CZ299125B6 - Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors, their use and pharmaceutical compositions containing thereof - Google Patents

Abstract

In the present invention, there are described diphenyl ureas substituted with {omega}-carboxyaryl group being selected from the group consisting of 4-chloro-3-(trifluoromethyl)phenyl ureas, 4-bromo-3-(trifluoromethyl)phenyl ureas and 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas, their use in treating raf kinase mediated diseases as well as pharmaceutical compositions intended for use in such therapy, in particular carcinoma, myeloid leukemia or large intestine villous adenoma.

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 sraf-related diseases and the use of pharmaceutical compositions for the treatment of the disease.

BACKGROUND OF THE INVENTION

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, 165-174; Bos. Cancer Res. 1989, 49, 4682-4689). 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, 279-283). Biochemically, ras is a guanine nucleotide binding protein, and cyclization between the GTP-linked activated form and the GDP-linked quiescent form is precisely regulated by the activity of endogenous ras GTPase and other regulatory proteins. In cancer cell mutants, endogenous GTPase activity is low, and therefore the protein transmits constitutive growth signals to downstream effectors, such as the raffinase enzyme, resulting in cancerous growth of cells that carry these mutants (Magnuson et al., Semin. Cancer Biol. 1994 5, 247-253). It has been found that inhibiting the effect of active ras by inhibiting the rafkinase signaling pathway by applying inactivated antibodies to rafkinase or by coexpressing dominant negative rafkinase or dominant negative MEK, a substrate of rafkinase, results in reverse transformed cells to normal growth phenotype (see: Daum et al., Trends Biochem. Sci., 1994, 19, 474-480, Fridman et al., J. Biol. Chem., 1994, 269, 30105-30108. Kolch et al (Nature 1991, 349, 426-28) further suggests that inhibition expression of raf using antisense

RNA blocks cell proliferation in membrane-associated oncogenes. In a similar manner, 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, 668-675).

SUMMARY OF THE INVENTION

The present invention provides compounds that are inhibitors of the enzyme rafkinase. Since the enzyme is a downstream effector of p21 ^ras , inhibitors are effective in pharmaceutical formulations for use in human or veterinary subjects where inhibition of the rafkinase pathway is indicated, e.g. in the treatment of tumors and / or cancerous growth of cells related to rafkinase. In particular, the compounds are useful in the treatment of human or animal cancers, e.g., murine cancers, since the progression of these cancers is dependent on the cascade of signal transduction of ras protein and is therefore prone to cascade disruption treatment, i.e. inhibition of raffinase. Thus, the compounds of the invention are effective in the treatment of solid tumors, e.g., cancers (e.g., lung, pancreatic, thyroid, bladder or colon cancer), myeloid diseases (e.g., myeloid leukemia), or adenoma (e.g., villous colon adenoma).

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

-1 CZ 299125 B6

The compound of the invention is selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenyl ureas:

N-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea,

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

N - (4-chloro-3- (trifluoromethyl) phenyl) - (N- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea),

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

N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-N- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea;

4-bromo-3- (trifluoromethyl) phenyl urea:

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

And ^L - (4-bromo-3- (trifluoromethyl) phenyl> -N '(4- (2- (A ^/ methylcarbamoyl) -4-pyridyloxy) phenyl) urea,

N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea,

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

N- (4-bromo-3- (trifluoromethyl) phenyl) -N- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea;

2-methoxy-A-chloro-5- (trifluoromethyl) phenyl urea:

N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (2H-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, and

N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N (2-chloro-N- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, or a pharmaceutically acceptable salt thereof acceptable salt.

The present invention also provides 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, for example, hydrochloric, hydrobromic, sulfuric, orthophosphoric, methanesulfonic, trifluoromethanesulfonic, benzenesulfonic, ptoluenesulfonic, 1-naphthalenesulfonic, 2-naphthalenesulfonic, tartaric, tartaric, citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic and phenylglycolic acids. In addition, pharmaceutically acceptable salts include acidic salts of inorganic bases, 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 acidic salts of organic bases including an aliphatic and aromatic group substituted with amo-2CN and quaternary ammonium cations, e.g., resulting from the protonation or peralkylation of triethylamine,?,? -diethylamine,? -dicyclohexylamine, A, lysine, pyridine -dimethylaminopyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5] , 4,0] undec-7-ene (DBU).

Many compounds of the formula 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 in the application having both rafkinase inhibitory activity.

General methods of preparation

The compounds of the invention may be prepared by known chemical reactions and procedures, some of the starting materials being commercially available. However, the following general methods of preparation are set forth below and are intended to serve as guidance to those skilled in the art of synthesizing these compounds. Methods of preparation are provided with more detailed examples described in the experimental section.

Substituted anilines can be prepared by standard methods (March. Advanced Organic Chemistry, 3 ^rd Ed .; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). According to Scheme I, arylamines are generally synthesized by reduction of nitroaryls with catalysts (metals), e.g., Ni, Pd or Pt and H ₂ , or a 25 µm hydride transfer agent, e.g., format, cyclohexadiene or borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK) (1985)). Nitroaryls can also be directly reduced by a strong hydride source such as LiAlH ₄ (Seyden-Penne. Reductions by Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)) or zero-charge metals such as Fe, Sn , or Ca, usually in an acidic medium. There are many methods for nitroaryl synthesis (March. Advanced Organic Chemistry, 3 ^rd Ed .; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)).

Ha (catalyst) (e.g., MM, Ø ArNOj -EJ-ArNHj (e.g. Fe.Sn, Ca)

Scheme I. Reduction of nitroaryls to arylamines

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

HNO,

Ar-H → AlNQ 1 with a strong leaving group (eg F, Cl, Br, etc.) may undergo substitution reactions at 45 reaction with nucleophiles, eg thiolate (shown in the examples in Scheme II) or phenoxide.

Nitroaryls may also undergo Ullman-type coupling reactions (Scheme II).

-3 CZ 299125 B6

OjN,

RAfSH base

CuO / base

Scheme II: Selected nucleophilic aromatic substitution by nitroaryls

Nitroaryls may also undergo metal-mediated cross-coupling reactions in the transit state. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo cross-coupling reactions with palladium-mediated aryl nucleophiles, such as arylboronic acids (Suzuki reaction shown below), arylcins (Stille reaction), or arylzines (Negishi reaction) to obtain biaryls ( 5).

OjN. AfB (ORlj> y_ _x -► _R XL_ / Pd {0)

5

Either nitroaryls or anilines can be converted to the corresponding arensulfonyl chlorides (7) by reaction with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source such as KF provides the sulfonyl fluoride (8). Reaction of sulfonyl chloride 8 with trimethylsilyltrifluoromethane in the presence of a fluoride source such as tris (dimethylamino) sulfonium difluorotrimethylsiliconate (TASF) affords the corresponding trifluoromethylsulfone (9). Alternatively, the sulfonyl chloride 7 can be reduced to arenthiol (10) by, for example, zinc amalgam. Reaction 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).

-4GB 299125 B6

SOjCI

Scheme 3: Selected Methods for Synthesis of Fluorinated Arylsulfones

According to Scheme IV, 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, eg, trichloromethylchloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene) or N, N-carbonyldiimidazole (CDI). The isocyanate may also be derived from a derivative of a heterocyclic carboxylic acid, 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 $ 1 ^000.2

At ¹ -NCO ^HZN "A?

H H

14 \ ^ DPPA 0 0 ^{X 1} Ar ^{1 x} OH «17

Scheme IV: Selected methods of preparation of unsymmetrical urea

-5GB 299125 B6

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

The invention also includes pharmaceutical compositions comprising a compound of Formula I and a physiologically acceptable carrier.

The compounds may be administered orally, topically, parenterally, by inhalation or spray, or rectally in dosage unit formulations. The term "injections" includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as the use of infusion techniques. The one or more compounds may be together with 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, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and tablet disintegrating agents such as corn starch or alginic acid; and binders such as 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, retarding agents such as glyceryl monostearate or glyceryl ryldistearate may be used. These compounds may also be prepared in a solid, rapidly releasing form.

Formulations for oral use may be solid gelatin capsules wherein the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or they may be soft gelatin capsules where the active ingredient is admixed 30 with water or an oil medium, 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 such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; dispersants or detergents may be natural phosphatides such as lecithin or condensation products or alkene oxide with fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols such as heptadecaethyleneoxycethanol, or condensation products of ethylene oxide with partial esters derived from fatty esters and hexitol such as polyoxyethylene40 sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives (e.g., ethyl or n-propyl-6-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 illustrated in the above examples. Other excipients, such as sweetening, flavoring and coloring agents, may also be present.

The compounds may also be in the form of anhydrous liquid preparations, e.g., oily suspensions, which may be prepared by suspending the active ingredients in a vegetable oil, e.g. arachis oil, olive oil, sesame oil or arachis oil, or in a mineral oil, e.g. paraffin oil. The oily suspensions may contain a thickening agent, eg beeswax, hard

-6C 299125 B6 Paraffin or cetyl alcohol. Sweetening agents, e.g., those mentioned above, and flavoring agents may be added to provide readily digestible oral preparations. These compositions may be protected by the addition of an antioxidant, such as 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, such as olive oil or arachis oil, or a mineral oil, such as paraffin oil or mixtures thereof. Suitable emulsifiers may be natural gums such as gum arabic or tragacanth, natural phosphatides such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate and condensation products of said partial esters with ethylene oxide , such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, such as 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 preparations can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at normal temperature but fluid at rectal temperature and therefore dissolves in the rectum or vagina to release the drug. Such materials include cocoa oil and polyethylene glycols.

For all treatment regimens used herein, the daily oral dose will preferably be from 0.01 to 200 mg / kg of total body weight. The daily dose administered by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and the use of infusion techniques will preferably be from 0.01 to 200 mg / kg of total body weight. The daily dose for rectal administration will preferably be from 0.01 to 200 mg / kg of total body weight. The daily dose for topical administration will preferably be from 0.1 to 200 mg to 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. all that are commonly considered when therapeutic agents are applied. Obviously, the specific dose 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 rate. combination and severity of the ongoing therapy. Nevertheless, it will be further clear to the professional public that the optimal course of treatment, i.e.. the method of treatment and the daily number of doses of the compounds of Formula I or a pharmaceutically acceptable salt thereof administered over a specified number of days can be ascertained by persons skilled in the art using conventional treatment tests.

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

The compounds of Figure 1 can be prepared from known compounds (or starting materials that can be prepared from known compounds), for example, using the general preparation methods outlined above. The activity of the provided compound to inhibit raffinase can be routinely determined, eg, by the procedures set forth below. 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 which have been previously flame-dried or in an oven under a positive pressure of dry argon or dry nitrogen. Stirring was performed mag-7 unless otherwise stated. The appropriate liquids and solutions were operated via syringe or cannula and introduced into reaction vessels via a rubber septum. Unless otherwise stated, the term "reduced pressure concentration" refers to the use of a Buchi rotary evaporator at about 15 mmHg. Unless otherwise stated, the term "high vacuum" refers to a vacuum of 0.4 to 1.0 mmHg.

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. V-Cyclohexyl-V (methylpolystyrene) carbodiimide was purchased from Calbiochem-Novabiochem Corp. and purchased 3-tert-butylaniline, 5- tert -butyl-2-methoxyaniline, 4-bromo-3- (trifluoromethyl) aniline and 4-chloro-3- (trifluoromethyl) aniline, 2-methoxy-5- (trifluoromethyl) aniline , 4- (tert -butyl-2-nitroaniline),

3-Amino-2-naphthol, ethyl -4-isocyanatobenzoate, N-acetyl N-chloro-2-methoxy-5- (trifluoromethyl) aniline and 4-chloro-3- (trifluoromethyl) phenyl isocyanate and used without further purification. Synthesis of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem., 3, 1995, 129), 4-3-carbamoylphenoxy) 1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-Zer-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 above.

Thin layer chromatography (TLC) was performed on a glass plate coated with Whatman® silica gel, silica gel 60A F-254 250 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 tray in a 10% solution of molybdophosphoric acid in ethanol and subsequent heating, (d) immersion of the tray in cerium sulphate solution. and then heating and / or (e) immersing the tray in an acidic ethanol solution of 2,4-dinitrophenylhydrazine and then 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 melting point apparatus, and these melting points are not corrected. Fourier transform infrared spectroscopy spectra were obtained from a Mat35 tson 4020 Galaxy Series spectrophotometer. ¹ H NMR spectra were measured with a General Electric GNOmega 300 (300 MHz) spectrometer with either Me4Si (d 0.00) or residual protonated solvent (CHCl 3 δ 7.26; MeOH δ 3.30; DMSO δ 2.49) standard. 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 sensor for sample introduction. The ion source was maintained at 250 ° C. Electron ionization impacts were performed with an electron energy of 70 eV and a flow collector of 300 μΑ. Liquid cesium ionization secondary mass spectra (FAB-MS), the latest version of fast atom bombardment mass spectra, were obtained from a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained from a Hewlett Packard MS-Engine (5989A) spectrometer with methane or ammonia as the gaseous reagent (1 x 10 ⁴ tor to 2.5 x 10 ⁴ tor). Direct insertion desorption chemical ionization (DCI) sensor (Vaccumetrics, Inc.) Was ramped from 0 to 1.5 amps in 10 sec and held at 10 amps until all traces of samples disappeared (~ 1-2 min). Spectra were taken from 50-800 amu at 2 sec per image. HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, variable detector

-8GB 299125 B6 wavelength, C-18 column and Finnigan LCQ mass spectra with ion trap and electrospray ionization. Spectra were scanned from 120 to 800 amu using variable ion time according to the number of ions in the source. Ion-Selective Mass Spectrum Chromatography (GC-MS) was obtained using a Hewlett-Packard 5890 gas chromatograph equipped with an HP-1 methylsilicone column (0.33 mM coating; 25 mx0.2 mm) and a Hewlett-Packard 5971 mass-selective detector ( ionization energy 70 eV). Elemental analysis was performed at Robertson Microlit Labs, Madison NJ.

All compounds shown by NMR spectra, LRMS and either elemental analysis or HRMS 10 are identical to the assigned structure.

List of abbreviations and acronyms

AcOH anh atm

BOC

CDI conc d

Dec

DMAC

DMPU

DMF

DMSO DPPA EDCI

EtOAc

EtOH

Et ₂ O Et ₃ N h

HOBT w-CPBA

MeOH pet. THF THF TFA

Tf acetic acid anhydrous (tert-butoxycarbonyl)

1,1'-carbonyldiimidazole concentrated day of degradation

N, N-dimethylacetamide

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

N, N-dimethylformamide dimethylsulfoxide diphenylphosphoryl azide 1- (3-diinethylaminopropyl) -3-ethylcarbodiimide ethyl acetate ethanol (100%) diethyl ether triethylamine hour

-hydroxybenzotriazole

3-chloroperoxybenzoic acid methanol petroleum ether (boiling range 30 to 60 ° C) tetrahydrofuran trifluoroacetic acid trifluoromethanesulfonyl

-9EN 299125 B6

A. General methods for the synthesis of substituted anilines

Al. General process for preparing 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 (about 0.5 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10 mL). , 30 g): 1 HNMR (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, IH), 7.84 (d, J = 8.09 Hz, IH), 7.90 (s, IH) , 8.21 (s, 1H).

Step 2. 3-Methoxy-2-naphthoic acid

A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room temperature was treated with a solution of 1 N NaOH (33.4 mL, 33.4 mmol). The mixture was heated at reflux for 3 hours, cooled to room temperature and acidified with 10% citric acid solution. The resulting solution was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was triturated with hexanes then washed several times with hexanes to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): 1 H NMR (DMSO-d ₆ ) δ 3.88 (s) 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.38 (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 allowed to react

A solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) was pipetted into the reaction mixture. The resulting mixture was heated at 80 ° C for 2 hours. After cooling the mixture to room temperature, benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was then heated to 80 ° C overnight. The 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%): * HNMR ( DMSOd 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 - (k ^ar bobenzyloxy) amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd / C (0.5 g) in EtOAc (70 mL) was maintained through the The 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 HNMR (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, 1 H); EI-MS m / z 173 (M ^& lt ^{; +} & gt ^; ).

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

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

0 ° at NHMe

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 generate 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 completion of the bubble formation, the reaction was heated at 60 ° C for 16 hours. The resulting cloudy brown solution was diluted with H ₂ O (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with saturated NaCl solution (3 x 150 mL), then combined, dried (MgSO ₄ ) and filtered through a pad of silica gel and washed with EtOAc. The resulting brown oil was purified by silica gel column chromatography with a gradient of 50% EtOAc / 50% hexanes to 80% EtOAc / 20% hexanes). The resulting yellow oil crystallized at 0 ° C after 72 hours to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc / 50% hexane) R f = 0 , 50; 1 H NMR (DMSO-d 6) δ 3.04 (d, J = 5.1 Hz, 3H), 7.43 (dd,> 5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J = 5.1 Hz, 1H);

CI-MS m / z 171 ((M + H) < + & gt ^; ).

- 11 GB 299125 B6

Cl

HCl

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

Anhydrous DMF (6.0 mL) was slowly added to SOCl ₂ (180 mL) over a temperature range of 40 to 50 ° C. The solution was stirred in this temperature range for 10 min, then picolinic acid (60.0 g, 487 mmol) was added portionwise over 30 min. The resulting solution was heated at 72 ° C (vigorous SO ₂ release) for 16 hours to form yellow solid precipitates. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. The addition of toluene 10 and subsequent concentration was carried out two more times. 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%).

0 ° γγ \ »ι.

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 in this temperature range for 10 min, then picolinic acid (100 g, 812 mmol) was added over 30 min. The resulting solution was heated at 72 ° C (vigorous SO ₂ 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 performed 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 put 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 both 45 min, cooled to 5 ° C and treated dropwise with Et ₂ O (200 mL). The resulting solid was filtered, washed with EtO ₂ (200 mL) and dried under reduced pressure at 35 ° C to give methyl 4-chloropyridine-2-carboxylate hydrochloride as a white solid (110g, 65%): mp 108 up to 112 ° C; 1 HNMR (DMSOd 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) < + & gt ^; ).

O

Xú NHMe

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

A suspension of methyl 4-chloropyridine-2-carboxylate hydrochloride (89.0 g, 428 mmol) in MeOH (75 mL) at 0 ° C was treated with a 2.0 M solution of methylamine in THF (1 L) to an extent such that the temperature of the mixture was kept 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 a pale yellow crystal. 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, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.85 (brd, 1H); CI-MS m / z 171 ((M + H) < + & gt ^; ).

O

Step 3b. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carbonyl chloride io 4-chloropyridine-2-carbonyl chloride hydrochloride (7.0 g, 32.95 mmol) was added portionwise to a 2.0 M mixture. 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 415 chloro-A-methyl-2-pyridinecarboxamide as a yellow crystalline solid (4.95 g, M.p. 37-40 ° C.

H ₂ N

NHMe

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 for 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 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 (17.9g, 84%); 1 HNMR (DMSO-4 ₆₎ ) δ 2.77 (d, J = 4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (ΑΑ'ΒΒ '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) < + & gt ^; ).

A3. General method of synthesis of anilines by nucleophilic aromatic addition and reduction of nitroarene.

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

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

To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in concentrated AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated to temperature

- 13 GB 299125 B6

120 ° C for 45 min, then the clear, light yellow mixture is 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 10 N with NaOH solution. This 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 light yellow to green mixture was allowed to warm to room temperature while 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; Ή NMR (DMSO 2 O ₆₎ ) δ 7.32 (d, J = 12Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J = 7.8Hz, 1H) 8.29 (d, J = 9Hz, 2H).

11.43 (brs, 1H); CI-MS m / z 285 ((M + H) < + & gt ^; ).

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 was added slowly and iron powder (0.59 g, 55.9 mmol) was added slowly. 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) < + & gt ^; , 100%).

A4. General method of pyrrolylaniline synthesis

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

- 14GB 299125 B6

Step 1. Synthesis of 1- (4-ZerZ-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 5 mL syringe with AcOH (0.1 mL) and acetonylacetone (0.299 g, 2 mL). , 63 mmol). The reaction mixture was 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 solution (15 mL) and 1 N NaOH solution (15 mL) and saturated NaCl solution (15 mL), dried (MgSO ₄ ) and concentrated under reduced pressure. pressure. The resulting orange to brown solid 10 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 (DMSO-d ₃ ) δ 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H), 7 62 (dd, 1H); 7.88 (d, J = 2.4 Hz, 1H); CI-MS m / z 273 ((M + H) < + & gt ^; , 50%).

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

A slurry of 1- (4- tert -butyl-2-nitrophenyl) -2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10% Pd / C (0.056 g) and EtOAc (50 mL) under 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-ZerZ-butyl2- (2,5-dimethylpyrrolyl) aniline as a yellowish solid (0.30 g, 99%): TLC (10% EtOAc / 90% hexane) R _f = 0.43; ¹ H NMR (DMSO-d ₃ ) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.7325 6.96 (m 3H), 7.28 (brs, 1H).

A5. General method for 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 ZerZ-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 residual black oil was treated with Et ₂ O (50 mL) and sonicated. The solution is then reacted with HCl (IM Vet 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 HNMR (DMSO-d ₆ ) δ 2.41 (s, 3H), 2.78 (d, J = 4.4Hz,

- 15GB 299Í25 B6

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

A6. General method for the synthesis of anilines from hydroxyanilines by introducing a nitrogen protecting group, nucleophilic aromatic substitution, and deprotecting

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 off from the solution and the residue 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 precipitates out of solution is removed. The filtrate was slowly quenched with sodium bicarbonate solution until the product was visibly separated from the solution (small flask work was selected 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 ) δ 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.

Step 2. Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl- (2,2,2-trifluoro) acet30 amide

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 brown mixture was stirred at room temperature until the reaction mixture in methyl-2-pyridine-35 carboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 ° C below atm. argon for 4 days. The black reaction mixture was cooled to room temperature and poured into cold water (100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by silica gel column chromatography with a gradient of 20% EtOAc / petroleum ether to 40% EtOAc / petroleum ether to give 4- (2- (N-methylcarbamoyl) -440 pyridyloxy) -2-chlorophenyl- (2,2,2) (trifluoro) acetamide as a yellow solid (8.59 g, 23.0 mmol).

NHMe

HjN

- 16GB 299125 B6

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

A solution of crude 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl- (2,2,2-trifluoro) acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL). ml) was treated with 1N NaOH solution (20 ml). The brown solution was stirred for 8 hours. To this solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x 40 mL) and concentrated to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline as a green oil which solidified on standing (2.86 g, 10 mL). , 30 mmol); 1 HNMR (DMSO-4 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), 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,> 4.8, 1H ).

A7. General method of deprotecting from acetylated aniline

Synthesis of 4-chloro-2-methoxy-5- (trifluoromethyl) aniline

A suspension of 3-chloro-6- N -acetyl) -4- (trifluoromethyl) anisole (4.00 g, 14.95 15 mmol) in 6M HCl solution (24 mL) was heated at reflux for 1 hour. The resulting solution was cooled to room temperature, solidifying somewhat. 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-d6 ₎ ) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

A8. General method for the synthesis of ω-alkoxy-ω-carboxyphenylanilines

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

Step 1,4- (3-Methoxycarbonyl-methoxyphenoxy) -1-nitrobenzene

To a solution of 4- (3-carboxy-4-hydroxyphenoxy) -1-nitrobenzene (prepared from 2,5-dihydroxy-35 benzoic 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-i-nitrobenzene as a yellow powder (3). g): mp 115-118 ° C.

OjN

- 17GB 299125 B6

Step 2. 4- (3-Carboxy-N-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 heated at reflux for

4 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure.

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

Step 3. 4- (3- (N-Methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene

To a solution of 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (0.50 g, 1.75 mmol) in CH 2 Cl 2 15 (12 mL) was added portionwise SOCl ₂ (0.64 mL, 8.77) 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 a 1N solution

NaOH, then extracted with CH ₂ C1 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

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 d, then was filtered through 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%): TEC (0.1% Et ₂₎ N / 99.9% EtOAc) R _f = 0.36.

A9. General process for the preparation of ω-alkylphthalimide anilines

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

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

A slurry of 5- (4-nitrophenoxy) isoindoline-1,3-dione (A3 step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) is stirred at room temperature for 1 hour, then

The reaction was treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temperature overnight, cooled 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-methyl-isoindoline-1,3-dione A slurry of 5- (4-nitrophenoxy) -2-methyl-isoindoline-1,3-dione (0.87 g, 2.78) mmol) and 10% Pd / C (0.10 g) in MeOH were stirred under 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 a yellow solid compound (0.67 g, 86%): TLC (40% EtOAc / 60% hexane) R _f = 0.27.

A10. General method of 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 25

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, 2, 55 mL, 19.4 mmol) and the resulting solution was heated at reflux for 20 h, cooled to room temperature and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to give 4-chloro-2- (V (2-morpholin-4-ylethyl) carbamoyl) pyridine as a yellow oil (1.25 g, 95%): TLC ( 10% MeOH / 90% EtOAc) R _f = 0.50.

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

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium t-butoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temperature for 2 hours then reacted sequentially with 4-chloro-2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridine (1.22 g, 4.52 mmol) and K ₂ CO ₃ (0.31 g,

2.26 mmol). The resulting mixture was heated at 75 ° C overnight, cooled to room temperature and partitioned between a layer of EtOAc (25 mL) and saturated NaCl solution (25 mL). The aqueous layer was re-extracted with EtOAc (25 mL). The combined organic layers were washed with saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure. The resulting brown solid was purified by silica gel column chromatography (58 g) with a gradient of 100% EtOAc to 25% MeOH / 75% EtOAc) to afford 4-19GB 299125 B6 (2 - (N - (2-morpholine-4-)). ylethyl) carbamoyl) pyridyk) yloxy) aniline (1.0 g, 65%): TLC (10% MeOH / 90% EtOAc) R _f = 0.32.

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

O

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 ) R f = 0.44 (elongated dot).

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

HIM

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 at 25 zinc powder (47.6 g, 729 mmol), then the mixture was heated at reflux for 40 min. , hot filtered and concentrated 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) < + & gt ^; ).

o ₂ no

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-isoindol-4-non-5-yloxy) -1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) R _f = 0 , 35.

-20EN 299125 B6 .NH

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

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

ίο A13. General method of 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-ethoxycarbonyl) -1-nitrobenzene

A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K ₂ CO ₃ (41 g, 300 mmol) in DMF (125 mL) was heated at reflux through The reaction mixture was 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) 30 in THF / 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 = 2 with 1M 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%).

-21 GB 299125 B6

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

A mixture of 4- (3-carboxyphenoxy) -1-nitrobenzene (3.72 g, 14.4 mmol), EDCI.HCl (3.63 g, 18.6 mmol), N-methylmorpholine (1.6 mL, 14, 5 mmol) and methylamine (2.0 M in THF; 8 mL,

16 mmol) in CH ₂ Cl ₂ (45 mL) was stirred at room temperature for 3 days, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with 1M HCl solution (50 mL). The aqueous layer was re-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with saturated NaCl solution (50 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure to give 4- (3- (N-methylcarbamoyl) phenoxy) -1-nitrobenzene as an oil (1). 89 g).

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

A slurry of 4- (3- (N-methylcarbamoyl) phenoxy) -1-nitrobenzene (1.89 g, 6.95 mmol) and 5% Pd / C (0.24 g) in EtOAc (20 mL) was 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 column chromatography on silica gel in 5% MeOH-95% CH ₂ C1 _2nd 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 of 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). ml), followed by water (50 ml). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by 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 column chromatography

Silica gel 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 (DMSO-d ₆₎ ) δ 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (d, 1H, 8.51) (d, 1H); 8.87 (d, 1H).

Al 5. Synthesis of aniline by electrophilic nitration and reduction Synthesis of 4- (3-methylsulfamoylphenoxy) aniline

io

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

To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0 ° C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was warmed to room temperature and stirred at room temperature overnight. The resulting mixture was partitioned between EtOAc (25 mL) and 1M HCl solution (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%).

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

To a slurry of phenol (1.9 g, 20 mmol), K ₂ CO ₃ (6.0 g, 40 mmol) and CuI (4 g, 20 mmol) in DMF (25 mL) was added A-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 residual oil was purified by silica gel column chromatography using 30% EtOAc and 70% hexane to give 4- (3-A-methylsulfamoyl) phenyloxy) benzene (0.30 g).

Step 3. Synthesis of 4- (3- (N-methylsulfamoyl) phenyl) -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 g) portionwise over 5 minutes. , 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.

-23 GB 299125 B6

IN

NHMe

H2N

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

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

A16. Modification of ω-ketones

Synthesis of 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline hydrochloride)

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% pet ether) R _f = 0.78; H NMR (DMSO-d ₆₎₎ δ 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m / z 257 ((M + H) < + & gt ^; ).

A17. Synthesis of A - (O-silyloxyalkyl) amides

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 35 as in Example A2, step 3b; 1.5 g, 7.4 mmol) in anhydrous DMF (7 mL) was added. add triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv) aimidazole (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 - (/ V- (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide as an orange oil (2.32 g, 88%). This material was used in the next step without further purification.

-24GB 299125 B6

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 ° C in an ice bath, then slowly added dropwise. water (about 1 mL) was added. 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- (215 (N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline) as a clear light brown oil (0.99 g). 38%).

Al 8. 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 25

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 (2x

100 mL) and saturated NaCl solution (100 mL), dried (MgSO ₄ ), and concentrated under reduced pressure to give 4- (5- (2-methyl) pyridinyl) -1-nitrobenzene as a brown solid (12.3 mL). G).

O

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. 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.

-25GB 299125 B6. 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).

O

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 the atom. H ₂ (balloon) overnight The resulting mixture was filtered through a pad of Celite®, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography on 70% EtOAc and 30% hexane to give

4- (5- (2-methoxycarbonyl) pyridyloxy) aniline (0.40 g).

A19. Synthesis of ω-sulfonylphenylanilines 15

Synthesis of 4- (4-methylsulfonylphenyloxy) 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 1 N 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

Β1. General method for the synthesis of isocyanates from anilines by CDI Synthesis of 4-bromo-3- (trifluoromethyl) phenyl isocyanate: F ₃

Br

-26GB 299125 B6

Step 1. Synthesis of 4-bromo-3- (t ^r ifluormethyl) aniline

To a solution of 4-bromo-3- (trifluoromethyl) aniline (64 g, 267 mmol) in Et ₂ O (500 mL) was added dropwise a solution of HCl (1 M in Et ₂ O; 300 mL) and the resulting mixture was stirred at 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 4-bromo-3- (trifluoromethyl) phenyl isocyanate obtained is a brown solid (35.1 g, 86%): GC-MS m / z 265 (M ^& lt ^{; +} & gt ^; ).

C. Methods of preparation of ureas

Cla. General method of urea synthesis by reaction of isocyanate with aniline

Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoy]) - 4-pyridyloxy) phenyl) urea

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- (V-methylcarbamoyl) -4- pyridyloxy) aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH ₂ Cl ₂ (35 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 22 hours. The resulting yellow solid was removed by filtration, washed with CH ₂ Cl ₂ (2 x 30 mL) and dried under reduced pressure (about 1 mmHg) to yield N - (4-chloro-335 (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 HNMR (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 = 2.5Hz, 1H), 8.49 (d, J = 5.5Hz, 1H), 8.77 (br d, 1H) 1.99 (s, 1H); 9.21 (s, 1H); HPLC ES-MS m / z 465 (M + H) < + &^gt;

-27GB 299125 B6

Clb. General method of urea synthesis by reaction of isocyanate with aniline

Synthesis of N- (4-bromo-3- (trifluoromethyl) phenyl) -N - (4- (2- (N-methylcarbamoyl) -4pyridyloxy) 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- (methylcarbamoyl) -4 -pyridyloxy) 10 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, washed with CH ₂ Cl ₂ (2 x 50 mL) and dried under reduced pressure (about 1 mmHg) at 40 ° C to give N - (4-bromo-3- (trifluoromethyl) phenyl) N - (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea as a pale yellow solid (13.2 g, 90%): mp 203-205 ° C; 1 H NMR (DMSO-d6) 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 (brd, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m / z 509 ((M + H) < + >)^>

Cle. General method of urea synthesis 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

A solution of 2-methylH- (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-N- (2 - (N-methylcarbamoyl)) (4 -pyridyloxy) phenyl) urea as a brown oil (0.11 g, 0.22 mmol): 1 HNMR (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) < + & gt ^; ).

-28GB 299125 B6

Cld. General method of urea synthesis by reaction of isocyanate with aniline

Synthesis of # (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4-aminophenyl) urea

To a solution of (4-chloro-3- (trifluoromethyl) phenyl isocyanate (2.27 g, 10.3 mmol) in CH ₂ C1 ₂ (308 mL) was added in one 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 to afford the resulting pink solid in a mixture of EtOAc (110 mL) and MeOH (15 mL). and the clear solution was washed with 0.05 N HCl solution, and the organic layer was concentrated under reduced pressure to give impure N - (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4-aminophenyl) urea (3). , 3 g): TLC (100% EtOAc) R _f = 0.72.

Cle. General method of urea synthesis by reaction of isocyanate with aniline

Synthesis of N - (4-chloro-3- (trifluoromethyl) phenyl) -A '- (4-ethoxycarbonylphenyl) urea

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

Clf. General method of urea synthesis 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 (1.21 g, 5.46 mmol) in CH ₂ C1 ₂ (8 mL) was added 4- (3-carboxyphenoxy) aniline (Method 1 Al; 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, 1, 2). 21 g, 76%).

-29GB 299125 B6

C2a. General method for the synthesis of urea by reacting aniline with N ´, V V karb carbonyldiimidazole and adding a second aniline

Synthesis of (2-methoxy-5- (trifluoromethyl) phenyl) ^-N (4- (2- (N-methylcarbamoyl) ^ l5 pyridyloxy) phenyl) Urea

To a solution of 2-methoxy-5- (trifluoromethyl) aniline (0.15 g) in anhydrous CH ₂ Cl ₂ (15 mL) at 0 ° C was added CDI (0.13 g). The resulting solution was warmed to room temperature for 1 hour, stirred at room temperature for 16 hours, treated with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 72 hours, treated with H ₂ O (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with saturated NaCl solution (100 mL), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was triturated (90% EtOAc / 10% hexane). The resulting white solid was collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil was purified by column chromatography on silica gel in a gradient of 33% EtOAc / 67% hexane, 50% EtOAc / 50% hexane to 100% EtOAc to afford N - (2-methoxy-5). - (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as a light brown solid (0.098 g, 30%); TEC (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, Δ (m, 1H), 8.75 (d, J = 4.8 Hz, 1H), 9.55 (s, 1H); FAB-MS m / z 461 ((M + H) < + & 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 preparation of N, N-carbonyl25 diimidazole.

Synthesis of bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

To a stirred solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH ₂ Cl ₂ (15 mL) 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 = 4.8 Hz, 2H; HPLC ES-MS m / z 513 ((M + H) < + & gt ^; )).

-30GB 299125 B6

C2c. General method of urea synthesis by reaction of isocyanate with aniline

Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea

To a stirred solution of 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.47 mmol) in CH ₂ C1 ₂ (1.5 ml) was added in one portion 5- (4-aminophenoxy) isoindoline-l, 3 -dione (Method A3, Step 3; 0.12 g, 0.47 mmol). The resulting mixture was stirred for 12 hours, treated with CH ₂ Cl ₂ (10 mL) and MeOH (5 mL). The resulting mixture was washed successively with 1N HCl solution (15 mL) and saturated NaCl solution (15 mL), dried (MgSO ₄ ), and concentrated under reduced pressure to give N- (2-methoxy-5- (trifluoromethyl) phenyl) -. 1- (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea as a white solid (0.2 g, 96%): TLC (70% EtOAc / 30% hexane) R _f = 0.50; 1 H NMR (DMSO-d ₆₎ ) δ

3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J = 9.3 Hz, 2H), 7.80 (d, J = 8.7 Hz) (1H), 8.53 (brs, 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 V- (5- (tert -butyl) -2- (2,5-dimethylpyrrolyl) phenyl) -Y (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

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, 0.267 mmol) was added in one portion. The resulting mixture was heated at 36 ° C overnight, cooled to room temperature and diluted with EtOAc (5 mL). 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 V- (5- (ZerZ-butyl) -2-). (2,5-dimethylpyrrolyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4pyridyloxy) phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc / 60) % hexane) R _f = 0.24; 1 H NMR (acetone-d ₆₎ ) δ 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J = 4.8 Hz, 3H), 5.83 (s (2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J = 5.4) Hz, 1H), 8.57 (d,

J = 2.1 Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M + H) < + & 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 was added to an 8 mL flask (0.5 mL) containing dichloroethane (1 mL). To this flask was added a solution of bis (trichloromethyl) carbonate (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv) followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv) .). Seal the flask and heat at 80 ° C for 5 hours, heat at room temperature for 10 hours, then add the second aniline (0.10 M in dichloroethane, 0.5 mL, 1 mL). 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 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-phenethylcarbamoyl) -4-pyridyloxy) phenyl) urea

To a stirred solution of phosgene (1.9 M in toluene; 2.07 mL 0.21 g, 1.30 mmol) in CH ₂ Cl ₂ (20 mL) at 0 ° C was added anhydrous pyridine (0.32 mL). followed by 2-methoxy-5- (trifluoromethyl) aniline (0.75 g). The yellow solution was allowed to warm to room temperature 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- (V-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, a hot concentrated EtOAc solution was obtained which was washed with hexane (10 mL) to slowly form N - (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2- ( (Methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.44 g): TLC (1% Et ₃ N / 99% EtOAc) R _f = 0.40.

D. Interconversion of ureas

Dia. Conversion of ω-aminophenylureas to (B- (aroylamino) phenylureas)

Synthesis of N - (4-chloro-3 - ((trifluoromethyl) phenyl) -A '- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea

To a solution of N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N - (4-aminophenyl) urea (Method Cd; 0.050 g, 1.52 mmol), obtained isomethyl isophthalate (0.025 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). The resulting mixture was diluted with EtOAc (25 mL) overnight at room temperature and washed sequentially with water (25 mL) and saturated NaHCO ₃ (25 mL).

Dry (Na ₂ SO ₄ ) and concentrate under reduced pressure. The resulting solid was triturated with EtOAc solution (80% EtOAc / 20% hexane) to give N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea (0). , 27 g, 43%): mp 121-122 ° C; TLC (80% EtOAc / 20% hexane) R _f = 0.75.

Dlb. Conversion of ω-carboxyphenylureas to co- (arylcarbamoyl) phenylureas

Synthesis of V (4-chloro-3 - ((trifluoromethyl) phenyl) - 'V' - (4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea

To a solution of V- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '(4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline ( 0.080 g, 0.53 mmol),

HOBT.H ₂ O (0.14 g, 1.07 mmol) and N-methylmorpholine (0.5 mL, 1.07 mmol) in DMF (3 mL) at 0 ° C were added EDCI.HCl (0, 10 g, 0.53 mmol). The resulting mixture was warmed to room temperature and stirred overnight. The resulting mixture was treated with water (10 mL) and extracted with EtOAc (25 mL). The organic phase was concentrated under reduced pressure. The resulting yellow solid was dissolved in EtOAc (3 mL), filtered through a pad of silica gel (17 g) with a gradient of 70% EtOAc / 30% hexane to 10%

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

According to. Combination Method for the Conversion of ω-Carboxyphenylureas to Co- (Arylcarbamoyl) Phenylurea25

Synthesis of N - (4-chloro-3 - ((trifluoromethyl) phenyl) -V '- (4- ^(L (3- ^(N (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) Urea

A mixture of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (3-carboxyphenyl) urea (Method C1f; 0.030 g, 0.067 mmol) and N-cyclohexyl-N- (methylpolystyrene) carbodiimide (55 mg) ) in 1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CH ₂ C1 ₂ (1 M; 0.074 ml,

0.074 mmol). (In case of insolubility or turbidity, a small amount of DMSO is added).

The resulting mixture was heated at 36 ° C overnight. The cloudy reaction mixture was then treated with THF (1 mL) and heating was 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. The resulting solution was filtered through a pad of silica gel (1 g). Concentration under reduced pressure gives N - (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4 - (γ - (3- (N - (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea (0.024 g, 59%): TLC (70% EtOAc / 30% hexane) R _f = 0.12.

-33 GB 299125 B6

D2. Conversion of ω-carboalkoxyarylureas ω-carbamoylarylureas

Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea

To a sample of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF (1 mL, 1.7 mmol) and the resulting mixture was stirred at room temperature overnight, 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 ° C; TLC (100% EtOAc) R _f = 0.35.

D3. Conversion of ω-carboalkoxyarylureas to ω-carboxyarylureas 15

Synthesis of A- (4-chloro-3 - ((trifluoromethyl) phenyl) -A '' (4-carboxyphenyl) urea

To a slurry of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -2 '- (4-ethoxycarbonylphenyl) urea (Method Cl; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added aqueous KOH solution (2.5 N, 10 mL, 23 mmol) The resulting mixture was heated at reflux for 12 h, cooled to room temperature and concentrated under reduced pressure, and the residue diluted with water (50 mL), treated with 1 N aq. 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. compound (5.05 g, 92%).

D4. General method for the conversion of ω-alkoxy esters to o-alkylamides

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

Cl? F ₃

O.

OH

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

N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea) prepared from 4-chloro-3- (trifluoromethyl) phenyl isocyanate and 4- ( 3- (5-methoxycarbonylpyridyl) 40 oxyaniline (Method A14, Step 2) analogously to Method Cla. A suspension of N- (4-chloro-3 (trifluoromethyl) phenyl) -N '((4- (3- (5-methoxycarbonylpyridyl)) oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water

(1 mL) and stirred at room temperature for 1 hour. The resulting mixture was adjusted to pH 5 with 1 N HCl solution. The resulting precipitate was removed by filtration and washed with water. The resulting solid was dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced pressure. This procedure was repeated for 2 s to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5-carboxypyridyl) 5 oxyphenyl) urea) (0.18 g, 71%).

Step 2. Synthesis of N - (4 - chloro - 3 -) trifluoromethyl - phenyl - - N - (4 - 3 - 5 - 2 - dimethylaminoethyl) carbamoy 1) Pyrides l) Oxyphenyl l) Urea

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 The 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 under reduced pressure. The residue was dissolved in a minimum 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, 1H), 9.14 (s, 1H); HPLC ES-MS m / z 522 ((M + H) ⁺ ).

D5. General method for deprotecting A- (m-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) -Y- (4- (4- (2 - (N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea (prepared analogously to Example Cla) 0.25 g, 0.37 mmol) in anhydrous THF (2 mL) was added tetrabutylammonium fluoride (1.0 M in THF; 2 mL), and the mixture was stirred at room temperature for 5 minutes, treated with water (10 mL). ml).

The aqueous mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography in 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) pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).

The compounds listed in the tables below are synthesized according to the detailed experimental examples above. Further, in Examples 42-45, 49, 85-87, 89, 93, 95 and 96, they refer to the compounds of the invention. The remaining compounds refer to the comparative compounds.

-35GB 299125 B6

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

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

Example 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to give 4- (4-acetylphenoxy) -1-nitrobenzene. 4- (4-Acetylphenoxy) -1-nitrobenzene is reduced according to Method A13, Step 4 to give 4- (4-acetylphenoxy) aniline. And by the way

C3 is reacted with 3-tert-butylaniline 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 CD1 followed by 4- (3-A-methyl-20 carbamoyl-4-methoxyphenoxy) aniline, which was prepared according to Method A8 to give the urea.

Example 4: 5-tert-Butyl-2-methoxyaniline was converted to 5- tert -butyl-2-methoxyphenylisocyanate according to Method B1. 4- (3-N-Methylcarbamoylphenoxy) aniline prepared according to the method

A13, is reacted with an isocyanate according to the method of Cla to give urea.

Example 5: According to Method C2d, 5- (tert-butyl-2-methoxyaniline) was reacted with CDI, followed by 430 (3-A-methylcarbamoyl) -4-methoxyphenoxy) aniline, which was prepared according to Method A8 to give urea.

Example 6: 5- (4-Aminophenoxy) isoindoline-1,3-don was prepared according to Method A3. According to Method 35 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 40 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-A-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-A-methylcarbamoylphenoxy) aniline to give urea.

Example 9: 4-Hydroxyacetophenone is reacted with 2-chloro-5-nitropyridine to give 450 (4-acetylphenoxy) -5-nitropyridine according to Method A3, Step 2. A according to Method A8, Step 4, with 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 the method of Cla to give the urea.

-36GB 299125 B6

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

Example 11: 4-Chloro-A-methyl-2-pyridinecarboxamide, prepared according to Method A2, Step 10 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 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 using DMAC instead of DMF to give 3- (2-carbamoyl-4-pyridyloxy) aniline. And according to method C2a, 220 methoxy-5- (trifluoromethyl) aniline is reacted with phosgene followed by 3- (2-carbamoyl-pyridyloxy) aniline to give urea.

Example 13: 4-Chloro- N -methyl-2-pyridinecarboxamide was prepared according to Method A2, Step 3b. 425 Chloro-A-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4, using DMAC instead of DMF to give 4- (2- (A-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-1-pyridyloxy) aniline. And according to Method C4, 235 methoxy-5- (trifluoromethyl) aniline was reacted with phosgene followed by 4- (2-carbamoyl-4-pyridyloxyjaniline) to give urea.

Example 15: According to Method C2d, 5- (trifluoromethyl) -2-methoxyaniline was reacted with CDI, 40 followed by 4- (3-N-methylcarbamoyl) -4-methoxyphenoxyjaniline, which was prepared according to the method

A8 to obtain 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 was reacted with 4- (2- ^{(N-methylcarbamoyl)} -4pyridyloxy) -2-methylaniline according to Method Cle 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-methoxyphenylisocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyl) -2-chloroaniline according to Method C a to give urea.

-37GB 299125 B6

Example 18: According to Method A2, Step 4, 5-amino-2-methylphenol is reacted with 4-chloro-Amethyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 3 (2- (A (methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. 5- (Trifluoromethyl) -2-methoxyaniline

5. is converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline according to Method C a 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 was 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-methoxyphenylisocyanate according to Method B1 5- (Trifluoromethyl) -2-methoxyphenylisocyanate was reacted with 415 (2- (A-ethylacarbamoyl) -4-pyridyloxy with aniline according to method C1a, whereby urea is obtained.

Example 20: According to Method A2, Step 4, 4-Amino-2-chlorophenol was reacted with 4-chloro-Amethyl-2-pyridinecarboxamide, which was prepared according to Method A2, Step 3b, to give 420 (2- (J). (methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 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- (2- (A-methylcarbamoyl) -4 (pyridyl-oxy) -3-chloroaniline according to the method of Cla to give urea.

Example 21: 4- (4-Methylthiophenoxy) -1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. Nitrobenzene is reduced according to Method A19, Step 2 to give 4- (4-methylsulfonylphenoxy) -1-aniline. According to the method of Cla, 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (4-methylsulfonylphenoxy) -1-aniline to give the 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-methoxyphenylisocyanate cyanate is reacted with 4- (3-carbamoylphenoxy) aniline to give the urea.

Example 23: 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 is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N, N-dimethylcarbamoyl) -445 pyridyloxyjaniline. 5- ( Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1 5- (Trifluoromethyl) -2-methoxyphenylisocyanate is reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) with an aniline according to the method of Cla to yield 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.

-38GB 299125 B6

Example 26: 4-Hydroxyacetophenone is reacted with 4-fluorometrobenzene according to Method A13, Step 1 to give 4- (4-acetylphenoxy) nitobenzene, nitrobenzene reduced according to Method A13, Step 4 to give 4- (4- acetylphenoxy) aniline which is converted to 4- (4- (1- (A-methoxy) iminoethyl) phenoxyaniline hydrochloride according to Method A16) 5- (Trifluoromethyl) -2-methoxy5 aniline is converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1, 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (4- (1- (2-methoxy) iminoethyl) phenoxyaniline hydrochloride according to Method C1 a 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) 2- (Methoxyphenylisocyanate) according to Method B1 5- (Trifluoromethyl) -2-methoxyphenylisocyanate was reacted with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline according to Method C1a) to afford the urea.

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

Example 29: 4-Chloro-2H-methylpyridine carboxamide was prepared according to Method A2, Step 3b. The chloro-25 pyridine 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 C1 a to obtain 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) -435 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-pyridyloxyjaniline according to method C a 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-methoxyphenylisocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C a to give urea. N- (545 (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 is converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C a to give urea. N- (5 (Trifluoromethyl) -2-methoxyphenyl) -N - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea

A 299125 B6 was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to give the amide.

Example 33: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to Method A14. 5 (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C a to give the urea N - (5 (Trifluoromethyl) -2-methoxyphenyl) -N '- ( 4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea is saponified according to Method D4, Step 1, and the corresponding acid is coupled with N, N-dimethylethylenediamine according to Method D4, Step 2 to give the amide.

Example 34: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A11. 5- (Trifluoromethyl) -215 methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) urea, which according to method D1 is coupled with 3-aminopyridine.

Example 35: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) urea, which according to Method D1 is coupled with N - (4-fluorophenyl) piperazine.

Example 36: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -1 '- (3-carboxyphenyl) ) urea which is coupled with 4-fluoroaniline according to Method D1.

Example 37: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A11. 5- (Trifluoromethyl) -235 methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N- (3-carboxyphenyl) urea which is coupled with 4- (dimethylamino) aniline according to Method D1.

Example 38: 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-methoxyphenylisocyanate 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 D1.

Example 39: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1.

4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) - N '- (3-carboxyphenyl) ) urea which is coupled with 4-morpholinoaniline according to Method D1.

-40GB 299125 B6

Example 40: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) 15 urea which is coupled with N- (2-pyridyl) piperazine according to Method D1.

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 4o (3- (N-methylcarbamoyl) phenoxy) aniline to give the urea.

Example 42: 4- (2-A-Methylcarbamyl-4-pyridyloxy) aniline was prepared according to Method A2. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2-A methylcarbamyl-4-pyridyl-15-oxy) aniline according to Method C1a to give the urea.

Examples 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-pyridine-20-carboxamide 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 according to the method of Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2-carbamoyl-4-pyridyloxy) aniline to give urea.

Example 45: 4-Chloro-A-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- (Amethylcarbamoyl) - 4-Pyridyloxy (aniline). According to method C a, 4-chloro-3- (trifluoromethyl) phenyl isobutane cyanate is 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. According to the method of Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is 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 Cle, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is 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 50a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (N-methylsulfamoyl) phenyloxy) aniline to give urea.

-41 CZ 299125 B6

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 is reacted with 4- (2 (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to give urea.

Example 50: According to Method A2, Step 4,5-amino-2-methylphenol was reacted with 4-chloro-V-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) -4,10-methylaniline to give urea.

Example 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide is reacted with 4-amino-15 phenol according to Method A2, Step 4 to give 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. And according to the method of Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

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

Example 53: 4- (4-Methylthiophenoxy) -1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. Nitrobenzene is reduced according to Method A19, Step 2 to give 4- (4-methylsulfonylphenoxy) -1-aniline. And according to the method of Cla, 430 chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4-methylsulfonylphenoxy) -1-aniline to give urea.

Example 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method 35 A15, Step 1 to give N-methyl-4-bromobenzenesulfonamide. The α-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 was converted to 4- (4- (Amethylsulfamoyl) phenoxy) -1-nitrobenzene according to Method A15, Step 3. 4- (4- (N-Methylsulfamoyl) phenoxy) - The 1-nitrobenzene is reduced to 4- (4- (A-methylsulfamoyl) phenyloxy) aniline according to method A15, step 4. According to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (A-methylsulfamoyl) phenyloxy) aniline to give the urea.

Example 55: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to Method 45 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. 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 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- (255-methoxycarbonyl) pyridyloxy) -1-nitrobenzene. Nitrobenzene is reduced according to Method A18, Step

-42GB 299125 B6

3 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline. The aniline is reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to the method of 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 C1d. N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4-aminophenyl) urea was coupled with 10oM-methyl isophthalate according to method Dia to give urea.

Example 58: N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4-aminophenyl) urea was prepared according to Method C1d. N - (4-Chloro-3- (trifluoromethyl) phenyl) - N - (4-aminophenyl) urea was coupled with mono-methylisophthalate according to Method Dia to give N - (4-chloro-3- (trifluoromethyl) phenyl) N - (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea. And according to Method D2, 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 4aminophenol according to Method A2, Step 4 to give 4- (2- (N, N-dimethylacarbamoyl) -4-pyridyloxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (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) aniline, which was converted to 4- (4- (1- (3030 methoxy)) hydrochloride. iminoethyl) phenoxyaniline according to Method A16. And according to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4-acetylphenoxy) aniline to give urea.

Example 61: 4- (3-Carboxyphenoxy) -1-nitrobenzene was prepared according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with 4- (2-aminoethyl) morpholine according to Method A13, Step 3, to give 4- (3- (N- (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene. And according to Method A13 step 4, 4- (3- (N - (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (3- (N - (2-morpholinylethyl) carbamoyl) phenoxy) aniline. And, according to method C1a, 4-chloro-340 (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (Y- (2-morpholinylethyl) carbamoyl) phenoxy) aniline to provide urea.

Example 62: 4- (3-Carboxyphenoxy) -1-nitrobenzene was prepared according to Method A13, Step 2. 4-345 (Carboxyphenoxy) -1-nitrobenzene was coupled with 1- (2-aminoethyl) piperidine according to Method A13, Step 3 to give 4- (3- (N - (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene. A according to Method A13, Step 4, 4- (3- (7- (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (7- (2-piperidylethyl) carbamoyl) phenoxy) aniline . And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was 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 tetrahydrofurfurylamine according to Method A13, Step 3 to give 4- (3). - (N - (tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene. and according to method A13, step 4, 4- (3 - (N - (tetrahydro-furylmethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3 - (N - ( tetrahydrofirylmethyl) carbamoyl) phenoxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is 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-ethylmethyl-pyrrolidine according to Method A13, Step 3, thereby 4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1'-nitrobenzene is obtained. And according to Method A13 step 4, 4- (3- (A - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (A - ((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-A-methylpyridine carboxamide 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. According to Method C1a, 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 was reacted with 425 aminophenol according to Method A2 to give 4- (2- (N isopropylcarbamoyl) -4-pyridyloxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 67: N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- (4-ethoxycarbonylphenylurea) was prepared according to Method Cle. V- (4-Chloro-3- (trifluoromethyl) phenyl) -N' - ( 4-ethoxycarbonylphenyl) urea was saponified according to Method D3 to give N - (4-chloro-3- (trifluoromethyl) phenyl) N - (4-carbonylphenyl) urea N - (4-Chloro-3- (trifluoromethyl)) phenyl) -N '- (4-carboxyphenyl) urea was coupled with 3-methylcarbamoylaniline according to Method Db to give N- (435 chloro-3- (trifluoromethyl) phenyl) -N' - (4- (3-methylcarbamoyl- phenyl) carbamoylphenyl) urea.

Example 68: 5- (4-Aminophenoxy) -2-methyl-isoindoline-1,3-dione was prepared according to Method A9. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 5- (4-amino-40-phenoxy) -2-methylisoindoline-1,3-dione to give urea.

Example 69: 4-Chloro-N-methylpyridine carboxamide was prepared according to Method A2, Step 3b. The chloropyridine is reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (445 (2- (N-methylcarbamoyl) phenylthio) aniline. According to Method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is left. with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline) to give the urea.

Example 70: 4- (2- (N - (2-Morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to afford the urea.

-44GB 299125 B6

Example 71: 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 C a to give urea. N - (4-Chloro-3- (trifluoromethyl) phenyl) - N - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea is saponified according to the method

D4, step 1, and the corresponding acid was coupled with 4- (2-aminoethyl) morpholine to give the amide.

Example 72: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to Method A14. 4o Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxyjaniline according to method C a to give urea. N- (5 - ('[difluoromethyl) -2-methoxyphenyl) - N - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea is saponified according to method

D4, step 1, and the corresponding acid was coupled with methylamine according to method D4, step 2 to give the amide.

Example 73: 4- (3- (5-Methoxycarbonyl) pyridyl) 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 C a to give urea. N- (5- (Trifluoromethyl) -2-methoxy20 phenyl) -N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with N, N -dimethylethylenediamine according to Method D4, Step 2 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 followed by 4-aminophenol according to Method A17 to give 4- (4- (2- (A- (2-triisopropylsilyloxy) ethylcarbamoyl)) and according to the method

Duty is reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (4- (2- (N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline) to give N - (4-chloro-3 - ((trifluoromethyl) (phenyl) -N '- (4- (4- (2- (X- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea).

Example 75: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A11. 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.

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 D1.

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 urea which is coupled with 4-fluoroaniline according to Method D1.

Example 78: 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- (dimethylamino) aniline according to Method D1.

-45 GB 299125 B6

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 Λ-phenylethylenediamine according to Method D1.

Example 80: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A11. 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 D1.

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-methoxypyridine according to Method D1.

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 D1.

Example 83: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A11. 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 '- (2-pyridyl) piperazine according to Method D1.

Example 84: 4-Chloropyridine-2-carbonyl chloride hydrochloride was reacted with 2-hydroxyethylamine according to Method A2, Step 3b, to give 4-chloro- N - (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide. 4-Chloro-A (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide is reacted with triisopropylsilyl chloride followed by 4-aminophenol according to Method A17 to give 4- (4- (2- (N - (2-triisopropylsilyloxy) ethylcarbamoyl)) And according to Method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (A- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline) to give A- (4-chloro- 3 - ((trifluoromethyl) phenyl) -N '- (4- (4- (2- (N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea).

The urea was deprotected according to Method D5 to give N - (4-chloro-335 ((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. 4Bromo-3- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. And according to the method of Cla, 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

A6. 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) -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- (Λ -A-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 4-Bromo-3- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. A method according to Cla, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ^{(N-methylcarbamoyl)} -455 pyridyloxy) -3-chloroaniline to afford the urea.

-46GB 299125 B6

Example 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2 - (N ethylcarbamoyl) -4-pyridyloxy) aniline. 45 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 is 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- (Ά) (methylcarbamoyl) -4-pyridyloxy) aniline. 4-Bromo-3- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. A method according to Cla, 4-bromo-3- (trifluormethyljfenylizokyanát reacted with 3- (2- ^{(N-methylcarbamoyl)} -4-pyridyloxy) aniline to afford the urea.

Example 90: According to Method A2, Step 4, 5-amino-2-methylphenol is reacted with 4-chloro-V-methyl-2-pyridinecarboxamide, prepared according to Method A2, Step 3b to afford 320 (2- (J) (methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. 4-Bromo- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. And according to method C a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate 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 is reacted with 4aminophenol 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 phenyl isocyanate according to Method B1. And according to method C a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is 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 4 to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 4-Bromo-3- (trifluoromethyl) aniline. converts to 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline) to give urea.

Example 93: 4-Chloro-N-methylpyridine carboxamide was prepared according to Method A2, Step 3b. The chloropyridine is reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 4-Bromo-3- (trifluoromethyl) aniline is converted to 4-bromo- 3- (Trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-345 (trifluoromethyl) phenyl isocyanate was reacted with 3- (4-2- (N-methylcarbamoyl) phenylthio) aniline to give urea.

Example 94: 4- (2- ^(N - (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was synthesized according způ50 Sobu A10. 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 is reacted with 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to give urea.

-47GB 299125 B6

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 C a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is 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 the method of Cla, 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-Amethyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 4 (2- (2V) (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 the method of Cla, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 4- [2- (V-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to give 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-230 methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method Β1. And according to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-methyl-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 40 isocyanate according to Method Β1. 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- (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 B1A according to Method C1a with 4-chloro-2-methoxy-5 (trifluoromethyl) ) phenyl isocyanate is reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

-48GB 299125 B6

Example 101: 4-Chloro-N-methyl-2-pyridinecarboxamide, prepared according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to give 3- (2- (N-methylcarbamoyl) (4-Pyridyloxy) aniline. 2-Amino-3-methoxynaphthalene was prepared according to Method A1. And according to Method C3, 2-amino-3-methoxynaphthalene is reacted with bis (trichloromethyl) carbonate followed by 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to form urea.

Example 102: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) aniline was prepared according to Method A2. 57-Butyl-2- (2,5-dimethylpyrrolyl) aniline was prepared according to Method A4. 5- tert -Butyl-2- (2,5-dimethylpyrrolyl) aniline was reacted with CDI followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline according to Method C2d to give the urea. .

Example 103: ^4-Chloro-N- methyl-2-pyridinecarboxamide was prepared according to Method A2, Step 3b. 415 Chloro- N -methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4, using DMAC instead of DMF to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline . And according to method C2b, the reaction of 3-amino-2-methoxyquinoline with CDI, followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline affords bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) ) urea.

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

Tables

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

-49GB 299125 B6

Table 1

3-tert-butylphenyl ureas

FHUad R Temperature tfoi fC) HPLC (mb) TLC Rf TLC System MS Ikeabaeel Zpňsofc eyatfay 1 In NH -oo * $ 22 50% EtOAc / 30% 418 (M + H < + >) (HPLC ES-MS) A13 α 2 - £ WH 0.58 30% EtOAc / 30% hexane 403 (M + H) < + >. (HPLC ES-MS) A13 C3 3 % -nh oo * 133 * 133 0.68 100% EtOAc 448 (M + H) < + >. (FAB) A8 Qd

Table 2

5- tert -Butyl-2-ethoxyphenylurea

Example R Temperature ttai Γ9 HPLC (min) TLC Rf TLC System MS flaatocd Zpteab lýatézy 4 and Vnh 0-0 * 3.93 448 (M + H < + >) (HPLC ES-MS) A13 Bl Cla 5 Vnh -O- ° -O— 120 · 122 0/57 100% EtOAc 478 (M + H) < + >. (FAB) A8 CM 6 oo 0 0 ^ 40 30% EtOAc / 50% hexane 460 (M-Hh (HPLC ES-MS) A3 CM

-50GB 299125 B6

7 -O- 6p9 50% 446 A12 EtOAc (M + H) < + >. C2d NH / 50% (HPLC hexane ES-MS)

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

MkM R Temperatures * t * «i pq HPLC (min) TLC Ttc System MS ZfR & Mtb »Y» tfay 8 Vnh -CH) 250 (<fcc) 460 (M + HH +) (FAB) A13 C2a 9 -OoOf ' ^CS N * 206- 208 IN* 10 * MeOH / 90 * CH2Cl 2 446 (M + H > f (HPLC ES-MS) A3 step 2, A8 step 4. Bl. Cla 10 -O-O-C. 0 ^ 33 50 * BtGAc / 50 * five β & βί 445 (M + H) &lt; + &gt;. (HPLC ES-MS) A13 C3 11 —N-NH / = <Me We 0.20 2 * BON / 98% EtOAc «61 (M + H &lt; + &gt;) (HPLC ES-MS) A2 C4 12 -O 3 ^nh2 '' and / ⁸⁸ ¾ ° ' ^E Op 1 * aaw CMM & ysn » EtOAc 447 (M + H) &lt; + &gt;. (HPLC ES-MS) A2 C4 15 Dec Op 100 * EtOAc 461 (M + H &lt; + &gt;) (FAB) A2 C2a 14 y- nkí -CH) 114. 117 Op 1 * EON/ 99 * EtOAc 447 (M + HH +) (FAB) A2 C4

-51 CZ 299125 B6

15 Dec - / Λ-ο- Ό -NH Me -About me 232- 235 0p4 100% EtOAc 490 (M + H) &lt; + &gt;. (FAB) A8 C2d 16 Q 210. 0.29 5% 475 AS Me -NH 213 MeOH (M + H) &lt; + &gt;. Bl Cle zsssC Μβ / 45% (HPLC - ^ Λ-ο- VL> N EtOAc ES-MS) X fí 750% five ether 17 O 187 * 0.17 50% 495 A6 α -NH 188 EtOAc (M + H) &lt; + &gt;. Bt Cla Me / 50% (HPLC X-Q. -Ol pct ES-MS) Χ -— / X fí ether 18 F'\ 0.48 100% 475 A2 step —7 rM · z-nh. EtOAc (M + H) &lt; + &gt;. 4. \ SSS < / “SSS \ (HPLC Bl Cla w ¹ ES-MS) 19 Dec 194. 0.31 5% 475 A2 -NH 196 MeOH (M + H) &lt; + &gt;. Bl Cla -ZVn. / 5BBS \ Et / 45% (HPLC -4, N EtOAc ES-MS) \ sstf X fí / 50% five ether 20 May 214. 0.25 5% 495 A2 Cla P -NH 216 MeOH (M + H &lt; + &gt;) JfiSSSSS \ Me / 45% (HPLC V-o- 4 JN EtOAc ES-MS) Xss / X fí / 50% five ether 21 and —w f = \ 0 _Λ 208. 0-30 50% 481 A19C2a x and ~ -S * ° 210 EtOAc (M + H +) \ = z \ -! ί Me / 50% (HPLC hexane ES-MS) 22nd <K 188- opo 70% 447 A15. -NHj 190 EtOAc (M + Hh Step 4 A ......... A. «Β / / 50% (HPLC Cla U ^-0 · O hexane ES-MS) 23 / Ά ~ _ / = \ zO 0.50 70% 472 A3 —AuZf * »t> 4 Vzr Y EtOAc (M + H) &lt; + &gt;. Bl Cla , NH / 30% (FAB) r hexane 0 24 α Me 203 * ομ3 100% 479 A2 Bi X- -N 205 EtOAc (M * H) * Cla O ^-0 · / == \ Ό Me <HPLC ES-MS)

-52EN 299125 B6

25 ~ c > ~ f ⁰ ' _# 09 75% EtOAc / 25% hexane 458 (M + HF (HPLC ES-MS) A12 C2d 26 Meq τχχ 169- 171 <^ 67 50% EtOAc / 50% five ether 474 (M + HF (HPLC ES-MS) A13 «Epi, A13 step 4, A16, Bl Cla 27 Mar: -0-3. < χ ~ ^ΝΗ = (Μβ y 218- 219 C ^ 40 50% EtOAc / 50% five csocr 477 (M + HF (HPLC ES-MS) A2step 3b, A2krek 4, Bl, Cla 28 -Q-Ο- < w Ny-NMe 0 212- 214 OpO 40% EtOAc / 60% hexane A9 Bl Cla 29 Vnh (Me Cp3 50% EtOAc / 50% five ether 474 (M + HF (HPLC ES-MS) A2step 3b, A2step 4, Bl. Cla 30 __Z ~ V ₀ _ X / ~ nh s (PH N 210. 211 A2 Bl Cla 31 —Q ......... -NH '' 'X Q 210- 204 0.43 10% MeOH / CH2Cl 2 A14 Bl Cle D4 32 -0-0- < 0 [-NH =] Me 3 247. 249 0.57 10% MeOH / CH2Q 2 A14 Bl Cla D4 33 - # - 0— \ SSSSZ \ m -N -NH N ~ M < Me 217 219 0j07 10% MeOH / CH2Cl 2 AI4 Bl Cla D4

-53CL 299125 B6

34 you 0.11 70% EtOAc / 30% hexane All Bl Clf According to 35 ^F V Q O M) bsO -0-0 0.38 79% EtOAc / 30% tm » All Bl Clf According to 36 r p mu and 0.77 70% EtOAc / 30% hexane All Bl Clf According to 37 ii * \ sss / V— mw -Q- ^ Q 0.58 70% EtOAc / 39% hexane All Bl Clf According to 38 N- &. μλ4) -νη -CMO * QjSS 70% EtOAc / 39% hexane All Bl Clf According to 39 /you, \ aaáK »f XSSSf ySSrQ -o ° -o 70% EtOAc / 30% hexane All Bl Clf According to 40 Oo-o * \ = / \ __ / \ eatZ \ ss0 “0 ^ 0 ^ <^ 21 70% EtOAc / 30% boom All Bl Clf According to

Table 4.

3- (Trifluoromethyl) -4-chlorophenylinurea

-54GB 299125 B6

PMdad R Temperature tfai pq HPLC (mm.) TLC Rf TLC System MS ffoalxftcel Způtob ayattzy 41 fc γ-NH *** 163 * 165 φ » 50% EtOAc / 50% pet ether 464 (M + H) &lt; + &gt;. (HPLC ES-MS) A13 C3 42 Vnh -0 ^ 0 * 215 <^ 06 50% EtOAc / 50% pct ether 465 (M + H) + (HPLC ES-MS) A2 Cla 43 5 ~ ^ΝΜ 2 -Ο- ° -0 · 0) 10 50% EtOAc / 50% pet ether 451 (M + H) &lt; + &gt;. (HPLC ES-MS) A2 Cla 44 0.25 30% EtOAc / 70% pet ether 451 (M + H) &lt; + &gt;. (HPLC ES-MS) A2 Cla 4 $ - () 7 ^NH opi 30% EtOAc / 70% pet ed » 465 (M + H) &lt; + &gt;. (HPLC ES-MS) A2 Cla 44 176 * 179 23) 23 40% EtOAc / 60% hexane 476 (M + HK (PAB) Λ3 Cla 47 0) 29 5% MeOH / 45% EtOAc / 50% pet ether 478 (M + H) &lt; + &gt;. (HPLC ES-MS) A5 Cle 48 ° / nh from * 206- 209 A15 Cla 49 0 ct γ-NH / x / == < 147- 151 0) 22 50% EtOAc / 50% pet ether 499 (M + H) &lt; + &gt;. (HPLC ES-MS) A6 Cla SO - / ~ ^NH 0 — ζ N 0) 54 100% EtOAc 479 (M * Hh (HPLC ES-MS) A2 Cla

-55GB 299125 B6

51 ά_ _νη 187- 189 0.33 5% MeOH / 45% EtOAc / 50% pet etber 479 (M + H) + (HPLC ES-MS) A2 Cla 52 0 α / -ΝΗ - ** · 219 0.18 5% MeOH / 45% EtOAc / 50% pct ether 499 (M + H) + (HPLC ES-MS) A2 Cla 53 -O- ° -Q-fe 246- 248 0.30 50% EtOAc / 50% hexane 485 (M + H) &lt; + &gt;. (HPLC ES-MS) A19, Cla 54 -0-0¾ Μβ 196- 200 0) 30 70% EtOAc / 30% hexane) 502 (M + H> +) (HPLC ES-MS) AIS Cla 55 0 -τν-ο-Λ ** 228- 230 ορο 30% EtOAc / 70% CH2Cl2 466 (M + HH- (HPLC ES-MS) 5 « -ČWHh Μβ 238- 245 57 -Ο- “ ¹ -» · 221- 222 0.75 80% EtOAc / 20% hexane 492 (M + H) &lt; + &gt;. (FAB) Cld Ola 58 y — NH 247 <^ 35 100% EtOAc Cld Dia D2 59 Ο Μβ FOR 198- 200 0.09 100% EtOAc 479 (M + H) &lt; + &gt;. (HPLC ES-MS) A2 Cla 60 ΜβΟ ₍ -οο-ί 158- 160 ¥ * 50% EtOAc / 50% pet ether 61 ο _κ , ^ - ΝΗ 195- 197 0p9 10% MeOH / CH2Cl 2 A13 Cla

-56GB 299125 B6

62 0, 170- 172 <^ S2 10% MeOH / CH2Cl 2 A13 Cla 63 168- 171 0p9 10% MeOH / CH2Cl 2 A13 Cla 64 176 177 0p5 10% MeOH / CH2Cl 2 A13 Cla 65 O γ-NH 130- 133 487 (M + H) (HPLC ES-MS) A2 Bl Cla 66 Vnh 155 A2 Cla 67 Q Vnh 225- 229 <p3 100% EtOAc Cle D3 Dlb 68 ^- About ^_o- QV ⁵ V. NMe 234- 236 φΐ9 40% EtOAc / 60% hemt A9 Cla 69 -Q _8H > p. 0j48 50% EtOAc / 50% pet ether 481 (M + H) &lt; + &gt;. (HPLC ES-MS) 70 0 ’^ -ΗΗ 0 | 46 5% MeOH / 95% CH2O2 564 (M + H) &lt; + &gt;. (HPLC ES-MS) A10 Cla

-57GB 299125 B6

71 0 '' n — i ^N Q 199- 201 0 ^ 0 10% MeOH / CH2Cl 2 A14 Cla D4 72 Vnh -θ-0-O '* vaaz N 235- 237 0 ^ 55 10% MeOH / CH2Cl 2 A14 Cle D4 73 V- NH 0—0 O. 200- 201 cpi 50% MeOH / CH2Cl 2 A14 Cle D4 74 O W-UU rIWI - (Vo- <) OSKPr-J), \ fiSS8 »Ιμμμ ^ ι 145- 148 75 fy <i \ = / \ sbQ "O ^ °" W 0 ^ 12 70% EtOAc / 30% hexane 527 <M + H> (HPLC ES-MS) All Clí According to 76 O -o-J ” 0jl8 70% EtOAc / 30% hexane All Clf According to 77 F-f V-NH 1 = / \ = 0 -0-0 0j74 70% EtOAc / 30% hexane All Clf According to 78 vu Me > = 0 0-0 Oj58 70% EtOAc / 30% hexane AU. Clf According to

-58GB 299125 B6

79 ~ O ^_c ^ Q 'D * ¥ ⁷ 70% EtOAc / 30% 569 (MW (HPLC ES-MS} AU Clf According to 80 K nu 0 ^ 18 70% EtOAc / 30% ^ 508 (M * Hh (HPLC ES-MS) Alt Clf According to 81 -Οχ Ό — w 0 ^ 58 70% & ΩΛλ / 30% 557 (MW (HPLC ES-MS) AU Clf According to 82 P ~ \ / ΓΛ -OO _¥ 7 70% EtOAc / 30% [ 611 (MW (HPLC ES-MS) AU Clf According to 83 -o-cČ 0 ^ 19 70% EtOAc / 30% AU Clf According to 84 ά_ _νη -OO% 179- 183 A2 A17 CU D5

Table 5. 3-Trifluoromethyl) -4-broniphenylureas

-59GB 299125 B6

PHktad R Warm tini Γ9 HPLC (mm.) TLC Rf TLC System MS (ionization) Way synthesis 85 and P — NH of> and Me // * 186- 187 0.13 50% EtOAc / 50% pct ether 509 (M + H) &lt; + &gt; (HPLC ESMS) A2 Bl Cis 86 Ol __ / ~ ⁿ .h 1 ». 152 Opi 50% EtOAc / 50% pet ether 545 (M + H) &lt; + &gt; (HPLC ESMS) A6 Bl Cis 87 x JH1 -OO 217- 219 0.16 50% EtOAc / 50% pet βοΟΒΓ 545 (M + H) &lt; + &gt; (HPLC ESMS) A2 Bl Cl » 88 Qa p-nh 183- 184 Opi 50% EtOAc / 50% pet 525 (M + H) &lt; + &gt; (HPLC ESMS) A2 Bl Cis 89 -ΖΛ In NH / = / Me ⁰ in / opi 50% EtOAc / 50% pct ether 511 (M + H) + (HPLC ESMS) A2 Bl Cl * 90 —Σ V-Me V-NH ope 50% EtOAc / 50% pet ether 525 (M + H) &lt; + &gt; (HPLC ESMS) A2 Bl Cla 91 0 Me -cw? ” 214- 216 0 ^ 8 50% EtOAc / 50% pet ether 522 (M + H) &lt; + &gt; (HPLC ESMS) A2 Bl Cla 92 0. Y-NH-O ^{with N} 0 / (7 50% EtOAc / 50% pet ether 527 (M + H) &lt; + &gt; (HPLC ESMS) A2 step 3b. A2 step 4. Bl, CIS 93 XJ * - 0 / (6 50% EtOAc / 50% ether 527 (M + H) &lt; + &gt; (HPLC ESMS) A2step 3b. A2 step 4. Bl. Target

-60GB 299125 B6

Table 6.

5- (trifluoromethyl) -4-chloro-2-methoxyphenyl urea

PNUM R Temperature Hol Γ9 HPLC (min) TLC Rf TLC System MS Uabacel Zpóaofc ayatízy 95 / -NH -0-0 · 140- 144 φ » 5 * MeOH / 45% EtOAc / 50% pot 495 (M + Hh (HPLC ES-MS) A2 A7 Bl Cla 96 0. and / —NH-O-K? ¹ ” 244- 245 ψ9 5% MeOH / 45% EtOAc / 50% swt ether 529 (M + Hh (HPLC ES-MS) A6 A7 Bl Cls 97 and / -NH / - </ == 220- 221 0.25 5% MeOH / 45% EtOAc / 50% pot 529 (M + Hh (HPLC ES-MS) A2 A7 Bl Cla 98 -% - NM / «« χ M · ° ~ v / Op 5% MeOH / 45% EtOAc / 50% pet ether 495 (M + H) &lt; + &gt;. (HPLC ES-MS) A2 A7 Bl CH 99 S-NH-0-0 ^B 180- 181 Op 5% MeOH / 45% EtOAc / 50% pet edter 509 (M + H) (HPLC ES-MS) A2 A7 Bl Cla 100 ALIGN! 0 V-NH -0—0 162- 165 A2 A7 Bl Cla

-61 CZ 299125 B6

Table 7.

More ureas

PHktad R Temperature tini R HPLC TLC Rf TLC System MS [ionization] Way synthesis 101 OM »” 162- 165 Al A2 C3 102 OjlO 50% EtOAc / 50% hex * B 442 (M + HH +) (HPLC ES-MS) A2 A4 C2d 193 X HN NH 0 0 v 0 0 o = (y = o NH-β-Me-NH 125- 130 0jj24 40% EtOAc / 60% hexane ₅₁₂ (M + H) &lt; + &gt; (FAB) A2 C2b

The synthesis of the compound of the above examples can be repeated with similar success by replacing the generically or specifically described reactants and / or reaction conditions of the present invention in the above-described examples.

Claims (18)

PATENT CLAIMS A compound selected from the group consisting of 2-Methoxy-4-chloro-5- (trifluoromethyl) phenyl urea: ^N - (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) ^-N '- (4- (2- (íYmethylkarbamoyl) -4pyridyloxy) phenyl) urea and -66GB 299125 B6 7V- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) - / V - (2-chloro-4- (2- (methylcarbamoyl ^A) (4pyridyloxy)) phenyl) urea, or a pharmaceutically acceptable salts for the preparation of a medicament for the treatment of tumors. 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl urea. / V- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) ^-N-f (4- (2- (N-methylcarbamoyl) -4pyridyloxy) phenyl) urea and N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- ^{(t-methylcarbamoyl)} (4pyridyloxy)) phenyl) urea, or a pharmaceutically acceptable salts for the preparation of a medicament for treatment (i) cancer of the lung, pancreas, thyroid, bladder, colon, (ii) myeloid leukemia, or 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl urea: The compound of claim 1 which is a pharmaceutically acceptable salt thereof selected from the group consisting of (a) basic salts of organic and inorganic acids selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, trifluorosulfonic, benzenesulfonic, t-toluenesulfonic (tosylate), 1-naphthalenesulfonic, 2-naphthalenesulfonic, acetic, trifluoroacetic, malic, wine, lemon, milk, oxal, succinic, fumaric, maleic, 35 benzoic, salicylic, phenylacetic and mandelic acids; and (b) acidic salts of organic and inorganic bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cation, aliphatic-substituted ammonium cations and aromatic-substituted ammonium cations 40 parts. 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl urea: 20 N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) ^-N '- (4- (2 - (/ V-methylcarbamoyl) -4pyridyloxy) phenyl) urea and N - (2-methoxy-N-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-N- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, or a pharmaceutically acceptable salt thereof . A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. The compound of claim 1 selected from the group consisting of N - (4-chloro-3- (trifluoromethyl) phenyl) - N - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) ethynyl) urea, 50 N- (4-chloro-3- (trifluoromethyl) phenyl) -Ν- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (R-methylcarbamoyl) -4-pyridyloxy) phenyl urea), -63EN 299125 B6 N- (4-bromo-3- (trifluoromethyl) phenyl) -N '(4- (2' (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -V '- (4- (2- (methylcarbamoyl ^L) -45 pyridyloxy) phenyl) urea and N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea or a pharmaceutically acceptable salt thereof acceptable salt. 4-bromo-3- (trifluoromethyl) phenyl urea: And ^L - (4-bromo-3- (trifluoromethyl) phenyl) - / V '- (3- (2- ^{(A-methylcarbamoyl)} -4-pyridyloxy) phenyl) urea, ^N - (4-bromo-3- (trifluormetliyl) phenyl) ^-N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea 40, N- (4-bromo-3- (trifluoromethyl) phenyl) -AC- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, 45 ^A, - (4-bromo-3- (trifluoromethyl) phenyl) - / V - (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea and ^N - (4-bromo-3- (trifluoromethyl) phenyl) ^-N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea; 4-bromo-3- (trifluoromethyl) phenyl urea: N- (4-bromo-3- (trifluoromethyl) phenyl) - _; N- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) 45 urea, N- (4-bromo-3- ( trifluoromethyl) phenyl) ^-N '- (2-chloro-4- (2 - (/ V-methylcarbamoyl) (4-pyridyloxy)) phenyl (urea 50 Y- (4-bromo-3- (trifluoromethyl) phenyl) - (3-chloro-4- {2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl urea; -65GB 299125 B 6 4-chloro-3- (trifluoromethyl) phenyl urea: N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea, 25 N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N - (4-chloro-3- (trifluoromethyl) phenyl) - N - (4- (2 'carbamoyl-4-pyridyloxy) phenyl) urea, 30 N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea; and N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (2-chloro-4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl urea); 4-bromo-3- (trifluoromethyl) phenyl urea: N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (V-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, And ^C (4-bromo-3- (trifluoromethyl) phenyl) - / V '- (4- (2- ^(N -methylkarbamoylpl-pyridyloxy) phenyl) urea, And ^L (4-bromo-3- (trifluoromethyl) phenyl) -N- (3- (2- (N-mcthylkarbamoyl) -4-pyridylthio) phenyl) urea 55, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '(2-chloro-4- (2- (N ^- methylcarbamoyl) (4-pyridyloxy)) phenyl) urea; and 4-chloro-3- (trifluoromethyl) phenyl urea: N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea, 35 N- (4-chloro-3- (trifluoromethyl) phenyl) -N (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, (4-Chloro-3- (trifluoromethyl) phenyl) - N - (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea 40 N- (4-chloro-3- (trifluoromethyl) phenyl) _-N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea and N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (2-chloro-4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea; 4-bromo-3- (trifluoromethyl) phenyl urea: N - (4-bromo-3- (trifluoromethyl) phenyl) - N - (3- (2 - (N - methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbonylthioyl) -4-pyridyloxy) phenyl) urea, N - (4-bromo-3- (trifluoromethyl) phenyl) - N '- (3- (2 - (N - methylcarbamoyl) -4-pyridylthio) phenyl) urea N - (4-bromo-3) - (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl urea and 4-chloro-3- (trifluoromethyl) phenyl urea: N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-1-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (3) - (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, A ^L (4-chloro-3- (trifluoromethyl) phenyl) -N- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea and N- (4-chloro-3- (trifluoromethyl) (phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea; -62EN 299125 B6 5 / N- (4-bromo-3- (trifluoromethyl) phenyl) - / V '- (3-clilor-4- (2- ^{(N-methylcarbamoyl)} (4-pyridyloxy)) phenyl) urea; The compound of claim 4, which is a pharmaceutically acceptable salt thereof selected from the group consisting of A pharmaceutical composition comprising a compound according to claim 4, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. Use of a compound according to claim 1 selected from the group consisting of Use of a compound according to claim 1 selected from the group consisting of Use of a compound according to claim 1 selected from the group consisting of 4-chloro-3- (trifluoromethyl) phenyl ureas: ^N - (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea, And ^C (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N - (4-chloro-3- (trifluoromethyl) phenyl) - N - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea and A ^I - (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- ^{(N-methylcarbamoyl)} -4-pyridyloxy) phenyl) urea; Use of a compound according to claim 4 selected from the group consisting of A ^/ - (4-chloro-3- (trifluoromethyl) phenyl) ^-N '- (4- (2- ^{(A-methylcarbamoyl)} -4-pyridyloxy) phenyl) Urea / N- (4-chloro-3 - (trifluoromethyl) phenyl) - N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N - (4-chloro-3- (trifluoromethyl) phenyl} -7' - (2-chloro) -4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl urea, ^N - (4-bromo-3- (trifluoromethyl) phenyl) - / V '- (4- (2- ^(L methylcarbamoyl) -4-pyridyloxyjfěnyl) urea N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N- (4- (2- (N-methylcarbamoyl) -4-pyridyl20 oxy) phenyl) urea, and Y- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) - / V - (2-chloro-4- (2- (methylcarbamoyl ^s) (4pyridyloxy)) phenyl) urea 25, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating raf kinase mediated cancerous cell growth. 10 N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4pyridyloxy) phenyl) urea, and N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer cell growth mediated by rafkinase. Use of a compound according to claim 4 selected from the group consisting of 30 7V- (4-chloro-3- (trifluoromethyl) phenyl) - / V '- (4- (2- ^(L methylcarbamoyl) -4-pyridyloxy) phenyl) Urea / N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, 35- N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N - (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) - N - (4- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea, and N - (2-methoxy-4- chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (445 pyridyloxy)) phenyl) urea or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of (i) lung, pancreatic, thyroid, bladder, colon cancer, (ii) myeloid leukemia, or (iii) villous colon adenoma. -67EN 299125 B6 Use of a compound according to claim 4 selected from the group consisting of 2V- (4-chloro-3- (trifluoromethyl) phenyl) -N ^' - (4- (2 - (/ V-methylcarbamoyl) -4-pyridyloxy) phenyl) Urea 5, / V- (4-chloro-3 - (trifluoromethyl) phenyl} -2 '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) - N' (2-chloro-4) - (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl phenyl urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, A compound according to claim 1 which is N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-pyridyloxy) phenyl) urea. The compound of claim 1 which is N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (2-methylcarbamoyl) -4-pyridyloxy) phenyl) urea. 15. A pharmaceutical composition comprising N- (4-chloro-3- (tri30 fluoromethyl) phenyl) -N- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable salt thereof and physiologically acceptable salts thereof. an acceptable carrier. 15 N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4pyridyloxy) phenyl) urea, and N- (2-methoxy- 4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N'-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of tumors . (Iii) a villous colon adenoma. 15 (a) basic salts of organic and inorganic acids selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, trifluorosulfonic, benzenesulfonic, β-toluenesulfonic (tosylate salt), 1-naphthalenesulfonic, 2-naphthalenesulfonic, acetic, trifluoroacetic , malic, tartaric, citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic and mandelic acids; and b) acidic salts of organic and inorganic bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cation, ammonium cations substituted with an aliphatic moiety and ammonium cations substituted with an aromatic moiety. 15 N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N' - methylcarbamoyl) (4-pyridyloxy)) phenyl urea; A pharmaceutical composition comprising N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea or a urea thereof A pharmaceutically acceptable salt and a physiologically acceptable carrier. Use of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer growth cells mediated by raf kinase. Use of N - (4-chloro-3- (trifluoromethyl) phenyl) - N - (4- (2 - (N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer cell growth mediated by raf kinase.