phenyl)urea.

Indicated in the tables below are compounds which have been synthesized according to the detailed experimental procedures reproduced above:

Tables

The compounds listed in Tables 1-6 below were synthesized according to the general procedures shown above, and the more detailed exemplary procedures are found in the above numbered list, and characterizations are provided in

the tables.

Claims (42)

1. Connection, characterized in that it is selected from or a pharmaceutically acceptable salt thereof, wherein D is -NH-C(O)-NH-, A is a substituted residue with the formula: -L-M-L<1>, where L is phenyl, optionally substituted with substituents selected from the group consisting of halogen and C 1 -C 10 alkyl; L<1> is pyridinyl substituted with the substituent -C(O)Rx; M is one or more bridging groups selected from the group consisting of -0- and -S-, where Rx is NRaRb and Ra and Rb are independently: a) hydrogen, b) C1-C10 alkyl and c) C1-C10 alkyl substituted with hydroxy, C3-C12 cycloalkyl having 1-3 heteroatoms selected from 0, N and S, or -OSi(R f ) 3 , where R f is C 1 -C 10 alkyl; and B is an unsubstituted phenyl group or a phenyl group substituted with substituents selected from the group consisting of halogen up to per-halo and Wn, where n is 0-3, and each W is independently selected from the group consisting of: a) Ci-Cio alkyl . -(5-(trifluoromethyl)-2-methoxy-phenyl)-N'-(4-(2-(N-(2-dimethylamine)ethylcarbamoyl)-4-pyridyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof, and C) N-(3-(trifluoromethyl)-4-chlorophenyl)-N'-(4-(2-(N-(2-dimethylamine)ethylcarbamoyl)-4-pyridyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof. 2. Connection according to claim 1, characterized in that Bi formula I is phenyl substituted with a substituent selected from halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy and halo-substituted C 1 -C 10 alkyl. 3. Connection according to claim 1, characterized in that Bi formula I is phenyl substituted with 1-3 substituents independently selected from the group consisting of chlorine, bromine, fluorine, trifluoromethyl, methoxy and tert-butyl. 4. Connection according to claim 1, characterized in that L is phenyl, optionally substituted with halogen. 5. Connection according to claim 1, characterized in that L is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of chlorine and methyl. 6. Connection according to claim 1, characterized in that M is -0-. 7. Connection according to claim 2, characterized in that M is -0-. 8. Connection according to claim 3, characterized in that M is -0-. 9. Connection according to claim 4, characterized in that More -0-. 10. Connection according to claim 1, characterized in that Ra and Rb are independently selected from hydrogen and Ci-Cio alkyl. 11. Compound according to claim 3, characterized in that Ra and Rb are independently selected from hydrogen and Ci-Cio alkyl. 12. Compound according to claim 6, characterized in that Ra and Rb are independently selected from hydrogen and Ci-Cio alkyl. 13. Compound according to claim 7, characterized in that Ra and Rb are independently selected from hydrogen and Ci-Cio alkyl. 14. Compound according to claim 8, characterized in that Ra and Rb are independently selected from hydrogen and Ci-Cio alkyl. 15. Compound according to claim 9, characterized in that Ra and Rb are independently selected from hydrogen and Ci-Cio alkyl. 16. Connection, characterized in that it has formula I: or a pharmaceutically acceptable salt thereof, wherein D is -NH-C(O)-NH-, A has the formula: -L-M-L<1>, where L is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of methyl and halogen, L<1> is pyridinyl substituted with -C(0)NRaRb, M is selected from the group consisting of -0- and -S-, where Ra and Rb are independent of each other: hydrogen, C 1 -C 10 alkyl and substituted C 1 -C 10 alkyl, substituted with hydroxy, B is an unsubstituted phenyl group or a phenyl group substituted with substituents selected from the group consisting of halogen and Wn where n is 0-3 and each W is independently selected from the group consisting of C 1 -C 10 alkyl C 1 -C 10 -Alkoxy and halosubstituted C 1 -C 10 alkyl. 17. Connection, characterized in that it has formula I: or a pharmaceutically acceptable salt thereof, wherein D is -NH-C(O)-NH-, A has the formula: -L-M-L<1>, where L is phenyl, M is -0-, L<1> is pyridinyl substituted with -C(0)NRaRb, where Ra and Rb are independently hydrogen and C 1 -C 10 alkyl, and B is a phenyl group substituted with substituents selected from the group consisting of: halogen, C 1 -C 10 alkyl, C 1 -C 10 -Alkoxy and halosubstituted C 1 -C 10 alkyl. 18. Compound according to claim 16, characterized in that Ra and Rb are independently selected from H and Ci-Cio alkyl. 19. Compound according to claim 17, characterized in that Ra and R are independently selected from H and methyl. 20. Compound according to claim 1, characterized in that it is a pharmaceutically acceptable salt of a compound of formula I 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-toluenesulfonic acid (tosylate salt), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatically substituted ammonium cations and aromatically substituted ammonium cations. 21. Compound according to claim 16, characterized in that it is a pharmaceutically acceptable salt of a compound of formula I 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-toluenesulfonic acid (tosylate salt), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatically substituted ammonium cations and aromatically substituted ammonium cations. 22. Compound according to claim 17, characterized in that it is a pharmaceutically acceptable salt of a compound of formula I 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-toluenesulfonic acid (tosylate salt), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatically substituted ammonium cations and aromatically substituted ammonium cations. 23. Pharmaceutical preparation for the treatment of cancer, characterized in that it comprises a compound according to claim 1 or a pharmaceutically acceptable salt of a compound of formula I, and a physiologically acceptable carrier. 24. Pharmaceutical preparation according to claim 23, characterized in that the compound of formula I is the one defined in claim 3. 25. Pharmaceutical preparation according to claim 23, characterized in that the compound of formula I is the one defined in claim 16. 26. Pharmaceutical preparation according to claim 23, characterized in that the compound of formula I is the one defined in claim 17. 27. Connection according to claim 1, characterized in that it is selected from the group consisting of The 2-methoxy-5-(trifluoromethyl)phenyl-urea compounds: N-(2-methoxy-5-(trifluoromethyl)phenyl)-N' -(3-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(2 -methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)- N' -(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4 -pyridyloxy)phenyl)urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl)urea, N-(2- methoxy-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy)phenyl)urea and N-(2-methoxy-5-(trifluoromethyl)phenyl )-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea; the 4-chloro-3-(trifluoromethyl)phenylurea compounds: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, The 4-bromo-3-(trifluoromethyl)phenyl-urea compounds: N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea , N-(4-bromo-3-(trifluoromethyl)phenyl)-N<1->(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-bromo-3- (trifluoromethyl)phenyl)-N<1->(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; and the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl-urea compounds: N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3-(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 and N-(2-Methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea. 28. Pharmaceutically acceptable salt of a compound according to claim 27, characterized in that the 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-toluenesulfonic acid (tosylate salt), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatically substituted ammonium cations and aromatically substituted ammonium cations. 29. Use of the compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of the drugs for inhibiting cancer cell growth mediated by raf-kinase. 30. Use of the compound of formula I according to claim 3 or a pharmaceutically acceptable salt thereof for the preparation of the drugs for inhibiting a cancer cell growth mediated by raf kinase. 31. Use of the compound of formula I according to claim 16 or a pharmaceutically acceptable salt thereof for the preparation of the drugs for inhibiting cancer cell growth mediated by raf-kinase. 32. Use of the compound of formula I according to claim 17 or a pharmaceutically acceptable salt thereof for the preparation of the drugs for inhibiting cancer cell growth mediated by raf-kinase. 33. Use according to claim 29, where the compound is selected from the group consisting of The 2-methoxy-5-(trifluoromethyl)phenyl-urea compounds: N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-( 2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)- N<1->(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl) -4-pyridyloxy)phenyl)urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N<*->(4-(2-(N-methylcarbamoyl)-4-pyridylthio)phenyl)urea, N -(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea and N-(2-methoxy-5 -(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea; The 4-chloro-3-(trifluoromethyl)phenyl-urea compounds: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea and N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea; The 4-bromo-3-(trifluoromethyl)phenyl-urea compounds: N-(4-bromo-3-(trifluoromethyl)phenyl)-N<1->(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl )urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N<1->(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; and the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl-urea compounds: N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3-(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 and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N<1->(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea. 34. Compound according to claim 1, characterized in that the possible substituents on B are independently selected from the group consisting of methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl, tert-butyl, sec-butyl, isobutyl, methoxy, ethoxy, propoxy , Cl and F. 35. Pharmaceutical preparation according to claim 23, characterized in that the compound is N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof. 36. Pharmaceutical preparation according to claim 23, characterized in that the compound is N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof. 37. Pharmaceutical preparation according to claim 23, characterized in that the pharmaceutically acceptable salt is: a) a basic salt of an organic acid or an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid ( tosylate salt), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic 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; or b) an acid salt of an organic or inorganic base containing an alkali metal cation, an alkaline earth cation, a ammonium cation, an aliphatic substituted ammonium cation or an aromatic substituted ammonium cation. 38. Pharmaceutical preparation according to claim 23, characterized in that the pharmaceutically acceptable salt is the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea. 39. Pharmaceutical preparation according to claim 23, characterized in that the pharmaceutically acceptable salt is the tosylate salt of N-(4-chloro-3(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) )phenyl)urea. 40. Compound according to claim 1, characterized in that it is N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof. 41. Compound according to claim 40, characterized in that it is a pharmaceutically acceptable salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) )phenyl)urea. 42. Compound according to claim 41, characterized in that it is the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea.