SK287419B6 - Use of omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors - Google Patents

Abstract

Disclosed are aryl urea derivatives and use thereof in the preparation of medicaments for the treatment of cancerous cell growth mediated by raf kinase.

Description

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 down-stream 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). It has been found that inhibiting the effect of active ras by inhibiting the rafkinase signaling pathway by applying inactivated anti-rafkinase antibodies or by coexpressing dominant negative rafkinase or dominant negative MEK, a rafkinase substrate, leads to reversed transformed cells to normal growth phenotype (see: Daum et al., Trends Biochem. Sci., 1994, 19, 414-80, 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 (Monia et al, Nat. Med., 1996, 2, 668-75).

SUMMARY OF THE INVENTION

The present invention provides compounds that are inhibitors of the enzyme rafkinase. Because 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 raffinase pathway is indicated, ie 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 the cascade of signal transduction of ras protein and is therefore prone to treatment by disrupting the cascade, ie, by inhibiting raffinase. 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 the use of a compound of formula (I):

A-D-B (I) or a pharmaceutically acceptable salt thereof, wherein

D is -NH-C (O) -NH-,

A is a substituted moiety of the formula -1- (ML *) _q having up to 40 carbon atoms, wherein L is a substituted or unsubstituted phenyl or pyridyl moiety Directly bonded to D, L ¹ contains a substituted phenyl or pyridyl moiety, M is a moiety forming a bridge having at least one atom; q is an integer from 1 to 3; and B is a substituted or unsubstituted phenyl group bonded directly to D, wherein L 1 is substituted with -C (O) R _X , wherein R _x is NR _and R _b, and R _a and R _b are independently hydrogen and a carbon-based moiety, having up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted with halogen, hydroxy and carbon-based substituents having up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and are optionally substituted with halogen; and wherein the substituents for B and L and additional substituents for L ¹ is selected from the group consisting of C _r C ₀ alkyl, Ci-Cio alkyl substituted by halogen up to full-scale substitution by halogen, CN, OH, halogen, C Cm alkoxy and C _r C 10 alkoxy substituted by halogen until total halogen substitution, wherein M is one bridge forming group selected from the group consisting of -O- or -S-; for the preparation of a medicament for the treatment of carcinogenic cell growth mediated by rafkinase.

SK 287419 Β6

Suitable alkyl groups and alkyl moieties, e.g. alkoxy groups etc. ", throughout the text, include methyl, ethyl, propyl, butyl, etc., including all branched or unbranched isomers such as e.g. isopropyl, isobutyl, sec-butyl, tert-butyl, etc. '.

Suitable halogen groups include F, Cl, Br and / or I, one to persubstitution is possible (all H atoms in the group replaced by halogen atoms), wherein the alkyl group is halogen substituted, with mixed substitution possible.

The present invention also relates to the use of pharmaceutically acceptable salts of formula (I). 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 as well as acid salts of organic bases including aliphatic and an aromatic group substituted with ammonia and quaternary ammonium cations, e.g. resulting from protonation or peralkylation of triethylamine, N, N-diethylamine, Ν, Ν-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) α1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).

Many compounds of formula (I) have asymmetric carbon atoms and can therefore exist in racemic and optically active forms. Methods for separating enantiomeric and diastereomeric mixtures are well known 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

Compounds of formula (I) 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 set forth later 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, 3rd 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 H2, 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, 3rd Ed .; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)).

H ₂ / catalyst

M (O) 2 * (eg Fe, Sn. Ca)

Scheme I Reduction of nitroaryls to arylamines

Nitraryls 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

Ar-H

HNO ₃

----------- AtNO _{2 with 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, undergo cross-coupling reactions with palladium-mediated aryl nucleophiles, e.g. with aryl boronic acids (Suzuki reaction, shown later), arylcines (Stille reaction) or arylzines (Negishi reaction) to obtain biaryls (5).

ArB (OR ') ₂

Pd (O)

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 provides difluoromethylmercaptan (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. Org. Khim. 1970, 6). , (568).

(Me ₂ N) ₃ With MeiFi MeiFi

IN

SO _and CF ₃

CHCIF ₂ base

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 N, N-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-NH ₂ 13

1 ^coc ' ² <h ₂ on?

Ar’-NCO ------- 1

"7 DPPA about \ ABOUT .A 16 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 formula (I) and a physiologically acceptable carrier for use as described above.

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. lecithin or condensation products or an alkene oxide with fatty acids, 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 but one

Or more preservatives, eg. 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 dispersant or detergent, a 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. Sweeteners, e.g. mentioned above, and flavorings 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. polyoxyethylene. 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 compounds of formula (I) used herein will preferably be a daily oral dose of 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. 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 sex and lifestyle of the patient, the 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 the treatment, i.e., the treatment, can be achieved. the method of treatment and the daily number of doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof administered over a specified number of days may 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 during therapy. .

Compounds of formula (I) may be prepared from known compounds (or starting materials which may be prepared from known compounds), e.g. using the general methods of preparation mentioned above. The activity of the provided compound for inhibiting rafkinase can be routinely determined, e.g. following 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.

SK 287419 Β6

Unless otherwise stated, the term "concentrated under reduced pressure" refers to the use of a Buchi rotary evaporator at 19.98 x 10 ² Pa (15 mmHg). Unless otherwise stated, the term "high vacuum" refers to a vacuum of 0.53 x 10 ² Pa - 1.332 x 10 ² Pa (0.4 - 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-3- (trifluoromethyl) phenyl isocyanate, and were used without further purification Synthesis of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98 / A. Cordi et al., EP 542,609; IBID Bioorg. Med. Chem. 3, 1995, 129), 4- (3-carbamoylphenoxy) -1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-tert-butylphenyl isocyanate (O. Rohr et al. DE 2,436,108) and 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70 1967, 491) has been described.

Thin layer chromatography (TLC) was performed on a glass plate covered with Whatman® silica gel, 60A F-254 silica gel, 250 µm thick. 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 sulphate solution; followed by heating and / or (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine and subsequent 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 surges were performed with an electron energy of 70 eV and a 300 µuuA 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 (1.332 x 10 ^-2 Pa, ie 1 x 10 ^-4 torr to 3.33 x 10 ² Pa, i.e. 2.5 x 10 ^-4 torr). Direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped 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. in the slide. HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC instrument equipped with a quaternary pump, variable wavelength detector, C-18 column, and 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) were 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 selective mass 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 Ι, Γ-carbonyldiimidazole

conc concentrated D day (s) dec degradation DMAC N, N-dimethylacetamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1 H) -pyridinidinone DMF N, N-dimethylformamide DMSO dimethyl sulfoxide DPPA diphenylphosphoryl EDCI 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide EtOAc acetate EtOH ethanol (100%) Et20 diethyl ether Et 3 N triethylamine h lesson HOBT 1-Hydroxybenzotriazole mCPBA 3-chloroperoxybenzoic acid MeOH methanol pet. ether petroleum ether (boiling range 30-60 ° C) THF tetrahydrofuran TFA trifluoroacetic acid tf trifluoromethanesulfonyl

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

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 (53.3 Pa, 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, 1 H), 8.21 (s, 1 H).

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 mL). , 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. , 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 ₆₎ δ 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 5H), 7.72-7.75 (m, 2H); 8.20 (s, 1H); 8.76 (s, 1H).

Step 4. 2-Amino-3-methoxynaphthalene

A slurry of 2- (N- (carbobenzyloxy) amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd / C (0.5 g) in EtOAc (70 mL) was 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), 7.04-7.16 (m, 2H);

7.43 (d, J = 8.0 Hz, 1H); 7.56 (d, J = 8.0 Hz, 1H); EI-MS m / z 173 (M &lt; + &gt;).

A2. Synthesis of ω-carbamylanilines involving preparation of carbamylpyridine and nucleophilic coupling with arylamine

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

Step 1a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide by Menisci reaction

Warning: this reaction is very dangerous and potentially explosive. To a stirred solution of 4-chloropyridine (10.0 g) in N -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;

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

Δ 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, 1H), 8.21 (s, 1H), 8.44 (d, J = 5.1Hz, 1H); CI-MS m / z 171 ((M + H) &lt; ^{+ &gt;} ).

Anhydrous DMF (6.0 mL) was slowly added to the SOC1 ₂ (180 ml) in a temperature range of 40 ⁰ 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 evolution) 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%).

ABOUT

HCl

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. The solution was stirred at this temperature range for 10 min, then picolinic acid (100 g, 812 mmol) was added over 30 min. The resulting solution was heated at 72 ° C (vigorous SO ₂ 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-carbonyl chloride hydrochloride 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. Ή NMR (DMSO-d 6) δ 3.88 (s, 3H); 7.82 (dd, J = 5.5, 2.2 Hz, 1H); 8.08 (d, J = 2.2Hz, 1H); 8.68 (d, J = 5.5Hz, 1H); 10.68 (brs, 1H); HPLC ES-MS m / z 172 ((M + H) &lt; ^{+ &gt;} ).

Step 3a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxainide 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, 1 H), 8.85 (br d, 1 H); CI-MS m / z 171 ((M + H) &lt; ^{+ &gt;} ).

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.

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 to 80 ° C. ° 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, 1H), 8.73 (br d, 1H); HPLC ES-MS m / z 244 ((M + H) &lt; ^{+ &gt;} ).

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

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

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 adjusted to pH 10 with 1 N 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 yellow solid (3.3 g, 62%): TLC (30 % EtOAc / 70% hexane) R f = 0.28; 1 H NMR (DMSO-d ₆ ) δ 7.32 (d, J = 12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 9Hz, 2H), 11.43 (brs, 1H); CI-MS m / z 285 ((M + H) +, 100%).

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

A solution of 5- (4-nitrophenoxy) isoindoline-1,3-dione (0.6 g, 2.11 mmol) in 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) R f = 0.27; 1 H NMR (DMSO-d 6) δ 5.14 (br s, 2H), 6.62 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H) 7.03 (d, J = 2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J = 8.4 Hz, 1H), 11.02 (s, 1H ); HPLC ES-MS m / z 255 ((M + H) &lt; ^{+ &gt};, 100%).

A4. General method for the synthesis of pyrolylanilines. Synthesis of 5-tert-butyl-2- (2,5-dimethylpyrolyl) aniline

Step L 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 sequentially with 1 N HCl (15 mL) and 1 N NaOH (15 mL) and saturated NaCl (15 mL), dried (MgSO ₄ ), and concentrated 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) &lt; ^{+ &gt};, 50%).

Step 2. Synthesis of 5-TERC-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) R f = 0.43; Δ 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 (br s, 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-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline

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

Iron (3.24 g, 58.00 mmol) was added to 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.

NHMe

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 remaining brown oil was purified by silica gel column chromatography with a gradient of 20% EtOAc / petroleum ether to 40% EtO Ac / petroleum ether to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl- (2,2 2-trifluoro) acetamide as a yellow solid (8.59 g, 23.0 mmol).

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, 1 H).

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 give 4-chloro-2-methoxy-5- (trifluoromethyl) aniline as a brown oil (3.20 g, 14.2 mmol): 1 H NMR (DMSO-d ₆₎ δ 3.84 (s, 3H);

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

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

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

To a solution of 4- (3-carboxy-4-hydroxyphenoxy) -1-nitrobenzene (prepared from 2,5-dihydroxybenzoic acid by the method of Example A13, Step 1, 12 mmol) in acetone (50 mL) was 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.

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

Step 3. 4- (3- (N-Methylcarbamoyl) -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 was acidified with 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to give 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (1.04 g) ·

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 SOCl 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% ).

ABOUT 0 0 '' ΝΗΜθ h ₂ n ^z \) Me

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

A slurry of 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd / C (0.20 g) in EtOH (55 mL) 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.

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

A9. General process for the preparation of ω-alkylphthalimide anilines. Synthesis of 5- (4-aminophenoxy) -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) The reaction mixture was stirred at room temperature for 1 hour, then treated 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% EtOAc) (65% hexane) R f = 0.61.

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 ω-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- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridine as a yellow oil (1.25 g, 95%) TLC (10% MeOH / 90% EtOAc) Rf = 0.50.

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

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert -butoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temperature for 2 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 for

Wash with saturated NaCl solution (3 x 25 mL) and concentrate 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-ylethyl) 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.

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 C1 ₂ ) Rf = 0.44 (elongated dot).

A12. General method for the synthesis of isoindolinone-containing anilines. Synthesis of 4- (1-oxoisoindol-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) R f = 0.17; HPLC ES-MS m / z 150 ((M + H) &lt; ^{+ &gt;} ).

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 combined to give 4- (1-isoindolinon-5-yloxy) -1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) R f = 0.35.

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

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.

A13. General method for synthesis of ω-carbamoylanilines via amide prepared by EDCI and nitroarene reduction. Synthesis of 4- (3-N-methylcarbamoylphenoxy) aniline.

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

A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K ₂ CO ₃ (41 g, 300 mmol) in DMF (125 mL) is heated at reflux through 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%).

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

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

A mixture of 4- (3-carboxyphenoxy) -1-nitrobenzene (3.72 g, 14.4 mmol), EDCl.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 an oil. (1.89 g).

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- (N-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.

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)

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

A slurry of 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd / C in MeOH / EtOAc was stirred under 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% EtOAc / 70% hexane to 50% EtOAc / 50% hexane) to give 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline ( 0.28 g, 60%) 1 H NMR (CDCl ₃ ) δ 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, 1H),

8.51 (d, 1 H), 8.87 (d, 1 H).

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

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

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

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 1 M 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 give N -methyl-3-bromobenzenesulfonamide as a white solid ( 2.8 g, 99%)

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-methylsulfamoyl) phenyloxy) benzene (0.30 g).

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

To a solution of 4- (3- (N-methylsulfamoyl) phenyloxy) benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10 ° C was added portionwise NaNO ₂ (0.097) over 5 minutes. 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) phenoxy aniline hydrochloride).

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

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

To a solution of 4-chloro-N- (2-hydroxyethyl) pyridine-2-carboxamide (prepared 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). 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-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline)

To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anhydrous DMF (8 mL) was added potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv) in one portion. 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 potassium tert-butoxide (0.34 g, 3 mmol, 0.5 equiv.) Was added and the mixture was stirred at 80 ° C for an additional 4 hours, cooled to 0 ° C in an ice bath, then slowly added. water (about 1 mL) was added dropwise. The organic layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with saturated NaCl solution (20 mL), dried (MgSO ₄ ) and concentrated under reduced pressure. The brown oily residue was purified by 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) pyridyloxy) aniline.

Step 1 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene.

A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-nitrobenzene (9.8 mL, 91.6 mmol, 1.0 equiv), K ₂ CO ₃ (25 g, 183 mmol, 2.0 equiv) in DMF (100 mL) was heated at reflux 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 give 4- (5- (2-methyl) pyridyloxy). 1-nitrobenzene as a brown solid (12.3 g).

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

A mixture of 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 minol, 3.0 equiv) in pyridine (20 mL) was heated at reflux for 5 hours, then cooled to room temperature here. 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).

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 EtOAc (20 mL) and MeOH (5 mL) was 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.

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) - 1-nitrobenzene as a solid (2.1 g).

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

B. Synthesis of urea precursors

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

Step 1. Synthesis of 4-bromo-3- (trifluoromethyl) aniline 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 (1M in Et ₂ O; 300 mL) and the resulting mixture was stirred at room temperature. 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 ⁺ ).

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

NHMe

A solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (14.60 g, 65.90 mmol) in CH ₂ C1 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 (1.332 x 10 ² Pa, ie 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) &lt; ^{+ &gt;} ).

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) urea

A solution of 4-bromo-3- (trifluoromethyl) phenyl isocyanate (Method B1, Step 2; 8.0 g, 30.1 mmol) in CH ₂ Cl ₂ (80 mL) was added dropwise to a solution of 4- (2- (N (methylcarbamoyl) -4-pyridyloxy) aniline (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 (1.332 x 10 ² Pa, ie 1 mm Hg) at 40 ° C to give N- (4 -bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as a pale yellow solid (13.2 g, 90%): 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, 1H),

9.21 (s, 1 H); HPLC ES-MS m / z 509 ((M + H) &lt; ^{+ &gt;} ).

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

NHMe

A solution of 2-methyl-4- (2- (N-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- (N- methylcarbamoyl) (4-pyridyloxy)) phenyl) urea as a brown oil (0.11 g, 0.22 mmol): 1 H NMR (DMSO-d ₆ ) δ 2.27 (s, 3H), 2.77 (d J = 4.8 Hz, 3H), 7.03 (dd, J = 8.5, 2.6 Hz, 1H), 7.11 (d, J = 2.9 Hz, 1H), 7.15 (dd, J = 5.5, 2.6, Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H), 7.62 (app d, J = 2.6 Hz, 2H) 7.84 (d, J = 8.8 Hz, 1 H), 8.12 (s, 1 H), 8.17 (s, 1 H); 8.50 (d, J = 5.5Hz, 1H), 8.78 (q, J = 5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m / z 479 ((M + H) &lt; + &gt;).

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

H H

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. Concentrate the organic layer under reduced pressure to give impure N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4-aminophenyl) urea (3.3 g): TLC (100% EtOAc) Rf 0.72.

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

To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH ₂ Cl ₂ (30 mL) is 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) R f = 0.44.

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

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (1.2 µg, 5.46 mmol) in CH ₂ Cl ₂ (8 mL) was added 4- (3-carboxyphenoxy) aniline (Method A1); 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. The resulting mixture was concentrated under reduced pressure. The resulting brown solid was triturated with EtOAc: hexane (1: 1) to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3-carboxyphenyl) urea as an off-white solid (1, 21 g, 76%).

C2a. General method for the synthesis of urea by reacting aniline with Ν ', Ν'-carbonyldiimidazole and adding a second aniline. Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea.

NHMe

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 and 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 N - (2-methoxy-5- ( trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as a light brown solid (0.098 g, 30%): TLC (100% EtOAc) R f = 0.62 ; 1 H NMR (DMSO-d 6) δ 2.76 (d, J = 4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 ( m, 11H), 8.75 (d, J = 4.8Hz, 1H), 9.55 (s, 1H); FAB-MS m / z 461 ((M + H) &lt; ^{+ &gt;} ).

C2B. General method for the synthesis of urea by reacting aniline with N, N'-carbonyldiimidazole and adding a second aniline. Symmetrical ureas as by-products in the reaction of Ν, Ν'-carbonyldiimidazole. Synthesis of bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (not a compound of the invention).

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 (0.081 g, 44%): TLC (100% EtOAc) R f = 0.50; 1 H NMR (DMSO-d ₆ ) δ 2.76 (d, J = 5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J = 5.4) Hz, 1H), 8.75 (d, J = 4.8Hz, 2H),

8.86 (s, 2 H); HPLC ES-MS m / z 513 ((M + H) &lt; ^{+ &gt;} ).

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 (not a compound of the invention).

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 = 9.3Hz, 2H), 7.80 (d, J = 8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS 472.0 ((M + H) ⁺ , 100%).

C2d. General method for the synthesis of urea by reacting aniline with N, N'-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 (not a compound) according to the invention).

NHMe

To a stirred solution of CDI (0.21 g, 1.30 mmol) in CH ₂ C1 ₂ (2 ml) was added in one portion 5- (tert-butyl) -2- (2,5-dimethylpyrrolyl) aniline (Method A4, Step 2; 0.30 g, 1.24 mmol). The resulting mixture was stirred at room temperature for 4 hours, then 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.065 g, 0.267mmol) was added in one portion. The resulting mixture was heated at 36 ° C overnight, cooled to room temperature and diluted with EtOAc (5 mL). The resulting mixture was washed sequentially with water (15 mL) and 1N HCl solution (15 mL), dried (MgSO ₄ ), and filtered through a pad of silica gel (50 g) to give N- (5- (tert-butyl) -2). - (2,5-dimethylpyrolyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc) (60% hexane) R f = 0.24; 1 H NMR (acetone-d ₆ ) δ 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J = 4.8Hz, 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 = 5.4Hz, 1H) ), 8.57 (d, J = 2.1 Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M + H) &lt; + &gt; 100%).

C3. Combination method of diphenylurea synthesis using triphosgene

One of the anilines to be coupled is dissolved in dichloroethane (0.10 M). This solution is 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 N- (2-methoxy-5- (trifluoromethyl) phenyl) -N- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea.

NHMe

To a stirred solution of phosgene (1.9 M in toluene; 2.07 mL 0.21g, 1.30 mmol) in CH 2 Cl 2 (20 mL) at 0 ° C was added anhydrous pyridine (0.32 mL) then 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 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 / 66% hexane, 1% Et ₃ N / 99% EtOAc to 1% Et ₃ N / 20% MeOH / 79% EtOAc, then concentrated under reduced pressure at 45 ° C to obtain a hot concentrated solution in EtOAc, which was washed with hexane (10 mL) to slowly form N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- ( 2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.44 g): TLC (1% Et ₃ N / 99% EtOAc) R f = 0.40.

D. Interconversion of ureas

D la. Conversion of ω-aminophenylureas to <D- (aroylamino) phenylureas. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea (not a compound of the invention)

To a solution of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4-aminophenyl) urea (Method Cld; 0.050 g, 1.52 mmol), monomethyl isophthalate (0.25 g, 1). , 38 mmol), HOBT.H ₂ O (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) were added EDCI.HCl (0, 29 g, 1.52 mmol) The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (25 mL) and washed sequentially with water (25 mL) and saturated NaHCO ₃ solution (25 mL). Na ₂ SO ₄ ) and concentrated under reduced pressure, and the resulting solid was triturated with EtOAc (80% EtOAc / 20% hexane) to give N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N ' - (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122 ° C; TLC (80% EtOAc / 20% hexane) R f = 0.75.

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

To a solution of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-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) at temperature 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 reaction mixture was treated with water (10 mL) and extracted with EtOAc (25 mL). 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 70% gradient.

EtOAc / 30% hexane to 10% MeOH / 90% EtOAc to give N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea as a white solid (0.097 g, 41%) Mp 225-229 ° C TLC (100% EtOAc) R f = 0.23.

Dlc. Combination method for the conversion of ω-carboxyphenylureas to o) - (arylcarbamoyl) phenylureas. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (N- (3- (N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea (not a compound) according to the invention).

A mixture of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (3-carboxyphenyl) urea (Method C1f; 0.030 g, 0.067 mmol) and N-cyclohexyl-N' - (methylpolystyrene) carbodiimide (55). mg) in 1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CH ₂ 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) -N '- (4- (N- (3- (N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea (0.024 g, 59%): TLC (70% EtOAc / 30% hexane) R f = 0.12.

D2. Conversion of ω-carboalkoxyarylureas to ω-carbamoylarylureas. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methylcarbamoyl-phenyl) carboxyaminophenyl) urea (not a compound of the invention).

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) -N'- (4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea as a white solid: mp 247 DEG 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

To a slurry of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4-ethoxycarbonylphenyl) urea (Method C1;

5.93 g, 15.3 mmol) in MeOH (75 mL) was added aqueous KOH (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated at reflux for 12 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water (50 mL), treated with 1 N HCl and the pH was adjusted to 2-3. The resulting solid was combined and dried under reduced pressure to give N- (4-chloro-3-). ((trifluoromethyl) phenyl) -N '- (4-carboxyphenyl) urea as a white solid (5.05 g, 92%).

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

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

N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea) is prepared from 4-chloro-3- (trifluoromethyl) phenyl isocyanate and 4- ( 3- (5-methoxycarbonylpyridyl) oxyaniline (Method A14, Step

2) analogously to 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 for 1 hour, and the resulting mixture was adjusted to pH 5 with 1N HCl solution. The resulting solid was dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced pressure This procedure was repeated twice to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N 1 - ((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) oxyphenylurea)

A mixture of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5-carboxypyridyl) oxyphenyl) urea (0.050 g, 0.011 mmol), N, N-dimethylethylenediamine) (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N-methylmorpholine (0.035 g, 0.28 mmol) and EDCI.HCl (0.032 g, 0.17 mmol) in DMF (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 (MgSO ₄ ) 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, 1H), 8.58 (t, 1H), 8.69 (s, 1H), 8.90 (s) s, 1H); 9.14 (s, 1H); HPLC ES-MS m / z 522 ((M + H) &lt; + &gt;).

D5. General method for deprotecting N - (.alpha.-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) Example C; 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 EtOAc (3 x 10 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 a gradient of 100% hexane to 40% EtOAc. / 60% hexane to give N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (4- (2- (N- (2-hydroxy) ethylcarbamoyl) pyridopyloxyphenyl) 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-tert-butylaniline was reacted with bis (trichloromethyl) carbonate followed by 4- (3-N-methylcarbamoylphenoxy) aniline to give the 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-N-methylcarbamoyl) -4-methoxyphenoxy) aniline, 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-methoxyphenylisocyanate 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 is reacted with CDI, followed by 4- (3-N-methylcarbamoyl) -4-methoxyphenoxy) aniline, prepared according to Method A8 to give urea. .

Example 6: 5- (4-Aminophenoxy) isoindoline-1,3-dione was prepared according to Method A3. According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI, followed by 5- (4-aminophenoxy) isoindoline-1,3-dione 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 was 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-methylcarbamoylphenoxy) aniline 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- (trifluoromethyl) aniline 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 was reacted with bis (trichloromethyl) carbonate followed by 4- (4-acetylphenoxy) aniline to give the 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 - (- 2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. And according to Method C4, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene followed by 3 - (- 2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give 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-N-methyl-2-pyridinecarboxamide was prepared according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide is 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- (N-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-N-methylcarbamoyl) -4-methoxyphenoxy) aniline, prepared according to Method A8 to give the 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 provide 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). - (N-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 Cla to give urea.

Example 19: 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. 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-ethylcarbamoyl) -4-pyridyloxy) aniline according to Method Cla to give urea.

Example 20: According to Method A2, Step 4, 4-Amino-2-chlorophenol was 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. 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) -3-chloroaniline according to Method C1a 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-carbamoyl-phenoxyjaniline) 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, N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2

The methoxyphenyl isocyanate is reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline according to Method Cla to give 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-yloxy) aniline 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) aniline, which is converted to 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline hydrochloride according to Method A16.) 5- ( Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (4- (1- (N-methoxy) iminoethyl) hydrochloride ) of phenoxyanil according to method Cla to obtain urea.

Example 27: 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. 5- (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) The 2- (methoxyphenylisocyanate) according to Method B1 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate 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-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. 5- (Trifluoromethyl) -2-methoxyaniline 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 provide 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) 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) pyridyloxy) aniline according to Method Cla to give urea. N- (5- (Trifluoromethyl) -2-methoxyphenyl) -N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea saponifies 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) pyridyloxy) aniline according to Method Cla to give urea. N- (5- (Trifluoromethyl) -2-methoxyphenyl) -N- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea saponifies according to Method D4, Step 1, and the corresponding acid is coupled with methylamine according to Method D4 Step 2 to obtain 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) pyridinyl oxyjaniline) according to the method of Cla to give urea N- (5- (Trifluoromethyl) -2-methoxyphenyl) -N 1- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea is saponified according to Method D4, Step 1, and the corresponding acid is coupled with Λ) N-dimethylethylenediamine according to Method D4, Step 2 to give the amide.

Example 34: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 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 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 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-methoxyamine 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 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 5-amino-2-methoxypyridine according to Method D1c.

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 Dc.

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-methoxyphenyl isocyanate 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 Dc.

Example 41: 4- (3- (N-Methylcarbamoyl) phenoxy) aniline was prepared according to Method A13. And according to Method C3, 4-chloro-3- (trifluoromethyl) aniline is converted to an isocyanate and reacted with 4- (3- (N-methylcarbamoyl) phenoxyjaniline) 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-N-methylcarbamyl-4-pyridyloxy) aniline according to Method Cla 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 C a, 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-pyridyloxy) aniline. And by the way

Customs are reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 3- (2-carbamoyl-4-pyridyloxy) aniline to give 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- (N- 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) isoindoline-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 C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-N-methylsulfamoyl) phenyloxy) aniline to give urea.

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

Example 50: According to Method A2, Step 4,5, 5-amino-2-methylphenol was 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. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylanilm 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 C1a, 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 was 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) - The 1-nitrobenzene is reduced to 4- (4-N-methylsulfamoyl) phenyloxy) aniline according to method A15, step 4. And according to method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-N- methylsulfamoyl) phenyloxy) aniline to give the 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 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. Aniline is reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method Cla to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (methoxycarbonyl) - 5-pyridyloxy) phenyl) urea. The methyl ester is reacted with methylamine according to Method D2 to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (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 D1a to give 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. N- (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, 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. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline to give 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-acetylphenoxy) aniline which is converted to 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline hydrochloride according to Method A16). Customs are reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate 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) phenoxyjaniline). Customs are reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (3- (N- (2-morpholinylethyl) carbamoyl) phenoxy) aniline to afford the 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. And according to Method A13, Step 4, 4- (3- (N- (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (N- (2-piperidylethyl) carbamoyl) phenoxy) aniline. And, according to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (N- (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 tetrahydrofurofurylamine according to Method A13, Step 3 to give 4- (3- (N- (fetrahydrofurylmetyl) carbamoyl) phenoxy) -l-nitrobenzene. And according to method 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- according to Method A13, Step 3. ethylpyrrolidine 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 give 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) phenylthio) aniline and according to Method C a 4-chloro-3- (trifluoromethyl) phenyl isocyanate is left. with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline) to afford the 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 is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline. And, according to method C1a, 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-ethoxycarbonylphenyl) urea is 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-carboxyphenyl) urea was coupled with 3-methylcarbamoylaniline 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 C1a, 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-ylethyl) carbamoyl) pyridyloxy) anilm was prepared according to Method A10. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to afford the 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 is saponified according to Method D4, Step 1, and the corresponding acid is 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 N- (5- (Trifluoromethyl) -2-methoxyphenyl) -N 1- (4- (3- (5-methoxycarbonyl-pyridyl) 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 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 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 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)) 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) 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 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 urea which is coupled with N- (4-acetylphenyl) piperazine according to Method D1c.

Example 77: 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 4-fluoroaniline according to Method D1c.

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 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 C1f to give urea which is coupled with 2-methoxyethylamine according to Method D1c.

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 afford the urea which is coupled with N- (2-pyridyl) piperazine according to Method D1c.

Example 84: 4-Chloropyridine-2-carbonyl chloride hydrochloride was treated with 2-hydroxyethylamine according to Method A2, Step 3b, to give 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide. 4-Chloro-N- (2-triisopropyl-silyloxy) ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride then 4-aminophenol according to Method A17 to give 4- (4- (2- (N- (2- 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) pyridyloxyphenyl) urea) The urea was deprotected according to Method D5 to afford N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (4- (2- (N- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea).

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 is 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- (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) -2-chloroaniline to give urea.

Example 87: 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. 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 afford the 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 is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-ethylcarbamoyl) -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 C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 89: 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. 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 is reacted with 3 - (- 2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 90: 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). - (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 C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline 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, 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-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-pyridyloxy) aniline 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) phenylthioyaniline), 4-Bromo-3- (trifluoromethyl) aniline is converted to 4-bromo- 3- (Trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline) to give urea.

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 BI.A according to method Cla, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline) urea is obtained.

Example 94: 4- (2- (N- (2-Morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was prepared according to Method A10. 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- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) amine to provide urea.

Example 95: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) aniline was prepared according to Method A2. 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-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 give 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). - (N-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. And, according to method C1a, 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- (N- 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 is 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-dimethyl-2-pyridinecarboxamide is 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- (trifluoromethyljaniline) 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 B1 A according to Method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline to provide 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-pyridyloxyjaniline to form urea.

Example 102: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) aniline was prepared according to Method A2. 5-tert-Butyl-2- (2,5-dimethylpyrolyl) aniline was prepared according to Method A4. 5-tert-Butyl-2- (2,5-dimethylpyrolyl) aniline is 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-methyl-2-pyridinecarboxamide was prepared according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide is 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 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline affords bis (4- (2- (N-methylcarbamoyl) -4-pyridlyoxy) ) phenyl) urea.

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

table

The compounds listed 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.

The compounds marked with an asterisk are not subject of the invention.

Table 1 3-tert-butylphenyl urea

EDKU R Hot melt talk HPLC (mm) TLC Rf TLC System MS (lonization) Synthesis method 1 ABOUT. IGB 00:22 50% EtOAc / 50% hext 418 (M + H) &lt; + &gt; (HPLC ES-MS) A13 C3 2 * CHX 00:58 50% EtOAc / 50% hexane 403 (M + H) &lt; + &gt; (HPLC ES-MS) A13 C3 3 characterized _in a> NH 133- 133 0.68 100% EtOAc 448 (M + H +) (FAB) A8 C2d

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

Example R Heat melt Γ9 HPLC (min) TLC Rf TLC System MS llonizácial Synthesis method 4 δ _in V-NH 5.93 448 (M + H) &lt; + &gt; (HPLC ES-MS) AI3 BI Cla 5 JVnh 120- 122 0.67 100% EtOAc 478 (M + H) &lt; + &gt; (FAB) A8 C2d 6 ý Y ^NH o 00:40 50% EtOAc / 50% hexane 460 (M-H) &lt; + &gt; (HPLC ES-MS) A3 C2d

7 T 0.79 50% EtOAc / 50% hexane 446 (M + H) &lt; + &gt; (HPLC ES-MS) A12 C2d

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

rrflo * d R Hot melting Γ9 HPLC (min) TLC Rf TLC System MS (Ionization) Spteob ynlázy 8 ΰ IGB -0-0 " 250 (Dec) 460 (M + H) + (FAB) A13 C2a 9 T <HX 206- 208 00:54 10% MeOH / 90% CH2C1 2 446 (M + H) + (HPLC ES-MS) A3step 2, ABkrak 4. BI. Cla 10 * -o-o < 00:33 50% EtOAc 150% EtOAc 445 (M + H) &lt; + &gt; (HPLC ES-MS) A13 C3 11 -Q JVnh O-o // ^N 00:20 2% EON7 98% EtOAc 461 (M + H) &lt; + &gt; (HPLC ES-MS) A2 C4 at -O JA 'O-ZYN 00:27 1% Et 3 N / 99% EtOAc 447 (M + H) &lt; + &gt; (HPLC ES-MS) A2 C4 B O _K Vnh -0—0 “ 0.62 100% EtOAc 461 (M + H) &lt; + &gt; (FAB) A2 C2a 14 V Vnh ₂ Ό-Ό 114- 117 00:40 1% Et 3 N / 09% EtOAc 447 (M * H) &lt; + &gt; (FAB) A2 C4

15 S-NH 232- 235 00:54 100% EtOAc 490 (M + H) + (FAB) A8 C2d 16 the y-Me NH - \ / ° C // ~ ^N 210213 00:29 5% MeOH / 45% EtOAc / $ 0% pet 475 (M + H) &lt; + &gt; (HPLC ES-MS) A5 BI Cic 17 The C-V NH / = ^<Me - \ / ~ ° C, and ^N 187- 188 00:17 50% EtOAc / 50% ether 495 (M + H) &lt; + &gt; (HPLC ES-MS) A6 BI Cla 18 p \ Y -2-Me _9-NH2 Ο-γ ^ Ν 00:48 100% EtOAc 475 (M + H) + (HPLC ES-MS) A2 step 4. BI Cit 19 O _K V-NH 194- 196 00:31 5% MeOH / 45% EtOAc / 50% pet ether. 475 (M + H +) (HPLC ES-MS) A2 BI Cla 20 0 Cl &lt; - &gt; -NH &lt; == &lt; - & gt ^; 214216 $ 0.2 5% MeOH / 45% EtOAc / 50% Ph 495 (M + H +) (HPLC ES-MS) A2 Cla 21 ¥ -0-0¾ 208- 210 00:30 50% EtOAc / 50% hexMh 481 (M * H > * (HPLC ES-MS) A19C2a 22 O = = ^NH2- O ° O 188- 190 00:30 70% EtOAc / 50% hexanes 447 (M + H) &lt; + &gt; (HPLC ES-MS) A15. Step 4 Cla 23 ¥ O-Q-f ° Y " 0 00:50 70% EtOAc / 30% hexane 472 (M + H) &lt; + &gt; (FAB) A3 BI Cla 24 O Me 203 ' 205 00:13 100% EtOAc 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2 BI Cla

25 * 00:09 75% EtOAc / 25% hexane 458 (M + H) &lt; + &gt; (HPLC ES-MS) A12 c2d 26 * MeO -Ο-θ-^ Ό Ι 169- 171 0.67 50% EtOAc / 30% pet < tef 474 (M + H + (HPLC ES-MS)) A13 kiokl, A13 step 4. A16. BI feeling 27 0th IGB 218- 219 00:40 50% EtOAc / 30% ethyl acetate 477 (M + H) &lt; + &gt; (HPLC ES-MS) A2step 3b. A2krok 4, BI. Cla 28 X ^ O-o-Q-NMe 0 212- 214 030 40% EtOAc / 60% H2O A9 BI Cla 29 —4 / * ~ ^WH 033 50% EtOAc / 50% pet ether 474 (M + H) &lt; + &gt; A2krek 3b. A2kr 4, BI. Cla 30 O _x y-nh - € K> ^Pr ” 210211 A2 BI Cla 31 0th IGB -Ao-Q ^ -o 210204 00:43 10% MeOH / CH 2 Cl 2 2 A14 BI Cla D4 32 ABOUT IGB -o <f " 247- 249 00:57 10% MeOH / CH 2 Cl 2 2 A14 BI Cla D4 33 Vnh —Xn-m <^ = ⁷ '—N Me 217219 00:07 10% MeOH / CH 2 Cl 2 AM BI Cla D4

34 O V — NH ~ Ο- ° -Ο 0 ^N 00:11 70% EtOAc / 30% hxx Al 1 BI Clf DIc 35 Y b about 00:38 70% EtOAc / 30% hexane Al 1 BI Clf D1C 36 ^F 0 ^, ± _t , - & - Ό 0.77 70% EtOAc 30% hexane All BI Clf Dlc 37 ^F \ ^ ry _NH Me 00:58 70% EtOAc / 30% hexane All BI Clf Dlc 38 MeO 00:58 70% EtOAc / 30% hexane All B1 Clf Dlc 39 O-O-a O ~ O 00:17 70% EtOAc / 30% hexane All BI Clf Dlc 40 Ο-Ό 00:21 70% EtOAc / 30% hexane All BI Clf Dlc

Table 4

3- (trifluoromethyl) -4-chlorophenylurea

H H

Example R Melting wallpaper Γ9 HPLC (mm, ¹⁾ TLC Rf TLC System MS POBÍUcia} Spôwb tyrttty 4] 0th Vnh -0-0 “ 163- 165 00:08 50% EtOAc / 50% pet ether 464 (M + H) &lt; + &gt; (HPLC ES-MS) A13 C3 42 'IGB -σο " 215 00:06 50% EtOAc / 50% pet ether 465 (M + H H (HPLC ES-MS)) A2 Cla 43 0 ^NHl 00:10 50% EtOAc / 50% pe (ether 451 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 44 ° O ^N 025 30% EtOAc / 70% pet ether 451 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 45 -f? ^ -NH '- / = (m · 0-4 4 ^Ν) OJI 30% EtOAc / 70% pat ether 465 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 4 ' X o-qt ABOUT 176- 179 00:23 40% EtOAc / 60% hexafe 476 (M + H > * (FAB) A3 Cla 47 Me 7 - NH -O-ohQ "· 00:29 5% MeOH / 45% EtOAc / 50% pet ether 478 (M + H) &lt; + &gt; (HPLC ES-MS) A5 Cle 48 7 206- 209 A1S Cla 49 0. Cl>-NH_> X_ / = <0- ° -G ⁿ 147- 151 022 50% EtOAc / 30% pet ether 499 (M + H) &lt; + &gt; (HPLC ES-MS) A6 Cla 50 —7Λ-Μ · ° ý-NH> = (z = A M · ° u 00:54 100% EtOAc 479 (M + H) + (HPLC ES-MS) A2 Cla

51 Vnh - ^ 0-0 ^E ' 187- 189 033 5% MeOH / 45% EtOAc / 50% five; 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 52 0. ay — nh / / = (Me - / / o ^N 219 018 5% MeOH / 45% EtOAc / 50% pet ether 499 (M + H +) (HPLC ES-MS) A2 Cla S3 The -0 = 0¾ 246- 248 030 50% EtOAc / 50% hr 485 (M + H +) (HPLC ES-MS) A19. Cla 54 F -οοΛη Me 196- 200 030 70% EtOAc / 30% hexane) 502 (M + H) &lt; + &gt; (HPLC ES-MS) A15 Cla 55 V-0 -OO ' 228- 230 030 30% EtOAc / 70% CH2O2 466 (M + H &lt; + &gt; (HPLC ES-MS) 56 H <H Me 238- 245 57 F 231- 222 0.75 80% EtOAc / 20% hexanes 492 (M + H) &lt; + &gt; (FAB) Cld Dla 58 X o _in NH -o »o 247 035 100% EtOAc Cld Dla D2 59 O _in Me N -oo 198- 200 00:09 100% EtOAc 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 60 F MeO, oo 158- 160 0.64 50% EtOAc / 50% pet ether 61 jy- ^NH -o ° o 195- 197 039 10% MeOH / CH 2 Cl 2 A13 Cla

62 0th > -NH - ^ - d q 170- 172 00:52 10% MeOH / CH 2 Cl 2 A13 Cla 63 168th 171 00:39 10% MeOH / CH 2 Cl 2 A13 Cla 64 y ". in O-H 176th 177 0J5 10% MeOH / CH2C1 2 A13 Cla 65 <5 Vnh 130th 133 487 (M + H) &lt; + &gt; (HPLC ES-MS) A2 BI Cla 66 a, -O- IGB ° <p ^{p '4} 155 A2 Cla 67 * In NH P-O ^ d ^ 225th 229 023 100% EtOAc Cle D3 Long 68 * O-QV Xy NM® 234th 236 029 40% EtOAc / 60% hexine A9 Cla 69 —Fyy — NH ^X = \ / = {Me S— <N 00:48 50% EtOAc / 50% pet ether 481 (M + H) &lt; + &gt; (HPLC ES-MS) 70 O-NH 00:46 5% MeOH / 95% CH 2 Cl 2 564 (M + H) &lt; + &gt; (HPLC ES-MS) AtO Cla

71 In NH X > -Q Yy 199- 201 00:50 10% MeOH / CH 2 Cl 2 A14 Cla D4 72 0 _in Vnh -W 235- 237 00:55 10% MeOH / CH 2 Cl 2 AI4 Cla D4 73 S-NH ~ xy ° ~ Q ζ · · ^Μβ 200th 201 00:21 50% MeOH / CH 2 Cl 2 2 A14 Cla D4 74 o _v y — NH 'λβΚΡτ-Ο, 145ms 75 fV _N H 2 O = O -0-0 00:12 70% EtAde 30%, hexaa 527 (M + H) &lt; + &gt; (HPLC ES-MS) AU Cl Dlc 76 * about '-N 00:18 70% EtOAc / 30% beiuin AH Clf Dlc 77 XXJ = ⁰ O ₀ -O 0.74 70% EtOAc / 30% hexane All Clf dlc 78 ^Me ' _NH by _NH Me ^ = O oo 00:58 70% EtOAc / 30% hexane AU Cl Dlc

79 O _in Vnh> W 00:47 70% EtOAc / 30% bexit 569 (M + H) &lt; + &gt; (HPLC ES-MS) All Clf dlc 80 0 “ ^NH -cy ° -o ^ ^om · 00:18 70% EtOAc / 30% hex 508 (M + H) &lt; + &gt; (HPLC ES-MS) ΑΠ Clf Dlc 81 MeO-p-NH \ = / 038 70% EtOAc / 30% hextin 357 (M + H) &lt; + &gt; (HPLC ES-MS) All Clf dlc 82 Ο <> ^ = ο 00:37 70% EtOAc / 30% 611 (M + H) &lt; + &gt; (HPLC ES-MS) All Clf dlc 83 * ~ Q * ABOUT 00:19 70% EtOAc / 30% hexane All Clf Dlc 84 O _K NH - ^h O - O - Q 1 O 4 ^H 179- 183 A2 A17 Cl » D5

Table 5

3- (trifluoromethyl) -4-bromophenyl urea

Example R warm Γ9 HPLC (min) TLC * t TLC System MS flonized Spócob i «yléléry 85 Q IGB 186- 187 00:13 50% EtOAc / 50% pet ether 509 (M + H) &lt; + &gt;. HPLC ESMS) A2 BI Cla 86 ABOUT Cl-NH Ir * 150- 152 00:31 50% EtOAc / 50% pet ether 545 (M + H) &lt; + &gt; (HPLC ESMS) A6 BI Cla «7 about. Cl P-NH ΌΧ / 217219 00:16 50% EtOAc / 30% ether 345 (M + H) + HPLC ESMS) A2 B) Cla 88 o _t Vnh ^E ' 183- 184 00:31 50% EtOAc / 50% pet ether 325 (M + H) &lt; + &gt; (HPLC ESMS) A2 BI Cla 89 011 50% EtOAc / 50% pet ether 511 (M + H) &lt; + &gt; (HPLC ESMS) TO BI Cla 90 —C y — M · 2 “NH O — G .N 018 50% EtOAc / 50% pet ether * 525 (M + H +) HPLC ESMS) A2 BI Cla 91 O M · O-O * 214216 038 50% EtOAc / 50% ether 522 (M + H) &lt; + &gt;. HPLC ESMS) A2 BI Cla 92 o, Vnh Ό-Ο * 00:47 50% EtOAc / 50% pet ether 527 (M + H) &lt; + &gt; (HPLC ESMS) Up to 3b. Up to 4. BI. Cla 93 -ΖΛ Vnh / = (M · S — G N 00:46 50% EtOAc / 50% pet ether 527 [M + H] &lt; + &gt; (HPLC ESMS) Shouting 3b. A2 kr BI, Cla 94 ABOUT P-NH -0 ~ 0 0 0 '' O 145- 130 0 41 5% MeOH / 95% CH 2 Cl 2 A10 BI Cla

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

ľríklud R Heat melt Γ9 HPLC (min) TLC ^R r TLC System MS (Ionization). Synthesis method 95 0 In NH 140- 144 0J9 5% MeOH / 45% EtOAc / 50% pet ether 495 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 BI Cle 96 o Cl r-NH j = \ ^M · - \ Z ~ ° A _ / * 244245 00:39 5% MeOH / 45% EtOAc / 50% pet ether 529 (M + H > (HPLC ES-MS) A6 A7 BI Cla 97 o Cl 'y - NH -? - OH? ^Me; 220- 221 00:25 5% MeOH / 45% EtOAc / 50% ether 529 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 Bi Cla 98 -ΛΛ Vnh / == (Me ° ~ W / 00:27 5% MeOH / 45% EtOAc / 50% pet ether 495 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 BI Cla '99 0, V-nh ^and 180181 00:52 5% MeOH / 45% EtOAc / 50% pet ether 509 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 BI Cla IOO o _x Vnh yy ^ ^{p, i} 162165 A2 A7 BI Cla

Table 7 Other ureas

Example R Heat · * melting (• q HPLC (min) TLC Rf TLC System MS [Ionization]] Method of aynthosis 101 * OMe ”” 162- 165 At A2 C3 102 / 00:10 50% EtOAc / 50% hexine 442 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A4 c2d 103 F 'K. > = O about 125- 130 00:24 40% EtOAc / 60% hexane 512 (M + H) A2 C2b

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

PATENT CLAIMS

Claims (3)

Use of a compound of formula (I): A-D-B (I), or a pharmaceutically acceptable salt thereof, wherein D is -NH-C (O) -NH-, A is a substituted moiety of the formula -L- (ML *) _q having up to 40 carbon atoms, wherein L is a substituted or unsubstituted phenyl or pyridyl moiety bonded directly to D, L ¹ contains a substituted phenyl or pyridyl moiety, M is a moiety forming a bridge having at least one atom; q is an integer from 1 to 3; and B is a substituted or unsubstituted phenyl group bonded directly to D, wherein L ¹ is substituted with -C (O) RX, wherein R x is NR a R b and R a and R b are independently hydrogen and a carbon-based moiety having up to 30 atoms carbon optionally containing heteroatoms selected from N, S and O and optionally substituted with halogen, hydroxy and carbon-based substituents having up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted with halogen; and wherein the substituents for B and L and the additional substituents for L ¹ are selected from the group consisting of C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted with halogen until total halogen substitution, CN, OH, halogen, C 1 -C 10 alkoxy and C 1 -C 10 alkoxy substituted halogen up to total halogen substitution, wherein M is one bridging group selected from the group consisting of -O- or -S-; for the preparation of a medicament for the treatment of carcinogenic cell growth mediated by raf kinase. Use according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, trifluorosulfonic, benzenesulfonic acid. p-toluenesulfone (tosylate salt), 1-naphthalene-sulfone, 2-naphthalenesulfone, acetic, trifluoroacetic, cider, wine, lemon, milk, oxal, amber, fumaric, maleic, benzoic, salicylic, phenylacetic; and acidic salts of organic and inorganic bases containing cations selected from the group consisting of alkali metal cations, alkaline earth metal cations, ammonium cation, aliphatic-substituted ammonium cations and aromatic-substituted ammonium cations. The use according to claim 1 or 2, wherein the raf kinase-mediated carcinogenic cell growth is lung, pancreas, thyroid, bladder or colon cancer, myeloid leukemia, or villous colon adenoma.