SK285532B6 - Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors, their use and pharmaceutical compositions containing them - Google Patents

Abstract

This invention relates to a group of aryl ureas, their use for the treatment of diseases mediated by raf kinase and pharmaceutical compositions containing them.

Description

Technical field

The present invention describes the use of aryl ureas in the treatment of raf-related diseases and the use of pharmaceutical compositions for the treatment of this disease.

BACKGROUND OF THE INVENTION

The p21 ^ras oncogene is the major contributor to the development and progression of solid cancers in human subjects 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 growth factor receptor-regulated signal transduction cascade in almost all tissues (Avruch et al., Trends Biochem. Sci. 1994, 19, 279-83). The ras guanine nucleotide binding protein is biochemical, and cyclization between the GTP-bound activated form and the GDP-bound resting form is precisely regulated by the activity of ras endogenous GTPase and other regulatory proteins. In cancer mutant ras cells, endogenous GTPase activity is small, and therefore the protein imparts constitutive growth signals to downstream effectors, e.g. the enzyme rafkinase, resulting in cancerous growth of cells that carry these mutants (Magnuson et al., Semin. Cancer Biol. 1994, 5, 247-53). Inhibition of the effect of active ras by inhibiting the rafkinase signaling pathway by applying inactivated anti-rafkinase antibodies or by coexpression of dominant negative rafkinase, or dominant negative MEK, a rafkinase substrate, has been found to reverse transformed cells to normal growth phenotype (see: Daum et al., Trends Biochem Sci., 1994, 19, 474-80, Fridman et al, J. Biol. Chem., 1994, 269, 30105-8. Kolch et al (Nature 1991, 349, 426-28) further suggests that inhibition expression of raf with antisense RNA blocks cell proliferation in membrane-associated oncogenes.In a similar way, inhibition of raffinase (antisense oligodeoxynucleotides) was correlated in vitro and in vivo with inhibition of growth of various human tumor types (Klonia et al., Nat. Med., 1996, 2). , 668-75).

SUMMARY OF THE INVENTION

The present invention provides compounds that are inhibitors of the enzyme rafkinase. Since the enzyme is a downstream effector of p21 ^ras , inhibitors are effective in pharmaceutical formulations for use in human or veterinary subjects where inhibition of the rafkinase pathway, e.g. in the treatment of tumors and / or cancer cell growth associated with raffinase. In particular, the compounds are useful in the treatment of human or animal cancers, e.g. mouse carcinomas, since the progression of these carcinomas is dependent on a cascade of signal transduction of ras protein and is therefore sensitive to treatment by disrupting the cascade, ie, by inhibiting rafkinase. Thus, the compounds of the invention are effective in the treatment of solid tumors, e.g. carcinomas (e.g., lung, pancreas, thyroid, bladder or colon cancer), myeloid diseases (e.g., myeloid leukemia), or adenoma (e.g., villous colon adenoma).

Therefore, the present invention provides compounds generally referred to as aryl ureas, including both aryl and heteroaryl analogs that inhibit the rafkinase pathway. Thus, the invention provides compounds that inhibit the enzyme rafkinase, as well as compounds, compositions and methods for treating cancer cell growth mediated by rafkinase, wherein the compound of the invention is an acceptable salt thereof.

The compound of the invention is selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenyl ureas: N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy)) N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea; 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 N - (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl)) - 4-pyridyloxy) phenyl) urea;

4-bromo-3- (trifluoromethyl) phenyl urea n: N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea N - (4-bromo-3- ( trifluoromethyl) phenyl) - N - (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, N - (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro- 4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl urea and N- (4-bromo-3- (trifluoromethyl) phenyl) -N- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy) phenyl) urea 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl urea: N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea and N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, or a pharmaceutically acceptable salt thereof.

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

Suitable pharmaceutically acceptable salts are well known to the skilled artisan and include basic salts of inorganic and organic acids, including e.g. hydrochloric, hydrobromic, sulfuric, orthophosphoric, methanesulfonic, trifluoromethanesulfonic, benzenesulfonic, p-toluenesulfonic, 1-naphthalenesulfonic, 2-naphthalenesulfonic, acetic, trifluoroacetic, benzal, oxalic, tartaric, tartaric, tartaric, tartaric, tartaric, tartaric salicylic, phenylacetic and phenylglycolic acids. In addition, pharmaceutically acceptable salts include the acid salts of inorganic bases, e.g. salts containing alkali metal cations (e.g. Li ⁺ , Na ⁺ or K '), alkaline earth metal cations (e.g. Mg ²⁺ , Ca ²⁺ or Ba ²⁺ ), ammonium cation, and acidic salts of organic bases including aliphatic and an ammonia-substituted aromatic group and quaternary ammonium cations, e.g. resulting from the protonation or peralkylation of triethylamine, N, 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).

Many of the compounds have asymmetric carbon atoms and can therefore exist in racemic and optically active forms. Methods for separating enantiomeric and diastereomeric mixtures are well known to those skilled in the art. The present invention encompasses any isolated racemic or optically active form of the compounds described by formula (I) having rafkinase inhibitory activity.

General methods of preparation

The compounds of the invention may be prepared by known chemical reactions and procedures, some of which may be prepared from starting materials that are commercially available. However, the following general methods of preparation are provided and are intended to serve as guidance for the skilled artisan in the synthesis of these compounds. Methods of preparation are provided with more detailed examples described in the experimental section.

Substituted anilines can be prepared by standard methods (March. Advanced Organic Chemistry, 3 ^rd Ed .; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). According to Scheme I, arylamines are generally synthesized by reducing nitroaryls with catalysts (metals), e.g. Ni, Pd or Pt and H ₂ , or hydride transfer agents such as e.g. formate, cyclohexadiene or borohydride (Rylander, Hydrogenation Metods; Academic Press: London, UK (1985)). Nitroaryls can also be directly reduced by a strong hydride source, e.g. LiAlH ₄ (Seyden-Penne, Reductions by Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)) or zero-charge metals, e.g. Fe, Sn or Ca, usually in acidic medium. There are many methods for nitroaryl synthesis (March. Advanced Organic Chemistry, 3 ^rd Ed .; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)).

H ₂ (Catalyst /( Nap. Ni, Pd, Pt)

ArtJOj -------- KJ ------ ►- AiNH ₂ \ ^M (°> X (eg Fe, Sn, Ca)

Scheme I Reduction of nitroaryls to arylamines

Nitroaryls are commonly prepared by electrophilic aromatic nitration with HNO ₃ or alternatively by a NO ₂ ⁺ source. The nitroaryls may be further processed prior to reduction. Thus substituted nitroaryls

HNO ₃

Ar-H ----------------- ►- ArNO} a strong leaving group (e.g. F, Cl, Br, etc.) may undergo substitution reactions when reacting with nucleophiles, e.g. thiolate (shown in the examples in Scheme II) or phenoxide. Nitroaryls may also be subject to Ullman-type coupling reactions (Scheme II).

Selected nucleophilic aromatic substitution by nitroaryl

Nitroaryls may also undergo metal-mediated cross-coupling reactions in transit. For example, nitroaryl electrophiles, e.g. nitroaryl bromides, iodides or triflates are subject to cross-coupling reactions with palladium-mediated aryl nucleophiles, e.g. with aryl boronic acids (Suzuki reaction), arylcines (Stille reaction) or arylzines (Negishi reaction) to obtain biaryls (5).

ArS (OFT) ₂

Pd (0)

Either nitroaryls or anilines can be converted to the corresponding arenesulfonyl chlorides (7) by reaction with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source, e.g. KF, provides sulfonyl fluoride (8). Reacting the sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, e.g. tris (dimethylamino) sulfonium difluorotrimethylsiliconate (TASF) to give the corresponding trifluoromethylsulfone (9). Alternatively, the sulfonyl chloride 7 can be reduced to arenethiol (10) e.g. zinc amalgam. Treatment of thiol 10 with CHCl ₃ in the presence of a base gives difluoromethyl mercaptan (11), which can be oxidized to sulfone (12) by any of various oxidants, including a mixture of CrO ₃ and acetic anhydride (Sedova et al., Zh. 6, (568).

Scheme III Selected Methods for Synthesis of Fluorinated Arylsulfones

According to Scheme IV, the unsymmetrical preparation of urea involves the reaction of an arylisocyanate (14) with an arylamine (13). The heteroaryl isocyanate can be synthesized from heteroarylamine by reaction with phosgene or phosgene equivalent, such as e.g. trichloromethylchloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene) or Λ ', Α' '- carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, e.g. an ester, an acid halide or an anhydride by Curtius rearrangement. Thus, reaction of the acid derivative 16 with an azide source and subsequent rearrangement affords an isocyanate. The corresponding carboxylic acid (17) can be subjected to Curtius rearrangements using diphenylphosphoryl azide (DPPA) or similar agents.

Ar'-NHj 13 | COCIj Ar’-NCO

TSD-Ar ² ^ ^Ν Λ Ν '^ HH

N, -7 DPPA / ABOUT \ 0 Λ Ar ^ OH s 17

Scheme IV Selected methods for the preparation of unsymmetrical urea

In the final step, the ureas may be further processed by methods known to the skilled artisan.

The invention also encompasses pharmaceutical compositions comprising a compound of the invention and a physiologically acceptable carrier.

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

Formulations intended for oral use may be prepared according to any suitable processing methods for pharmaceutical preparations. Such compositions may contain one or more agents selected from the group consisting of diluents, sweeteners, flavoring agents, coloring agents and preservatives to provide readily digestible compositions. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be e.g. inert diluents, e.g. calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and tablet disintegrants, e.g. corn starch or alginic acid; and binders, e.g. magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby prolong the effect. For example, retardants, e.g. glyceryl monostearate or glyceryl distearate. These compounds may also be prepared in a solid, rapid release form.

Formulations for oral use may be solid gelatin capsules, wherein the active ingredient is admixed with an inert solid diluent, e.g. calcium carbonate, calcium phosphate or kaolin, or they may be soft gelatin capsules, wherein the active ingredient is admixed with water or an oil medium such as e.g. peanut oil, mineral oil or olive oil.

Aqueous suspensions containing the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used. Such excipients are suspending agents, e.g. sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia; dispersants or detergents may be natural phosphatides, e.g. Iecithin or condensation products, or fatty acid alkene oxide, e.g. polyoxyethylene stearate, or the condensation products of ethylene oxide with long-chain aliphatic alcohols, e.g. heptadecaethyleneoxycethanol, or the condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, e.g. polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, e.g. , polyethylene. Aqueous suspensions may also contain one or more preservatives, e.g. ethyl or n-propyl (p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents and one or more sweetening agents such as sucrose or saccharin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or detergent, suspending agent and one or more preservatives. Suitable dispersing or detergent and suspending agents are shown in the examples. Other excipients, e.g. sweeteners, flavorings and coloring agents.

The compounds may also be in the form of anhydrous liquid preparations, e.g. as oily suspensions, which may be prepared by suspending the active ingredients in a vegetable oil, e.g. peanut oil, olive oil, sesame oil or peanut oil, or in mineral oil, e.g. in paraffin oil. The oily suspensions may contain a thickening agent, e.g. beeswax, hard paraffin or cetyl alcohol. For example, said sweeteners and flavoring agents may be added to provide readily digestible oral preparations. These compositions may be protected by the addition of an antioxidant, such as e.g. ascorbic acid.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, e.g. olive oil or peanut oil, or mineral oil, e.g. paraffin oil or mixtures thereof. Suitable emulsifiers may be natural gums, e.g. gum arabic or tragacanth, natural phosphatides, e.g. soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, e.g., sorbitan monooleate and condensation products of said partial esters with ethylene oxide, e.g. polyoxyetylénsorbitanmonoolcát. The emulsions may also contain sweetening and flavoring agents.

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

The compounds may also be administered in the form of suppositories for rectal administration of the drug. These formulations can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at normal temperature but liquid at rectal temperature and therefore dissolves in the rectum to release the drug. Such materials include cocoa oil and polyethylene glycols.

For all treatment regimens used herein, the daily oral dose will preferably be from 0.01 to 200 mg / kg of total body weight. The daily dose administered 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 dose for rectal administration will preferably be from 0.01 to 200 mg / kg of total body weight. The daily topical dosage will preferably be from 0.1 to 200 mg, which will be administered one to four times daily.

The daily dose for inhalation will preferably be from 0.01 to 10 mg / kg of total body weight.

However, it will be clear to the professional public that the various routes of administration will depend on various factors, i. j. from all those commonly considered when therapeutic agents are applied. Obviously, the specific dosage level for any individual patient will depend on various factors including the activity of the specific compound used, the patient's age, the patient's body weight, the general health of the patient, the patient's sex and lifestyle, time of administration, route of administration and excretion. the combination and severity of the ongoing therapy. Nevertheless, it will be further clear to the professional public that the optimal course of treatment, i.e. the treatment of the patient. j. the method of treatment and the daily number of doses of a compound of the invention or a pharmaceutically acceptable salt thereof administered over a specified number of days can be ascertained by persons skilled in the art using conventional treatment tests.

Obviously, the specific dose level for any patient will depend on various factors, including the activity of the specific compound used, age, body weight, general health, sex, eating habits, time and mode of administration, excretion rate, drug combination and other conditions throughout therapy.

The compounds of the invention may be prepared from known compounds (or starting materials that may be prepared from known compounds), e.g. using the above general methods of preparation. The activity of the provided compound for inhibiting rafkinase can be routinely determined, e.g. by the above procedures. The following examples are for illustrative purposes only and are not intended to limit the present invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

All reactions are carried out in glass containers that have been previously flame dried or in an oven under dry argon or dry nitrogen pressure. Stirring was performed magnetically unless otherwise indicated. Appropriate liquid substances and solutions were operated via syringe or cannula and introduced into reaction vessels through a rubber septum.

Unless otherwise stated, the term "concentrated under reduced pressure" refers to the use of a Buchi rotary evaporator at about 15 mm Hg. Unless otherwise stated, the term "under high vacuum" refers to a vacuum of 0.4 to 1.0 mm Hg.

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

Technically pure reagents and solvents were used without further purification. N-Cyclohexyl-N '- (methylpolystyrene) carbodiimide was purchased from Calbiochem-Novabiochem Corp. Purchased were: 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 Synthesis of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem. 3, 1995, 129), 4- (3-carbamoylphenoxy) -1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79, J959, 760; Chem. Abstr. 53, 1959, 12761b), 3- tert -butylphenylisocyanate ( O. Rohr et al. (DE 2,436,108) and 2-methoxy

-5- (trifluoromethyl) phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491) has been described.

Thin layer chromatography (TLC) was performed on a glass plate covered with Whatman® silica gel, 60A F-254 silica gel with 250 gm thickness. The visualization was performed by one or more of the following techniques: a) ultraviolet radiation, b) exposure to iodine vapor, c) immersion of the plate in a 10% solution of molybdophosphoric acid in ethanol and subsequent heating, d) immersion of the plate in cerium sulfate solution and subsequent heating and / or e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science® silica gel.

Melting points were determined using a Thomas-Hoover instrument or a Mettler FP 66 automated to determine the melting point, and these melting points are not corrected. Fourier transform infrared spectroscopy spectra were obtained from a Mattson 4020 Galaxy Serie spectrophotometer. 1 H NMR spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with a standard of either Me ₄ Si (δ 0.00) or residual protonated solvent (CHCl ₃ δ 7.26; MeOH δ 3.30; DMSO δ) 2.49). ¹³ C NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (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 were obtained either as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact ionization mass spectra (EI-MS) were obtained from a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics desorption chemical ionization probe for sample introduction. The ion source was maintained at 250 ° C. Electron ionization impacts were performed with an electron energy of 70 eV and a 300 μΑ flux trap. Liquid cesium ionization secondary mass spectra (FAB-MS), the latest version of the fast atom bombardment mass spectrum, were obtained from a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained from a Hewlett Packard MS-Engine (5989A) spectrometer with methane or ammonia as the gaseous reagent (1 x 10 ⁴ torr to 2.5 x 10 ^-4 torr). The Direct Advertising Desorption Chemical Ionization (DCI) probe (Vaccumetrics, Inc.) was ramped with 0-1.5 amps in 10 sec and held at 10 amps until all traces of samples disappeared (~ 1-2 min). Spectra were taken from 50-800 amu at 2 sec per image. HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC instrument equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-800 amu using variable ion time according to the number of ions in the source. Gas Chromatography - Ion-Selective Mass Spectra (GC-MS) was obtained using a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM surface layer; 25 mx 0.2 mm) and a Hewlett Packard 5971 mass-selective detector (ionization) energy 70 eV). Elemental analysis was performed by Robertson Microlit Labs, Madison NJ.

All compounds shown by NMR spectra, LRMS and either elemental analysis or HRMS are consistent with the assigned structure.

List of abbreviations and acronyms

AcOH acetic acid anh anhydrous atm atmosphere

BOC tert-butoxycarbonyl

CDI 1,1'-carbonyldiimidazole conc concentrated d day (s) dec degradation

DMAC N, N-dimethylacetamide

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

DMF / N, N-dimethylformamide

DMSO dimethylsulfoxide

DPPA diphenylphosphoryl azide

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

EtOAc ethyl acetate

EtOH ethanol (100%)

Et ₂ O diethyl ether

Et ₃ N triethylamine h hour

HOBT I -hydroxybenzotriazole m-CPBA 3-chloroperoxybenzoic acid MeOH methanol pet. ether petroleum ether (boiling range 30-60 ° C)

THF tetrahydrofuran

TFA trifluoroacetic acid

Tf trifluoromethanesulfonyl

DETAILED DESCRIPTION OF THE INVENTION

A. General Methods for Synthesis of Substituted Anilines

Al. General process for the preparation of arylamine, including ether formation, ester saponification, Curtius rearrangement, and deprotection of the carbamate.

Synthesis of 2-amino-3-methoxynaphthalene

OMe

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 stirred at room temperature for 15 min, then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was stirred at room temperature overnight, then treated with water (200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with saturated NaCl solution (100 mL), dried (MgSO ₄ ), concentrated under reduced pressure (about 0.4 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil ( 10.30 g) 1 H NMR (DMSO-d ₆ ) δ 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J = 8.09 Hz, 1H) 7.44 (s, 1H), 7.53 (app t, J = 8.09 Hz, 1H), 7.84 (d, J = 8.09 Hz, 1H), 7.90 (s, 1H 8.21 (s, 1H).

OMe

Step 2. 3-Methoxy-2-naphthoic acid

A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room temperature was treated with a solution of 1 N NaOH (33.4 mL, 33.4 mmol). The mixture was heated at reflux for 3 hours, cooled to room temperature and acidified with 10% citric acid solution. The resulting solution was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was triturated with hexanes then washed several times with hexanes to give 3-methoxy-2-naphthoic 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-naphthoic acid (3.36 g, 16.6 mmol) and Et ₃ N (2.59 mL, 18.6 mmol) in anhydrous toluene (70 mL) was stirred at room temperature for 15 min. The reaction mixture was then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) by pipetting into the reaction mixture. The resulting mixture was heated at 80 ° C for 2 hours. After the mixture was cooled to room temperature, benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was then heated to 80 ° C overnight. The resulting mixture was cooled to room temperature, quenched with 10% citric acid solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 14% EtOAc and 86% hexanes to give 2- (N - (carbobenzyloxy) amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%): 1 H NMR (DMSO-d _d) δ 3.89 (s, 3H), 5.17 (s, 2H), 7.27 to 7.44 (m, 5 H), 7.72 to 7.75 (m, 2H) 8.20 (s, 1H); 8.76 (s, 1H).

OMe

Step 4. 2-Amino-3-methoxynaphthalene

A slurry of 2- (N - (carbobenzyloxy) amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd / C (0.5 g) in EtOAc (70 mL) was kept at room temperature overnight The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a light pink powder (2.40 g, 85%): 1 H NMR (DMSO-d ₆₎ δ 3.86 (s, 3H), 6.86 (s, 2H), 7.04 to 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 involving the preparation of carbamylpyridine and nucleophilic coupling with arylamine.

Synthesis of 4- (2-N'-methylcarbamyl-4-pyridyloxy) aniline

ABOUT

Step 1a. Synthesis of 4-chloro-N ^, -methyl-2-pyridinecarboxamidii by Menisci reaction

Warning: this reaction is very dangerous and potentially explosive. To a stirred solution of 4-chloropyridine (10.0 g) in Λ'-methylformamide (250 mL) at room temperature was added concentrated H ₂ SO ₄ (3.55 mL) to form an exothermic reaction. 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 form another exothermic reaction. The resulting mixture was stirred in a dark room at room temperature for 1 hour, then slowly warmed at 45 ° C for 4 hours. After bubbling is complete, the reaction is heated at 60 ° C for 16 hours. 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 x 500 mL). The organic phases were washed separately with saturated NaCl solution (3 x 150 mL), then combined, dried (MgSO ₄ ) and filtered through a pad of silica gel and washed with EtOAc. The resulting brown oil was purified by silica gel column chromatography with a gradient of 50% EtOAc / 50% hexanes to 80% EtOAc / 20% hexanes). The resulting yellow oil crystallized at 0 ° C after 72 hours 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 (CDCl 3) δ 3.04 (d, J = 5.1 Hz, 3H), 7.43 (dd, J = 5.4, 2.4 Hz, 1H), 7.96 (br s 1 H, 8.21 (s, 1H), 8.44 (d, J = 5.1 Hz, 1H); CI-MS m / z 171 ((M + H) < ^{+ >} ) ·

ABOUT

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

Anhydrous DMF (6.0 mL) was slowly added to SOCl ₂ (180 mL) over a temperature range of 40 ° to 50 ° C. The solution is stirred in this temperature range for 10 min, then portionwise over 30 min. add picolinic acid (60.0 g, 487 mmol). The resulting solution was heated at 72 ° C (vigorous SO ₂ release) for 16 hours to form a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. Addition of toluene and subsequent concentration was done twice more. The resulting almost dry residue was filtered and the solid was washed with toluene (2 x 200 mL) and dried under high vacuum for 4 hours to give 4-chloropyridine-2-carbonyl chloride hydrochloride as a yellow to orange solid (92.0 g, 89%).

YťHCI

Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate hydrochloride

Anhydrous DMF (10.0 mL) was slowly added to SOCl ₂ (300 mL) at 40-48 ° C. Stir the solution at this temperature range for 10 min, then add picolinic acid (100 g, 812 mmol) over 30 min. The resulting solution was heated at 72 ° C (vigorous SO ₂ release) for 16 hours to give a yellow solid. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. Addition of toluene and subsequent concentration was done twice more. The resulting almost dry residue was filtered and the solid was washed with toluene (50 mL) and dried under high vacuum for 4 hours to give 4-chloropyridine-2 hydrochloride.

-carbonyl chloride as a white solid (27.2 g, 16%). This substance is set aside.

The red filtrate was added to a solution of MeOH (200 mL) to maintain the temperature of the mixture below 55 ° C. The mixture was stirred at room temperature for 45 min, cooled to 5 ° C and treated dropwise with Et ₂ O (200 mL). The resulting solid was filtered, washed with Et ₂ O (200 mL) and dried under reduced pressure at 35 ° C to give methyl 4-chloropyridine-2-carboxylate hydrochloride as a white solid (110 g, 65%) Melting point 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 (br s, 1H); HPLC ES-MS m / z 172 ((M + H) < ^{+ >} ).

ABOUT

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

A suspension of methyl 4-chloropyridine-2-carboxylate hydrochloride (89.0 g, 428 mmol) in MeOH (75 mL) at 0 ° C was treated with a 2.0 M solution of methylamine in THF (1 L) to such an extent to maintain the temperature of the mixture below 5 ° C. The resulting mixture was stored at 3 ° C for 5 hours, then concentrated under reduced pressure. The resulting solid was suspended in EtOAc (1 L) and filtered. The filtrate was washed with 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%) : 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) 1 H, 8.61 (d, J = 5.1 Hz, 1H), 8.85 (br d, 1H); CI-MS m / z 171 ((M + H) < ^{+ >} ).

ABOUT

Step 3b. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carbonyl chloride

4-Chloropyridine-2-carbonyl chloride hydrochloride (7.0 g, 32.95 mmol) was added portionwise to a mixture of a 2.0 M solution of methylamine in THF (100 mL) and MeOH (20 mL) at 0 ° C. The resulting mixture was stored at 3 ° C for 4 hours, then concentrated under reduced pressure. The resulting almost dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate was washed with saturated NaCl solution (2 x 100 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure to give 4-chloro-N '- methyl-2-pyridinecarboxamide as a yellow crystalline solid (4, 95 g, 88%): mp 37-40 ° C.

ABOUT

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 red to brown mixture was stirred at room temperature. temperature for 2 hours. The mixture was 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), then heated at room temperature. 80 ° C for 8 hours. The mixture was cooled to room temperature and partitioned between EtOAc (500 mL) and saturated NaCl (500 mL). The aqueous phase was re-extracted with EtOAc (300 mL). The combined organic layers were washed with saturated NaCl solution (4 x 1000 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 ° C for 3 hours to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline as a light brown solid (17.9 g, 84%); 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 ¹ quartet), J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J 2.5 Hz, 1H), 8.44 (d, J = 5.5 Hz, 1 H), 8.73 (br d, 1 H); HPLC ES-MS m / z 244 ((M + H) < ^{+ >} ).

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

ABOUT

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

To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in concentrated AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120 ° C for 45 min, then the clear, light yellow mixture was heated at 160 ° C for 2 hours. The resulting mixture was kept at 160 ° C and concentrated to approximately 15 mL, then cooled to room temperature and the pH was adjusted to 10 with NaOH solution. The mixture was cooled to 0 ° C and slowly acidified to pH 5 with 1N HCl solution. The resulting precipitate was collected by filtration and dried under reduced pressure to give 5-hydroxyisoindoline-1,3-dione as a pale yellow powder (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 dropwise a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL). The pale yellow to green mixture was allowed to warm to room temperature on standing and stirred for 1 hour, then 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe three to four times. The resulting mixture was heated at 70 ° C overnight, then cooled to room temperature and diluted slowly with water (150 mL), extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure to give 5- (4-nitrophenoxy) isoindoline-1,3-dione as a rye solid (3.3 g, 62%): TLC (30 % EtOAc / 70% hexane) _Rf = 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 = 9Hz, 2H), 11.43 (brs, 1H); CI-MS m / z 285 ((M + H) < ^{+ &gt};, 100%).

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

A solution of 5- (4-nitrophenoxy) isoindoline-1,3-dione (0.6 g, 2.11 mmol) in concentrated AcOH (12 mL) and water (0.1 mL) was stirred under atm. Argon and slowly add iron as a powder (0.59 g, 55.9 mmol). The mixture was stirred at room temperature for 72 hours, 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 brownish solid (0.4 g, 75%): TLC (50 % EtOAc / 50% hexane) _Rf = 0.27; H NMR (DMSO- d _d) 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) < ^{+ &gt};, 100%).

A4. General method for the synthesis of pyrolylanilines.

Synthesis of 5- tert -butyl-2- (2,5-dimethylpyrolyl) 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 via syringe AcOH (0.1 mL) and acetonylacetone (0.299 g, 2.63 mmol). ). The reaction mixture is heated at 120 ° C for 72 hours while removing the volatiles in an azeotropic manner. The reaction mixture was cooled to room temperature, diluted with CH ₂ Cl ₂ (10 mL) and washed successively with 1 N HCl solution (15 mL) and 1 N NaOH solution (15 mL) and saturated NaCl solution (15 mL), dried (MgSO ₄ ). and concentrated under reduced pressure. The resulting orange to brown solid was purified by silica gel column chromatography (60 g SiO ₂ ; gradient 6% EtOAc / 94% hexane to 25% EtOAc / 75% hexane) to give 1- (4-tert-butyl-2- nitrophenyl) -2,5-dimethylpyrrole as an orange to yellow solid (0.34 g, 49%): TLC (15% EtOAc / 85% hexane) R _f 0.67; 1 H NMR (CDCl 3) δ 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H), 7.62 (dd, 1H), 7.88 (d, J = 2.4Hz, 1H); CI-MS m / z 273 ((M + H) < ^{+ &gt};, 50%).

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

A slurry of 1- (4-tert-butyl-2-nitrophenyl) -2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10% Pd / C (0.056 g) and EtOAc (50 mL) under atm. The hydrogen (balloon) was stirred for 72 hours, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give 5-tert-butyl-2- (2,5-dimethylpyrolyl) aniline as a yellowish solid (0.30 g, 99%): TLC (10% EtOAc / 90% hexane) _Rf = 0.43;

1 H NMR (CDCl 3) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 ( m, 3H), 7.28 (brs, 1H).

A5. General method for the synthesis of anilines by nucleophilic aromatic substitution of anilines.

Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline hydrochloride

A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the black mixture was stirred at room temperature until the temperature in the flask reaches room temperature. The mixture was 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 hours. The mixture was cooled to room temperature and diluted with water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with saturated NaCl solution (200 mL), dried (MgSO ₄ ) and concentrated under reduced pressure. The remaining black oil was treated with Et ₂ O (50 mL) and sonicated. The solution was then treated with HCl (1 M in Et ₂ O; 100 mL) and stirred at room temperature for 5 minutes. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration from the solution and stored at 0 ° C before use in the absence of air: 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. A general method for the synthesis of anilines from hydroxyanilines by introducing a protecting group on nitrogen, by nucleophilic aromatic substitution and by removing the protecting group.

Synthesis of 4- (2-N-methylcarbamoy (N-pyridyloxy) -2-chloroanilirole)

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

Iron (3.24 g, 58.00 mmol) was added to a stirred solution of 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 stirred at room temperature for 6 days. The iron is filtered from the solution and the remaining substance is concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To this yellow solution was added saturated NaHCO ₃ solution (50 mL). The solid which precipitated from solution was removed. The filtrate was slowly quenched with sodium bicarbonate solution until the product was visibly separated from the solution (a small flask was chosen for determination). The slightly dark yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with saturated NaCl solution (125 mL), dried (MgSO ₄ ) and concentrated under reduced pressure. According to 1 H NMR (DMSO-d ₆ ), the starting nitrophenol and the desired 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol were 1: 1. The crude material was used in the next step without further purification.

ABOUT

Step 2. Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl- (2,2,2-trifluoro) acetamide

A solution of crude 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 mL) was treated with potassium tert-butoxide (5.16 g, 45.98 mmol) and the brownish mixture was stirred at room temperature until the reaction mixture was cooled to room temperature in the flask. The resulting mixture was treated with 4-chloro-N'-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 ° C under atm. argon for 4 days. The black reaction mixture was cooled to room temperature and poured into cold water (100 mL). Extract the mixture with EtOAc (3 x 75 mL) and concentrate the combined organic layers under reduced pressure. The residual brown oil was purified by chromatography on silica gel using 20% EtOAc / petroleum ether to 40% EtOAc / petroleum ether to give 4- (2- ^{(f-methylcarbamoyl)} -4-pyridyloxy) -2-chlorophenyl (2.2 , 2-trifluoro) acetamide as a yellow solid (8.59 g,

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). ml) was treated with 1N NaOH solution (20 ml). The brown solution was stirred for 8 hours. To this solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x 40 mL) and concentrated to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline as a green oil that solidifies on standing (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, 1H).

A7. General method for deprotecting from acylated aniline. Synthesis of 4-chloro-2-methoxy-5- (trifluoromethyl) aniline

OMe

A suspension of 3-chloro-6- (N-acetyl) -4- (trifluoromethyl) anisole (4.00 g, 14.95 15 mmol) in 6M HCl solution (24 mL) was heated at reflux for 1 hour. The resulting solution was cooled to room temperature, solidifying a little. The resulting mixture was diluted with water (20 mL), then treated with a mixture of solid NaOH and 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 organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure to yield

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), 30 (s, 2H); 7.01 (s, 2H).

A8. General method for the synthesis of .alpha.-alkoxy .alpha.-carboxyphenylanilines. Synthesis of 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline.

about

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 by the method of Example A13, step 1.12 mmol) in acetone (50 mL) is added K ₂ CO ₃ ( 5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated at reflux overnight, cooled to room temperature and filtered through a pad of Celite®. The resulting solution was concentrated under reduced pressure, absorbed onto silica gel, and purified by silica gel column chromatography using 50% EtOAc and 50% hexane to give 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene as a yellow powder (3). g): mp 115-118 ° C.

ABOUT

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

A mixture of 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temperature overnight, then heat at reflux for 4 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50 mL) and the aqueous mixture acidified with 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to give 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (1.04 g).

ABOUT

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 portionwise SOCi ₂ (0.64 mL, 8 mL). , 77 mmol). The resulting solution was heated at reflux for 18 hours, cooled to room temperature, and concentrated under reduced pressure. The resulting yellow solid was dissolved in CH ₂ Cl ₂ (3 mL), then the resulting solution was treated portionwise with a solution of methylamine (2.0 M in THF, 3.5 mL, 7.02 mmol) (caution vigorously). gas) and stirred at room temperature for 4 hours. The resulting mixture was treated with 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% ).

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

A slurry of 4- (3- ^{(N-methylcarbamoyl)} -4-methoxyphenoxy) -l-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd / C (0.20 g) in EtOH (55 ml ) is stirred under 1 atm. H ₂ (balloon) for 2.5 days, then filtered through a pad of Celite ®. The resulting solution was concentrated under reduced pressure to give 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et ₃ N) (99.9% EtOAc) R _f = 0.36.

A9. General process for the preparation of ω-alkylphthalimide anilines. Synthesis of 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione

ABOUT

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 added. Stir at room temperature for 1 hour then react with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temperature overnight, cooled to ° C and treated with water (10 mL). The resulting solids were combined and dried under reduced pressure to give 5- (4-nitrophenoxy) -2-methyl-isoindoline-1,3-dione as a pale yellow solid (0.87 g, 83%): TLC (35% EtO) ac / 65% hexane) _Rf = 0.61.

ABOUT

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

A slurry of 5- (4-nitrophenoxy) -2-methylisoindoline-1,3-dione (0.87 g, 2.78 mmol) and 10% Pd / C (0.10 g) in MeOH was stirred under 1 atm. H ₂ (balloon) overnight. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) and filtered through a pad of silica gel (60% EtOAc / 40% hexane) to give 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione as yellow solid (0.67 g, 86%): TLC (40% EtOAc / 60% hexane) R f = 0.27.

A10. General method for the synthesis of α-carbamoylarylanilines 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 hydrochloride (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added dropwise 4- (2-aminoethyl) morpholine (2, 2, 2, 2, 3, 55 mL, 19.4 mmol) and the resulting solution was heated at reflux for 20 h, cooled to room temperature and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to give 4-chloro-2- (V- (2-

(morpholin-4-ylethyl) carbamoyl) pyridine as a yellow oil (1.25 g,

%): TLC (10% MeOH / 90% EtOAc) _Rf = 0.50.

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

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert -butoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temperature for 2 hours, then gradually allowed to stir. react with 4-chloro-2- (N - (2-morpholin-4-ylethyl) carbamoyl) pyridine (1.22 g, 4.52 mmol) and K ₂ CO ₃ (0.31 g, 2.26 mmol) . The resulting mixture was heated at 75 ° C overnight, cooled to room temperature and partitioned between EtOAc (25 mL) and saturated NaCl (25 mL). The aqueous layer was re-extracted with EtOAc (25 mL). The combined organic layers were washed with saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure. The resulting brown solid was purified by silica gel column chromatography (58 g) with a gradient of 100% EtOAc to 25% MeOH / 75% EtOAc) to give 4- (2- (N - (2-morpholin-4-yl-ethyl) carbamoyl) (Pyridyloxy) aniline (1.0 g, 65%): TLC (10% MeOH / 90% EtOAc) R f = 0.32.

Al 1. General method for reducing nitroarenes to arylamines. Synthesis of 4- (3-carboxyphenoxy) aniline.

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 portionwise 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol). The resulting slurry was warmed to room temperature and stirred for 45 minutes, then 4-fluoro-1-nitrobenzene was added and 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 solid was collected to give 4- (l-isoindoline-5-yloxy) -l-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) _Rf = 0.35 .

ABOUT

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

A slurry of 4- (1-isoindolinon-5-yloxy) -1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd / C20 (0.20 g) in EtOH (50 mL) was stirred under atm. H ₂ (balloon) for 4 hours, then filtered through a pad of Celite ®. The filtrate was concentrated under reduced pressure to give 4- (1-oxoisoindolin-5-yloxy) aniline as a dark yellow solid: TLC (100% EtOAc) R f = 0.15.

The A13. General method for the synthesis of ω-carbamoylanilines via an amide prepared by EDC1 and nitroarene reduction. Synthesis of 4- (3-N-methylcarbamoylphenoxy) 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 stirred under atm. H ₂ (balloon) for 2 days. The resulting mixture was filtered through a pad of Celite®, then concentrated under reduced pressure to give 4- (3-carboxyphenoxy) aniline as a brown solid (2.26 g, 48%): TLC (10% MeOH / 90% CH ₂ CI ₂ ) Rf = 0.44 (elongated dot).

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

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

To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly added portionwise zinc powder (47.6 g, 729 mmol), then the mixture was heated at reflux for 40 min., filter hot and concentrate under reduced pressure. Further work-up to the same scale was performed and the combined oily residue was purified by column chromatography in a gradient of 60% EtOAc / 40% hexane to 25% MeOH / 75% EtOAc to give 5-hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) _Rf = 0.17; HPLC ES-MS m / z 150 ((M + H) +).

Step 1. Synthesis of 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K ₂ CO ₃ (41 g) , 300 mmol) in DMF (125 mL) was heated at reflux overnight, cooled to room temperature and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were washed successively with water (3 x 100 mL) and saturated NaCl solution (2 x 100 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 10% EtOAc and 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 mixture of THF and water (3: 1) (75 mL) was added LiOH.H ₂ O solution (1). , 50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50 ° C overnight, then cooled to room temperature, concentrated under reduced pressure, and acidified to pH = 2M with HCl solution. The resulting pale yellow solid was removed by filtration and washed with hexane to give 4- (3-carboxyphenoxy) -1-nitrobenzene (4.40 g, 95%).

ABOUT

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 stirred at room temperature for 3 days, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with 1M HCl solution (50 mL). The aqueous layer was re-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with 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

Step 4. Synthesis of 4- (3- ^{(t-methylcarbamoyl)} phenoxy) aniline

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

A14. General method for synthesis of ω-carbamoylanilines via amide prepared by EDCI and nitroarene reduction. Synthesis of 4-3- (5-methylcarbamoyl) pyridyloxy) aniline

ABOUT

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

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

ABOUT

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

A slurry of 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd / C in MeOH / EtOAc was stirred under atm. H ₂ (balloon) for 72 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient of 10% EtOAc / 90% hexane, 30% EtO-Ac / 70% hexane to 50% EtOAc / 50% hexane to give 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline (0.28 g,

%): 1 H NMR (CDCl 3) 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 by electrophilic nitration and 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 warmed to room temperature and stirred at room temperature overnight. The resulting mixture was partitioned between EtOAc (25 mL) and 1M HCl (25 mL). The aqueous phase was re-extracted with EtOAc (2 x 25 mL). The combined organic phases were washed successively with water (2 x 25 mL) and saturated NaCl solution (25 mL), dried (MgSO ₄ ), and concentrated under reduced pressure to afford 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 overnight, cooled to room temperature and partitioned between EtOAc (50 mL) and 1 N HCl (50 mL). The aqueous phase was re-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed successively with water (2 x 50 mL) and saturated NaCl solution (50 mL), dried (MgSO ₄ ), and concentrated under reduced pressure. The remaining oil was purified by silica gel column chromatography using 30% EtOAc and 70% hexane to give 4- (3- (N ^, -methyisulfamoyl) 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 portionwise over 5 minutes NaNO ₂ ( 0.097 g, 1.14 mmol). The resulting solution was stirred at -10 ° C for 1 hour, then warmed to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (10 mL) and water (10 mL). The organic phase was washed successively with water (10 mL) 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 used 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 (0.30 g) and 10% Pd / C (0.030 g) in EtOAc (20 mL) was stirred under atm. H ₂ (balloon) overnight. The resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 30% EtOAc and 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 hydrochloride (0.34 g, 3 mmol, 0.5 equiv.) And stirred at 80 ° C for an additional 4 hours, cooled The mixture was extracted with EtOAc (3 x 10 mL) and the combined organic layers were washed with saturated NaCl (20 mL), dried (MgSO 4) and the organic layer was extracted with EtOAc (3 x 10 mL). ₄ ) and concentrated under reduced pressure The brown oily residue was purified by silica gel column chromatography using 30% EtOAc and 70% petroleum ether to give 4- (4- (2- (N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline). as a clear light brown oil (0.99 g, 38%).

A18. Synthesis of 2-pyridinecarboxylate esters by oxidation of 2-methylpyridines. Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxyjaniline).

To a slurry of 4- (4-acetylphenoxy) aniline hydrochloride (prepared analogously to Example A13, Step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0 mL) was added. O-methylhydroxylamine hydrochloride (0.65 g, 7.78 mmol, 2.0 equiv) was added. The resulting solution was heated at reflux for 30 minutes, cooled to room temperature, and concentrated under reduced pressure. The resulting solid was triturated with water (10 mL) and washed with water to give 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline hydrochloride 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 - (.alpha.-silyloxyalkyl) amides. Synthesis of 4- (4- (2- (N - (2-triisopropylsilyloxy) ethylcarbanioyl) pyridyloxyaniline).

Step 1. ^4-Chloro-A, - (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide

To a solution of 4-chloro- N - (2-hydroxyethyl) pyridine-2-carboxamide (prepared analogously to Example 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) were added. The resulting yellow solution was stirred for 3 hours at room temperature, then concentrated under reduced pressure. The residue was partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried (MgSO ₄ ) and concentrated under reduced pressure to give 4-chloro-2- (N - (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide as an orange oil (2.32 g, 88%). This material was used in the next step without further purification.

Step 2. 4- (4- (2 - (N - (2-Triisopropylsilyloxyjetylcarbamoyl) pyridyloxyaniline)

To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anhydrous DMF (8 mL) was added potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) In one portion. The reaction is exothermic. After cooling to room temperature, a solution of 4-chloro-2- (N- (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv) in DMF (4 mL) was added followed by K ₂ CO ₃ (0.42 g, 3.0 mmol, 0.50 equiv). The resulting mixture was heated at 80 ° C overnight. Another portion of tert-butoxide tert -butoxide was added

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 overnight. The resulting mixture was cooled to room temperature, treated with water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed successively with water (2 x 100 mL) and saturated NaCl solution ((100 mL), dried (MgSO ₄ ) and concentrated under reduced pressure to afford 4- (5- (2-methyl) pyridyloxy). 1-nitrobenzene as a brown solid (12.3 g).

ABOUT

Step 2. Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene.

A mixture of 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv) in pyridine (20 mL) was heated at reflux for 5 hours, then cooled to room temperature. The resulting slurry was filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The solution was treated with concentrated HCl solution (7 mL), then heated at reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (50 mL) and 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 saturated NaCl solution (50 mL), dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% EtOAc and 50% hexane to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.70 g).

ABOUT

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 EtO-Ac (20 mL) and MeOH (5 mL) was added. left under atm. H ₂ (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 silica gel column chromatography using 70% EtOAc and 30% hexane to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline (0.40 g).

A19. Synthesis of ω-sulfonylphenylanilines.

Synthesis of 4- (4-methylsulfonylphenyoxy) aniline.

O □

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

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

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

B. Synthesis of urea precursors

Bl. General method for the synthesis of isocyanates from anilines by CDI. Synthesis of 4-bromo-3- (trifluoromethyl) phenyl isocyanate.

C. Methods for the preparation of ureas

Duty. General method for the synthesis of ureas by reaction of isocyanate with aniline. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl), N- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

A solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (14.60 g, 65.90 mmol) in CH ₂ Cl ₂ (35 mL) was added dropwise to a suspension of 4- (2- (N-methylcarbamoyl) -4- pyridyloxy) aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH ₂ Cl ₂ (35 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 22 hours. The resulting yellow solid was removed by filtration, washed with CH ₂ Cl ₂ (2 x 30 mL) and dried under reduced pressure (about 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) < ^{+ >} ).

Clb. General method for the synthesis of ureas by reaction of isocyanate with aniline. Synthesis of N- (4-Bromo-3- (trifluoromethyl) phenyl) -N- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) mono-

Step 1. Synthesis of 4-bromo-3- (trifluoromethyljaniline hydrochloride)

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

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

A suspension of 4-bromo-3- (trifluoromethyl) aniline hydrochloride (36.8 g, 133 mmol) in toluene (278 mL) was treated dropwise with trichloromethyl chloroformate and the resulting mixture was heated at reflux for 18 hours. 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 residue was re-treated with CH ₂ Cl ₂ and concentrated to give a yellow oil, which was stored at -20 ° C for 16 hours. The obtained 4-bromo-3- (trifluoromethyl) phenyl isocyanate is a brown solid (35.1 g, 86%): GC-MS m / z 265 (M ⁺ ).

A solution of 4-bromo-3- (trifluoromethyl) phenyl isocyanate (Method Bl, Step 2, 8.0 g, 30.1 mmol) in CH ₂ C1 ₂ (80 ml) was added dropwise to a solution of 4- (2- (7V -methylcarbamoyl) -4-pyridyloxyjaniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH ₂ Cl ₂ (40 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 16 hours. The resulting yellow solid was removed by filtration, washed with CH ₂ Cl ₂ (2 x 50 mL) and dried under reduced pressure (about 1 mm Hg) at 40 ° C to give N '- (4-bromo-3-). (trifluoromethyl) phenyl) -A- (4- (2- ^{(N-methylcarbamoyl)} -4-pyridyloxy) phenyl) urea as a light yellow solid (13.2 g, 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, 25 J = 2.5 Hz, 1H ), 7.58 (m, 3H), 7.77 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H), 8.19 (d J = 5.5 Hz; 1H), 8.77 (br d, 1H), 8.99 (s, IH), 9.21 (s, IH); HPLC ES-MS m / z 509 (( M + H ⁺ ).

Cle. General method for the synthesis of ureas by reaction of isocyanate with aniline. Synthesis of ^f - (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-methyl-4- (2- (N-methylcarbamoyl ^I') (4-pyridyloxy)) phenyl) urea

A solution of 2-methyl-4- (2 - (/ V-methylcarbamoyl) (4-pyridyloxy)) aniline (Method A5; 0.11 g, 0.45 mmol) in CH ₂ C1 ₂ (1 mL) was treated with Et ₃ N (0.16 mL) and 4-chloro-3- (trifluoromethyl) phenyl isocyanate (10 g, 0.45 mmol). The resulting brown solution was stirred at room temperature for 6 days, treated with water (5 mL). The aqueous phase was re-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- (A ') (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 (d, J = 2.6 Hz, 1H), 7.62 (app d, J = 2.6 Hz, 2H) 7.84 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H) 8.78 (q, J = 5.2, 1H); 9.52 (s, 1H); HPLC ES-MS m / z 479 ((M + H) ⁺ ).

Cld. General method for the synthesis of ureas by reaction of isocyanate with aniline. Synthesis of N - (4-Chloro-3- (trifluoromethyl) phenyl) -N- (4-chlorophenyl) urea

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (2.27 g, 10.3 mmol) in CH ₂ C1 ₂ (308 ml) was added in one portion, p-phenylenediamine (3.32 g, 30.7 mmol). The resulting mixture was stirred at room temperature for 1 hour, treated with CH ₂ Cl ₂ (100 mL), and concentrated under reduced pressure. The resulting pink solid was dissolved in a mixture of EtOAc (110 mL) and MeOH (15 mL) and the clear solution was washed with 0.05 N HCl solution. The organic layer was concentrated under reduced pressure to give impure N- (4-chloro-3- (trifluoromethyl) phenyl) -A- (4-aminophenyl) urea (3.3 g): TLC (100% EtOAc) R _f = 0.72.

Cle. General method for the synthesis of ureas by reaction of isocyanate with aniline. Synthesis of V- (4-chloro-3- (trifluoromethyl) phenyl) -N- (4-ethoxycarbonylphenyl) urea The resulting mixture was concentrated under reduced pressure. The resulting brown solid was triturated with EtOAc-hexane (1: 1) to provide the A ^f - (4-chloro-3- (trifluoromethyl) phenyl) -V- (3-carboxyphenyl) urea as an off-white solid (1. 21 g, 76%).

C2a. General method for the synthesis of urea by reacting aniline with N, N '-carbonyldiimidazole and adding 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) at 0 ° C was added CDI (0.13 g). The resulting solution was warmed to room temperature for 1 hour, stirred at room temperature for 16 hours, treated with 4- (2- (N'-methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 72 hours, treated with H ₂ O (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with saturated NaCl solution (100 mL), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was triturated (90% EtOAc / 10% hexane). The resulting white solid was collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil was purified by silica gel column chromatography in a gradient of 33% EtOAc / 67% hexane, 50% EtOAc / 50% hexane to 100% EtOAc to give V- (2-methoxy-5- ( trifluoromethyl) phenyl) -N- (4- (2- (N ^{& apos} methylcarbamoyl) -4-pyridyl oxy) phenyl) urea as a light brown solid (0.098 g, 30%): TLC (100% EtOAc) _Rf = 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 = 4.8Hz, 1H), 9.55 (s, 1H); FAB-MS m / z 461 ((M + H) < ^{+ >} ).

H H

C2B. General method for the synthesis of urea by reacting aniline with N-carbonyldiimidazole and adding a second aniline. Symmetrical ureas as by-products in the reaction of N, N-carbonyldiimidazole. Synthesis of bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

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

CLF. General method for the synthesis of ureas by reaction of isocyanate with aniline. Synthesis of A- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3-carboxyphenylurea)

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (1.21 g, 5.46 mmol) in CH ₂ C1 ₂ (8 mL) was added 4- (3-karboxyfenoxyjanilín (Al a method 1; 0.81 g, 5.76 mmol) and the resulting mixture was stirred at room temperature overnight, then treated with MeOH (8 mL) and stirred for an additional 2 hours.

To a stirred solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH ₂ Cl ₂ (15 mL) at 0 ° C was added CDI (0.13 g). The resulting solution was warmed to room temperature for 1 hour, stirred at room temperature for 16 hours. The resulting mixture was treated with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 72 hours, treated with water (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with saturated NaCl solution (100 mL), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was triturated in a mixture of 90% EtOAc and 10% hexane. The resulting white solid was collected by filtration and washed with EtOAc to give bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.08 1 g, 44%): TLC (100% EtOAc) Rf = 0.50; H NMR (DMSO- d _d) δ 2.76 (d, J = 5.1 Hz, 6H), 7.1 to 7.6 (m, 12H), 8.48 (d, J = 5.4 Hz, 1H), 8.75 (d, J = 4.8Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m / z 513 ((M + H) < ^{+ >} ).

C2c. General method for the synthesis of ureas by reaction of isocyanate with 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 C1 ₂ (1.5 ml) was added in one portion 5- (4-aminophenoxy) isoindoline-l, 3 -dione (Method A3, Step 3; 0.12 g, 0.47 mmol). The resulting mixture was stirred for 12 hours, treated with CH ₂ Cl ₂ (10 mL) and MeOH (5 mL). The resulting mixture was washed successively with 1N HCl solution (15 mL) and saturated NaCl solution (15 mL), dried (MgSO ₄ ), and concentrated under reduced pressure to give N- (2-methoxy-5- (trifluoromethyl) phenyl) - N - (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea as a white solid (0.2 g, 96%): TLC (70% EtOAc / 30% hexane) 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 O ((M + H) ⁺ , 100%).

C2d. General method for the synthesis of urea by reacting aniline with ACV-carbonyldiimidazole and adding a second aniline. Synthesis of N - (5- (tert -butyl) -2- (2,5-dimethylpyrolyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

To a stirred solution of CD 1 (0.21 g, 1.30 mmol) in CH ₂ C1 ₂ (2 ml) was added in one portion 5- (tert-butyl) -2- (2,5-dimethyl lyljanil yne (Method A4, Step The resulting mixture was stirred at room temperature for 4 hours, 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, cooled to room temperature and diluted with EtOAc (5 mL), washed sequentially with water (15 mL) and 1 N HCl (15 mL), dried (MgSO 4). ₄ ) and filtered through a pad of silica gel (50 g) to give N- (5- (tert-butyl) -2- (2,5-dimethylpyrolyl) phenyl) -N- (4- (2- (A'- 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 (brs, 1H); HPLC ES-MS 512 ((M + H) < ^{+ &gt};, 100%).

C3. Combination method of diphenylurea synthesis using triphosgene

One of the anilines with which the coupling reaction is to be carried out is dissolved in dichloroethane (0.10 M). This solution was added to an 8 mL flask (0.5 mL) containing dichloroethane (1 mL). To this flask was added a solution of bis (trichloromethyl) carbonate (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv) followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv) .). Seal the flask and heat at 80 ° C for 5 hours, warm to room temperature for 10 hours, then add the second aniline (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.), Diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv). The resulting mixture was heated at 80 ° C for 4 hours, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.

C4. General method for the synthesis of urea by reacting aniline with phosgene and adding a second aniline. Synthesis of cis- (2-Methoxy-5- (trifluoromethyl) phenyl) -N ^d '- (4- (2- (N-methylcarbamoyl) -

To a stirred solution of phosgene (1.9 M in toluene; 2.07 mL 0.21 g, 1.30 mmol) in CH ₂ Cl ₂ (20 mL) at 0 ° C was added anhydrous pyridine (0.32 mL). followed by 2-methoxy-5- (trifluoromethyl) aniline (0.75 g). The yellow solution was allowed to warm to room temperature during which time a precipitate formed. The yellow mixture was stirred for 1 hour, then concentrated under reduced pressure. The resulting solid was treated with anhydrous toluene (20 mL) followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (prepared according to Method A2; 0.30 g) and the resulting suspension was heated to temperature at 80 ° C for 20 hours and then cooled to room temperature. The resulting mixture was diluted with water (100 mL), basified with saturated NaHCO ₃ solution (2-3 mL). The basified solution was extracted with EtOAc (2 x 250 mL). The organic layers were washed separately with saturated NaCl solution, combined, dried (MgSO ₄ ) and concentrated under reduced pressure. The resulting pink to brown residue was dissolved in MeOH and absorbed onto silica gel (100 g). Purification by silica gel column chromatography (300 g) with a gradient of 1% Et ₃ N / 33% EtOAc / 6% hexane, 1% Et ₃ N / 99% EtOAc to 1% Et ₃ N / 20% MeOH / 79% EtOAc, then concentrated under reduced pressure at 45 ° C, a hot concentrated solution in EtOAc was obtained which was washed with hexane (10 mL) to slowly form N - (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2) crystals). ((N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.44 g): TLC (1% Et ₃ N / 99% EtOAc) R _f = 0.40.

D. Interconversion of ureas

Dl a. Conversion of ω-aminophenylureas to u- (aroylamino) phenylureas. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) -

To a solution of N -44-chloro-3 - ((trifluoromethyl) phenyl) -N- (4-aminophenylurea) (Method C1d; 0.050 g, 1.52 mmol), methyl methyl isophthalate (0.25 g, 1.38 mmol) , HOBT.H ₂ O (0.41 g, 3.03 mmol) and N -methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added EDCI.HCl (0.29 g, The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (25 mL) and washed sequentially with water (25 mL) and saturated NaHCO ₃ solution (25 mL) .The organic layer was dried (Na ₂ SO 4). ₄ ) and concentrated under reduced pressure, and the resulting solid was triturated with EtOAc (80% EtO-Ac / 20% hexane) to give N ^' - (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4- (3-methoxycarbonylphenyl) carboxyaminophenylurea (0.27 g, 43%): mp 121-122 ° C; TLC (80% EtOAc / 20% hexane) R _f = 0.75.

DLB. Conversion of ω-carboxyphenylureas to ω-arylcarbamoyl-phenylureas. Synthesis of ^N - (4-chloro-3 - ((trifluoromethyl) phenyl) -A- (4- (3-metylkarbamoylfenyl) carbamoylphenyl) urea

H H

To a solution of N - (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methylcarbamoyl-phenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoyl -aniline (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) EDCI.HCl (0.10 g, 0.53 mmol) was added at 0 ° C and the resulting mixture was allowed to warm to room temperature and stirred overnight The resulting mixture was treated with water (10 mL) and extracted with EtOAc. The organic phase was concentrated under reduced pressure, and the resulting yellow solid was dissolved in EtOAc (3 mL), filtered through a pad of silica gel (17 g) with a gradient of 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%). 225-229 ° C; TLC (100% EtOAc) R _f = 0.23.

D1 c. Combination method for the conversion of ω-carboxyphenylureas to ω- (arylcarbamoyl) phenylureas. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N ^' - (4- (N - (3- (N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea

H H

A mixture of 7V- (4-chloro-3 - ((trifluoromethyl one) phenyl) -N '- (3-karboxyfenyljmočoviny (Method Clf; 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 C1 ₂ (1 M; 0.074 mL, 0.074 mmol). (in the case of insolubility or cloud point, a small amount of DMSO). the The mixture was heated at 36 ° C overnight The turbid reaction mixture was then treated with THF (1 mL) and heating continued for 18 hours. The resulting mixture was treated with poly (4- (isocyanatomethyl) styrene) (0.040 g). ) and the resulting mixture was stirred at 36 ° C for 72 hours, then cooled to room temperature and filtered, and the resulting solution was filtered through a pad of silica gel (1 g) and concentrated under reduced pressure to give N - (4-chloro-3). - ((trifluoromethyl]) phenyl) - _J W '- (4 - (/ V- (3- (N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea (0.024 g, 59%): TLC (70% EtOAc / 30% hexane) Rt _r = 0.12.

D2. Conversion of ω-carboalkoxyarylureas to ω-carbamoylarylureas. Synthesis of V- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methylcarbamoyl-phenyl) carboxyaminophenylurea)

H H

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

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

H H

To a slurry of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4-ethoxycarbonylphenyl) urea (Method Cl; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added aqueous solution of KOH (2.5 N, 10 mL, 23 mmol) The resulting mixture was heated at reflux for 12 h, cooled to room temperature and concentrated under reduced pressure, and the residue was diluted with water (50 mL), allowed to react. The resulting solid was combined and dried under reduced pressure to yield N - (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4-carboxyphenyl). urea as a white solid (5.05 g, 92%).

D4. General method for the conversion of ω-alkoxy esters to γ-alkyl amides. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N - ((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea

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

A ^it - (4-chloro-3- (trifluoromethyl) phenyl) -V - ((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea was prepared from 4-chloro-3- (trifluoromethyl) phenyl isocyanate and 4- ( 3- (5-metoxykarbonylpyridyljoxyanilínu (method A14, step 2) according to the method Cla. A suspension of ^N - (4-chloro-3- (trifluoromethyl) phenyl) ^-N, - ((4- (3- (5-methoxycarbonylpyridyl (oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and stirred at room temperature The mixture was adjusted to pH 5 with 1 N HCl solution, the resulting precipitate was removed by filtration and washed with water, the resulting solid was dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced pressure. 2x to give N- (4-chloro-3- (trifluoromethyl) phenyl) -7H- ((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

_J A mixture of N- (4-chloro-3- (trifluoromethyl) phenyl) ^-N '- ((4- (3- (5-carboxypyridyl) oxyphenyl) urea (0.050 g, 0.011 mmol), A'A'- dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), ^{N-methylmorpholine} (0.035 g, 0.28 mmol) and EDCI.HC1 (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room temperature overnight The resulting solution was partitioned between EtOAc (50 mL) and water (50 mL) and the organic phase was washed with water (35 mL), dried (MgSO4) and concentrated. The residue was dissolved in a minimal amount of CH 2 Cl 2 (about 2 mL) and the resulting solution was treated dropwise with Et 2 O to give N- (4-chloro-3- (trifluoromethyl) phenyl) - N ^, - ((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) 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 method for deprotection of N- (n-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 in an analogous manner to Example Cla) 0.25 g, 0.37 mmol) in anhydrous THF (2 mL) was added tetrabutylammonium fluoride (1.0 M in THF; 2 mL), and the mixture was stirred at room temperature for 5 minutes, treated with water (10 mL). The aqueous mixture was extracted with EtO-Ac (3x10 mL), the combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 100% hexane to 40% EtOAc / EtOAc. 60% hexane to afford / V- (4-chloro-3 - ((trifluoromethyl) phenyl) ^-N '- (4- (4- (2 - (/ V- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).

The compounds listed in the tables are synthesized according to the detailed examples given below:

Synthesis of compounds according to the invention (see tables for individual characteristics)

Example 1: 4- (3-N-Methylcarbamoylphenoxy) aniline was prepared according to Method A13. And according to Method C3, 3- t -butylaniline is reacted with bis (trichloromethyl) carbonate followed by 4- (3- N -methylcarbamoylphenoxy) aniline to give urea.

Example 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to give 4

- (4-acetylphenoxy) -1-nitrobenzene. 4- (4-Acetylphenoxy) -1-nitrobenzene is reduced according to Method A 13, Step 4 to give 4- (4-acetylphenoxy) aniline. And according to Method C3, 3-tert-butylaniline is reacted with bis (trichloromethyl) carbonate, followed by 4- (4-acetylphenoxy) aniline to give urea.

Example 3: According to Method C2d, 3-tert-butylaniline was reacted with CDI, followed by 4- (3-A-methylcarbamoyl) -4-methoxyphenoxyjaniline, which was prepared according to Method A8 to give the urea.

Example 4: 5-tert-Butyl-2-methoxyaniline is converted to 5-tert-butyl-2-methoxyphenyl isocyanate according to Method B1. The 4- (3-N-methylcarbamoylphenoxy) aniline, prepared according to Method A13, is reacted with an isocyanate according to Method Cla to give urea.

Example 5: According to Method C2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI followed by 4- ^{(3-N-methylcarbamoyl)} -4-methoxyphenoxy) aniline, which was prepared according to Method A8, to afford urea.

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

Example 7: 4- (1-Oxoisoindolin-5-yloxy) aniline was prepared according to Method A12. And according to method 2d, 5-tert-butyl-2-methoxyaniline is reacted with CDI, followed by 4- (1-oxoisoindolin-5-yloxy) aniline to give urea.

Example 8: 4- (3- N -Methylcarbamoylphenoxy) aniline was prepared according to Method A13. And according to method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI, followed by 4- (3- N -methylcarbamoylphenoxyiamine) to give urea.

Example 9: 4-Hydroxyacetophenone is reacted with 2-chloro-5-nitropyridine to give 4- (4-acetylphenoxy) -5-nitropyridine according to Method A3, Step 2. A according to Method A8, Step 4, 4- (4-acetylphenoxy) -5-nitropyridine reduces to 4- (4-acetylphenoxy) -5-aminopyridine. 2-Methoxy-5- (trifluoromethyljaniline) is converted to 2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. The isocyanate is reacted with 4- (4-acetylphenoxy) -5-aminopyridine according to Method Cla to give urea.

Example 10: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to give 4- (4-acetylphenoxy) -1-nitrobenzene. 4- (4-Acetylphenoxy) -1-nitrobenzene is reduced according to Method A13, Step 4 to give 4- (4-acetylphenoxy) aniline. According to Method C3, 5- (trifluoromethyl) -2-methoxybutylaniline is reacted with bis (trichloromethyl) carbonate followed by 4- (4-acetylphenoxy) aniline to give urea.

Example 11: 4-Chloro-N ^, -methyl-2-pyridinecarboxamide, prepared according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to give 3- ( According to Method C4, 2-methoxy-5- (trifluoromethyl) aniline is reacted with phosgene, then with

3 - (- 2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give the urea.

Example 12: 4-Chloropyridine-2-carbonyl chloride hydrochloride was reacted with ammonia according to Method A2, Step 3b to give 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide is reacted with 3-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to give 3- (2-carbamoyl-4-pyridyloxy) aniline. And according to method C2a, 2-methoxy-5- (trifluoromethyl) aniline is reacted with phosgene, followed by 3- (2-carbamoyl-4-pyridyloxy) aniline to give urea.

Example 13: 4-Chloro-77-methyl-2-pyridinecarboxamide was prepared according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4, using DMAC instead of DMF to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. And according to method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI, followed by 4- (2- (7-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 14: 4-Chloropyridine-2-carbonyl chloride hydrochloride was reacted with ammonia according to Method A2, Step 3b to give 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4, using DMAC instead of DMF to give 4- (2-carbamoyl-4-pyridyloxy) aniline. And according to Method C4, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene followed by 4- (2-carbamoyl-4-pyridyloxy) aniline to give urea.

Example 15: According to Method C2d, 5- (trifluoromethyl) -2-methoxyaniline was reacted with CDI followed by 4- (3-7-methylcarbamoyl) -4-methoxyphenoxy) aniline, which was prepared according to Method A8 to give urea.

Example 16: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was prepared according to Method A5. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5-trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. The isocyanate is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline according to Method Cic to give the urea.

Example 17: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was prepared according to Method A6. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline according to Method Cla to give urea.

Example 18: According to Method A2, Step 4, 5-amino-2-methylphenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 3- (2). - (7V-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline according to Method C1a to afford the urea.

Example 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. resultant

4-Chloro- N -ctyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2-N-ethylcarbamoyl) -4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (77-ethylcarbamoyl) -4-pyridyloxy) aniline according to Method C1a to afford the urea.

Example 20: According to Method A2, Step 4, 4-Amino-2-chlorophenol was reacted with 4-chloro-77-methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 4- (2). - (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (77-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline according to Method Cla to give urea.

Example 21: 4- (4-Methylthiophenoxy) -1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. The nitrobenzene is reduced according to Method A19, Step 2 to give 4- (4-methylsulfonylphenoxy) -1-aniline. According to method Cla, 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (4-methylsulfonylphenoxy) -1-aniline to give urea.

Example 22: 4- (3-Carbamoylphenoxy) -1-nitrobenzene is reduced to 4- (3-carbamoylphenoxy) aniline according to method A15, step 4. And according to method C a 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4 - (3-carbamoylphenoxyjaniline) to give urea.

Example 23: 5- (4-Aminophenoxy) isoindoline-1,3-dione was prepared according to Method A3. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione according to Method Cla to give urea.

Example 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-, N ' -dimethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (77,7-dimethylcarbamoyl) -4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1.

5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (7777-dimethylcarbamoyl) -4-pyridyloxy) aniline according to Method C1a to afford the urea.

Example 25: 4- (1-Oxoisoindolin-5-yloxy) aniline was prepared according to Method A12. 5- (Trifluoromethyl) -2-methoxyaniline was reacted with CDI followed by 4- (1-oxoisoindolin-5-yloxyjaniline according to Method C2d) to give the urea.

Example 26: 4-Hydroxyacetophenone was reacted with 4-fluorometrobenzene according to Method A13, Step 1 to give 4- (4-acetylphenoxy) nitrobenzene. Nitrobenzene is reduced according to Method A13, Step 4 to give 4- (4-acetylphenoxy) amine, which is converted to 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline hydrochloride according to Method A16. 5- (Trifluoromethyl) The 2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (4- (1- (77-methoxy) iminoethyl) hydrochloride of phenoxyaniline according to method Cla to obtain urea.

Example 27: ^4-Chloro-Af -metylpyridínkarboxamid was prepared according to Method A2, Step 3b. The chloropyridine is reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 5- (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1 5- (Trifluoromethyl) -2-methoxyphenylisocyanate was reacted with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline according to Method Cla to give urea) .

Example 28: 5- (4-Aminophenoxy) -2-methyl-isoindoline-1,3-dione was prepared according to Method A9. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione according to Method Cla to give urea.

Example 29: 4-Chloro-A-methylpyridinecarboxamide was prepared according to Method A2, Step 3b. The chloropyridine is reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 5- (Trifluoromethyl) -2-methoxyethanol) is converted to 5- ( Trifluoromethyl-2-methoxyphenyl isocyanate according to Method B1 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline according to Method Cla to give urea).

Example 30: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline according to Method Cla to give urea.

Example 31: 4- (3- (5-Methoxycarbonyl) pyridyioxy) aniline was prepared according to Method A14. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxyjaniline according to Method C a to give urea. N '- p - (Trifluoromethyl) -2-methoxyphenyl) - N - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea is saponified according to Method D4, Step 1, and the corresponding acid is coupled according to Method D4, Step 2, with 4- (2-aminoethyl) morpholine to give the amide.

Example 32: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to Method A14. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxyjaniline according to Method C a to give urea) N - (5- (Trifluoromethyl) -2-methoxyphenyl) -N '- (4 - (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea is saponified according to Method D4, Step 1, and the corresponding acid is coupled with methylamine according to Method D4, Step 2 to give the amide.

Example 33: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to Method A14. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxyjaniline according to Method C a to give urea) N '- (5- (Trifluoromethyl) -2-methoxyphenyl) -A- (4

- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea is saponified according to Method D4, Step 1, and the corresponding acid is coupled with N, N-dimethylethylenediamine according to Method D4, Step 2 to give the amide.

Example 34: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A1. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) ) urea which, according to method D1c, is coupled with 3-aminopyridine.

Example 35: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A1. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N- (3-carboxyphenyl) urea which, according to Method D1c, is coupled with N - (4-fluorophenyl) piperazine.

Example 36: 4- (3-Carboxyphenoxy) aniline was prepared 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 reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) ) urea which is coupled with 4-fluoroaniline according to Method D1c.

Example 37: 4- (3-Carboxyphenoxy) aniline was prepared 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 reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl). ) urea which is coupled with 4- (dimethylamino) aniline according to Method D1c.

Example 38: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A1. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method C1f to give N '- (5- (trifluoromethyl) -2-methoxyphenyl) -N- (3-carboxyphenyl) urea which is coupled with 5-amino-2-methoxy-pyridine according to Method D1 c.

Example 39: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N- (3-carboxyphenyl) urea which is coupled with 4-morpholinoaniline according to Method D1c.

Example 40: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) ) urea which is coupled with N- (2-pyridyl) piperazine according to Method D1c.

Example 41: 4- (3- (N'-Methylcarbamoyl) phenoxyjaniline) was prepared according to Method A13. And according to Method C3, 4-chloro-3- (trifluoromethyl) aniline was converted to an isocyanate and reacted with 4- (3-N, N- methylcarbamoyl) phenoxy aniline to give urea.

Example 42: 4- (2-N-Methylcarbamyl-4-pyridyloxy) aniline was prepared according to Method A2. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2-A-methylcarbamyl-4-pyridyloxyjaniline according to Method C1a to give urea).

Example 43: 4-Chloropyridine-2-carbonyl chloride hydrochloride was reacted with ammonia according to Method A2, Step 3b to give 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2-carbamoyl-4-pyridyloxy) aniline. And, according to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2-carbamoyl-4-pyridyloxy) aniline to give urea.

Example 44: 4-Chloropyridine-2-carbonyl chloride hydrochloride was treated with ammonia according to Method A2, Step 3b, to give 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide is reacted with 3-aminophenol according to Method A2, Step 4 to give 3- (2-carbamoyl-4-pyridyloxyjaniline) And according to Method C, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2-carbamoyl-4-pyridyloxy) aniline to give the urea.

Example 45: 4-Chloro-N-methyl-2-pyridinecarboxamide, prepared according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to give 3- (- 2- (7H- methylcarbamoyl) -4-pyridyloxy) aniline. And, according to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 46: 5- (4-Aminophenoxy) isoindoline-1,3-dione was prepared according to Method A3. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) isomdoline-1,3-dione to give urea.

Example 47: 4- (2-N-Methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was prepared according to Method A5. And according to Method C18, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to give urea.

Example 48: 4- (3-N-Methylsulfamoyl) phenyloxy) aniline was prepared according to Method A15. And, according to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-7-N-methylsulfamoyl) phenyloxyjaniline to give urea.

Example 49: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was prepared according to Method A6. And, according to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to afford the urea.

Example 50: According to Method A2, step 4,5-amino-2-methylphenol is reacted with 4-chloro-7'-methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 3- (2) - (A-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. And, according to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to give urea.

Example 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-, N -ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 52: According to Method A2, Step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N'-methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 4- ( 2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to afford the urea.

Example 53: 4- (4-Methylthiophenoxy) -1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. The nitrobenzene is reduced according to Method A19, Step 2 to give 4- (4-methylsulfonylphenoxy) -1-aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4-methylsulfonylphenoxy) -1-aniline to give urea.

Example 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to give N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-bromobenzenesulfonamide is coupled with phenol according to Method A15, Step 2 to give 4- (4- (N-methylsulfamoyl) phenoxy) benzene. 4- (4- (N-Methylsulfamoyl) phenoxy) benzene is converted to 4 - (4- (N-methylsulfamoyl) phenoxy) -1-nitrobenzene according to Method A15, Step 3. 4- (4- (N-Methylsulfamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (4-N-methylsulfamoyl) phenyloxy) aniline according to method A15, step 4. And according to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-7 N-methylsulfamoyl) phenyloxy) aniline to give urea.

Example 55: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene. Methylpyridine is oxidized to the carboxylic acid, esterified according to Method A18, Step 2 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene. The nitrobenzene is reduced according to Method A18, Step 3 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline. The aniline is reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to method Cla to give the urea.

Example 56: 5-Hydroxy-2-methylpyridine is coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene. Methylpyridine is oxidized to the carboxylic acid, esterified according to Method A18, Step 2 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene. The nitrobenzene is reduced according to Method A18, Step 3 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline. The aniline was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method Cla to give the ^L - (4-chloro-3- (trifluóirnetyl) phenyl) ^-N '- (4- (2- (methoxycarbonyl ) -5-pyridyloxy) phenyl) urea.

The methyl ester was reacted with methylamine according to either SPOS D2 to give N - ( ^{'4-chloro-3-ímfluórmt,} the]) phenyl)) - 7V - (4- (2- (N-methylcarbamoyl) -5 -pyridyloxy) phenyl) urea.

Example 57: N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4-aminophenyl) urea was prepared according to Method C. N- (4-Chloro-3- (trifluoromethyl) phenyl) -N' - ( 4-aminophenyl) urea is coupled with mono-methylisophthalate according to Method D 1a to give the urea.

Example 58: N- (4-Chloro-3- (trifluoromethyl) phenyl-N- (4-aminophenyl) urea was prepared according to Method C. N- (4-Chloro-3- (trifluoromethyl) phenyl- N - (4) -aminophenyl) urea is coupled with mono-methylisophthalate according to Method D 1a to give N- (4-chloro-3- (trifluoromethyl) phenyl-N- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea. According to Method D2, A- ( 4-Chloro-3- (trifluoromethyl) phenyl N - (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea is reacted with methylamine to give the corresponding methylamide.

Example 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro- N -dimethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-dimethylcarbamoyl) -4-pyridyloxy) aniline. And, according to method C1a, the 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline to give the urea.

Example 60: 4-Hydroxyacetophenone was reacted with 4-fluorometrobenzene according to Method A13, Step 1 to give 4- (4-acetylphenoxy) nitrobenzene. The nitrobenzene is reduced according to Method 13, Step 4 to give 4- (4-acetylphenoxyjaniline) which is converted to 4- (4- (1- (A-methoxy) iminoethyl) phenoxyaniline hydrochloride according to Method A16). 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4-acetylphenoxy) aniline to give urea.

Example 61: 4- (3-Carboxyphenoxy) -1-nitrobenzene was prepared according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with 4- (2-aminoethyl) morpholine according to Method A13, Step 3 to give 4- (3- (N '- (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene. And according to Method A13 step 4, 4- (3- (N - (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (N - (2-morpholinylethyl) carbamoyl) phenoxy) aniline. And, according to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N- (2-morpholinylethyl) carbamoyl) phenoxy) aniline to give urea.

Example 62: 4- (3-Carboxyphenoxy) -1-nitrobenzene was prepared according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with 1- (2-aminoethyl) piperidine according to Method A13, Step 3 to give 4- (3- (N - (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene. A, according to Method A13, Step 4, 4- (3- (N - (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (3- (N - (2-piperidylethyl) carbamoyl) phenoxy) aniline A. And, according to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (AA - (2-piperidylethyl) carbamoyl) phenoxy) aniline to give urea.

Example 63: 4- (3-Carboxyphenoxy) -1-nitrobenzene was prepared according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4- (3- (N- (tetrahydrofurylmethyl) carbamoyl) phenoxy) -l-nitrobenzene. And by the way

A13 step 4, 4- (3- (N - (tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (N - (tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline. And, according to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N ^' - (tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline to give urea.

Example 64: 4- (3-Carboxyphenoxy) -1-nitrobenzene was prepared according to Method A13, Step 2.4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with 2-aminomethyl-1-ethylpyrrolidine according to Method A13, Step 3, to give 4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene. And according to Method A13 step 4, 4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (N - ((1-methylpyrrolidinyl) methyl) ) carbamoyl) phenoxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) aniline to provide urea.

Example 65: 4-Chloro-N ^- methylpyridinecarboxamide was prepared according to Method A2, Step 3b. The chloropyridine is reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4- (4- (2- (N-methylcarbamoyl) phenyithio) aniline. According to Method C, 4-chloro-3- (trifluoromethyl) phenylisocyanate is reacted with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline) to give urea.

Example 66: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N'-isopropylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 67: N- (4-Chloro-3- (trifluoromethyl) phenyl-N- (4-ethoxycarbonylphenyl) urea was prepared according to Method Cle, N- (4-chloro-3- (trifluoromethyl) phenyl-N- (4-chloro-3- (trifluoromethyl) phenyl) urea). -ethoxycarbonylphenyl) urea was saponified according to Method D3 to give N - (4-chloro-3- (trifluoromethyl) phenyl-N- (4-carboxyphenyl) urea) N- (4-Chloro-3- (trifluoromethyl) ) phenyl-N- (4-carboxyphenylurea) was coupled with 3-methylcarbamoylanine according to Method D1b to give N '- (4-chloro-3- (trifluoromethyl) phenyl-N- (4- (3-methylcarbamoyl-) -). phenyl) carbamoyl-phenyl) -urea.

Example 68: 5- (4-Aminophenoxy) -2-methyl-isoindoline-1,3-dione was prepared according to Method A9. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione to give urea.

Example 69; 4-Chloro-N-methylpyridinecarboxamide was prepared according to Method A2, Step 3b. The chloropyridine is reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. According to Method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate reacted with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline to give urea.

Example 70: 4- (2- (N - (2-Morpholin-4-yl-ethyl) -carbamoyl) -pyridyloxy-aniline was prepared according to Method A10. And according to Method C a 4-chloro-3- (trifluoromethyl) -phenylisocyanate was reacted with 4- ( 2- (N - (2-morpholin-4-ylethyl) carbamoyl) pyridyloxyjaniline to give urea.

Example 71: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to Method A14. 4-Chloro-3- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method Cla to give urea. N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4- (2-aminoethyl) morpholine to give the amide.

Example 72: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to Method A14. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method Cla to give urea. A ^L (5- (Trifluoromethyl) -2-methoxyphenyl) -N ^&apos' - (4- (3- (5-methoxycarbonyl-pyridinyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with with methylamine according to Method D4, Step 2 to give the amide.

Example 73: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to Method A14. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method Cla to give urea. N- (5- (Trifluoromethyl) -2-methoxyphenyl) -N '- (4- (3- (5-methoxycarbonyl-pyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with N, N -dimethylethylenediamine according to Method D4, Step 2 to obtain the amide.

Example 74: 4-Chloropyridine-2-carbonyl chloride hydrochloride was reacted with 2-hydroxyethylamine according to Method A2, Step 3b to give 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide. 4-Chloro- N - (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide is reacted with triisopropylsilyl chloride then 4-aminophenol according to Method A17 to give 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl)) And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline) to give N - (4-chloro). -3 - ((trifluoromethyl) phenyl) -7V - (4- (4- (2- (TV- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea.

Example 75: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1f to give the urea which is coupled with 3-aminopyridine according to Method D1 c.

Example 76: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to give the urea which is coupled with N- (4-acetylphenyl) piperazine according to Method D1 c.

Example 77: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxy-phenoxy) aniline according to Method C1f to give urea which is coupled with 4-fluoroaniline according to Method D1 c.

Example 78: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxy-phenoxy) aniline according to Method C1f to give urea which is coupled with 4- (dimethylamino) aniline according to Method D1c.

Example 79: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to give the urea which is coupled with N-phenylethylenediamine according to Method D1c.

Example 80: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method Cl f to give urea which is coupled with 2-methoxyethylamine according to Method Dc.

Example 81: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to give urea which is coupled with 5-amino-2-methoxy-pyridine according to Method D1c.

Example 82: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to give urea which is coupled with 4-morpholinoaniline according to Method D1c.

Example 83: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to give the urea which is coupled with N- (2-pyridyl) piperazine according to Method D1c.

Example 84: 4-Chloropyridine-2-carbonyl chloride hydrochloride was reacted with 2-hydroxyethylamine according to Method A2, Step 3b, to give 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide. 4-Chloro- N - (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide is reacted with triisopropylsilyl chloride then 4-aminophenol according to Method A17 to give 4- (4- (2- (N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyl) oxyyloxy) And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline) to give N- (4-chloro-3). - ((trifluoromethyl) phenyl) -N '- (4- (4- (2- ^(N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyfenyljmočovina. urea was deprotected according to method D5 to give <N ( 4-chloro-3 - ((trifluoromethyl) phenyl) -N ^&apos' - (4- (4- (2- ^(N - (2-hydroxy) etylkarbamoyljpyridyloxyfenyljmočovina.

Example 85: 4- (2- (N'-Methylcarbamoyl) -4-pyridyloxy) aniline was prepared according to Method A2. 4-Bromo-3- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. And, according to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 86: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was prepared according to Method A6. 4-Bromo-3- (trifluoromethyljaniline) is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenylisocyanate is reacted with 4- (2- (N-methylcarbamoyl) (4-Pyridyloxy) -2-chloroaniline to give the urea.

Example 87: According to Method A2, Step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N ¹ -methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 4- ( 2- (N-methylcarbamoyl) -4-pyridyloxy) -3

chloroaniline. 4-Bromo-3- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. And according to method C a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N'-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to give urea.

Example 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting ^{4-chloro-N-ethyl-2-pyridinecarboxamide} was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (7V-ethylcarbamoyl) -4-pyridyloxy) aniline. 4-Bromo-3- (trifluórmetyljanilín is converted to 4-bromo-3- (trifluórmetyljfenylizokyanát according to Method Bl. According to Method Cla, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ^(I - ethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 89: 4-Chloro-R-methyl-2-pyridinecarboxamide, prepared according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4, to give 3- (- 2 - (1 -) W-methylcarbamoyl) -4-pyridyloxy) aniline. 4-Bromo-3- (trifluoromethyljaniline) is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 3 - (- 2- (A ') (methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Example 90: According to Method A2, Step 4, 5-amino-2-methyl-phenol is reacted with 4-chloro-N ^, -methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 3- ( 2- ^{(N-methylcarbamoyl)} -4-pyridyloxy) -4-methylaniline. 4-Bromo- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. And according to method C a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylanilm to give urea.

Example 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N, A-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N, ^A, -dimctylkarbamoyl) -4-pyridyloxy) aniline . 4-Bromo-3- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. And according to method C a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N, N'-dimethylcarbamoyl) -4-pyridyloxyjaniline to give urea.

Example 92: 4-Chloro- N -methylpyridinecarboxamide was prepared according to Method A2, Step 3b. The chloropyridine is reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 4-Bromo-3- (trifluoromethyl) aniline is converted to 4 bromo-3- (trifluoromethyl) fcnylizokyanát according to method Bl. according to method Cla, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- (N ^{& apos} methylcarbamoyl) phenylthio) aniline urea is obtained.

Example 93: 4-Chloro- N -methylpyridinecarboxamide was prepared according to Method A2, Step 3b. The chloropyridine is reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 4-Bromo-3- (trifluoromethyl) aniline is converted to 4- bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1 A according to method C1 a 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline) to give urea.

Example 94: 4- (2- (N - (2-Morpholin-4-ylethyl) carbamoyl) pyridyloxyjaniline was prepared according to Method A10) 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1A according to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxyjaniline) to give urea.

Example 95: 4- (2- (A-Methylcarbamoyl) -4-pyridyloxy) aniline was prepared according to Method A2. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was prepared according to Method A. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method A7. of Method B1 A according to Method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N'-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 96: 4- (2- (N'-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was prepared according to Method A6. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was prepared according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline is converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to afford the urea.

Example 97: According to Method A2, Step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 4- ( 2- (7V-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was prepared according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline is converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method Cla, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ^{(N-methylcarbamoyl)} -4-pyridyloxy) -3-chloroaniline to afford the urea.

Example 98: 4-Chloro-N-methyl-2-pyridinecarboxamide, prepared according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to give 3 - (- 2- (A- methylcarbamoyl) -4-pyridyloxy) aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was prepared according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline is converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. And, according to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 3 - (- 2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N'-ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was prepared according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline is converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N, N -dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2 - (N, ^N' -dimethylcarbamoyl) -4- pyridyloxy) aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was prepared according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline is converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. And, according to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2 - (N, N -dimethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 101: 4-Chloro-N-methyl-2-pyridinecarboxamide, prepared 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. 2-Amino-3-methoxynaphthalene was prepared according to Method A1. And according to Method C3, 2-amino-3-methoxynaphthalene is reacted with bis (trichloromethyl) carbonate, followed by 3 - (- 2- (N-methylcarbamoyl) -4-pyridyloxy) amine to form urea.

Example 102: 4- (2- (N ^f: methylene) -4-pyridyloxy) aniline was synthesized according to Method A2. 5-tert-Butyl-2- (2,5-dimethylpyrolyljaniline) was prepared according to Method A4, 5-tert-Butyl-2- (2,5-dimethylpyrolyl) aniline was reacted with CDI, followed by 4- (2- ( N- ⁽ methylcarbamoyl) -4-pyridyloxy) aniline according to Method C2d to give the urea.

Example 103: ^4-Chloro-N -mctyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N'-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4, using DMAC instead of DMF to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline . And according to method C2b, reaction of 3-amino-2-methoxyquinoline with CDI, then with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline affords bis (4- (2- (N-methylcarbamoyl)) -4- pyridyloxy) phenyl) urea.

The compounds listed in the tables are synthesized according to the methods described in more detail.

table

The compounds shown in Tables 1-6 are prepared according to the general methods and the more detailed procedures in the examples. Individual characteristics are listed in the tables.

Table 1 3-tert-Butylphenylurea

Example R Melting point (° C) HPLC (min) TLC R TLC System MS [Ionization] Synthesis method 1 Vnh -OO " 0.22 50% EtOAc / 50% hexane 418 (M + H) &lt; + &gt; (HPLC ES-MS) A13C3 2 0.58 50% EtOAc / 50% hexane 403 (M + H) &lt; + &gt; (HPLC ES-MS) A13 C3 3 0> -ΝΗ -Ό-Ό-οΧ 133 -135 0.68 100% EtOAc 448 (M + H) &lt; + &gt; (FAB) A8 C2d

Table 2 5- tert -Butyl-2-methoxyphenyl urea

Example R Melting point (° C) HPLC (min) TLC R TLC System MS [Ionization] Synthesis method 4 -O-C NH Me 5.93 448 (M + H) &lt; + &gt; (HPLC ES-MS) A13 BI Cla

Example R Melting point (° C) HPLC (min) TLC R TLC System MS [Ionization] Synthesis method 5 N-NH 120-122 0.67 100% EtOAc 478 (M + H) + (FAB) A8 c2d 6 0 0.40 50% EtOAc / 50% hexane 460 (M-H) &lt; + &gt; (HPLC ES-MS) A3 c2d 7 0.79 50% EtOAc / 50% hexane 446 (M + H) &lt; + &gt; (HPLC ES-MS) A12 c2d

Table 3 5- (Trifluoromethyl) -2-methoxyphenyl urea

Example R Melting point (° C) HPLC (min) TLC R TLC System MS [Ionization] Synthesis method 8 ABOUT. Vnh -opí * 250 (Dec) 460 (M + H) + (FAB) A13 C2a 9 206-208 0.54 10% MeOH / 90% CH ₂ C1 ₂ 446 (M + HHPLPLC ES-MS) A3 step 2, A8 step 4, B1, Cla 10 0.33 50% EtOAc / 50% Pet ether 445 (M + H) &lt; + &gt; (HPLC ES-MS) A13 C3 11 V-NH] = (Me // ^N 0.20 2% Et3N / 98% EtOAc 461 (M + H) &lt; + &gt; L (HPLC ES-MS) A2 C4 12 In —c2y-NH _{ y-w 0.27 1% Et3N / 99% EtOAc 447 (MiHr (HPLC-MS) A2 C4 13 O-NH-0-0 ^{M <} 0.62 100% EtOAc 461 (M + H) + (FAB) A2 C2a 14 0. ~ cy ° A3 ^N 114-117 0.40 1% Et 3 N / 99% EtOAc 447 (M + H) + (FAB) A2 C4 15 / ~ NH 232-235 0.54 100% EtOAc 490 (M + H) + (FAB) A8 C2d 16 0 Me% -NH —CV-Ο-ζ λ ^Ν 210-213 0.29 5% MeOH / 45% EtOAc / 50% pet ether 475 (M + H > (HPLC ES-MS) A5 Bl Cic

Example R Melting point (° C) HPLC (min) TLC R TLC System MS [Ionization] Synthesis method 17 0 CI Y — NH M ' ^Me 187-188 0.17 50% EtOAc / 50% pet ether 495 (M + H) &lt; + &gt; (HPLCES-MS) A6 BI Cla 18 - ^ - NH O-C N 0.48 100% EtOAc 475 (M + H) + - (HPLCES-MS) A2 step 4, BI Cla 19 -oo " 194-196 0.31 5% MeOH / 45% EtOAc / 50% pet ether 475 (M + H) &lt; + &gt; (HPLC ES-MS) A2 BI Cla 20 0 Cl y-NH Z- / / = <Me ~~ \ / ° ~ A // ^N 214-216 0.25 5% MeOH / 45% EtOAc / 50% pet ether 495 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 21 AJ- ° about-to 208-210 0.30 50% EtOAc / 50% hexane 481 (M + H +) (HPLC ES-MS) A19 C2a 22 0> -nh ₂ -Q- ° -Q 188-190 0.30 70% EtOAc / 50% hexane 447 (M + H +) (HPLC ES-MS) A15 step 4, Cla 23 - \ Y ^NH o 0.50 70% EtOAc / 30% hexane 472 (M + H > (FAB) A3 BI Cla 24 ° ϊ W O-O-H 203 - 205 0.13 100% EtOAc 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2B1 Cla 25 0.09 75% EtOAc / 25% hexane 458 (M + H) &lt; + &gt; (HPLC ES-MS) A12C2d 26 MeO 169-171 0.67 50% EtOAc / 50% pet ether 474 (M + H) &lt; + &gt; (HPLC ES-MS) A13 step 1, A13 step 4, A16 BI Cla 27 o Vnh 218-219 0.40 50% EtOAc / 50% pet ether 477 (M + H) &lt; + &gt; (HPLC ES-MS) A2 step 3b, A2 step 4, BI, Cla 28 - ^ - ° -ζΎΥ ³ Ay-β 0 212-214 0.30 40% EtOAc / 60% hexane A9 BI Cla 29 —R 2 T ^{N N} , ^H S → _{Z /} N 0.33 50% EtOAc / 50% pet ether 474 (M + H) &lt; + &gt; (HPLC ES-MS) A2 step 3b, A2step4, B1, Cla 30 0 IGB ~ 210-211 A2 BI Cla

SK 285532 Β6

Example R Melting point (° C) HPLC (min) TLC R TLC System MS [Ionization] Synthesis method 31 About V-NH 210-204 0.43 10% MeOH / CH ₂ Cl ₂ A14 Bl Cla D4 32 The «H 4> ° -Q '* 247-249 0.57 10% MeOH / CH ₂ Cl ₂ A14 bl Cla D4 33 IGB \ = / V-N Me 217-219 0.07 10% MeOH / CH ₂ Cl ₂ A14 Bl Cla D4 34 O-NH 0.11 70% EtOAc / 30% hexane All Bl Clf Dlc 35 b ^C N— \ o VN> = O “Ζ ^ ⁰ Ο 0.38 70% EtOAc / 30% hexane All Bl CLF dlc 36 HľH = <—O ~ ° ~ C / 0.77 70% EtOAc / 30% hexane All Bl Clf Dlc 37 ^Μ \ _ΤΆ_ _ΝΗ Me> = C - <y ° -o 0.58 70% EtOAc / 30% hexane All Bl Clf Dlc 38 MeO-TNH \ = / ^ = C Cy ° ~ o 0.58 70% EtOAc / 30% hexane All Bl CLF dlc 39 N-Z, N-NH \ = / ^ = c 0.17 70% EtOAc / 30% hexane All Bl Clf Dlc 40 CCHCHĎjL,>> -O 0.21 70% EtOAc / 30% hexane All Bl Clf Dlc

Table 4 3- (Trifluoromethyl) -4-chlorophenyl urea

_% AH

Example R Melting point (° C) HPLC (min) TLC R TLC System MS [Ionization] Synthesis method 41 0th IGB -0-0 * 163-165 0.08 50% EtOAc / 50% pet ether 464 (M + H > (HPLC FS-MS) A13 C3 42 Vnh -fh-d 215 0.06 50% EtOAc / 50% pet ether 465 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 43 and V-NH ₂ 0.10 50% EtOAc / 50% pet ether 451 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 44 Q X H / 0.25 30% EtOAc / 70% pet ether 451 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 45 - <y Vnh y - <M «° A / 0.31 30% EtOAc / 70% pet ether 465 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 46 ΓΪ 176-179 0.23 40% EtOAc / 60% hexane 476 (M + H) + (FAB) A3 Cla 47 0. Me Y - NH - Y ° V / ^N 0.29 5% MeOH / 45% EtOAc / 50% pet ether 478 (M + H) &lt; + &gt; (HPLC ES-MS) A5 Cic 48 O-S & H 206-209 A15 Cla 49 o _x Cl Vnh yv / = < ^Me ~ Λ Γ ° Λ \ / 147-151 0.22 50% EtOAc / 50% pet ether 499 (M + H) &lt; + &gt; (HPLC ES-MS) A6 Cla 50 - / Ä-Me V-NH \ s = ^ Me ° Λ / 0.54 100% EtOAc 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 51 V-NH4 O ' ^o 0 187-189 0.33 5% MeOH / 45% EtOAc / 50% pet ether 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 52 0. and V-nh ~ \ / " ^ο " ζ / ^Ν 219 0.18 5% MeOH / 45% EtOAc / 50% pet ether 499 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla

Example R Melting point (° C) HPLC (Min.) TLC R TLC System MS [Ionization] Synthesis method 53 246-248 0.30 50% EtOAc / 50% hexane 485 (M + H) &lt; + &gt; (HPLC ES-MS) A19, Cla 54 -0-0¾ mb 196 -200 0.30 70% EtOAc / 30% hexane 502 (M + H) &lt; + &gt; (HPLC ES-MS) A15 Cla 55 228-230 0.30 30% EtOAc / 70% CH ₂ C1 ₂ 466 (M + H &lt; + &gt; (HPLC ES-MS) 56 Me 238 -245 57 221 -222 0.75 80% EtOAc / 20% hexane 492 (M + H) + (FAB) Cld Dla 58 c> IGB 247 0.35 100% EtOAc cld dla D2 59 0 Me 198-200 0.09 100% EtOAc 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 60 MAO 158-160 0.64 50% EtOAc / 50% pet ether 61 ---------- 3 Vnh O ~ ^o_ w '—D 195-197 0.39 10% MeOH / CH ₂ Cl ₂ A13 Cla 62 IGB 170-172 0.52 10% MeOH / CH ₂ Cl ₂ A13 Cla 63 about. 7-NH Οχ, 168-171 0.39 10% MeOH / CH ₂ Cl ₂ A13 Cla 64 cr ET IGB 176-177 0.35 10% McOH / CH ₂ Cl ₂ A13 Cla 65 about. IGB -0- ^ 7 * 130-133 487 (M + H) &lt; + &gt; (HPLC ES-MS) A2 BI Cla 66 o _x Vnh - €> ~ d ^{> M} 155 A2 Cla 67 about. IGB * 225-229 0.23 100% EtOAc Cle D3 DLB 68 -C ~ O ~ T ° ° ABOUT 234-236 0.29 40% EtOAc / 60% hexane A9 Cla

Example R Melting point (° C) HPLC (min) TLC R TLC System MS [Ionization] Synthesis method 69 ff Λ. -? } Vnh / = (Me H / · 0.48 50% EtOAc / 50% pet ether 481 (M + H) &lt; + &gt; (HPLC ES-MS) 70 _3 ~ ^nh vo 0.46 5% MeOH / 95% CH ₂ C1 ₂ 564 (M + H) &lt; + &gt; (HPLC ES-MS) A10 Cla 71 0 IGB - £ W / about 199-201 0.50 10% MeOH / CH ₂ Cl ₂ A14 Cla D4 72 0 _in Knh 235-237 0.55 10% MeOH / CH ₂ Cl ₂ A14 Cla D4 73 o _k JV-NH - \ y — O- / in N-Me ^ - = ⁷ + —N Me ' 200-201 0.21 50% MeOH / CH ₂ Cl ₂ A14 Cla D4 74 0. J> “ ^NH - ^ OSKPMh 145-148 75 (Λ-ΝΗ \ = = / * \ =: ₀ - <y ^ 0.12 70% EtOAc / 30% hexane 527 (M + H) &lt; + &gt; (HPLC ES-MS) AU CLF dlc 76 N— \ O _O “Ό'θΧΙ ^ 0.18 70% EtOAc / 30% hexane All CLF dlc 77 The F / V-NH ~ O O ^0_ 0.74 70% EtOAc / 30% hexane All Clf Dlc 78 Me YFY ^M _NH ^ = 0 0.58 70% EtOAc / 30% hexane All CLF dlc 79 _3 ~ ^nh 'lr. 0.47 70% EtOAc / 30% hexane 569 (M + H) &lt; + &gt; (HPLC ES-MS) All Clf Dlc

Example R Melting point (° C) HPLC (min) TLC R TLC System MS [Ionization] Synthesis method 80 0.18 70% EtOAc / 30% hexane 508 (M + H) &lt; + &gt; (HPLC ES-MS) All CLF dlc 81 MeO-NH 0.58 70% EtOAc / 30% hexane 557 (M + H) &lt; + &gt; (HPLC ES-MS) All CLF dlc 82 cf ^Λ ν— / Λ-νη O ⁰ O 0.37 70% EtOAc / 30% hexane 611 (M + H) &lt; + &gt; (HPLC ES-MS) All CLF dlc 83 Q ABOUT Y-N The "O 0.19 70% EtOAc / 30% hexane All CLF dlc 84 CT Vnh - ^s ' θπ 179- 183 A2 A17 Cla D5

Table 5 3- (Trifluoromethyl) -4-bromophenyl urea

H H

Example R Melting point HPLC (min) TLC R TLC System MS [Ionization] Synthesis method 85 0 ^ NH -ΟΌ · " 186-187 0.13 50% EtOAc / 50% pet ether 509 (M + H) &lt; + &gt; (HPLC ES-MS) A2 BI Cla 86 0 Cl y-NH ^Me - \ / ° “w 150-152 0.31 50% EtOAc / 50% pet ether 545 (M + H) &lt; + &gt; (HPLC ES-MS) A6 BI Cla 87 about Cl / NH z— <z = \ M · 217-219 0.16 50% EtOAc / 50% pet ether 545 (M + H) &lt; + &gt; (HPLC ES-MS) A2 BI Cla 88 o _in Vnh 183-184 0.31 50% EtOAc / 50% pet Cter 525 (M + H) &lt; + &gt; (HPLC ES-MS) A2 BI Cla

Example R Melting point HPLC (min) TLC R TLC System MS [Ionization] Synthesis method 89 —P / -NH Me 0.21 50% EtOAc / 50% pet ether 511 (M + H) &lt; + &gt; (HPLC ES-MS) A2 BI Cla 90 —Vnh _/ = / Me ° Λ / 0.28 50% EtOAc / 50% pet ether 525 (M + H) &lt; + &gt; (HPLC ES-MS) A2 BI Cla 91 y * · 214-216 0.28 50% EtOAc / 50% pet ether 522 (M + H) &lt; + &gt; (HPLC ES-MS) A2 BI Cla 92 ABOUT. IGB -0-0 * 0.47 50% EtOAc / 50% pet ether 527 (M + H) &lt; + &gt; (HPLC ES-MS) A2 step 3b, A2 step 4. BI, Cla 93 -O Ynh \ = (/ = (Me ^With “W 0.46 50% EtOAc / 50% pet ether 527 (M + H) &lt; + &gt; (HPLC ES-MS) A2 step 3b. A2 step 4, BI, Cla 94 0 In ++ ++ w 'Ί’λ' -d * 145-150 0.41 5% MeOH / 95% CH ₂ C1 ₂ A10 BI Cla

Table 6 5- (Trifluoromethyl) -4-chloro-2-methoxyphenyl urea

Example R Melting point (° C) HPLC (min) TLC R TLC System MS [Ionization] Synthesis method 95 \ NH - {ΗΓ 140-144 0.29 5% MeOH / 45% EtOAc / 50% pet ether 495 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 BI Cla 96 about Cl-NH 244-245 0.39 5% McOH / 45% EtOAc / 50% pet ether 529 (M-H) &lt; 1 &gt; (HPLC ES-MS) A6 A7 BI Cla 97 about Cl Vnh - & ° -O ' 220-221 0.25 5% MeOH / 45% EtOAc / 50% pet ether 529 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 BI Cla 98 -ΛΛ Vnh ^X = <Me ° O 0.27 5% MeOH / 45% EtOAc / 50% pet ether 495 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 BI Cla 99 O. Vnh d ^B 180-181 0.52 5% MeOH / 45% EtOAc / 50% pet ether 509 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 BI Cla

Example R Melting point (° C) HPLC (min) TLC R TLC System MS [Ionization] Synthesis method 100 In NH 162-165 A2 A7 BI Cla

Table 7 Other ureas

Example R MP ^(C C) HPLC (min) TLC R TLC System MS [Ionization] Synthesis method 101 Am * ^hh 162-165 Al A2 C3 102 0.10 50% EtOAc / 50% hexane 442 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A4 c2d 103 χ HN NH 0 Q .č k NH-Ma-Mb ___________ NH 125-130 0.24 40% EtOAc / 60% hexane 512 (M + H) + (FAB) A2 C2B

The synthesis of the compound of the examples can be repeated with similar success when the generic or specifically described reactants and / or reaction conditions of the invention described in the described examples are replaced.

From the foregoing description, the essential characteristics of the invention can be readily determined, and variations and modifications may be made to the invention unless departing from the spirit and scope of the invention.

Claims (18)

PATENT CLAIMS A compound selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenyl urea: N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea; 4-chloro-3- (trifluoromethyl) phenyl) - / V - (3- (2- (7V-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, 7V- (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; 4-bromo-3- (trifluoromethyl) phenyl ureas: N- (4-bromo-3- (trifluoromethyl) phenyl) ^-N '- (3- (2 - (/ V-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, A ^{I '-} (4-bromo-3- (trifluoromethyl) phenyl) ^-N, - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -A- (3- (2- (N-methylcarbamoyl) -4-pyridyItio) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (7'-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea N - (4 bromo-3- (trifluoromethyl) phenyl) -? V '- (3-chloro-4- (2- (N-rnetylkarbamoyl) (4-pyridyloxy)) phenyl) urea; 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl urea: N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N- (4- (2- (N-methylcarbamoyl)) - 4-pyridyloxy) phenyl) urea, and N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl)) (4-pyridyloxy) (phenyl) urea, or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is a pharmaceutically acceptable salt thereof selected from the group consisting of (a) basic salts of organic and inorganic acids selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, trifluorosulfonic, benzenesulfonic, p-toluenesulfonic (tosylate salt), 1-naphthalenesulfonic, acetic, 2-naphthalenesulfonic, , citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic and mandelic acids; and (b) acidic salts of organic and inorganic bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cation, aliphatic-substituted ammonium cations and aromatic-substituted ammonium cations. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. A compound according to claim 1 selected from the group consisting of N- (4-chloro-3- (trifluoromethyl) -phenyl-A ^I - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, AI- (4-chloro-3- (trifluoromethyl ) phenyl) -N- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, A ^f - (4-chloro-3- (trifluoromethyl) phenyl) -7Y '- (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, / V- (2-methoxy-4 -chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N'-methylcarbamoyl) -4-pyridyloxy) phenyl) urea and N - (2-methoxy-4-chloro-5- ( trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (AAmethylcarbamoyl) (4-pyridyloxy)) phenyl) urea or a pharmaceutically acceptable salt thereof. The compound of claim 4, which is a pharmaceutically acceptable salt thereof selected from the group consisting of (a) basic salts of organic and inorganic acids selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, trifluorosulfonic, benzenesulfonic, p-toluenesulfonic (tosylate salt), 1-naphthalenesulfonic, acetic, 2-naphthalenesulfonic, , citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic and mandelic acids; and (b) acidic salts of organic and inorganic bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cation, aliphatic-substituted ammonium cations and aromatic-substituted ammonium cations. A pharmaceutical composition comprising a compound according to claim 4, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. Use of a compound according to claim 1 selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenyl urea: N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (3- (2-carbamoyl-4-) pyridyloxy) phenyl) urea,? - (4-chloro-3- (trifluoromethyl) phenyl) ^-N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea A / - (4 chloro-3- (trifluoromethyl) phenyl) -N ^l - (4- (2-carbamoyl-4-pyridyloxyfenyljmočoviny, N - (4-chloro-3- (trifluoromethyl) phenyl) ^-N '- (4- ( 2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea ^and, - (4-chloro-3- (trifluoromethyl) phenyl) - _s N '- (2-chloro-4- (2- ^(I' methylcarbamoyl) -4-pyridyloxy) phenyl) urea; 4-bromo-3- (trifluoromethyl) phenyl ureas: ^A - (4-bromo-3- (trifluórmctyl) 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, ^A - (4-bromo-3- (trifluoromethyl) phenyl) -A- (2-chloro-4- (2- (N-mctylkarbamoyl) (4-pyridyloxy)) phenyl) urea and N - (4-bromo 3- (trifluórmctyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea; 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl urea: N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4) -pyridyloxy) phenyl) urea and N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) ^-N '- (2-chloro-4- (2- (Al-methylcarbamoyl) (4-pyridyloxy) (phenyl) urea, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer cell growth mediated by raffinase. 8. The method of claim 1 selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenyl ureas: Y- (4-chloro-3- (trifluoromethyl) phenyl) -N ^d '- (3- (2-carbamoyl- 4-pyridyloxy) phenyl) urea, a (4-chloro-3- (trifluoromethyl) phenyl) -N ^f '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea and ^L - ( 4-chloro-3- (trifluoromethyl) phenyl) ^-N, - (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N - (4-chloro-3- (trifluórmctyl) phenyl) -A- (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; 4-bromo-3- (trifluoromethyl) phenyl ureas: A ^I - (4-bromo-3- (trifluoromethyl) phenyl) -lv '- (3- (2 - (/ V-methylcarbamoyl) -4-pyridyloxy) phenyl) urea . N- (4-bromo-3- (trifluoromethyl) phenyl) -N ^d '- (4- (2- ^{(L-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) -A ^; '- (2-chloro- N - (2- (N'-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea and N' - (4-bromo-3- (trifluoromethyl) phenyl) - N '- (3- chloro-4- (2 - (<V-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea; 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl ureas: ^N - (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) ^-N, - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea and ^N - (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -7V - (2-chloro-4- (2 - (/ V-methylcarbamoyl) (4 -pyridyloxy) phenyl) urea, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treatment (i) carcinoma of the lung, pancreas, thyroid, bladder, colon, (ii) myeloid leukemia, or (iii) villous colon adenoma. Use of a compound according to claim 1 selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenyl urea: N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl- 4-pyridyloxy-phenylurea, 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) -; W ' - (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; 4-bromo-3- (trifluoromethyl) phenyl ureas: ^L - (4-bromo-3- (trifluoromethyl) phenyl) ^-N, - (3- (2- ^{(N-methylcarbamoyl)} -4-pyridyloxy) phenyl) urea N - (4-bromo-3- (trifluoromethyl) phenyl) -A- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, 7V- (4-bromo-3- (trifluoromethyl) phenyl) -7y '- (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 AE (4-bromo-3- (trifluoromethyl) phenyl) N- (3-solvent mixture, 4- (2 - (. V-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea; 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl ureas: N - (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) - N - (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea and N - (2-methoxy-4-chloro) -5- (trifluoromethyl) phenyl) N- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of tumors. The 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 ^f '- (4- (2-carbamoyl-4-pyridyloxyj-fenyljmočoviny, ^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 and X (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N ^&apos' - (2-chloro-4- (2- (7V-methylcarbamoyl) (4-pyridyloxy) (phenyl) urea or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer cell growth mediated by raffinase. 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-pyridyloxyjfenyljmočoviny, and ^I - (4-chloro-3- (trifluoromethyl) phenyl) -V- (2-chloro-4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) ^-N, - (4- (2- ( 7V-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, ^N - (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) N- (4- (2 - (. N-methylcarbamoyl) -4-pyridyloxy ) phenyl) urea and N-2 meto.xy-4-chloro-5-ítrifhiórmetyl) phenyl) - / V - _{(2-chloro-4-C} (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treatment (i) carcinoma of the lung, pancreas, thyroid, bladder, colon, (ii) myeloid leukemia, or (iii) villous colon 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-pyridyloxyjfenyljmočoviny, AA (4-chloro-3- (trifluoromethyl) phenyl) N - (2-chloro-4- (2- (Al-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N '- (4-bromo-3- (trifluoromethyl) phenyl) - N - (4- ( '2 - (.- V-mctylkarbamoyl) -4-pyridyloxy) phenyl) urea and ^L - (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -A- (4- (2- ^(L methylcarbamoyl) -4-pyridyloxy) phenyl) urea and N - (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N ^d '- (2-chloro-4- (2- (A'- methylcarbamoyl) (4-pyridyloxy)) phenyl) urea or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of tumors. A compound according to claim 1 which is N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea. 14. The compound of Claim I which is N- (4-chloro-3- (trifluoromethyl) phenyl) -N ^&apos' - (4- (2- (N-methylcarbamoyl ^s) -4-pyridyloxyjfenyljmočovina. 15. Pharmaceutical composition, characterized in that it comprises ^N - (4-chloro-3- (trifluoromethyl) phenyl phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable a salt 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 physiologically acceptable carrier. The use of N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancerous cell growth mediated by raf kinase. 18. The use of N - (4-chloro-3- (trifluoromethyl) phenyl) -N ^N - (4- (2- (N-methylcarbamoyl ^s) -4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer cell growth mediated by rafkinase.