DE60026822T2 - -G (V) -CARBOXYARYL SUBSTITUTED DIPHENYL UREAIDS AS RAF KINASE INHIBITORS - Google Patents

Description

Field of invention

These The invention relates to the use of a group of aryl ureas for the treatment of raf-mediated diseases and pharmaceutical Compositions for the preparation of medicaments for such Therapy.

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, non-mutated form, ras protein is a key element of the signal transduction cascade directed by growth factor receptors in nearly all tissues (Avruch et al., Trends Biochem. Sci., 1994, 19, 279-83). Biochemically, ras is a guanine nucleotide binding protein and cyclization between a GTP-bound activated and a GDP-bound quiescent form is strictly controlled by endogenous GTPase activity of ras and other regulatory proteins. In the ras mutants in cancer cells, the endogenous GTPase activity is attenuated and therefore the protein provides 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 inhibiting the action of active ras by inhibiting the raf kinase pathway by administering deactivating antibodies to raf kinase or coexpressing dominant negative raf kinase or dominant negative MEK, the substrate of raf kinase, Reversion of transformed cells into the normal growth phenotype (see Daum et al., Trends Biochem Sci., 1994, 19, 474-80, Fridman et al., J. Biol. Chem., 1994, 269, 30105-8, Kolch et (Nature 1991, 349, 426-28) have further stated that inhibition of raf expression by antisense RNA blocks blocks cell proliferation in membrane-associated oncogenes. Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) is inhibited. in vitro and in vivo has been correlated with the inhibition of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996, 2, 668-75).

Summary of the invention

The present invention provides compounds which are inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector of p21 ^ras , the inhibitors are useful in pharmaceutical compositions for human and veterinary use wherein inhibition of the raf kinase pathway is indicated, e.g. In the treatment of tumors and / or cancerous cell growth mediated by raf kinase. In particular, the compounds are useful in the preparation of medicaments for solid cancers in humans and animals, e.g. Mouse cancer, since the progression of these cancers is dependent on the ras protein signal transduction cascade and therefore responds to treatment by disrupting the cascade, ie by inhibiting raf kinase. Accordingly, the compounds of the invention are useful in the preparation of medicaments for the treatment of cancers, including solid cancers, such as, for example, carcinomas (eg, the lung, pancreas, thyroid, bladder, or colon), myeloid disorders (eg, mileoid leukemia), or adenomas ( eg colon villus adenoma).

The The present invention therefore provides compounds generally are described as aryl ureas, including both aryl and Heteroaryl analogs which inhibit the raf kinase pathway. Therefore the invention is directed to compounds containing the enzyme raf kinase and also compounds, compositions and A method of treating cancerous cell growth by Raf kinase is mediated, wherein a compound of the invention a tolerable Salt of it is.

A compound of the invention is selected from the group consisting of the 4-chloro-3- (trifluoromethyl) phenyl ureas: N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (3- (2-carbamoyl-4 -pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4 Chloro-3- (trifluoromethyl) phenyl-N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl-N' - (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenylurea and N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (2-chloro-4- (2- (N -methylcarbamoyl) ( 4-pyridyloxy)) phenylurea, the 4-bromo-3- (trifluoromethyl) phenylureas: N- (4-bromo-3- (trifluoromethyl) phenyl-N '- (3- (2- (N -methylcarbamoyl ) -4-pyridyloxy) phenylurea, N- (4-bromo-3- (trifluoromethyl) phenyl-N '- (4- (2-N-methylcarbamoyl) -4-pyridyloxy) phenylurea, N- (4 -Bromo-3- (trifluoromethyl) phenyl-N '- (3- (2- (N -methylcarbamoyl) -4-pyridylthio) phenylurea, N- (4-bromo-3- (trifluoromethyl) phenyl-N' (2-chloro-4- (2- (N-methylcarba moyl) (4-pyridyloxy)) phenyl) urea and N- (4-bromo-3- (trifluoromethyl) phenyl-N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, the 2-methoxy-4- Chloro-5- (trifluoromethyl) phenylureas: 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)) phenylurea or a pharmaceutically acceptable salt thereof.

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

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, malic, tartaric, citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic and α-hydroxyphenylacetic acids. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases such as salts containing alkali cations (eg Li ⁺ , Na ⁺ or K ⁺ ), alkaline earth cations (eg Mg ⁺² , Ca ^{+ 2} or Ba ⁺² ), the ammonium cation, as well as acid salts of organic Bases, including aliphatically and aromatically substituted ammonium and quaternary ammonium cations, such as those resulting from the protonation or peralkylation of triethylamine, N, N-diethylamine, N, N-dicyclohexylamine, lysine, pyridine, N, N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] undec-7-ene ( DBU).

A Variety of compound possesses asymmetric carbons and can therefore present in racemic and optically active forms. method for the separation of enantiomeric and diastereomeric mixtures are those skilled in the art well known in the art. The present invention includes any isolated racemic or optically active form of the compounds, that are described in the invention having raf inhibitory activity.

General preparative method

The Compounds of the invention can by the use of known chemical reactions and processes, some of them from starting materials that are commercially available, getting produced. Nonetheless, general preparative Method provided below to those skilled in the art to help synthesize these compounds, being detailed Examples are provided in the following experimental section become.

Substituted anilines can be generated using standard methods (March, Advanced Organic Chemistry, 3rd Edition, John Wiley: New York (1985), Larock, Comprehensive Organic Transformations, VCH Publishers: New York (1989)). As shown in Scheme I, arylamines are usually synthesized by reduction of nitroarylene using a metal catalyst such as Ni, Pd or Pt, and H ₂ or a hydride transfer agent such as formate, cyclohexadiene or borohydride (Rylander, Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls can also be reduced directly using a strong hydride source, such as LiAlH ₄ (Seyden-Penne, Reductions by the Alumino and Borohydrids in Organic Synthesis; CVH Publishers: New York (1991)), or using a metal with the Valence zero, such as Fe, Sn or Ca, often in acidic medium. There are many methods for the synthesis of nitroaryls (March: Advanced Organic Chemistry, 3rd ed., John Wiley: New York (1985), Larock, Comprehensive Organic Transformations, VCH Publishers: New York (1989)).

Schema I Reduktion von Nitroarylen zu Arylaminen

Scheme I Reduction of nitroaryls to arylamines

Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO _3, or an alternative NO ₂ ^- source. Nitroaryls can still be developed before reduction.

Therefore can Nitroaryls that react with potential leaving groups (e.g., F, Cl, Br etc.), substitution reactions upon treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide. Nitroaryls can also have coupling reactions of the Ullman type (Scheme II).

Schema II Ausgewählte nucleophile aromatische Substitution unter Verwendung von Nitroarylen

Scheme II Selected nucleophilic aromatic substitution using nitroarylene

Nitroaryls can also transition metal-mediated Enter into cross-coupling reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates palladium-mediated Cross-coupling reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reaction, exemplified below), aryl pinnacles (silence reactions) or aryl tines (Negishi reaction) to give the biaryl (5).

Both nitroaryl and anilines can be converted to the corresponding arenesulfonyl chloride (7) upon treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source, such as KF, then gives sulfonyl fluoride (8). The reaction of sulfonyl fluoride (8) with trimethylsilyl trifluoromethane in the presence of a fluoride source such as tris (dimethylamino) sulfonium difluorotrimethylsiliconate (TASF) leads to the corresponding trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 can be reduced to the arenethiol (10), for example with zinc amalgam. Reaction of thiol 10 with CHClF ₂ in the presence of base gives the difluoromethylmercaptan (11), which can be oxidized to the sulfone (12) with any of a variety of oxidants, including CrO ₃ -acetic anhydride (Sedova et al., Zh. Org. Khim., 1970, 6, (568)).

Schema III Ausgewählte Verfahren zur Synthese von fluoriertem Arylsulfon

Scheme III Selected methods for the synthesis of fluorinated arylsulfone

As Shown in Scheme IV, the formation of non-symmetric urea the reaction of an aryl isocyanate (14) with an aryl amine (13). The heteroaryl isocyanate can be synthesized from a heteroarylamine are treated by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis (trichloromethyl) carbonate (Triphogen) or N, N'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic Carboxylic acid derivative, such as an ester, an acid halide or an anhydride, by a rearrangement of the Curtius type. Therefore gives reaction of an acid derivative (16) with an azide source followed by rearrangement of the isocyanate. The corresponding carboxylic acid (17) Curtius-type rearrangements can also be subjected to using diphenylphosphoryl azide (DPPA) or the like Reagent.

Schema IV Ausgewählte Verfahren zur Bildung von nicht-symmetrischem Harnstoff

Scheme IV Selected procedures for the formation of non-symmetric urea

Finally, ureas may continue to be altered using techniques appropriate to the art Those skilled in the art are known.

The The invention also encompasses pharmaceutical compositions containing a Compound of the invention and a physiologically acceptable carrier contain.

The Connections can oral, topical, parenteral, by inhalation or spraying or be administered rectally in unit dose formulations. The term "administration by injection " intravenous, intramuscular, subcutaneous and parenteral injections as well as the use of Infusion techniques. One or more connections can be made in Compound with one or more non-toxic pharmaceutical acceptable carriers, and if desired is present, other active ingredients.

compositions the for are provided according to any suitable Processes are produced which are used in the art for the production of pharmaceutical compositions. Such compositions can contain one or more agents selected from the group consisting from diluents, sweetening matter, Flavoring agents, colorants and preservatives to produce edible preparations. tablets contain the active ingredient mixed with non-toxic pharmaceutically acceptable Excipients which are suitable for the production of tablets. These excipients may e.g. 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 can be coated by known techniques to disintegration and Absorption in the gastrointestinal tract to delay and thereby a lasting Effect over one to provide long duration. For example, a delay material such as glyceryl monostearate or glyceryl distearate. These connections can also be produced in solid, rapidly releasing form.

formulations for oral use also be present as hard gelatin capsules, wherein the active Ingredient mixed with an inert solid diluent, e.g. Calcium carbonate, calcium phosphate or kaolin, or as a soft Gelatin capsules wherein 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 containing are suitable for the preparation of aqueous Suspensions. Such excipients are suspending agents, e.g. Sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, Sodium alginate, polyvinyl pyrrolidone, gum tragacanth and acacia gum; Dispersing or wetting agents may be naturally occurring phosphatide, e.g. Lecithin, or condensation products of an alkylene oxide with fatty acids be, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example Heptadecaethylenoxycetanol or condensation products of ethylene oxide with partial esters of fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters, the of fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The watery Suspensions can also contain one or more preservatives, for example Ethyl or n-propyl p-hydroxybenzoate or one or more colorants, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

dispersible Powders and granules used to make an aqueous Suspension by the addition of water are suitable to supply 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 above are called. additional Excipient e.g. Sweetener, Flavoring and coloring agents, can also present.

The Connections can also in the form of non-aqueous liquid Be formulations, e.g. oily suspensions, which can be formulated by suspending the active ingredients in a vegetable oil, for example arachis, Olive oil, sesame oil or peanut oil, or in a mineral oil, like liquid Paraffin. The oily ones Suspensions can a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetener, such as those listed above and flavoring agents may be added become edible oral preparations provide. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, eg olive oil or arachis oil, or a mineral oil, eg liquid paraffin, or mixtures of these. Suitable emulsifiers may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, eg, soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, eg, sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, eg, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

syrups and elixirs can with sweeteners, e.g. Glycerol, propylene glycol, sorbitol or sucrose, formulated become. Such formulations can also a reducing agent, a preservative and flavor or dye contain.

The Connections can also be administered in the form of suppositories for rectal Administration of the drug or medication. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient, which among ordinary Temperatures is fixed, but liquid is at the rectal temperature and therefore it will melt in the rectum to release the medicine. Such materials include cocoa butter and polyethylene glycols.

For all application schemes, the here for Compounds of the invention used will be the daily oral Dose schedule preferably from 0.01 to 200 mg / kg total body weight be. The daily Dose for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and the use of infusion techniques will preferably be from 0.01 to 200 mg / kg of total body weight. The daily rectal Dose schedule is preferably from 0.01 to 200 mg / kg total body weight be. The daily topical dosage regimen will preferably be from 0.1 to 200 mg, administered between one to four times a day. The daily inhalation dose scheme will preferably be from 0.01 to 10 mg / kg of total body weight.

Of the Expert in engineering will appreciate that the special Method of administration depends It will be a variety of factors, all of which are routinely respected when administering therapeutics. It is also through It should be appreciated by those skilled in the art that the specific Dose content for a given patient depends on a variety of factors, including specific ones activity the compound administered, age, body weight, state of health, Gender, diet, Time and route of administration, excretion rate, etc. It will continue It should be appreciated by those skilled in the art that the optimum Course of treatment, ie the type of treatment and the daily number of doses of a compound of the invention or a pharmaceutical acceptable Salt from it, for administered by the skilled person for a defined number of days set in the art using conventional treatment tests can be.

It It is understood, however, that the specific dose content for each dependent on special patients will be a variety of factors, including the activity the specific compound used, age, body weight, the general health, the sex, the diet of the administration, the route of administration and the excretion rate, the drug combination and the severity of the condition to be treated.

The Connections can from known compounds (or from starting materials which can be prepared vice versa from known compounds), e.g. through the general preparative Methods shown below. The activity of a given compound for inhibiting raf kinase can be routinely examined, e.g. according to the methods disclosed below. The following examples are for illustrative purposes only and are not intended yet They should be construed to the invention in any way Kind of limit.

EXAMPLES

All Reactions were in flame-dried or oven-dried Glass materials under a positive pressure of dry argon or dry nitrogen and were stirred magnetically, it unless it is stated otherwise. Sensitive fluids and solutions were transferred via a syringe or cannula and into the reaction vessels inserted through a rubber septum. Unless otherwise stated is the term "concentration under reduced pressure "the Use of a Büchi rotary evaporator at about 15 mmHg. Unless otherwise indicated, the term "below High vacuum " Vacuum of 0.4-1.0 mmHg.

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

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

Thin layer chromatography (TLC) was performed using precoated Whatman ^® silica gel 60A F-254 250 .mu.m plates with glass support. Visualization of the plates was accomplished by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating (i.e. 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 EM Science ^® -Silikagel with mesh 230-400.

Melting points (m.p.) were determined using a Thomas Hoover Melting Point Device or Mettler FP66 Automated Melting Point Device and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy spectrometer. Proton ( ¹ H) nuclear magnetic resonance (NMR) spectra were measured on a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me ₄ Si (δ 0.00) or a residual protonated solvent (CHCl ₃ δ 7 , 26; MeOH δ 3.30; DMSO δ 2.49) as standard. Carbon ( ¹³ C) NMR spectra were measured on a General Electric GN-Omega 300 (75 MHz) solvent spectrometer (CDCl ₃ δ 77.0, MeOD-d ₃ δ 49.0, DMSO-d ₆ δ 39, 5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were obtained either as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained on a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe (Vacumetrics Desorption Chemical Ionization Probe) for sample introduction. The ion source was maintained at 250 ° C. Electron impact ionization was performed with an electron energy of 70 eV and a capture current of 300 μA. Liquid cesium secondary ion mass spectra (FAB-MS), an updated version of the Fast Atom Bombardment, were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS engine (5989A) with methane or ammonia as the reagent gas (1 x 10 ^-4 torr to 2.5 x 10 ^-4 torr). The direct inlet desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was operated at a ramp of 0-1.5 A in 10 seconds and held at 10 A until all traces of the sample had disappeared (~ 1-2 min). , Spectra were sampled from 50-800 amu at 2 sec per scan. HPLC electron spray 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-capture mass spectrometer Elektronensprühionisation. Spectra were sampled from 120-800 amu using a variable ion time corresponding to the number of ions in the source. Gas chromatography-ion selective mass spectra (GC-MS) were obtained on a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methylsilicone column (0.33 μm coating, 25 m × 0.2 mm) and a Hewlett Packard 5971 mass-selective Detector (ionization energy 70 eV). Elemental analyzes were performed by Robertson Microlit Labs, Madison, NJ.

AcOH

Essigsäure

wfr

wasserfrei

atm

Atmosphäre(n)

BOC

tert-Butoxycarbonyl

CDI

1,1'-Carbonyldiimidazol

konz.

Konzentriert

d

Tag(e)

zers.

Zersetzung

DMAC

N,N-Dimethylacetamid

DMPU

1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon

DMF

N,N-Dimethylformamid

DMSO

Dimethylsulfoxid

DPPA

Diphenylphosphorylazid

EDCI

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimid

EtOAc

Ethylacetat

EtOH

Ethanol (100 %)

Et₂O

Diethylether

Et₃N

Triethylamin

h

Stunde(n)

HOBT

1-Hydroxybenzotriazol

m-CPBA

3-Chlorperoxybenzoesäure

MeOH

Methanol

Pet.Ether

Petrolether (Siedebereich 30–60 °C)

Temp.

Temperatur

THF

Tetrahydrofuran

TFA

Trifluor-AcOH

Tf

Trifluormethansulfonyl

All compounds showed mass spectra, LRMS and either elemental analyzes or HRMS matching the assigned structures.

AcOH

acetic acid

anh

anhydrous

atm

Atmosphere (n)

BOC

tert-butoxycarbonyl

CDI

1,1'-carbonyldiimidazole

conc.

Concentrated

d

Day (s)

dec.

decomposition

DMAC

N, N-dimethylacetamide

DMPU

-pyrimidinone 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)

DMF

N, N-dimethylformamide

DMSO

dimethyl sulfoxide

DPPA

diphenylphosphorylazide

EDCI

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

EtOAc

ethyl acetate

EtOH

Ethanol (100%)

Et ₂ O

diethyl ether

Et ₃ N

triethylamine

H

Hour (s)

HOBT

1-hydroxybenzotriazole

m-CPBA

3-chloroperoxybenzoic

MeOH

methanol

pet.ether

Petroleum ether (boiling range 30-60 ° C)

Temp.

temperature

THF

tetrahydrofuran

TFA

Trifluoro-AcOH

tf

trifluoromethanesulfonyl

A. General Methods for the Synthesis of Substituted Anilines A1. 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 K ₂ CO ₃ (7.96 g, 57.6 mmol) in DMF (200 mL) was added at room temp. stirred for 15 min, then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to come at room temp. Stir overnight, then treat 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 ), concentrated under reduced pressure (about 0.4 mmHg, overnight) to give 3-methoxy-2-naphthoate as an amber oil (10.30 g): ¹ H-NMR (DMSO-d ₆ ) δ 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (apparent t, J = 8, 09 Hz, 1H), 7.44 (s, 1H), 7.53 (apparent t, J = 8.09 Hz, 1H), 7.84 (d, J = 8.09 Hz, 1H), 7 , 90 (s, 1H), 8,21 (s, 1H).

Step 2. 3-Methoxy-2-naphthalenecarboxylic acid

A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 ml) was taken at room temp. treated with 1N NaOH solution (33.4 mL, 33.4 mmol). The mixture was at the reflux temp. heated for 3 h, at room temp. cooled and acidified with 10% citric acid solution. The resulting solution was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was triturated with hexane then washed several times with hexane to give 3-methoxy-2-naphthalenecarboxylic acid as a white solid (5.40 g, 92%): ¹ H-NMR (DMSO-d ₆ ) δ 3, 88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d, J = 8.09 Hz, 1H), 7 , 91 (d, J = 8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (br s, 1H).

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

A solution of 3-methoxy-2-naphthalenecarboxylic acid (3.36 g, 16.6 mmol) and Et ₃ N (2.59 mL, 18.6 mmol) in anhydrous toluene (70 mL) was added at room temp. stirred for 15 min, then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resulting mixture was heated at 80 ° C for 2 h. After cooling the mixture to room temp. Benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was then heated at 80 ° C overnight. The resulting mixture was brought to room temp. cooled, quenched with 10% citric acid solution and extracted with EtOAc (2 × 100 ml). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (14 EtOAc / 86% hexane) to give 2- (N- (carbobenzyloxy) amino-3-methoxynaphthalene g as a pale yellow oil (5.1 to obtain 100%): ¹ H NMR (DMSO-d ₆ ) δ 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H ), 8.20 (s, 1H), 8.76 (s, 1H).

Step 4. 2-Amino-3-methoxynaphthalene

A 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 added under H ₂ atmosphere (balloon) at room temp. kept overnight. The resulting mixture was filtered through Celite ^® and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink-colored powder (2.40 g, 85% ¹ H-NMR (DMSO-d ₆ ) δ 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 ( d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H); EI-MS m / z 173 (M ⁺ ).

A2. Synthesis of ω-carbamylanilines via formation of a carbamylpyridine followed by nucleophilic coupling with an arylamine. Synthesis of 4- (2-N-methylcarbamyl-4-pyridyloxy) aniline

Step 1a. Synthesis of 4-Chloro-N-methyl-2-pyridinecarboxamide via the Menisci reaction

Attention: This is an extremely dangerous, potentially explosive reaction. To a stirred solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 ml) was added at room temp. conc. H ₂ SO ₄ (3.55 ml) was added to generate an exotherm. To this mixture was added H ₂ O ₂ (30 wt% in H ₂ O, 17 ml), followed by FeSO ₄ .7H ₂ O (0.56 g) to produce another exotherm. The resulting mixture was incubated at room temp. In the dark. stirred for 1 h, then slowly heated to 45 ° C over 4 h. When the bubbling had subsided, the reaction was heated at 60 ° C for 16 h. The resulting cloudy 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 × 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 with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc / 50% hexane to 80% EtOAc / 20% hexane). The resulting yellow oil crystallized at 0 ° C for 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc / 50% hexane), R _f 0.50; ¹ H-NMR _(CDCl3) δ 3.04 (d, J = 5.1 Hz, 3H), 7.43 (dd, J = 5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J = 5.1 Hz, 1H); CI-MS m / z 171 ((M + H) ⁺ ).

Step 1b. Synthesis of 4-Chloropyridine-2-carbonyl chloride HCl salt over picolinic acid

Anhydrous DMF (6.0 mL) was added slowly to SOCl ₂ (180 mL) between 40 ° C and 50 ° C. The solution was stirred in this temperature range for 10 min, then picolinic acid (60.0 g, 487 mmol) was added in portions over 30 min. The resulting solution was heated at 72 ° C (vigorous SO ₂ evolution) for 16 h to produce a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 ml. The toluene addition / concentration procedure was repeated twice. The resulting near dry residue was filtered and the 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 added slowly to SOCl ₂ (300 ml) at 40-48 ° C. The solution was stirred in this temperature range for 10 min, then picolinic acid (100 g, 812 mmol) was added over 30 min. The resulting solution was heated at 72 ° C (vigorous SO ₂ evolution) for 16 h to give a yellow solid. The resulting mixture was brought to room temp. cooled, diluted with toluene (500 ml) and concentrated to 200 ml. The toluene addition / concentration procedure was repeated twice. The resulting, nearly dry residue was filtered and the solids were washed with toluene (50 ml) and dried under high vacuum for 4 hours to give 4-chloropyridine-2-carbonyl chloride HCl salt as an off-white solid (27.2 g , 16%). This material has been set aside.

The red filtrate was added to MeOH (200 mL) at a rate leaving the internal temperature below 55 ° C. The contents were at Raumtemp. stirred for 45 min, 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%). to give: mp 108-112 ° C; ¹ H-NMR (DMSO-d ₆ ) δ 3.88 (s, 3H); 7.82 (dd, J = 5.5, 2.2 Hz, 1H); 8.08 (d, J = 2.2 Hz, 1H); 8.68 (d, J = 5.5 Hz, 1H); 10.68 (brs, 1H); 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) was stirred at 0 ° C with a 2.0 M methylamine solution in THF (1 L) treated at a rate which left the internal temperature below 5 ° C. The resulting mixture was stored at 3 ° C for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500 ml), dried (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%) ben: mp 41-43 ° C; ¹ H-NMR (DMSO-d ₆ ) δ 2.81 (s, 3H), 7.74 (dd, J = 5.1, 2.2 Hz, 1H), 8.00 (d, J = 2, 2, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.85 (br d, 1H); CI-MS 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 in portions to a mixture of 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0 ° C given. The resulting mixture was stored at 3 ° C for 4 h, then concentrated under reduced pressure. The resulting, nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate was washed with a saturated NaCl solution (2 × 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%): mp 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 became at room temp. stirred 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 at 80 ° C for Heated for 8 h. The mixture was brought to room temp. cooled and partitioned between EtOAc (500 ml) and a saturated NaCl solution (500 ml). The aqueous phase was back-extracted with EtOAc (300 ml). The combined organic layers were washed with a saturated NaCl solution (4x1000ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure h at 35 ° C for 3 to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (17.9 g, 84%) as a light brown solid: ¹ H -NMR (DMSO-d ₆ ) δ 2.77 (d, J = 4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB 'quartet, J = 8.4Hz, 4H), 7.06 (dd, J = 5.5, 2.5Hz), 1H), 7.33 (d, J = 2.5Hz, 1H), 8.44 (d, J = 5.5Hz, 1H), 8.73 (br d, 1H); 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-Hydroxyisoindolin-dione 1,3-

To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was added slowly to 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120 ° C for 45 min, then the clear, bright yellow mixture was heated at 160 ° C for 2 h. The resulting mixture was kept at 160 ° C and was concentrated to approximately 15 ml, then it was allowed to reach room temp. cooled and adjusted to pH 10 with 1N NaOH solution. The mixture was cooled to 0 ° C and slowly acidified to pH 5 using a 1N 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 a product (3.24 g, 72%): ¹ H NMR (DMSO); d ₆ ) δ 7.00-7.03 (m, 2H), 7.56 (d, J = 9.3 Hz, 1H).

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

To a stirred slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 ° C was added a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol ) in DMF (40 ml) was added dropwise. The bright yellow-green mixture was allowed to reach room temp. and stirred for 1 h, then 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated at 70 ° C overnight, then at room temp. cooled and diluted slowly with water (150 ml) and extracted with EtOAc (2 × 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) R _f 0.28; ¹ H-NMR (DMSO-d ₆ ) δ 7.32 (d, J = 12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J = 7.8 Hz , 1H), 8.29 (d, J = 9 Hz, 2H), 11.43 (br s, 1H); CI-MS 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 conc. AcOH (12 ml) and water (0.1 ml) were stirred under argon flow while iron powder (0.59 g, 55.9 mmol) was added slowly. This mixture was stirred at room temp. for 72 h, 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) R _f 0.27; ¹ H NMR (DMSO d ₆ ) δ 5.14 (br s, 2H), 6.62 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H ), 7.03 (d, J = 2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J = 8.4 Hz, 1H), 11.02 (s, 1H ); HPLC ES-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-dimethylpyrrole

To a stirred solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added AcOH (0.1 mL) and acetonylacetone (0.299 g, 2.63 mmol). given over a syringe. The reaction mixture was heated at 120 ° C for 72 h with azeotropic removal of volatiles. The reaction mixture was brought to room temp. cooled, diluted with CH ₂ Cl ₂ (10 mL) and then washed with a 1N HCl solution (15 mL), a 1N NaOH solution (15 mL) and a saturated NaCl solution (15 mL), dried (MgSO ₄ ) 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 To give 5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc / 85% hexane) R _f 0.67; ¹ H-NMR _(CDCl3) δ 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H), 7 , 62 (dd, 1H), 7.88 (d, J = 2.4 Hz, 1H); CI-MS 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) was added under a H ₂ atmosphere (balloon) stirred for 72 h, then filtered through a pad of Celite ^® . The filtrate was concentrated under reduced pressure to give 5-tert-butyl-2- (2,5-dimethylpyrrolyl) aniline as yellowish solids (0.30 g, 99%): TLC (10% EtOAc / 90% hexane). R _f 0.43; ¹ H-NMR _(CDCl3) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73 to 6.96 (m , 3H), 7.28 (br s, 1H).

A5. General procedure for the synthesis of anilines from anilines by 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 at room temp. stirred until the flask had reached room temperature. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b, 7.52 g, 44.2 mmol) and heated at 110 ° C for 8 h. The mixture was brought to room temp. cooled and diluted with water (75 ml). The organic layer was extracted with EtOAc (5 x 100 ml). The combined organic layers were washed with a saturated NaCl solution (200 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residual black oil was treated with Et ₂ O (50 mL) and sonicated. The solution was then treated with HCl (1M in Et ₂ O, 100 mL) and stirred at room temp. stirred for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed from the solution by filtration and stored under anaerobic conditions at 0 ° C before use: ¹ H-NMR (DMSO-d ₆ ) δ 2, 41 (s, 3H), 2.78 (d, J = 4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J = 8.5, 2.6 Hz, 1H), 7.23 (dd, J = 5.5, 2.6 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 5.9 Hz, 1H), 8.99 (q, J = 4.8 Hz, 1H).

A6. General procedure for the synthesis of anilines from hydroxyanilines by N-protection, nucleophilic aromatic substitution and deprotection. Synthesis of 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline

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

Iron (3.24 g, 58.00 mmol) was added to stirred TFA (200 mL). To this slurry was added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 ml). The gray slurry was taken at room temp. stirred for 6 d. The iron was filtered off 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 was added a saturated NaHCO ₃ solution (50 ml). The solid which precipitated out of the solution was removed. The filtrate was quenched slowly with the sodium bicarbonate solution until the product visibly separated from the solution (determined using a mini-work-up vessel). The slightly turbid 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. ¹ H-NMR (DMSO-d ₆ ) showed a 1: 1 ratio of nitrophenol starting material and 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 crude 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 ml) was treated with potassium tert-butoxide (5.16 g, 45.98 mmol) and the brownish-black mixture became at room temp. touched until the piston is at room temp. had cooled. The resulting Mixture was treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, step 3b; 1.99 g, 11.7 mmol) and at 100 ° C under argon for 4 d heated. The black reaction mixture was allowed to come to room temperature chilled and then poured into cold water (100 ml). The mixture was washed with EtOAc (3 x 75 ml) and the combined organic layers were concentrated under reduced pressure. The brown oily residue was purified by column chromatography purified (gradient from 20% EtOAc / petroleum ether to 40 EtOAc / petroleum ether), 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-dioxane (20 ml) was treated with 1N NaOH solution (20 ml). This brown solution was allowed to stir for 8 h. To this solution was added EtOAc (40 ml). The green organic layer was extracted with EtOAc (3 x 40 mL) and the solvent was concentrated to give 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline as a green oil, which was added are solidified (2.86 g, 10.30 mmol): ¹ H-NMR (DMSO-d ₆₎ δ 2.77 (d, J = 4.8 Hz, 3H), 5.51 (s, 2H). 6.60 (dd, J = 8.5, 2.6 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H ), 7.07 (dd, J = 5.5, 2.6 Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 8.46 (d, J = 5.5 Hz , 1H), 8.75 (q, J = 4.8 Hz, 1H).

A7. General procedure for the 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 6M HCl solution (24 mL) was added at reflux temp. heated for 1 h. The resulting solution was allowed to reach room temp. cool down, during which time it solidified slightly. The resulting mixture was diluted with water (20 ml), then treated with a combination of solid NaOH and a saturated NaHCO ₃ solution until the solution was 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): ¹ H-NMR (DMSO-d ₆ ) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

A8. General procedure for the synthesis of ω-alkoxy-ω-carboxyphenyl-anilines. 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 a manner analogous to that in Method A13, step 1, 12 mmol) in acetone (50 ml), K ₂ CO ₃ (5 g) and dimethyl sulfate (3.5 ml) were added. The resulting mixture was at the reflux temp. heated overnight, then at room temp. cooled and filtered through a pad of Celite ^®. The resulting solution was concentrated under reduced pressure, absorbed on 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 ): mp 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 added at room temp. stirred overnight and then at the reflux temp. heated for 4 h. The resulting mixture was brought to room temp. cooled and concentrated under reduced pressure. The residue was dissolved in water (50 ml) and the aqueous mixture was made acidic with a 1N HCl solution. The resulting mixture was extracted with EtOAc (50 ml). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to give 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (1.04 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 at the reflux temp. heated for 18 h, at room temp. cooled and concentrated under reduced pressure. The resulting yellow solids were dissolved in CH ₂ Cl ₂ (3 mL), then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02 mmol) in portions (CAUTION: gas evolution) and at room temp. stirred for 4 h. The resulting mixture was treated with a 1N NaOH solution, 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%). to surrender.

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 of H ₂ (balloon) for 2.5 d, then it became filtered through a pad of Celite ^®. The resulting solution was concentrated under reduced pressure to give 4- (3- (N -methylcarbamoyl) -4-methoxyphenoxy) aniline as a off-white solid (0.68 g, 96%): TLC (0.1%). Et ₃ N / 99.9 EtOAc) R _f 0.36.

A9. General procedure for the preparation of ω-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 at room temp. stirred for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temp. Stirred overnight, then cooled to ° C and cooled with water (10 ml). The resulting solids were collected and dried under reduced pressure to give 5- (4-nitrophenoxy) -2-methylisoindoline-1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35%). EtOAc / 65% hexane) R _f 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 became under 1 atm of H ₂ (balloon) overnight touched. The resulting mixture was then 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 pad 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) R _f 0.27.

A10. General procedure for the synthesis of ω-carbamoylaryl-anilines by reaction of ω-alkoxycarbonylaryl precursors with amines. Synthesis of 4- (2- (N-2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline

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

To a solution of methyl 4-chloropyridine-2-carboxylate 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) was added dropwise and the resulting solution was taken at the reflux temp. heated for 20 h, at room temp. cooled and treated with water (50 ml). The resulting mixture was extracted with EtOAc (50 ml). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to give 4-chloro-2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridine as a yellow oil (1.25 g, 95%). TLC (10% MeOH / 90% EtOAc) R _f 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 added at room temp. stirred for 2 h, was then treated sequentially with 4-chloro-2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridine (1.22 g, 4.52 mmol) and K ₂ CO ₃ (0, 31 g, 2.26 mmol). The resulting mixture was heated at 75 ° C overnight, at room temp. cooled 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) R _f 0.32.

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

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 added under H ₂ atmosphere (Balloon) for 2 d stirred. The resulting mixture was filtered through a pad of celite ^®, then concentrated under reduced pressure to give 4- (3-carboxyphenoxy) aniline as a brown solid (2.26 g, 48%) of: TLC (10% MeOH / 90 % CH ₂ Cl ₂ ) R _f 0.44 (banding).

A12. General procedure for the synthesis of isoindolinone-containing anilines. Synthesis of 4- (1-oxosioindolin-5-yloxy) aniline

Step 1. Synthesis of 5-Hydroxyisoindolin-1-one

To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was added zinc dust (47.6 g, 729 mmol) portionwise, then the mixture was refluxed. heated for 40 min, filtered hot and concentrated under reduced pressure. The reaction was repeated on an equal scale and the combined oily 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-1. on (3.77 g): TLC (100% EtOAc) R _f 0.17; HPLC ES-MS m / z 150 ((M + H) ⁺ ).

Step 2. Synthesis of 4- (1-isoindolinon-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) portionwise. The resulting slurry was allowed to reach room temp. was heated and stirred for 45 minutes, then 4-fluoro-1-nitrobenzene was added and then the mixture was heated at 70 ° C for 3 hours. The mixture was cooled to 0 ° C and treated dropwise with water until a precipitate formed. The resulting solids were collected to give 4- (1-isoindolinone-5-yloxy) -1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) R _f 0.35.

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

A slurry of 4- (1-isoindolinone-5-yloxy) -1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd / C (0.20 g) in EtOH (50 mL) was added under a H ₂ atmosphere (balloon) for 4 h, then filtered through a pad of Celite ^® filtered. 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 ω-carbamoyl anilines via EDCI-mediated amide formation, followed by nitroarene reduction. Synthesis of 4- (3-N-methylcarbamoylphenoxy) aniline.

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

A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate (25 g, 150 mmol) and K ₂ CO ₃ (41 g, 300 mmol) in DMF (125 mL) was added the reflux temp. heated overnight, at room temp. cooled and treated with water (250 ml). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were washed successively with water (3 × 100 ml) and a saturated NaCl solution (2 × 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 3: 1 THF / water solution (75 mL) was added a solution of LiOH · H ₂ Add O (1.50 g, 35.8 mmol) in water (36 ml). The resulting mixture was heated at 50 ° C overnight, then at room temp. cooled, concentrated under reduced pressure and adjusted to pH 2 with 1M HCl solution. The resulting light 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-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 added at room temp. stirred for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 ml) and the resulting mixture was extracted with 1 M HCl solution (50 ml). The aqueous layer was 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 (1.89 g).

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 added a H ₂ atmosphere (balloon) stirred 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 ω-carbamoyl anilines via EDCI-mediated amide formation, followed by nitroarene reduction. Synthesis of 4- (3- (5-methylcarbamoyl) pyridyloxy) aniline

Step 1. Synthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene

To a slurry of NaH (0.63g, 26.1mmol) in DMF (20ml) was added a solution of Methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture became a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting Mixture was at 70 ° C overnight heated, at room temp. chilled 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 added under H ₂ atmosphere (balloon) Stirred for 72 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% EtOAc / 90% hexanes to 30% EtOAc / 70% hexanes to 50% EtOAc / 50% hexanes) to give 4- (3- (5-methoxycarbonyl) -pyridyloxy) aniline (0 , 28 g, 60%): ¹ H-NMR _(CDCl3) δ 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (1H) , 8.51 (d, 1H), 8.87 (d, 1H).

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

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

To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0 ° C was added methylamine (2.0 M in THF, 28 mL, 56 mmol). The resulting solution was allowed to reach room temp. warm and she was at room temp. stirred 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 × 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 CuI (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 temperature overnight, at room temp. cooled and partitioned between EtOAc (50 mL) and 1N HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed successively with water (2 × 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 (0.30 g).

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

To a solution of 4- (3- (N-methylsulfamoyl) phenyloxy) benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10 ° C was added NaNO ₂ (0.097 g, 1.14 mmol ) was added portionwise over 5 min. The resulting solution was stirred at -10 ° C for 1 h, then allowed to warm to room temp. and it was concentrated under reduced pressure. The residue was partitioned between EtOAc (10 ml) and water (10 ml). The organic phase was washed successively with water (10 ml) and 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 taken over in 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 (0.30g) and 10% Pd / C (0.030g) in EtOAc (20ml) was added under an H ₂ atmosphere (balloon ) stirred 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 ω-ketones. Synthesis of 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt.

To a slurry of 4- (4-acetylphenoxy) aniline HCl salt (prepared in a manner analogous to that in Method A13, Step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and Pyridine (1.0 mL) was added to O-methylhydroxylamine HCl salt (0.65 g, 7.78 mmol, 2.0 equiv.). The resulting solution was heated at the 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 To give 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt as a yellow solid (0.85 g): TLC (50% EtOAc / 50% petroleum ether), R _f 0.78; ¹ H-NMR (DMSO-d ₆ ) δ 3.90 (s, 3H), 5.70 (s, 3H), HPLC-MS m / z 257 ((M + H) ⁺ ).

A17. Synthesis of N- (ω-silyloxyalkyl) amides. Synthesis of 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline.

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

To a solution of 4-chloro-N- (2-hydroxyethyl) pyridine-2-carboxamide (prepared in a manner analogous to that in Method A2, step 3b, 1.5 g, 7.4 mmol) in anhydrous DMF (7 mL ) was added triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp. stirred, then it was 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%) result. 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 a Portion, whereby an exotherm was effected. 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 followed of K ₂ CO ₃ (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was heated at 80 ° C overnight. An additional portion of potassium tert-butoxide (0.34 g, 3 mmol, 0.5 equiv.) Was then added and the mixture was stirred at 80 ° C for additional 4 h. The mixture was cooled to 0 ° C with an ice / water bath, then water (about 1 ml) was slowly added dropwise. The organic layer was 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 oily residue was purified by column chromatography (SiO ₂ ; 30% EtOAc / 70% petroleum ether) to give 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline as a clear, light brown oil (O, m.p. 99 g, 38%).

A18. Synthesis of 2-pyridinecarboxylate 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 × 100 ml). The combined organic layers were washed successively 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) was heated at the reflux temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered, then concentrated under reduced pressure. The residue was dissolved in MeOH (100 ml). The solution was treated with a conc. HCl solution (7 ml), then heated at the reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (50 mL) and a 1N NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed successively 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 a H ₂ 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 ω-sulfonylphenylanilines. Synthesis of 4- (4-methylsulfonylphenyoxy) aniline.

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

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

Step 2. 4- (4-Methylsulfonylphenoxy) -1-aniline:

4- (4-methylsulfonylphenoxy) -1-nitrobenzene to the aniline in an analogous manner as in procedure A18, step 3, described, reduced.

B. Synthesis of urea precursors B1. General procedure for the synthesis of isocyanates from anilines using CDI. Synthesis of 4-bromo-3- (trifluoromethyl) phenyl isocyanate.

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 dropwise an HCl solution (1M in Et ₂ O, 300 mL) and the resulting Mixture was at room temp. stirred for 16 h. 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 stirred at reflux temp. heated for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 ml), then concentrated under reduced pressure. The residue was treated with CH ₂ Cl ₂ (500 ml), then concentrated under reduced pressure. The CH ₂ Cl ₂ treatment / concentration protocol was repeated and 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. Process for the formation of urea C1a. General procedure for the synthesis of ureas by reaction of 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 temp. stirred for 22 h. The resulting yellow solids were removed by filtration, then washed with CH ₂ Cl ₂ (2 x 30 mL) and dried under reduced pressure (approximately 1 mm Hg) to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea as an off-white solid (28.5 g, 93%): mp 207-209 ° C; ¹ H-NMR (DMSO-d ₆ ) δ 2.77 (d, J = 4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J = 2.5 Hz, 1H ), 7.62 (m, 4H), 8.11 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m / z 465 ((M + H) ⁺ ).

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

A solution of 4-bromo-3- (trifluoromethyl) phenyl isocyanate (Method B1, Step 2, 8.0 g, 30.1 mmol) in CH ₂ Cl ₂ (80 mL) was added dropwise to a solution of 4- (2-chloro). (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 temp. stirred for 16 h. The resulting yellow solids were removed by filtration, then washed with CH ₂ Cl ₂ (2 x 50 mL) and dried under reduced pressure (approximately 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 (13.2g, 90%): mp 203-205 ° C; ¹ H-NMR (DMSO-d ₆ ) δ 2.77 (d, J = 4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J = 2.5 Hz, 1H ), 7.58 (m, 3H), 7.77 (d, J = 8.8Hz, 1H), 8.11 (d, J = 2.5Hz, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m / z 509 ((M + H) ⁺ ).

C1c. General procedure for the synthesis of ureas by reaction of 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 added 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 temp. stirred for 6 d, then it was 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): ¹ H-NMR (DMSO-d ₆ ) δ 2.27 (s, 3H), 2, 77 (d, J = 4.8 Hz, 3H), 7.03 (dd, J = 8.5, 2.6 Hz, 1H), 7.11 (d, J = 2.9 Hz, 1H), 7.15 (dd, J = 5.5, 2.6 Hz, 1H), 7.38 (dd, J = 2.6 Hz, 1H), 7.62 (apparent d, J = 2.6 Hz , 2H), 7.84 (d, J = 8.8Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50 (d, J = 5.5 Hz, 1H), 8.78 (q, J = 5.2 Hz, 1H), 9.52 (s, 1H); HPLC ES-MS m / z 479 ((M + H) ⁺ ).

C1d. General procedure for the synthesis of ureas by reaction of an isocyanate with an aniline. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (1-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 given a portion. The resulting mixture was stirred at room temp. stirred for 1 h, 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 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 R _f 0.72.

C1E. General procedure for the synthesis of ureas by reaction of an isocyanate with an aniline. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4-ethoxycarbonylphenyl) urea

To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH ₂ Cl ₂ (30 mL) was added 4-chloro-3- (trifluoromethyl) aniline (3.21 g, 16.4 mmol ) and the solution was added at room temp. stirred overnight. The resulting slurry was diluted with CH ₂ Cl ₂ (50 mL) and filtered to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4-ethoxycarbonylphenyl) urea as a white solid (5, 93 g, 97%): TLC (40% EtOAc / 60% hexane) R _f 0.44.

C1f. General procedure for the synthesis of ureas by reaction of 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 A11, 0.81 g, 5.76 mmol) and the resulting mixture was stirred at room temp. Stirred overnight, 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 EtOAc / hexane solution 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 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) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

To a solution of 2-methoxy-5- (trifluoromethyl) aniline (0.15 g) in anhydrous CH ₂ Cl ₂ (15 ml) was added CDI (0.13 g) at 0 ° C. The resulting solution was allowed to reach room temp. Heat for 1 h, it was at room temp. stirred for 16 h, then treated with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temp. stirred for 72 h, then it was 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 residue 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 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) R _f 0.62; ¹ H-NMR (DMSO-d ₆ ) δ 2.76 (d, J = 4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8, 6 (m, 11H), 8.75 (d, J = 4.8 Hz, 1H), 9.55 (s, 1H); FAB-MS m / z 461 ((M + H) ⁺ ).

C2b. General procedure for urea synthesis by reaction of an aniline with N, N'-carbonyldiimidazole, followed by addition of a second aniline. Symmetrical ureas as by-products of an N, N'-carbonyldiimidazole reaction process. Synthesis of bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea.

To a stirred solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH ₂ Cl ₂ (15 ml) was added CDI (0.13 g) at 0 ° C. The resulting solution was allowed to reach room temp. Heat for 1 h and then it was at room temp. stirred for 16 h. The resulting mixture was treated with 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temp. stirred for 72 h, then it was treated with water (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with a saturated NaCl solution (100 ml), dried (MgSO 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 R _f 0.50; ¹ H-NMR (DMSO-d ₆ ) δ 2.76 (d, J = 5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J = 5, 4Hz, 1H), 8.75 (d, J = 4.8Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m / z 513 ((M + H) ⁺ ).

C2c. General procedure for the synthesis of ureas by reaction of an isocyanate with an aniline. Synthesis of N- (2-Methoxy-5- (trifluoromethyl) phenyl-N '- (4- (1,3-dioxoisoindolin-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, then it was treated with CH ₂ Cl ₂ (10 mL) and MeOH (5 mL). The resulting mixture was washed successively with a 1N 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 ) to give phenyl N '- (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea as a white solid (0.2g, 96%): TLC (70% EtOAc / 30% hexane) R _f 0.50; ¹ H-NMR (DMSO-d ₆ ) δ 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J = 9.3 Hz, 2H), 7.80 (d, J = 8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS 472.0 ((M + H) ⁺ , 100%).

C2d. General procedure for urea synthesis by reaction of an aniline with N, N'-carbonyldiimidazole, followed by 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 (0.21 g, 1.30 mmol) in CH ₂ Cl ₂ (2 mL) was added 5- (tert-butyl) -2- (2,5-dimethylpyrrolyl) aniline (Method A4, step 2, 0.30 g, 1.24 mmol) in one portion. The resulting mixture was stirred at room temp. for 4 h, then 4- (2- (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, then at room temp. cooled and diluted with EtOAc (5 mL). The resulting mixture was washed successively with water (15 ml) and a 1N HCl solution (15 ml), dried (MgSO ₄ ) and filtered through a pad of silica gel (50 g) to give N- (5- (tert-butyl) -2- (2,5-dimethylpyrrolyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) - 4-pyridyloxy) phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc / 60% hexane) R _f 0.24; ¹ H-NMR (acetone-d ₆ ) δ 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J = 4.8 Hz, 3H), 5.83 (s , 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J = 5.4 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M + H) ⁺ , 100%).

C3. Combinatorial method for the synthesis of diphenylurea using triphosgene

One the aniline to be coupled was in dichloroethane (0.10 M) solved. This solution was in an 8 ml vial (0.5 ml) containing dichloroethane (1 ml). For this was a bis (trichloromethyl) carbonate solution (0.12M in dichloroethane, 0.2 ml, 0.4 equiv.) followed by diisopropylethylamine (0.35M in dichloroethane, 0.2 ml, 1.2 equiv). The glass was sealed and at 80 ° C for 5 h heated, then left it on room temp. For approximately Cool for 10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 ml, 1.0 equiv.), followed by diisopropylethylamine (0.35M in dichloroethane, 0.2ml, 1.2 equiv.). The resulting mixture was heated at 80 ° C for 4 h, to room temperature chilled and treated with MeOH (0.5 ml). The resulting mixture became concentrated under reduced pressure and the products were passed through reverse-phase HPLC purified.

C4. General procedure for urea synthesis by reaction of an aniline with phosgene, followed by addition of a second aniline. Synthesis of N- (2-Methoxy-5- (trifluoromethyl) phenyl) -N '- (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 reach room temp. during which a precipitate formed. The yellow mixture was stirred for 1 h, then concentrated under reduced pressure. The resulting solids were treated with 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 added Heated to 80 ° C for 20 h, then allowed to room temp. cooling down. The resulting mixture was diluted with water (100 ml), 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 pink-brown residue was dissolved in MeOH and absorbed on SiO ₂ (100 g). Column chromatography (300 g SiO ₂ , gradient from 1% Et ₃ N / 33% EtOAc / 66% hexane to 1% Et ₃ N / 99% EtOAc to 1% Et ₃ N / 20% MeOH / 79% EtOAc) followed by concentration under reduced pressure at 45 ° C gave a warm concentrated EtOAc solution which was treated with hexane (10 ml) to slowly crystals of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- To form (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.44 g): TLC (1% Et ₃ N / 99% EtOAc) R _f 0.40.

D. Conversion of ureas D1a. Conversion of ω-aminophenyl ureas into ω- (arlyamino) phenylureas. 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 '- (4-aminophenyl) urea (Method C1d, 0.050 g, 1.52 mmol), mono-methylisophthalate (0.25 g, 1.38 mmol) HOBT · H ₂ O (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added EDCI · HCl (0 , 29 g, 1.52 mmol) The resulting mixture was stirred at room temp. Overnight, diluted with EtOAc (25 mL) and subsequently washed 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) carboxyaminophenyl). urea (0.27 g, 43%): mp 121-122 ° C, TLC (80% EtOAc / 20% hexane) R _f 0.75.

D1b. Conversion of ω-carboxyphenylureas into ω- (arylcarbamoyl) phenylureas. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea.

To a solution of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 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. EDCI.HCl (0.10 g, 0.53 mmol) was added, the resulting mixture was allowed to warm to room temp and stirred overnight The resulting mixture was treated with water (10 mL) and extracted with EtOAc (25 The organic phase was concentrated under reduced pressure and the resulting yellow solids were dissolved in EtOAc (3 mL), then passed 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%) m.p. 225-229 ° C; TLC (100% EtOAc) R _f 0.23.

D1c. A combinatorial approach to the conversion of ω-carboxyphenylureas into ω- (arylcarbamoyl) phenylureas. 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 C1f, 0.030 g, 0.067 mmol) and N-cyclohexyl-N' - (methylpolystyrene) Carbodiimide (55 mg) in 1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CH ₂ Cl ₂ (1 M, 0.074 mL, 0.074 mmol) (in cases of insolubility or turbidity, a small The resulting mixture was heated overnight at 36 ° C. Turbid reactions were then treated with THF (1 ml) and heating was continued for 18 h. The resulting mixtures were treated with poly (4- (isocyanatomethyl)). styrene) (0.040 g) and the resulting mixture was stirred at 36 ° C for 72 h, then cooled to room temp., filtered, filtered through a plug of silica gel (1 g), and the concentration reduced under reduced pressure N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (N- (3- (N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) - urea (0.024 g, 59%): TLC (70% EtOAc / 30% hexane) R _f 0.12.

D2. Conversion of ω-carboalkoxyarylureas into ω-carbamoylarylurea. 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 temp. Overnight, then concentrated under reduced pressure to give N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '. - (4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea as egg To give a white solid: mp. 247 ° C; TLC (100% EtOAc) R _f 0.35.

D3. Conversion of ω-carboalkoxyarylureas into ω-carboxyarylureas. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4-carboxyphenyl) urea

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

D4. General procedure for the conversion of ω-alkoxy esters into ω-alkylamides. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- ((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea.

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

N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea was from 4-chloro-3- (trifluoromethyl) phenyl isocyanate and 4- (3- (5-methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a manner analogous to that synthesized in method C1a. 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 washed with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and was added Room temp. for 1 h stirred. The resulting mixture was adjusted to pH 5 with a 1N 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 became concentrated under reduced pressure. The EtOH / Concentration Method was repeated twice to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5-carboxypyridyl) oxyphenyl) urea (0.18 g, 71%).

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

A mixture of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5-carboxypyridyl) oxyphenyl) urea (0.050 g, 0.011 mmol), N, N-dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N-methylmorpholine (0.035 g, 0.28 mmol) and EDCI · HCl (0.032 g, 0.17 mmol) in DMF 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 extracted (2.5 mL) The residue was dissolved in a minimal amount of CH ₂ Cl ₂ (approximately 2 ml) The resulting solution was treated dropwise with Et ₂ O to give N- (4-chloro-3- (trifluoromethyl) phenyl) -. N '- to give (4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea as a white precipitate (0.48 g, 84%): ¹ H-NMR (DMSO-d ₆ ) δ 2.10 (s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8, 05 (s, 1H), 8.43 (s, 1H), 8.58 (t, 1H), 8.69 (s, 1H), 8.90 (s, 1H), 9.14 (s, 1H); HPLC ES-MS m / z 522 ((M + H) ⁺ ).

D5. General procedure for the deprotection of N- (ω-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 a analogous manner as in Method C1a, 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 The aqueous mixture was extracted with EtOAc (3 x 10 mL) and 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%).

Below In the tables below, compounds are listed which according to the detailed experimental methods given above have been. Here, entries 42-45, 49, 85-87, 89, 93, 95 and 96 concern the Compounds according to the present invention Invention. The remaining compounds relate to the reference compounds.

Synthesis of example compounds (see tables for compound characterization)

entry 1: 4- (3-N-Methylcarbamoylphenoxy) aniline was prepared according to procedures A13 made. According to procedure C3 was reacted with 3-tert-butylaniline with bis (trichloromethyl) carbonate, followed by 4- (3-N-methylcarbamoylphenoxy) aniline to the urea to surrender.

entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were prepared according to procedures A13, Step 1, reacted to give the 4- (4-acetylphenoxy) -1-nitrobenzene to surrender. 4- (4-acetylphenoxy) -1-nitrobenzene was prepared according to procedures A13, step 4, reduced to give 4- (4-acetylphenoxy) aniline. According to procedure C3 was reacted with 3-tert-butylaniline with bis (trichloromethyl) carbonate, followed by 4- (4-acetylphenoxy) aniline, to give the urea.

entry 3: according to procedure C2d was treated with CDI 3-tert-butylaniline, followed by 4- (3-N-methylcarbamoyl) -4-methoxyphenoxy) aniline, which has been prepared according to method A8 to the urea to surrender.

entry 4: 5-tert-Butyl-2-methoxyaniline was converted into 5-tert-butyl-2-methoxyphenyl isocyanate according to procedure B1 transferred. 4- (3-N-Methylcarbamoylphenoxy) aniline, prepared according to method A13, was mixed with the isocyanate according to procedures C1a reacted to give the urea.

entry 5: According to procedure C2d was reacted with CDI 5-tert-butyl-2-methoxyaniline followed of 4- (3-N-methylcarbamoyl) -4-methoxyphenoxy) aniline, which was prepared had been according to procedures A8 to give the urea.

entry 6: 5- (4-Aminophenoxy) isoindoline-1,3-dione was prepared according to procedure A3 produced. According to method 2d, 5-tert-butyl-2-methoxyaniline reacted with CDI, followed by 5- (4-aminophenoxy) isoindoline-1,3-dione, to give the urea.

entry 7: 4- (1-Oxoisoindolin-5-yloxy) aniline was synthesized according to Method A12. According to method 2d was 5-tert-butyl-2-methoxyaniline with CDI followed by 4- (1-oxoisoindolin-5-yloxy) aniline to give the urea.

entry 8: 4- (3-N-Methylcarbamoylphenoxy) aniline was prepared according to procedures Synthesized A13. According to procedure C2a, 2-methoxy-5- (trifluoromethyl) aniline was used reacted with CDI, followed by 4- (3-N-methylcarbamoylphenoxy) aniline to give the To give urea.

entry 9: 4-hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine, 4- (4-acetylphenoxy) -5-nitropyridine according to method A3, step 2, to surrender. According to Method A8, Step 4, 4- (4-acetylphenoxy) -5-nitropyridine was used reduced to 4- (4-acetylphenoxy) -5-aminopyridine. 2-methoxy-5- (trifluoromethyl) aniline was in 2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to the method B1 transferred. The Isocyanate was treated with 4- (4-acetylphenoxy) -5-aminopypridine according to method C1a reacted to give the urea.

entry 10: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were prepared according to procedures A13, Step 1, reacted to give 4- (4-acetylphenoxy) -1-nitrobenzene to surrender. 4- (4-acetylphenoxy) -1-nitrobenzene was prepared according to procedures A13, step 4, reduced to give 4- (4-acetylphenoxy) aniline. According to procedure C3 was reacted with 5- (trifluoromethyl) -2-methoxybutylaniline with bis (trichloromethyl) carbonate, followed by 4- (4-acetylphenoxy) aniline to give the urea.

entry 11: 4-Chloro-N-methyl-2-pyridinecarboxamide, prepared according to method A2, step 3a, was synthesized with 3-aminophenol according to methods A2, step 4, implemented using DMAC instead of DMF to give 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to surrender. According to method C4, 2-methoxy-5- (trifluoromethyl) aniline reacted with phosgene followed by 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline, to give the urea.

entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was mixed with ammonia according to method A2, step 3b reacted to 4-chloro-2-pyridinecarboxamide to build. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to the procedure A2, step 4, using DMAC instead of DMF to give 3- (2-carbamoyl-4-pyridyloxy) aniline to surrender. According to procedure C2a, 2-methoxy-5- (trifluoromethyl) aniline was used reacted with phosgene, followed by 3- (2-carbamoyl-4-pyridyloxy) aniline, to give the urea.

entry 13: 4-Chloro-N-methyl-2-pyridinecarboxamide was prepared according to procedure 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 to surrender. According to procedure C2a, 2-methoxy-5- (trifluoromethyl) aniline was used reacted with CDI followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline, to give the urea.

entry 14: 4-Chloropyridine-2-carbonyl chloride HCl salt was mixed with ammonia according to procedure A2, step 3b, reacted to form 4-chloro-2-pyridinecarboxamide. 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 to surrender. According to method C4, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene, followed by 4- (2-carbamoyl-4-pyridiyloxy) aniline, to give the urea.

entry 15: According to procedure C2d, 5- (trifluoromethyl) -2-methoxyaniline was reacted with CDI, followed by 4- (3-N-methylcarbamoyl) -4-methoxyphenoxy) aniline, which corresponds to Method A8 was prepared to yield the urea.

entry 16: 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) -2-methylaniline according to procedure A5 synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate converted according to procedure B1. The Isocyanate was treated with 4- (2-N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline Method C1c reacted to yield the urea.

entry 17: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was prepared according to procedures A6 synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate converted according to procedure B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was treated with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline reacted according to method C1a to give the urea.

entry 18: According to procedure 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, 3- (2- (N -methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to surrender. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate converted according to procedure B1. 5- (trifluoromethyl) -2-methoxyphenolisocyanat was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline according to the procedure C1a to give the urea.

entry 19: 4-Chloropyridine-2-carbonyl chloride was treated with ethylamine according to procedures A2, step 3b, implemented. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, Step 4, reacted to give 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline to surrender. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate converted according to procedure B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline according to procedure C1a to give the urea.

entry 20: According to method A2, step 4, 4-amino-2-chlorophenol reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to method A2, step 3b, to give 4 (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to surrender. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate converted according to procedure B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline according to the procedure C1 to give the urea.

entry 21: 4- (4-Methylthiophenoxy) -1-nitrobenzene was oxidized accordingly Method A19, Step 1, to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene to surrender. The nitrobenzene was prepared according to method A19, step 2, reduced to 4- (4-methylsulfonylphenoxy) -1-aniline to surrender. According to Method C1a, 5- (trifluoromethyl) -2-methoxyphenyl isocyanate with 4- (4-methylsulfonylphenoxy) -1-aniline reacted to give the urea.

entry 22: 4- (3-Carbamoylphenoxy) -1-nitrobenzene became 4- (3-carbamoylphenoxy) aniline according to procedure A15, step 4, reduced. According to procedure C1a became 5- (trifluoromethyl) -2-methoxyphenylisocyanate with 4- (3-carbamoylphenoxy) aniline reacted to give the urea.

entry 23: 5- (4-Aminophenoxy) isoindoline-1,3-dione was prepared according to procedure A3 synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate converted according to procedure B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was treated with 5- (4-aminophenoxy) isoindoline-1,3-dione reacted according to method C1a to give the urea.

entry 24: 4-Chloropyridine-2-carbonyl chloride was treated with dimethylamine according to procedures A2, step 3b, implemented. The resulting 4-chloro-N, N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, step 4 to give 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to procedure B1 transferred. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was treated with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline according to the procedure C1a reacted to give the urea.

entry 25: 4- (1-Oxoisoindolin-5-yloxy) aniline was synthesized according to Method A12. 5- (trifluoromethyl) -2-methoxyaniline was treated with CDI followed of 4- (1-oxoisoindolin-5-yloxy) aniline according to method C2d to the urea to surrender.

entry 26: 4-Hydroxyacetophenone was treated with 4-fluoronitrobenzene according to Method A13, step 1, reacted to give 4- (4-acetylphenoxy) nitrobenzene result. The nitrobenzene was prepared according to method A13, step 4, reduced to 4- (4-aceylphenoxy) aniline which is converted into the 4 - (- 4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt according to procedure A16 was transferred. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to procedure B1 transferred. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was corresponding to 4- (4-1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt Method C1a reacted to give the urea.

entry 27: 4-Chloro-N-methylpyridinecarboxamide was synthesized as in Method A2, step 3b. The chloropyridine was with 4-aminothiophenol according to procedure A2, step 4, to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline result. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to procedure B1 transferred. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline according to procedure C1a reacted to give the urea.

entry 28: 5- (4-Aminophenoxy) -2-methylisoindoline-1,3-dione was prepared according to procedures A9 synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to procedure B1 transferred. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was treated with 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione according to procedure C1a reacted to give the urea.

entry 29: 4-Chloro-N-methylpyridinecarboxamide was used as in Method A2, Step 3b, described, synthesized. The chloropyridine was with 3-aminothiophenol according to method A2, step 4, to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline result. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to procedure B1 transferred. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was treated with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline according to procedure C1a reacted to give the urea.

entry 30: 4-Chloropyridine-2-carbonyl chloride was treated with isopropylamine according to procedure A2, step 3b, implemented. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide was with 4-aminophenol, according to procedures A2, step 4, reacted to give 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline to surrender. 5- (trifluoromethyl) -2-methoxyaniline was reacted in 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to the method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline according to procedure C1a to give the urea.

entry 31: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to procedures A14 synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to procedure B1 transferred. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was treated with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to the procedure C1a reacted to give the urea. N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl-urea was prepared according to procedures D4, Step 1, was saponified and the corresponding acid was treated with 4- (2-aminoethyl) morpholine coupled to the amide according to method D4, Step 2, to surrender.

entry 32: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to procedures A14 synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to procedure B1 transferred. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was treated with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to the procedure C1a reacted to give the urea. N- (5- (Trifluoromethyl) -2-methoxyphenyl) -N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was prepared according to procedures D4, step 1, saponified and the corresponding acid was treated with methylamine according to procedure D4, step 2, coupled to give the amide.

entry 33: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to procedures A14 synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to procedure B1 transferred. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was treated with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to the procedure C1a reacted to give the urea. N- (5- (Trifluoromethyl) -2-methoxyphenyl) -N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was prepared according to procedures D4, Step 1, saponified and the corresponding acid was treated with N, N-dimethylethylenediamine according to procedure D4, step 2, coupled to give the amine.

entry 34: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate converted according to procedure B1. 4- (3-carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method C1f reacted to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) urea, with 3-aminopyridine according to the method D1c was paired.

entry 35: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to procedure B1 transferred. 4- (3-carboxyphenoxy) aniline was treated with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method C1f convicted to N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) urea to give with N- (4-fluorophenyl) piperazine according to methods D1c was paired.

entry 36: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to procedure B1 transferred. 4- (3-carboxyphenoxy) aniline was treated with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N'- (3-carboxyphenyl) urea, with 4-fluoroaniline according to the method D1c was paired.

Entry 37: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was treated with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) urea surrender with 4- (dimethylamino) aniline according to method D1c was coupled.

entry 38: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to procedure B1 transferred. 4- (3-carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to the method C1f to N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) urea to give which with 5-amino-2-methoxypyridine according to procedure D1c was paired.

entry 39: 4- (3-carboxyphenoxy) aniline was synthesized according to procedure A11. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to procedure B1 transferred. 4- (3-carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to the method C1f to N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) urea to give which with 4-morpholinaniline according to procedure D1c was paired.

entry 40: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. 5- (trifluoromethyl) -2-methoxyaniline was converted into 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to procedure B1 transferred. 4- (3-carboxyphenoxy) aniline was treated with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N'- (3-carboxyphenyl) urea, which was coupled with N- (2-pyridyl) piperazine according to Method D1c.

entry 41: 4- (3- (N -methylcarbamoyl) phenoxy) aniline was prepared according to procedures A13 implemented. According to procedure C3 was converted to 4-chloro-3- (trifluoromethyl) aniline in the isocyanate, then reacted with 4- (3- (N-methylcarbamoyl) phenoxy) aniline to give the urea to surrender.

entry 42: 4- (2-N-Methylcarbamoyl-4-pyridyloxy) aniline was prepared according to procedures A2 synthesized. 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (2- (N-methylcarbamyl-4-pyridyloxy) aniline according to procedure C1a reacted to give the urea.

entry 43: 4-Chloropyridine-2-carbonyl chloride HCl salt was mixed with ammonia according to procedure A2, step 3b reacted to form 4-chloro-2-pyridinecarboxamide. 4-chloro-2-pyridinecarboxamide was carried out with 4-aminophenol according to method A2, step 4, to give 4- (2-carbamoyl-4-pyridyloxy) aniline form. According to procedure C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2-carbamoyl-4-pyridyloxy) aniline, to give the urea.

entry 44: 4-Chloropyridine-2-carbonyl chloride HCl salt was mixed with ammonia according to procedure A2, step 3b reacted to form 4-chloro-2-pyridinecarboxamide. 4-chloro-2-pyridinecarboxamide was treated with 3-aminophenol according to method A2, step 4, reacted to give 3- (2-carbamoyl-4-pyridyloxy) aniline to build. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 3- (2-carbamoyl-4-pyridyloxy) aniline reacted to give the urea.

entry 45: 4-Chloro-N-methyl-2-pyridinecarboxamide, prepared according to method A2, step 3a, was synthesized with 3-aminophenol according to methods A2, step 4, reacted to give 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to build. According to procedure C1a became 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline reacted to give the urea.

entry 46: 5- (4-Aminophenoxy) isoindoline-1,3-dione was prepared according to procedure A3 implemented. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to give the urea to surrender.

entry 47: 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) -2-methylaniline according to procedure A5 synthesized. According to Method C1c, 4-chloro-3- (trifluoromethyl) phenyl isocyanate reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to give the urea.

entry 48: 4- (3-N-Methylsulfamoyl) phenyloxy) aniline was prepared according to procedures A15 synthesized. According to method c1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was added with 4- (3-N-methylsulfamoyl) phenyloxy) aniline, to give the urea.

entry 49: 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was prepared according to procedures A6 synthesized. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate reacted with 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to give the urea to surrender.

entry 50: According to procedure A2, step 4, was 5-amino-2-methylphenol with 4-chloro-N-methyl-2-pyridinecarboxamide reacted, which had been synthesized according to procedures A2, step 3b, to give 3- (2- (N -methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate reacted with 3- (2- (N -methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to give the urea to surrender.

entry 51: 4-Chloropyridine-2-carbonyl chloride was treated with ethylamine according to procedures A2, step 3b, implemented. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, Step 4, reacted to give 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline to surrender. According to procedure C1a was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate 4- (2- (N -ethylcarbamoyl) -4-pyridyloxy) aniline to give the urea.

entry 52: According to procedure 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, to 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to surrender. According to procedure C1a became 4-chloro-3- (trifluoromethyl) phenyl isocyanate reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to give the urea to surrender.

entry 53: 4- (4-Methylthiophenoxy) -1-nitrobenzene was prepared according to procedures A19, step 1, oxidized to 4- (4-methylsulfonylphenoxy) -1-nitrobenzene to surrender. The nitrobenzene was prepared according to procedure A19, step 2, reduced to 4- (4-methylsulfonylphenoxy) -1-aniline to surrender. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate reacted with 4- (4-methylsulfonylphenoxy) -1-aniline, to give the urea.

entry 54: 4-Bromobenzenesulfonyl chloride was treated with methylamine according to procedures A15, Step 1, reacted to give N-methyl-4-bromobenzenesulfonamide result. N-Methyl-4-bromobenzenesulfonamide was coupled with phenol according to procedure A15, step 2, to give 4- (4- (N-methylsulfamoyl) phenoxy) benzene. 4- (4- (N-methylsulfamoyl) phenoxy) benzene was corresponding to 4- (4- (N-methylsulfamoyl) phenoxy) -1-nitrobenzene Method A15, step 3, transferred. 4- (4- (N-methylsulfamoyl) phenoxy-1-nitrobenzene became 4- (4-N-methylsulfamoyl) phenyloxy) aniline according to procedure A15, step 4, reduced. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate reacted with 4- (3-N-methylsulfamoyl) phenyloxy) aniline to give the urea to surrender.

entry 55: 5-Hydroxy-2-methylpyridine was reacted with 1-fluoro-4-nitrobenzene according to Method A18, Step 1, coupled to 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene to surrender. The methylpyridine was oxidized corresponding to the carboxylic acid and then according to procedures A18, step 2, esterified to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene to surrender. The nitrobenzene was prepared according to procedure A18, step 3, reduced to 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline to surrender. The aniline was treated with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to procedures C1a reacted to give the urea.

entry 56. 5-Hydroxy-2-methylpyridine was treated with 1-fluoro-4-nitrobenzene according to Method A18, Step 1, coupled to 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene to surrender. The methylpyridine was oxidized according to the carboxylic acid, then according to procedure A18, step 2, esterified to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene to surrender. The nitrobenzene was prepared according to procedure A18, step 3, reduced to 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline to surrender. The aniline was treated with 4-chloro-3- (trifluoromethyl) phenyl isocyanate correspondingly Method C1a reacted to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (methoxycarbonyl) -5-pyridyloxy) phenyl) urea. The methyl ester was reacted according to method D2 with methylamine, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -5-pyridyloxy) phenyl) urea to surrender.

entry 57: N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4-aminophenyl) -urea became corresponding Method C1d produced. N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4-aminophenyl) urea was coupled with mono-methyl isophthalate according to method D1a, to give the urea.

entry 58: N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4-aminophenyl) -urea became corresponding Method C1d produced. N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4-aminophenyl) urea was coupled with mono-methyl isophthalate according to method D1a, N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea to surrender. According to Method D2, N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea reacted with methylamine to give the corresponding methylamide.

entry 59: 4-Chloropyridine-2-carbonyl chloride was treated with dimethylamine according to procedures A2, step 3b, implemented. The resulting 4-chloro-N, N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, to give 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline. Corresponding Method C1a was 4-chloro-3- (trifluoromethyl) phenyl) isocyanate with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline reacted to give the To give urea.

entry 60: 4-Hydroxyacetophenone was treated with 4-fluoronitrobenzene according to Method A13, step 1, reacted to give 4- (4-acetylphenoxy) nitrobenzene result. The nitrobenzene was prepared according to procedure 13, step 4, reduced to 4- (4-acetylphenoxy) aniline in the 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt was converted according to procedure A16. According to method C1a was 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (4-acetylphenoxy) aniline reacted to give the urea.

entry 61: 4- (3-carboxyphenoxy) -1-nitrobenzene was prepared according to procedure A13, step 2, synthesized. 4- (3-carboxyphenoxy) -1-nitrobenzene was treated with 4- (2-aminoethyl) morpholine according to method A13, step 3, coupled to 4- (3- (N- (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene to surrender. According to Method A13, Step 4, 4- (3- (N- (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene to 4- (3- (N- (2-morpholinylethyl) carbamoyl) phenoxy) aniline reduced. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (3- (N- (2-morpholinylethyl) carbamoyl) phenoxy) aniline reacted to give the urea.

entry 62: 4- (3-carboxyphenoxy) -1-nitrobenzene was prepared according to procedure A13, step 2 synthesized. 4- (3-carboxyphenoxy) -1-nitrobenzene was treated with 1- (2-aminoethyl) piperidine according to method A13, step 3, coupled to give 4- (3- (N- (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene to surrender. According to Method A13, Step 4, 4- (3- (N- (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene was reduced 4- (3- (N- (2-Piperidylethyl) carbamoyl) phenoxy) aniline. Corresponding Method C1a was 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (3- (N- (2-piperidylethyl) carbamoyl) phenoxy) aniline reacted to give to give the urea.

entry 63: 4- (3-Carboxyphenoxy) -1-nitrobenzene was prepared according to Method A13, Step 2, synthesized. 4- (3-carboxyphenoxy) -1-nitrobenzene was treated with tetrahydrofurfurylamine coupled according to method A13, step 3, to give 4- (3- (N- (tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene to surrender. According to Method A13, Step 4, 4- (3- (N- (tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene to 4- (3- (N- (tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline reduced. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (3- (N- (tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline reacted to give the urea.

entry 64: 4- (3-carboxyphenoxy) -1-nitrobenzene was prepared according to procedure A13, step 2 synthesized. 4- (3-carboxyphenoxy) -1-nitrobenzene was treated with 2-aminomethyl-1-ethylpyrrolidine according to method A13, step 3, coupled to give 4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene to surrender. According to Method A13, Step 4, 4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene to 4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) aniline reduced. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) aniline reacted to give the urea.

entry 65: 4-chloro-N-methylpyridinecarboxamide was used as in Method A2, Step 3b, described, synthesized. The chloropyridine was with 4-aminothiophenol according to method A2, step 4, reacted to 4- (4- (2- (N-Methylcarbamoyl) phenylthio) aniline to surrender. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline reacted to give the urea.

entry 66: 4-Chloropyridine-2-carbonyl chloride was used according to procedure A2, step 3b, reacted with isopropylamine. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol, according to method A2, step 4, to give 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline. Corresponding Method C1a was 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline reacted to give the To give urea.

Entry 67: N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4-ethoxycarbonylphenyl) urea was synthesized according to Method C1e N- (4-chloro-3- (trifluoromethyl) phenyl-N'- (4-ethoxycarbonylphenyl) urea was saponified according to Method D3 to give N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4-carboxyphenyl) -harn to give substance. N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4-carboxyphenyl) -urea was coupled with 3-methylcarbamoylaniline according to Method D1b to give N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea.

entry 68: 5- (4-Aminophenoxy) -2-methylisoindoline-1,3-dione became corresponding Method A9 synthesized. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate reacted with 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione to afford the urea result.

entry 69: 4-Chloro-N-methylpyridinecarboxamide was used as in Method A2, Step 3b, described, synthesized. The chloropyridine was with 3-aminothiophenol according to method A2, step 4, reacted to 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline to surrender. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 3- (4- (2- (N -methylcarbamoyl) phenylthio) aniline reacted to give the urea.

entry 70: 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline synthesized according to method A10. According to procedure C1a became 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline reacted to give the urea.

entry 71: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was correspondingly Method A14 synthesized. 4-chloro-3- (trifluoromethyl) -2-methoxyphenyl isocyanate was corresponding to 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline Method C1a reacted to give the urea. N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to procedure D4, step 1, and the corresponding Acid became with 4- (2-aminoethyl) morpholine coupled to give the amide.

entry 72: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to procedures A14 synthesized. 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline reacted according to method C1a to give the urea. N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to procedure D4, step 1, and the corresponding Acid became with methylamine according to method D4, step 2, coupled to to surrender the amide.

entry 73: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was correspondingly Method A14 synthesized. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline reacted according to method C1a to give the urea. N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl urea was saponified according to procedure D4, step 1, and the corresponding Acid became with N, N-dimethylethylenediamine according to method D4, step 2, coupled to the amide result.

entry 74: 4-Chloropyridine-2-carbonyl chloride HCl salt was treated with 2-hydroxyethylamine according to method A2, step 3b reacted to give 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide to surrender. 4-Chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol, according to Method A17, 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline to surrender. According to method C1a was 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyanilin to give N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea to surrender.

entry 75: 4- (3-carboxyphenoxy) aniline was prepared according to Method A11 synthesized. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline reacted according to method C1f to give the urea, which is coupled with 3-aminopyridine according to Method D1c has been.

entry 76: 4- (3-carboxyphenoxy) aniline was prepared according to Method A11 synthesized. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was with 4- (3-carboxyphenoxy) aniline reacted according to method C1f to give the urea, which is coupled with N- (4-acetylphenyl) piperazine according to Method D1c has been.

entry 77: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to procedure C1f to give the urea which reacts with 4-fluoroaniline according to method D1c was paired.

entry 78: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to procedure C1f reacted to give the urea which reacts with 4- (dimethylamino) aniline according to procedure D1c was paired.

entry 79: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to procedure C1f to give the urea, which with N-phenylethylenediamine according to procedure D1c was paired.

entry 80: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to procedure C1f reacted to give the urea, which with 2-methoxyethylamine according to procedure D1c was paired.

entry 81: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to procedure C1f reacted to give the urea, which with 5-amino-2-methoxypyridine according to procedure D1c was paired.

entry 82: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to procedure C1f reacted to give the urea, which with 4-morpholinoaniline according to procedure D1c was paired.

entry 83: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to procedure C1f reacted to give the urea, which with N- (2-pyridyl) piperazine according to procedure D1c was paired.

entry 84: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-hydroxyethylamine according to procedure A2, step 3b, to give 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide to build. 4-Chloro-N- (2-triisopropylsilyloxy) ethylpridin-2-carboxamide was reacted with triisopropylsilyl chloride followed by 4-aminophenol according to procedure A17, 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline to build. According to procedure C1a became 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline reacted to give N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea to surrender. The urea was deprotected according to Method D5 to N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (4- (2- (N- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea to build.

entry 85: 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) aniline was prepared according to procedures A2 synthesized. 4-Bromo-3- (trifluoromethylaniline was dissolved in 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to procedure B1 transferred. According to procedure C1a became 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline reacted to give the urea.

entry 86: 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was prepared according to procedures A6 synthesized. 4-Bromo-3- (trifluoromethyl) aniline was converted into 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to procedure B1 transferred. Corresponding Method C1a was 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline reacted to give the urea.

entry 87: According to procedure 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, to 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to surrender. 4-Bromo-3- (trifluoromethyl) aniline was converted into 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to procedure B1 transferred. According to procedure C1a was reacted with 4-bromo-3- (trifluoromethyl) phenyl isocyanate 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to give the urea.

entry 88: 4-Chloropyridine-2-carbonyl chloride was treated with ethylamine according to procedures A2, step 3b, implemented. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, Step 4, reacted to give 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline to surrender. 4-bromo-3- (trifluoromethyl) aniline was in 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1 transferred. According to procedure C1a became 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline, reacted to give the To give urea.

Entry 89: 4-Chloro-N-methyl-2-pyridinecarboxamide synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to give 3- (2- (N-methylcarbamo yl) -4-pyridyloxy) aniline. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give the urea.

entry 90: According to procedure 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, 3- (2- (N -methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to surrender. 4-Bromo-3- (trifluoromethyl) aniline was converted into 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to procedure B1 transferred. Corresponding Method C1a was 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline reacted to give the urea.

entry 91: 4-Chloropyridine-2-carbonyl chloride was treated with dimethylamine according to procedures A2, step 3b, implemented. The resulting 4-chloro-N, N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, reacted to give 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline to surrender. 4-bromo-3- (trifluoromethyl) aniline was in 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1 transferred. According to procedure C1a was 4-bromo-3- (trifluoromethylphenyl isocyanate with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline to to give the urea.

entry 92: 4-Chloro-N-methylpyridinecarboxamide was used as in Method A2, Step 3b described, synthesized. The chloropyridine was with 4-aminothiophenol according to the method A2, step 4, to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline result. 4-Bromo-3- (trifluoromethyl) aniline was converted into 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to procedure B1 transferred. According to procedure C1a became 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline to give the To give urea.

entry 93: 4-Chloro-N-methylpyridinecarboxamide was used as in Method A2, Step 3b described, synthesized. The chloropyridine was with 3-aminothiophenol according to method A2, step 4, to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline result. 4-Bromo-3- (trifluoromethyl) aniline was converted into 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to procedure B1 transferred. Corresponding Method C1a was 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline to give the To give urea.

entry 94: 4- (2- (N-2-morpholin-4-yl-ethyl) -carbamoyl) -pyridyloxy) -aniline according to procedure A10 synthesized. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to procedure B1 transferred. Corresponding Method C1a was 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline reacted to give the urea.

entry 95: 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) aniline was prepared according to procedures A2 synthesized. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline synthesized according to method A7. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was in 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to procedure B1 transferred. According to procedure C1a became 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give the To give urea.

entry 96: 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was prepared according to procedures A6 synthesized. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline according to procedure A7 synthesized. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline in 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to the method B1 transferred. According to procedure C1a became 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate reacted with 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to give the urea to surrender.

entry 97: According to procedure A2, step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which has been synthesized according to method A2, step 3b, to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was according to procedures A7 synthesized. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline in 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to procedure B1 transferred. According to procedure C1a became 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate reacted with 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to give the urea to surrender.

Entry 98: 4-Chloro-N-methyl-2-pyridinecarboxamide synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4, to give 3- (2- (N-methylcarbamoyl) 4-pyridyloxy) aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synated according to Method A7 thesized. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline as it was to yield the urea.

entry 99: 4-Chloropyridine-2-carbonyl chloride was treated with ethylamine according to procedures A2, step 3b, implemented. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, Step 4, reacted to give 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline to surrender. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was according to procedures A7 synthesized. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline in 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to procedure B1 transferred. According to procedure C1a was 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline reacted to give the urea.

entry 100: 4-Chloropyridine-2-carbonyl chloride was treated with dimethylamine according to procedures A2, step 3b, implemented. The resulting 4-chloro-N, N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, to give 4- (2- (N, N-dimethylcarbamoyl) -4-pyridiyloxy) aniline to surrender. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was according to procedures A7 synthesized. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline in 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to procedure B1 transferred. According to procedure C1a became 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline reacted to give the urea.

entry 101: 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to procedure A2, step 3a, was reacted with 3-aminophenol according to method A2, step 4, reacted to form 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. 2-Amino-3-methoxynaphthalene was synthesized as described in Method A1. Corresponding Process C3 was reacted with 2-amino-3-methoxynaphthalene with bis (trichloromethyl) carbonate, followed by 3- (2- (N -methylcarbamoyl) -4-pyridyloxy) aniline to give the urea to build.

entry 102: 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) aniline was prepared according to procedures A2 synthesized. 5-tert-butyl-2- (2,5-dimethylpyrrolyl) aniline according to procedure A4 synthesized. 5-tert-butyl-2- (2,5-dimethylpyrrolyl) aniline reacted with CDI, followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline according to procedure C2d to give the urea.

entry 103: 4-chloro-N-methyl-2-pyridinecarboxamide was prepared according to procedure A2, step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was with 4-aminophenol according to procedure A2, step 4, implemented using DMAC instead of DMF to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. According to procedure C2b gave reaction of 3-amino-2-methoxyquinoline followed by CDI of 4- (2- (N -methylcarbamoyl) -4-pyridyloxy) aniline Bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea.

In The following tables list compounds which have been synthesized according to the detailed experimental procedures given above:

tables

The in Tables 1-6 listed below Compounds were prepared according to the general The methods shown above are synthesized, and the more detailed ones Exemplary procedures are listed in the entry listings above with the characterizations in the tables.

Table 1. 3-tert-butylphenyl ureas

Table 2. 5-tert-butyl-2-methoxyphenyl ureas

Table 3. 5- (Trifluoromethyl) -2-methoxyphenylureas

Table 4. 3- (trifluoromethyl) -4-chlorophenyl ureas

Table 5. 3- (trifluoromethyl) -4-bromophenylureas

Table 6. 5- (Trifluoromethyl) -4-chloro-2-methoxyphenylureas

Table 7. Additional ureas

The previous examples can with similar Success be repeated by swapping the generic or specific reactants and / or working conditions described of this invention used in the previous examples were.

Claims (18)

Compound selected from the group consisting out the 4-chloro-3- (trifluoromethyl) phenylureas: N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl-N' - (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenylurea and N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (2-chloro-4- (2- (N methylcarbamoyl) (4-pyridyloxy)) phenyl-urea; the 4-bromo-3- (trifluoromethyl) phenylureas: N- (4-bromo-3- (trifluoromethyl) phenyl-N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenylurea, N- (4-bromo-3- (trifluoromethyl) phenyl-N '- (4- (2-N-methylcarbamoyl) -4-pyridyloxy) phenyl urea, N- (4-bromo-3- (trifluoromethyl) phenyl-N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl urea, N- (4-bromo-3- (trifluoromethyl) -phenyl-N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea and N- (4-bromo-3- (trifluoromethyl) phenyl-N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, the 2-methoxy-4-chloro-5- (trifluoromethyl) phenylureas: N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl-N '- (4- (2- (N-methylcarbamoyl) - 4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl urea or a pharmaceutically acceptable Salt of it. A compound according to claim 1, which is a pharmaceutically acceptable salt thereof selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, trifluorosulfonic, benzenesulfonic , 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 alpha-hydroxyphenylacetic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof and a physiologically compatible Carrier. A compound according to claim 1, selected from the group consisting of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N'-2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, N- (4-bromo 3- (trifluoromethyl) phenyl-N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N' - (2- Chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea or a pharmaceutically acceptable Salt of it. A compound according to claim 4 which is a pharmaceutical compatible Salt of it is selected from the group consisting of a) basic salts 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 alpha-hydroxyphenylacetic acid; and b) acid salts organic and inorganic bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, the Ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. A pharmaceutical composition comprising a compound according to claim 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable Carrier. Use of a compound according to claim 1, selected from the group consisting of the 4-chloro-3- (trifluoromethyl) phenylureas: N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl urea, N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (3- (2- (N-methylcrbamoyl) -4-pyridyloxy) phenyl urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) - N '- (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenylurea and N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (2-chloro-4- (2 -N-methylcarbamoyl) (4-pyridyloxy) phenyl) urea, the 4-bromo-3- (trifluoromethyl) phenylureas: N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl urea, N- (4-bromo-3- (trifluoromethyl) phenyl-N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl-N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy) phenyl) urea and N- (4-bromo-3- (trifluoromethyl) phenyl-N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea; the 2-methoxy-4-chloro-5- (trifluoromethyl) phenylureas: N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy- 4-chloro-5- (trifluoromethyl) phenyl-N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl urea or a pharmaceutically acceptable A salt thereof for the manufacture of a medicament for the treatment of cancerous cell growth mediated by raf kinase. Use of a compound according to claim 1 selected from the group consisting of the 4-chloro-3- (trifluoromethyl) phenylureas: N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (3- (2 -carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea , N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) - N '- (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea and N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (2-chloro-4- ( 2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, the 4-bromo-3- (trifluoromethyl) phenylureas: N- (4-bromo-3- (trifluoromethyl) phenyl) -N'- (3- (2- (N-Methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methycarbamoyl) 4-pyridyloxy) phenylurea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N -methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-c chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenylurea and N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl urea; the 2-methoxy-4-chloro-5- (trifluoromethyl) phenylureas: N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl-N '- (4- (2- (N-methylcarbamoyl) 4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N -methylcarbamoyl) (4- pyridyloxy)) phenyl) urea or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of i) carcinomas of the lung, pancreas, thyroid, colonic bladder ii) myeloid leukemia or iii) colon villus adenomas. Use of a compound according to claim 1, selected from the group consisting of the 4-chloro-3- (trifluoromethyl) phenylureas: N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (n -methylcarbamoyl) -4-pyridyloxy) phenyl) urea and N- (4-chloro-3- (trifluoromethyl ) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, the 4-bromo-3- (trifluoromethyl) phenylureas: N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) - urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenylurea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N -methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (4-bromo-3- (trifluoromethyl ) phenyl) -N '- (2-chloro- (4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea and N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy) phenyl) urea; the 2-methoxy-4-chloro-5- (trifluoromethyl) phenylureas: N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea or a pharmaceutically acceptable A salt thereof for the manufacture of a medicament for the treatment of Tumors. Use of a compound according to claim 4 selected from the group consisting of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro) 3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl-urea; N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy- 4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea or a pharmaceutically acceptable A salt thereof for the manufacture of a medicament for the treatment of a cancerous cell growth mediated by raf kinase. Use of a compound according to claim 4 selected from the group consisting of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro) 3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (n -methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy- 4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl urea or a pharmaceutically acceptable A salt thereof for the manufacture of a medicament for the treatment of i) Carcinomas of the lungs, pancreas, thyroid, bladder, colon, ii) myeloid leukemia or iii) Colon villus adenoma. Use of a compound according to claim 4 selected from the group consisting of N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4- (2-N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3 - (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy- 4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea or a pharmaceutically acceptable A salt thereof for the manufacture of a medicament for the treatment of Tumors. The compound of claim 1, which is N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea is. A compound according to claim 1, which is N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamo yl) -4-pyridyloxy) phenyl) urea. A pharmaceutical composition comprising N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable Salt thereof and a physiologically acceptable carrier. A pharmaceutical composition comprising N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable Salt thereof and a pharmaceutically acceptable carrier. Use of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable A salt thereof for the manufacture of a medicament for the treatment of a cancerous cell growth mediated by raf kinase. Use of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable A salt thereof for the manufacture of a medicament for the treatment of a cancerous cell growth mediated by raf kinase.