BG65945B1 - Carboxyaryl substituted diphenil ureas as raf kinase inhibitors - Google Patents

Abstract

The invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.

Description

Technical field

The use of a group of aryl ureas in the treatment of RAF mediated diseases and to pharmaceutical compositions for use in 10 such treatments is disclosed.

BACKGROUND OF THE INVENTION

The p2l ^ras oncogene is one that mainly contributes to the development and progression of human solid cancers and mutates in 30% of all human cancers (Bolton et al. Ann. Rep. Med. Chem. 1994,29,16574; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, non-mutated form, the ras protein is a key element of the signal transduction cascade targeted by growth factor receptors in almost all tissues (Avruch et al. Trends Biochem. Sci. 1994, 19, 279-83). From a biochemical point of view, ras is a guanine nucleotide binding protein, and the cycle closure between GTP bond in activated form and resting GTP bond is strictly controlled by endogenous GTPase activity of ras, and 30 other regulatory proteins. In cancer mutants in cancer cells, endogenous GTPase activity is attenuated and therefore, the protein sends constitutive growth signals such as the raf 35 kinase enzyme to the effectors along the chain. This leads to malignant growth of the cells carrying these mutants (Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). It has been shown that by inhibiting the effect of active ras by inhibiting the signaling pathway of raf 40 kinase by administering inactivating antibodies to raf kinase, or by co-expressing a dominant negative raf kinase, or a dominant negative MEK, the substrate of the raf kinase results in the reverse development of transformed cells to a normal growth phenotype, (see: Daum et al. Trends Biochem. Sci. 1994, 19, 474-80); Frigman et al. J. Biol. Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 42628) further showed that inhibition of 50 raf expression by antisense RNA blocks cell proliferation in membrane-bound oncogenes. Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) was compared in vitro and in vivo with inhibition of the growth of different types of human tumors (Monia et al., Nat. Med. 1996, 2, 668-75).

SUMMARY OF THE INVENTION

The present invention provides compounds that are inhibitors of the raf kinase enzyme. Since the enzyme is a downstream p21 ras effector, the inhibitors are used in pharmaceutical compositions used in humans and for veterinary use when inhibition of the raf kinase pathway is indicated, i.e., in the treatment of tumors and / or malignancy cell growth mediated by raf kinase. In particular, the compounds are used in the treatment of solid cancers in humans and animals, for example, murine carcinoma, since the progression of these cancers depends on the signal transduction cascade of the ras protein, and is therefore sensitive to treatment by interrupting the cascade, i.e. , by inhibiting raf kinase. Accordingly, the compounds of the invention are used in the treatment of cancers, including solid cancers, such as, for example, carcinomas (e.g., lungs, pancreas, thyroid gland, bladder, or colon), myeloid diseases (e.g., myeloid leukemia), or adenomas (e.g., fibrous colon adenoma).

Therefore, the present invention provides the use of a compound of formula I:

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

D is -NH-C (O) -NHA is a substituted moiety of up to 40 carbon atoms of the formula:

-L- (M-L ') _q , where L is a substituted or unsubstituted phenyl or pyridyl moiety linked directly to D, L ¹ contains a substituted phenyl or pyridyl moiety, M is a moiety group

65945 Bl is a bond having at least one atom, q is an integer in the order of 1-3 and

B is a substituted or unsubstituted phenyl group bonded directly to D, where L ¹ is substituted by -C (O) R _x ,

R is NR R. and R and R are independently x adab hydrogen, part of a carbon base of up to 30 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen , hydroxy and carbon-based substituents of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen;

wherein substituents for B and L and additional substituents for L ¹ are selected from the group consisting of N-C alkyl to perhalo substituted C, -C ₁₀ alkyl, CN, OH, halogen, C -C alkoxy and up to per-halo substituted C C ₁ -C ₁₀ alkoxy and wherein M is a bridging group selected from the group consisting of -O- or -S-;

for the manufacture of a medicament for the treatment of malignant cell growth mediated by raf kinase.

Suitable alkyl groups and portions of alkyl groups, for example, alkoxy, etc., fully include methyl, ethyl, propyl, butyl, etc., including all straight and branched chain isomers such as isopropyl, isobutyl, sec -butyl, tert-butyl, etc.

Suitable halogen groups include F, Cl, Br and / or I, from one to displacement (i.e., all H atoms in the group substituted by a halogen atom) are possible when the alkyl group is substituted by halogen, mixed substitution with halogen species atoms are also possible in a given part.

The present invention is also directed to the use of pharmaceutically acceptable salts of formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2 naphthalenesulfonic acid, acetic acid and acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and almond acid. In addition, pharmaceutically acceptable salts include acidic salts of inorganic bases, such as salts containing alkali cations (e.g., Li +, Na + or K +), alkaline earth cations (e.g., Mg + ² , Ca + ² , or Ba + ² ), ammonium cation as well as acidic salts of organic bases, including aliphatic and aromatic substituted ammonium radicals, and quaternary ammonium cations, such as those resulting from the protonation or peralkylation of triethylamine, Ν,, diethylamine, Ν, Ν-dicyclohexylamine, pyrrolidinylamine, , Ν, Ν-dimethylaminopyridine (OMAR), 1,4-diazabicyclo [2.2.2] ca. ene (DABCO), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0.] undec-7-ene (DBU).

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

Basic methods of production

The compounds of formula I can be prepared; using known chemical reactions and methodologies, some of the starting materials that are commercially available. However, the basic preparation methods are shown below to assist those skilled in the art in synthesizing these compounds, with detailed examples shown in the experimental section that follows.

Substituted anilines can be prepared using standard methods (March. Advanced Organic Chemistry, 3 ^{rth Ed .; John Wiley: New York} ( 1985). Comprehnsive Organic Transformation; VCH Publishers : New York ( 1989)). As shown in Scheme I, aryl amines are typically synthesized by reducing nitroaryls using metal catalysts such as Ni, Pd or Pt, and H ₂ , or a hydride transfer agent such as formate, cyclohexadiene, or borohydride

65945 Bl (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls can also be reduced directly using a strong hydride source, such as LiAlH ₄ (Seyden-Penne. Reduction by the Aluminum and 5 Borohydrides in Organic Synthesis; VCH Publisher: New York (1991)), or using zero metal valence, such as Fe, Sn or Ca, often in an acidic medium. There are many methods for synthesizing nitroaryl (March. Advanced 10 Organic Chemistry, 3rd ^{ed .} ; John Wiley: New York (1985). Larock. Comprehnsive Organic Transformation; VCH Publishers: New York (1989))

H ₂ / © catalyst / (eg.Ni, Pd, Pt) \ ^

ArNO ₂ ------------- ► ArNH ₂ \ M (0) S (eg Fe, Sn, Ca)

Scheme I. Reduction of nitroaryl to aryl amines

Typically, nitroaryl is obtained by electrophilic aromatic nitration using 25 HNO ₃ or an alternative source of NO ₂ . Nitroaryls can be further fabricated prior to reduction. Thus, nitroaryl substituted with

HNO3 30

Ar-H ----------------- ► ArNOj potential leaving groups (e.g., F, Cl, Br, etc.) may undergo substitution reactions when treated with nucleophiles, such as thiolate (exemplified in Scheme II) or 5 phenoxide. Nitroaryls can also undergo Ullman-type coupling reactions (Scheme II).

ArSH basis

Br-Ar ^ base c

Scheme II. Selected nucleophilic aromatic substitution using nitroaryl

Nitroaryls can also undergo transient metal-mediated cross-linking reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodine di, or triflates, undergo palladium-mediated crosslinking reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reactions, shown below by example), Stille reactions) or aryl zinc (Negishi reaction), allowing the production of biaryl (5).

ArBCOR'h -------->. .- Pd (O).

Ο ₂ Ν _χ (Ar R ''

Ο ₂ Ν _χ <

Both nitroaryl and anilines can be converted to the corresponding arerenesulfonyl chloride (7) by treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source such as KF then enables the production of sulfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source such as tris (dimethylamino) sulfonium difluorotrimethylsiliconate (TASF) results in the corresponding trifluoromethylsulfone (9). Alternatively, the sulfonyl chloride 7 may be reduced to the areention (10), for example with zinc amalgam. Reaction of thiol 10 with CHC1F ₂ in the presence of a base gives trifluoromethyl mercaptan (11), which can be oxidized to the sulfone (12) by any of a variety of oxidizers, including CrO ₃ -acetic anhydride (Sedova et al. Zh. Org. Khim. 1970, 6; (568)).

(Me ₂ N) jS Me ₃ SiF ₂ Me ₃ SiCF ₃

CHCIFj ^ basis. h

65945 Bl

Scheme III. Selected methods for the synthesis of fluorinated aryl sulfone

As shown in Scheme IV, asymmetric urea formation may involve the interaction of aryl isocyanate (14) with aryl amine (13). The heteroaryl isocyanate may be synthesized from heteroaryl amine by treatment with a phosgene or phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene), or Ν, Ν'carbonyldiimidazoimidazo. Isocyanate can also be obtained from a heterocyclic carboxylic acid derivative such as an ester, acid halide or anhydride by Curtius-type rearrangement. Thus, reaction of an acidic derivative 16 with an azide source followed by rearrangement enables the production of isocyanate. The corresponding carboxylic acid (17) may also be Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent.

Ar ¹ —NHj 13

I soa _a . HjN-Ar ² 9

Ar ¹ —NCO ►

Oh Oh

Ar ^1X ^ X Ar ^1x ^ OH

1617

Scheme IV. Selected methods of asymmetric urea formation

Finally, ureas can also be obtained further using methods known to those skilled in the art.

The invention also includes pharmaceutical compositions comprising a compound of formula I as described above and a pharmaceutically acceptable carrier.

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

Formulations intended for oral administration may also be prepared according to any suitable method known in the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents to enhance the taste of the compositions. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients 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 and disintegrating agents, for example, corn starch or alginic acid; and binders, for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques to delay the disintegration and adsorption in the gastrointestinal tract and thus provide a delayed action over a longer period of time. For example, a delayed-action material such as glyceryl monostearate or glyceryl distearate may be used. These compounds can also be prepared in solid, fast release form.

Dosage forms for oral administration can also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium, for example, peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials mixed with excipients suitable for the manufacture of aqueous suspensions. Such inert fillers are suspending

65945 B1 agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth resin and acacia resin; dispersing or wetting agents may be naturally occurring phosphatides, for example, lecithin, or condensation products, or fatty acid alkali oxide, for example, polyoxyethylene stearate, or condensation products, of ethylene oxide with long chain aliphatic alcohols, e.g. , or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters, and derived from fatty acids and hexitol anhydride, for example, polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl or η-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersion powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example, by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present. The compounds may also be in the form of non-aqueous liquid dosage forms, for example, oily suspensions, which may be prepared by suspending the active ingredients in vegetable oil, for example, peanut oil, olive oil, sesame oil, or peanut oil, or in mineral oils. , such as liquid paraffin. Oily suspensions may contain thickening agents, for example beeswax, solid paraffin, or cetyl alcohol. Sweeteners such as those mentioned above and flavoring agents may be added to provide delicious oral compositions. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the form of oil-water emulsions. The oily phase may be a vegetable oil, for example, olive oil, or peanut oil, or a mineral oil, for example, liquid paraffin, or mixtures thereof. Suitable emulsifying agents may be natural resins, for example, acacia resin or tragacanth resin, natural phosphatides, e.g., soybean, lecithin, and esters, or partial esters derived from fatty acids and hexitol anhydrides, e.g., sorbitan monooleate and condensation products said ethylene oxide partial esters, for example, polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs can be prepared with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Some dosage forms may also contain agents that reduce irritation, preservatives and taste enhancers.

The compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperature but liquid at rectal temperature and is therefore melted into the rectum to release the drug. Such products include coconut oil and polyethylene glycols.

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

65945 Bl total body weight.

It should be noted by those skilled in the art that the specific method of administration depends on various factors, each of which is taken into account by the routine of the attending physician. It should also be noted by those skilled in the art that the specific dosage level for a patient depends on various factors including the specific activity of the compound administered, age, body weight, health, gender, diet, timing and route of administration. , the rate of excretion, etc. It should also be noted by one of ordinary skill in the art that the optimal course of treatment, i.e., the method of treatment and the number of doses of the compound of formula I, or a pharmaceutical thereof etc acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.

However, it must be known that the specific dosage level for each patient depends on various factors including the activity of the specific compound being used, age, body weight, general health, gender, diet, timing, route of administration. , and the rate of excretion, the combination of drugs, and the severity of the condition being treated.

The compounds can be obtained from known compounds (or from starting materials, which in turn can be obtained from known compounds), for example, by the general preparation methods shown below. The activity of a compound to inhibit raf kinase can be routinely investigated, for example, according to the procedures described below. The following examples are for illustrative purposes only and are not intended to be construed as limiting the invention in any way.

Examples of carrying out the invention

All reactions were carried out in glass vessels, flame-dried or oven-dried under positive pressure with dry argon or dry nitrogen and stirred with magnetic mud pellets, unless otherwise indicated. Sensitive liquids and solutions are transferred through a syringe or cannula and introduced into the reaction vessels through a rubber barrier. Unless otherwise stated, the term "reduced pressure concentration" refers to the use of a Buchi rotary evaporator at approximately 15.1.332.10 ² Pa (15 mmH). Unless otherwise stated, the term "high vacuum" refers to a vacuum of 0.4-1.0. 1.332.10 ² Ra (0.4-1.0 mmH).

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

Commercial grade reagents and solvents are used without further purification. Ncyclohexyl-No- (methylpolystyrene) carbodiimide is purchased from Calbiochem-Novabiochem Corp. 3-tert-butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-3- (trifluoromethyl) aniline, 4-chloro-3- (trifluoromethyl) aniline, 2-methoxy-5 (trifluoromethyl) aniline, 4-tert- butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-

5- (Trifluoromethyl) aniline, and 4-chloro-3- (trifluoromethyl) phenyl isocyanate were purchased and used without further purification. Syntheses of 3-amino-2-methoxyquinoline (E.Cho. Et al. WO 1998/000402; A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem. 3, 1995, 129), 4- (3carbamoylphenoxy) -1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79,1959, 560; Chem. Abstract 53, 1959,12761 b), 3-tert-butylphenyl isocyanate (Ο. Rohr et al. DE 2,436,108) and 2-methoxy-5 - (Trifluoromethyl) phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70,1967, 491) have been described previously.

Thin layer chromatography (TLC) was performed using Whatman® factory-made silica gel 60A F254 250 micrometer plates. The observation of the plates is carried out by one or more of the following techniques: (a) ultraviolet light, (b) exposure to iodine vapor, (c) immersion of the plate in 10% solution of phosphomolybdic acid in ethanol, followed by heating, (d ) immersing the plate in a solution of cerium sulphate followed by heating, and / or (e) immersing the plate in acidic ethanol solution

65945 Bl thiophene of 2,4-dinitrophenylhydrazine, followed by heating. Column chromatography (flash chromatography) was carried out using 230-400 mesh EM Science ® silica gel.

Melting points (mp) are determined using a ThomasHoover melting point apparatus or Mettler FP66 automatic melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton nuclear magnetic resonance (NMR) spectra (Ή) are measured with a General Electric GNOmega 300 (300 M Hz) spectrometer, or with M e ₄ Si (delta 0.00), or with a residual protonated solution (CHCl ₃ delta 7 , 26; MeOH delta 3.30; DMSO delta 2.49) as standard. Carbon NMR spectra ( ¹³ C) were measured with General Electric GN-Omega 300 (75 MHz) c solvent (CHC1 ₃ delta 77.00; MeOD delta 49.0; DMSO-d ₄ delta 39.5) as standard. Low resolution spectra (MS) and high resolution spectra (HRMS) are obtained either as electron impact (EI) mass spectra or as fast ion atomization (FAB) ionization spectra, electron impact (EI-) spectra MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with Vacumetrics Desorption Chemical Ionisation Probe for sample introduction. The ion source was maintained at 250 ° C. Electron impact ionization is carried out with an electron energy of 70 eV and a trap with a current of 300 microA. Secondary liquid cesium mass spectrometry (FAB - MS), a modern version of fast atom bombardment, was obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI - MS) were obtained using Hewlett Packard MS - Engine (5989A) with methane or ammonia as a gas reagent (1 x 10 · ⁴ 1,332.10 ² Pa (torr) up to 2.5 x 10 ⁴ 1.332.10 ² Ra (torr)). Direct insertion of a chemical ionization desorption probe (DCI) (Vaccumetrics, Inc.) is achieved from 0-1.5 amps in 10 s and maintained at 10 amps until all traces of the sample disappear (~ 1-2 min). The spectra were scanned from 50-800 amu for 2 s per scan. HPLC Electrospray Mass Spectra (HPLC ES - MS) were obtained using a Hewlett Packard 1100 HPLC equipped with a quaternary pump, variable wavelength detector, column C-18, and electrospray ionization spectrometer with Finningan IQ trap Q . The spectra were scanned from 120-800 amu using variable ion time according to the number of ions in the source. Gas Chromatography - Ion Selective Mass Spectra (GC - MS) was obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25 m x 0.2 mm) and with a Hewlett Packard 5971 mass selective detector (ionization energy 70 eV). Elemental analysis was performed by Robertson Microlit Labs, Madison NJ.

All reported NMR spectra of compounds, LRMS and / or elemental analysis, or HRMS are compatible with certain structures.

List of abbreviations and acronyms AsON acetic acid anh anhydrous atm atmosphere (s) BOC tert-butoxycarbonyl CDI 1,1 '-carbonyl diimidazole zones concentrated day (s) Dec degradation DMAC N, N-dimethylacetamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro- 2 (1H) -pyrimidinone DMF N, N-dimethylformamide DMSO dimethyl sulfoxide DPPA diphenylphosphorylamide EDCI 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide EtOAt ethyl acetate EtOH ethanol (100%) Etp diethyl ether Et ₃ N triethylamine Hourly (hourly) HOBT 1-hydroxybenzotriazole m-CPBA 3-chloroperoxybenzoic acid- rope Meon methanol petether petroleum ether (range of foam 30-60 ° C) temp. temperature THF tetrahydrofuran TFA trifluoroAcONE Tf trifluoromethanesulfonyl

A. Basic methods for the synthesis of substituted anilines

65945 Bl

A1. General method for the formation of aryl amine by the formation of ether, followed by saponification of the ester, Curtius rearrangement and deprotection of carbamate.

Synthesis of 2-amino-3-methoxynaphthalene.

Step 1. Methyl-methoxy-2-naphthoate

A suspension of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K ₂ CO, (7.96 g, 57.6 mmol) in DMF (200 ml) was stirred at room temperature for 15 min, then was treated with iodomethane (3.43 ml, 55.1 mmol). The mixture was allowed to stir 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 (0.4.1.332.10 ² Pa (0.4 mmHg) overnight to give methyl 3 methoxy-2-naphthoate as amber yellow oil (10.30 g): NM-NMR (DMSO-d ₆ ) 0 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, 1 = 8.09 Hz, 1H) , 7.44 (5, 1H), 7.53 (app t, 1 = 8.09 Hz, 1H), 7.84 (d, 1 = 8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (5, 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 1N NaOH solution (33.4 ml, 33.4 mmol). The mixture was refluxed 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 hexane, then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%); Ή-NMR (DMSO-d ₆ ) δ 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d, 1 = 8.09 Hz, 1H), 7.91 (d 1 = 8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (brs, 1H).

Step 3. 2- (L- (Carbobenzyloxy) amino-3-methoxynaphthalene

A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et ₃ N (2.59 ml, 18.6 mmol) in anhydrous toluene (70 ml) was stirred at room temperature for 15 min, then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 ml) by pipette. The resulting mixture was heated at 80 ° C for 2 h. 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 column chromatography (14% EtOAc / 86% hexane) to give 2- (L (carbobenzyloxy) amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%): NM-NMR (DMSO-d ₆ ) delta 3.89 (s, 3H) 5.77 (s, 2H) 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H), 8.76 (s, 1H).

Step 4.2-Amino-3-methoxynaphthalene

A suspension of 2- (L- (carbobenzyloxy) amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd / C (0.5 g) in EtOAc (7 ml) was kept under an H atmosphere. ₂ (balloon) at room temperature in pro

65945 Bl overnight. The resulting mixture was filtered through Celite (R) and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder (2.40 g, 85%). Ή NMR (DMSO-d ₆ ) δ 3.86 (s, 3H), 6.86 (s, 2H), 7.04 - 7.16 (m, 2H),

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

A2. Synthesis of omega-carbamyl anilines by formation of carbamylpyridine followed by nucleophilic coupling with aryl amine.

Synthesis of 4- (2-methylmethylcarbamyl-4-pyridyloxy) -aniline

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

Warning: This is an extremely dangerous, potentially explosive reaction. To a stirred solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 ml) at room temperature, concentrated H ₂ SO ₄ (3.55 ml) was added to generate the exotherm. To this mixture was added H, O ₂ (30% by weight in H ₂ O, 17 ml) followed by FeSO ₄ .7H ₂ O (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temperature for 1 hour, then slowly heated for 4 hours to 45 ° C. When the release of bubbles decreases, the reaction is heated at 60 ° C for 16 h. The resulting opaque brown solution was diluted with H ₂ O (700 ml) then 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 collected, dried (MgSO ₄ ), and filtered through a silica gel pad using EtOAc. The brown oil obtained was purified by column chromatography (gradient from 50% EtOAc / 50% hexane to 80% EtOAc / 20% hexane). The yellow oil obtained was crystallized at 0 ° C for 72 h to give 4-chloro-N-methyl-2-pyridine-carboxamide (0.61 g, 5.3%): TLC 50% EtOAc / 50% hexane) R _f 0.50; Ή NMR (CDCl ₃ ) δ 3.04 (d, J = 5, 1 Hz, 3H),

7.43 (dd, J = 5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J = 5.1) Hz, 1H); CI-MS m / z 171 ((M + H) ⁺ ).

Stage lb. Synthesis of 4-chloropyridine-2-carbonyl chloride HCl salt by picolinic acid

Anhydrous DMF (6.0 ml) was slowly added to SOCl ₂ (180 ml) between 40 ° C and 50 ° C. The solution was stirred at this temperature range for 10 min, then picolinic acid (60.0 g, 487 mmol) was added in portions for 30 min. The resulting solution was heated at 72 ° C (rapid SO ₂ separation) for 16 h to give a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 ml. The process of adding / concentrating toluene is repeated twice. The resulting almost dry residue was filtered off and the solid was washed with toluene (2 x 200 ml) and dried under high vacuum for 4 h to give 4-chloropyridine-2-carbonyl chloride HCl salt as a yellow-orange solid (92.0 g, 89%).

About ^α ΥΥ ^ ^0Μβ HCI

Step 2. Synthesis of HCl salt of methyl 4-chloropyridine-2-carboxylate

Anhydrous DMF (10.0 ml) was slowly added to SOCl ₂ (300 ml) at 40-48 ° C. The solution was stirred at these temperature limits for 10 min, then picolinic acid (100 g, 812 mmol) was added for 30 min. The resulting solution was heated at 72 ° C (rapid SO ₂ separation) for 16 h to give a yellow solid. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 ml. The process of toluene addition / concentration was repeated twice. The resulting almost dry residue was filtered off and the solid was washed with toluene (50 ml),

65945 B1 and dried under high vacuum for 4 h to give 4-chloropyridine-2carbonyl chloride HCl salt as a dirty white solid (27.2 g, 16%). This product is saved.

The red filtrate was added to MeOH (200 ml) at a rate that kept the internal temperature below 55 ° C. The contents were stirred at room temperature for 45 min, cooled to 5 ° C and treated with Et ₂ O (200 ml) dropwise. The resulting solids were filtered, washed with Et ₂ O (200 ml) and dried under reduced pressure at 35 ° C to give the HCl salt of methyl 4-chloropyridine-carboxylate as a white solid (110 g, 65 %): m.p. 108-112 ° C; Ή NMR (DMSO - (ζ) delta 3.88 (s, 3H), 7.82 (dd,> 5.5, 2.2 Hz, 1H), 8.08 (d,> 2.2 Hz, 1H), 8.68 (d, > 5.5 Hz, 1H), 10.68 (br s, 1H); HPLC ES - MS m / z 172 ((M + H) ⁺ ).

Stage 3. Synthesis of 4-chloro-L1-methyl-2-pyridinecarboxamide from methyl 4-chloropyridine-2carboxylate

A suspension of methyl 4-chloropyridine-2carboxylate HCl salt (89 g, 428 mmol) in MeOH (75 ml) at 0 ° C was treated with a 2.0 M solution of methylamine in THF (11) at a rate that kept the internal temperature below 5 ° C. The resulting mixture was stored at 3 ° C for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (11) 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-χπορο-Ν-Δβethyl-2-pyridinecarboxamide as pale yellow crystals (71,2 9 , 97%); mp 41-43 ° C; 1 H-NMR (DMSO-d ₆ ) δ 2.81 (s, 3H), 7.74 (dd,> 5.1, 2.2 Hz, 1H), 8.00 (d,> 2.2 Hz) , 1H), 8.61 (d,> 5.1 Hz, 1H), 8.85 (br d, 1H); Cl - MS m / z 171 ((M + H) ⁺ ).

Step 3b. Synthesis of 4-chloro-methyl-2-pyridine-carboxamide from 4-chloropyridine-2-carbonyl chloride

4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in portions to a mixture of 2.0 M methylamine solution in THF (100 ml) and MeOH (20 ml) at 0 ° S. The resulting mixture was stored at 3 ° C for 4 h, then concentrated under reduced pressure. The resulting almost dry solids were suspended in EtOAc (100 ml) and filtered. The filtrate was washed with saturated NaCl solution (2 x 100 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 4-chloro-N-methyl-2-pyridinecarboxamide as a yellow crystalline solid (4.95 g, 88%): m.p. 37-40 ° C.

Step 4. Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anhydrous DMF (150 ml) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at room temperature for 2 h. The contents were treated with 4-chloro-N-methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and K ₂ CO ₃ (6.50 g, 47.0 mmol) and then heated at 80 ° C for 8 h. The mixture was cooled to room temperature and partitioned between EtOAc (500 ml) and saturated NaCl solution (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 h to give 4- (2- (Nmethylcarbamoyl) -4-pyridyloxy) aniline as a light brown solid (17.9 g, 84%) : ΉNMR (DMSO - d ₆ ) delta 2.77 (d,> 4.8 Hz, 3H), 5.17 (br 5.2H), 6.64.6.86 (AA “BB” quartet,> 8 , 4 Hz, 4H), 7.06 (dd,> 5.5, 2.5 Hz, 1H), 7.33 (d,> 2.5 Hz, 1H), 8.44 (d,> 5, 5 Hz, 1H), 8.73 (br d, 1H); HPLC ES - MS m / z 244 ((M + H) ⁺ ) ·

A3. General method for the synthesis of anilines by

65945 B1 nucleophilic aromatic attachment followed by 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 at 120 ° C for 45 min, then the clear light yellow mixture was heated at 160 ° C for 2 h. The resulting mixture was kept at 160 ° C and concentrated for 15 ml, then cooled to room temperature and brought to pH 10 with a 1N NaOH solution. The mixture was cooled to 0 ° C and slowly acidified to pH 5 using 1 N HCl solution. The resulting precipitate was collected by filtration and dried under reduced pressure to give 5hydroxyisoindoline-1,3-dione as a pale yellow powder as a product (3.24 g, 72%): Ή NMR (DMSO-d) delta 7, 00-7.03 (m, 2H), 7.56 (d,> 9.3Hz, 1H), (DMSO-d6) 7.00-7.03 (m, 2H), 7.56 (d,> 9.3Hz, 1H).

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

To a stirred precipitate of NaH (1.1 g, 44.9 mmol) in DMF (40 ml) at 0 ° C was added dropwise a solution of 5-hydroxyisoindoline-1,3dione (3.2 g, 19.6 mmol) in DMF (40 ml). The light green mixture was allowed to reach room temperature and stirred for 1 h, then syringe 3-4 portions of 1-fluoro-4-nitrobenzene (2.67 & 18.7 mmol) was added with a syringe. The resulting mixture was heated at 70 ° C overnight, then cooled to room temperature and diluted slowly with water (150 ml) and extracted with EtOAc (2 x 100 ml). The combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure to give 5- (4-nitrophenoxy) isoindoline-1,3dione as a yellow solid (3.3 g, 62%): TLC (30 % EtOAc / 70% hexane) R _f 0.28; Ή NMR (DMSO - d ₆ ) δ 7.32 (d,> 12 Hz, 2H), 7.52 - 7.57 (m, 2H), 7.89 (d,> 7.8 Hz, 1H) , 8.29 (d, J = 9 Hz, 2H),

11.43 (br s, 1H); Cl - MS m / z 285 ((M + H) &lt; ⁺ & gt ^; ), 100%

J-NH O

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 in argon flow until iron powder (0.59 g, 55.9 mmol) was slowly added. This mixture was stirred at room temperature for 72 h, then diluted with water (25 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were dried (MgSO ₄ ), and concentrated under reduced pressure to give 5- (4-aminophenoxy) isoindoline-1,3-dione as a brownish solid (0.4 g, 75%); TLC (50% EtOAc / 50% hexane) R _f 0.27; Ή NMR (DMSO - d ₆ ) delta 5.14 (br s, 2H), 6.62, (d, J = 8.7 Hz, 2H), 6.84 (d,> 8.7 Hz, 2H) , 7.03 (d,> 2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d,> 8.4 Hz, 1H), 11.02 (s, 1H); HPLC ES - MS m / z 255 ((M + H) ⁺ , 100%).

A4. General method for the synthesis of pyrrolylanilines.

Synthesis of 5-tert-butyl-2- (2,5-dimethyl-

Step 1. Synthesis of 1- (4-tert-butyl-2nitrophenyl) -2,5-dimethylpyrrole

To a stirred solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 ml) was added AcOH (0.1 ml) and acetonylacetone (0.299 g, 2.63 mmol) by syringe . The reaction mixture was heated at 120 ° C for 72 h with azeotropic removal of the volatile products. Received

The 65945 B1 mixture was cooled to room temperature, diluted with H ₂ Cl ₂ (10 ml) and immediately washed with 1 N HCl solution (15 ml), 1 N NaOH solution (15 ml) and saturated solution. of NaCl (15 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The resulting orange-brown solid was purified by column chromatography (60 g SiO ₂ ; gradient from 6% EtOAc / 94% hexane to 25% EtOAc / 75% hexane) to give 1- (4-tert-butyl-2nitrophenyl) -2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%); TLC (15%) EtOAc / 85% hexane) R _f 0.67; 1 H-NMR- (CDCl ₃ ) d 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); Cl - MS m / z 273 ((M + H) ⁺ , 50%).

NH?

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

A suspension of 1- (4-tert-butyl-2-nitrophenyl) -2,5-dimethylpyrrole (0,341 g, 1.25 mmol), 10% Pd / C (0.056 g) in EtOAc (50 ml) under an atmosphere of H ₂ (balloon) was stirred for 72 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give 5-tert-butyl-2- (2,5-dimethylpyrrolyl) -aniline as a yellowish solid (0.30 g, 90%) TLC (10% EtOAc / 90% hexane) R _f 0.43; Ή-NMR (CDCl ₃ ) δ 1.28 (s, 9H), 1.87 - 1.91 (m, 8H), 5.85 (br s, 2H), 6.73 6.96 (m, 3H) ), 7.28 (br s, 2H).

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

Synthesis of the HCl salt of 4- (2- (1-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline

A solution of 4-amino-3-methylphenol (5.45 g,

44.25 mmol) in dry dimethylacetamide (75 ml) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol), and the black mixture was stirred at room temperature until the flask reached room temperature. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, step 3b; 7.52 g, 44.2 mmol) and heated at 110 ° C for 8 h. The mixture was 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 was then treated with HCl (1 M in Et ₂ O; 100 ml) and stirred at room temperature for 5 min. The residual dark pink solid (7.04 g, 24.1 mmol) was separated by filtration from the solution and stored under anaerobic conditions at 0 ° C before use: NM NMR (DMSO-d _s ) delta 2.41 ( s, 3H), 2.78 (d, J = 4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, 1 = 8.5, 2.6 Hz, 1H) , 7.23 (dd, J = 5.5, 2.6 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 5.9 Hz, 1H), 8.99 (q, J = 4.8 Hz, 1H) .

A6. General method for the synthesis of anilines from hydroxyanilines by N-protection, nucleophilic aromatic substitution and deprotection.

Synthesis of 4- (2- (1-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline

Step 1. Synthesis of 3-chloro-4- (2,2,2-trifluoroacetyl-amino) phenol

Iron (3.24 g, 58.00 mmol) was added to stirred TFA (200 ml). To this suspension was added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol), and trifluoroacetic anhydride (20 ml). This gray suspension was stirred at room temperature for 6 days. The iron was filtered off from the solution and the remaining product was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 ml). To the resulting yellow solution was added a saturated solution of NaHCO ₃ (50 ml). The solid product which precipitates in the solution is removed. The filtrate was slowly quenched once

65945 B1 sodium bicarbonate product until the product is visibly separated from the solution (use a small laboratory vessel). The slightly cloudy yellow solution was extracted with EtOAc (3 X 125 ml). The combined organic layers were washed with saturated HaNaCl solution (125 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. ΉNMR (DMSO-d ₆ ) shows a ratio of 1: 1 of the starting product nitrophenol and the expected product 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol. The crude product was taken to the next step without further purification.

Oh

0 ιίτ V ^ T'NHMe J1 FjC ^ N ' JU and N. Cl Stage 2. Synthesis of 4- (2- (E-methylcar-

bamoyl) -4-pyridyloxy) -2-chlorophenyl (2,2,2trifluoro) acetamide

A solution of crude 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 ml) was treated with potassium tert-butoxide (5.16 g, 45.98 mmol), and the brownish black mixture was stirred at room temperature until the flask was cooled to room temperature. The resulting mixture was treated with 4-chloro-14-methyl-2-pyridinecarboxamide (Method A2, step 3b; 1.99 g, 11.7 mmol) and heated at 100 ° C under argon for 4 h. . The black reaction mixture was cooled to room temperature and then poured into cold water (100 ml). The mixture was extracted with EtOAc (3 x 75 ml) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by column chromatography (gradient from 20% EtOAc / petroleum ether to 40% EtOAc / petroleum ether) to give 4- (2- (T4-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl ( 2,2,2-Trifluoro) acetamide as a yellow solid (8.59 g, 23.0 mmol).

Ο

Step 3. Synthesis of 4- (2- (1M-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline

A solution of crude 4- (2- (L-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl (8.59 g, 23.0 mmol) in dry 4-dioxane (20 ml) was treated with a 1 N solution of NaOH (20 ml). This brown solution was stirred for 8 h. EtOAc (40 ml) was added to this solution. The green organic layer was extracted with EtOAc (3 x 40 ml) and the solvent was concentrated to give 4- (2- (L-methylcarbamoyl) -4-pyridyloxy) 2-chloroaniline as a green solidifying oil. (2.86 g, 10.30 mmol): NM-NMR (DMSO-d ₆ ) δ 2.77 (d,> 4.8 Hz, 3H), 5.51 (s, 2H), 6.60 ( dd,> 8.5, 2.6 Hz, 1H), 6.76 (d,> 2.6 Hz, 1H), 7.03 (d,> 8.5 Hz, 1H), 7.07 (dd ,> 5.5, 2.6 Hz, 1H), 7.27 (d,> 2.6 Hz, 1H), 8.46 (d,> 5.5 Hz, 1H), 8.75 (q, > 4.8 Hz, 1H).

A7. A common method of deprotecting acylated aniline.

Synthesis of 4-chloro-2-methoxy-5- (triflu-

oromethyl) -aniline CF ₃ C1 _h Λ OMe

A suspension of 3-chloro-6- (N-acetyl) -4 (trifluoromethyl) anisole (4.00 g, 14.95 mmol) in 6M HCl (24 ml) was heated at reflux for 1 h. The resulting solution was allowed to cool to room temperature, during which time it slightly solidified. The resulting mixture was diluted with water (20 ml), then treated with a combination of solid NaOH and saturated NaHCO ₃ solution until the solution became basic. The organic layer was extracted with CH ₂ Cl ₂ (3 x 50 ml). The combined organic products 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, 14.95 mmol): NMR (DMSO - d ₆₎ delta 3,84 (s, H), 5,30 (s, 2H) , 7,01 (s, 2H).

A8. General method for the synthesis of omega-alkoxy-omega-carboxyphenyl anilines.

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

Oh

Step 1.4- (3-Methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene

65945 Bl

To a solution of 4- (3-carboxy-4-hydroxyphenoxy) -1-nitrobenzene (obtained from 2,5-dihydroxybenzoic acid in a manner analogous to that described in method A13, step 1.12 mmol) in acetone (50 ml) K ₂ CO ₃ (5 g) and dimethyl sulfate (3.5 ml) were added. The resulting mixture was heated at reflux overnight, then cooled to room temperature and filtered through a pad of Celite®. The resulting solution was concentrated under reduced pressure, absorbed in SiO ₂ and purified by column chromatography (50% EtOAc / 50% hexane) to give 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1 nitrobenzene as yellow dust (39): m.p. 115-118 ° C.

Oh

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

A mixture of 4- (3-methoxycarbonyl-4methoxyphenoxy) -1-nitrobenzene (1.2 g), KOH (0.33 g), and water (5 ml) in MeOH (45 ml) was stirred at room temperature for 2 h. overnight and then heated at reflux for 4 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50 ml), and the aqueous mixture was acidified with 1N HCl solution. The resulting mixture was extracted with EtOAc (50 ml). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to give 4- (3-carboxy-4methoxyphenoxy) -1-nitrobenzene (1.04 g).

ΧΤ ° ^ΧΧ ^ ^ΝΗΜβ

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

To a solution of 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (0.50 g, 1.75 mmol) in CH ₂ Cl ₂ (12 ml) was added portionwise SOCl ₂ (0.64 ml, 8, 77 mmol). The resulting solution was heated at reflux for 18 h, cooled to room temperature and concentrated under reduced pressure. The yellow solids obtained were dissolved in CH ₂ Cl ₂ (3 ml), then the resulting solution was treated with a solution of methylamine (2.0 M in THF, 3.5 ml, 7.02 mmol) in portions (Attention: separation gas) and stirred at room temperature overnight for 4 h. The resulting mixture was treated with a 1N NaOH solution, then extracted with CH, Cl ₂ (25 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 4- (3- (N-Methyl-carbamoyl) -4-methoxyphenoxy) -1-nitrobenzene as a yellow solid (0.50 g, 95).

Step 4.4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline

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

A9. General method for the preparation of omegaalkylphthalimide containing anilines.

Synthesis of 5- (4-aminophenoxy) -2-methyl-

zoindoline-1,3-dione L 11 1 1 N-Me 0

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

A suspension of 5- (4-nitrophenoxy) isoindoline-1,3-dione (AZ step 2; (1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 ml ) was stirred at room temperature for 1 h, then treated with methyl iodide (0.3 ml, 4.57 mmol). The resulting mixture was stirred at room temperature overnight, then cooled to 0 °. C and treated with water (15 ml) .The resulting solids were collected and dried under reduced pressure.

65945 B1 pressure to give 5- (4-nitrophenoxy) 2-methylisoindoline-1,3-dione as a light yellow solid (0.87 g, 83%); TLC (35% EtOAc / 65% hexane) R _f 0.61.

Ο

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

A suspension of nitrophenoxy-2-methylisoindoline-1,3-dione (0.87 g, 2.78 mmol) and 10% Pd / C (0.10 g) in MeOH was stirred at 1 at H ₂ (balloon), in overnight. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The yellow solids obtained were dissolved in EtOAc (3 ml) and filtered through SiO ₂ (60% EtOAc 140% hexane) to give 5- (4-aminophenoxy) 2-methyl-isoindoline-1,3-dione, as yellow solid (0.67 g, 86%); TLC (40% EtOAc / 60% hexane) R _f 0.27.

A10. General Method for the Preparation of Omega Carbamoyl Anilines by Interaction of Omega-Alkoxycarbonyl Precursors with Amines.

Synthesis of 4- (2- (N (2-morpholin-4-ylethyl) carbamoyl) -pyridyloxyaniline

h ₂ n

Step 2. Synthesis of 4- (2- (N- (2-morpholin4-ylethyl) carbamoyl) pyridyloxy) aniline.

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75 mol) in DMF (8 ml) was stirred at room temperature for 2 h after this was subsequently treated with 4-chloro-2- (19- (2-morpholin-4-ylethyl) carbamoyl) pyridine (1.22 g, 4.52 mmol) and K ₂ CO ₃ (0.31 g, 2 , 26 mmol). The resulting mixture was heated at 75 ° C overnight, cooled to room temperature and partitioned between EtOAc (25 ml) and saturated NaCl 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 brown solids obtained were purified by column chromatography (58 g; gradient from 100% EtOAc to 25% MeOH / 75% EtOAc) to give 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl ) pyridyloxy) aniline (1.0 g, 65%): TLC (10% MeOH / 90% EtOAc) R _f 0.32.

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

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

To a solution of the HCl salt of methyl 4-chloro- ^3,5- pyridine-2-carboxylate (Method A2, step 2; (1.01 g, 4.86 mmol) in THF (20 ml) was added dropwise 4- (2 -Aminoethyl) morpholine (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 The resulting mixture was extracted with EtOAc (50 ml), the organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to give -4- 5 or 4-chloro-2- (N- (2-morpholine) -4-ylethyl) carbamoyl) -pyridine as a yellow oil (1.25 g, 95%); TLC (10% MeOH / 90% EtOAc) R _f 0.50.

A suspension of 4- (3-carboxyphenoxy) -1nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd / C (0.05 g) in MeOH (120 ml) was stirred under an H ₂ atmosphere (balloon) for 2 days. The resulting mixture was filtered through a pad of Celite®, then concentrated under reduced pressure to give 4- (3-carboxyphenoxy) aniline as a brown solid (2.26 g, 48%): TLC (10% MeOH / 90% CIS) R _f 0.44 (in strips).

A12. General method for the synthesis of anilines containing isoindolinone.

Synthesis of 4- (1-oxoisoindolin-5-yloxy) aniline

Oh

65945 Bl

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

To a solution of 5-hydroxyfgalimide (19.8 g, 121 mmol) in AcOH (500 ml) was slowly added portionwise zinc powder (47.6 g, 729 mmol), then the mixture was heated at reflux temperature. refrigerate for 40 min, filter while hot and concentrate under reduced pressure. The reaction was repeated in the same scheme and the collected oil residue was purified by column chromatography (1.1 Kg SiO ₂ ; gradient from 60% EtOAc / 40% hexane to 25% MeOH / 75% EtOAc) to give 5-hydroxyisoindoline- 1-one (3.77 g): TLC (100% EtOAc) R _f 0.17; HPLC ES - MS m / z 250 ((M + H) ⁺ ) ·

Step 2. Synthesis of 4- (1-isoindolinone-5yloxy) -1-nitrobenzene

To a suspension of NaH (0.39 g, 16.1 mmol) in DMF at 0 ° C was added portions of 5-hydroxyisoindolin-1-one (2 g, 13.4 mmol). The resulting suspension was allowed to warm to room temperature and stirred for 45 min, then 4-fluoro-1-nitrobenzene was added, and then the mixture was heated to 70 ° C for 3 h. The mixture was cooled to 0 ° C and treated dropwise with water until a precipitate formed. The solids obtained were collected to give 4- (1-isoindolinone-5-yloxy) -1nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc): R _f 0.35 .

Ο

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

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

A13. General method for the synthesis of omega-car bamoyl anilines by the formation of EDCl-mediated amide, followed by reduction of nitroarene.

Synthesis of 4- (3-methylmethylcarbamoylphenoxy-

Step 1. Synthesis of 4- (3-ethoxycarbonylethoxy) -1 -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 refluxed overnight, cooled to room temperature and treated with water (250 ml). The resulting mixture was extracted with EtOAc (3 x 150 ml). The combined organic phases were washed sequentially with water (3 x 100 ml) and saturated NaCl solution (2 x 100 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc / 90% hexane) to give 4- (3-ethoxycarbonylphenoxy) -1-1 nitrobenzene as an oil (38 g).

Fr.

Step 2. Synthesis of 4- (3-carboxyphenoxy) 1-nitrobenzene

To a vigorously stirred mixture of 4- (3ethoxycarbonylphenoxy) -1 -1-nitrobenzene (5.14 g, 17.9 mmol) in 3: 1 THF / aqueous solution (75 ml) was added a solution of LiOH H ₂ O (150 g , 35.8 mmol) in water (36 ml). The resulting mixture was heated to 50 ° C overnight, then cooled to room temperature, concentrated under reduced pressure and adjusted to pH 2 with 1M HCl solution. The brownish-yellow solid obtained was separated by filtration and washed with hexane to give 4- (3carboxyphenoxy) -1-nitro-benzene (4,409.95%).

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

Mixture of 4- (3-carboxyphenoxy) -1-nitrobenzene (3.72 g, 14.4 mmol), EDC1-HCl (3.63 g,

65945 Bl

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 O ₂ (45 ml) was stirred at room temperature. temperature for 3 days, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 ml) and the resulting mixture 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- (1-methylcarbamoyl) phenoxy) -1-nitrobenzene , as an oil (1.89 g)

Oh

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

A suspension 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 H ₂ atmosphere (balloon). overnight. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH / 95% CH ₂ Cl ₂ ). The resulting oil was cured in vacuo overnight to give 4- (3- (L-methylcarbamoyl) phenoxy) aniline as a yellow solid (0.95 g, 56%).

A14. General Method for the Synthesis of Omega-Carbamoyl Anilines by Formation of EDCl-Mediated Amide, followed by Nitroarene Reduction.

Synthesis of 4-3- (5-methylcarbamoyl) pyridyloxy) aniline o

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

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

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

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

A15. Synthesis of aniline by electrophilic nitration followed by reduction.

Synthesis of 4- (3-H-methylcarbamoylphenoxy) aniline

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

To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 ml) at 0 ° C was added methylamine (2.0 M in THF; 28 ml, 56 mmol). The resulting solution was allowed to warm to room temperature overnight. The resulting mixture was partitioned between EtOAc (25 ml) and 1 M HCl solution (25 ml). The aqueous phase was re-extracted with EtOAc (2 x 25 ml). The combined organic phases were washed sequentially with water (2 x 25 ml), saturated NaCl solution (25 mL), dried (MgSO ₄ ) and concentrated under reduced pressure to give N-methyl-3-bromobenzenesulfonamide as

65945 B1 white solid (2.8 g, 99%).

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

To a suspension of phenol (1.9 g, 20 mmol), K ₂ CO ₃ (6.0 g, 40 mmol) and Cui (4 g, 20 mmol) in THF (25 ml) were added N-methyl-3- bromobenzenesulfonamide (2.5 g, 10 mmol), and the resulting mixture was stirred at reflux overnight, cooled to room temperature, and partitioned between EtOAc (50 ml) and 1N HCl solution (50 ml). The aqueous layer was re-extracted with EtOAc (2 x 50 ml). The combined organic phases were washed sequentially 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 column chromatography (30% EtOAc / 70% hexane) to give 4- (3- (N-methylsulfamoyl) phenoxy) benzene (0.30 g).

Step 3. Synthesis of 4- (3- (N ^t methylsulfamoyl) phenoxy) -1-nitrobenzene

To a solution of 4- (3- (N-methylsulfamoyl) phenoxy) benzene (0.30 g, 1.14 mmol) in TFA (6 ml) at -10 ° C was added NaNO ₂ (0.097 g, 1.14 mmol). in portions for 5 min. The resulting solution was stirred at -10 ° C for 1 h, then allowed to warm to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (10 ml) and water (10 ml). The organic phase was washed 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) phenoxy). -1-Nitrobenzene (0.20 g). This product is stored for the next step without further purification.

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

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

A16. Modification of omega-ketones.

Synthesis of the HCl salt of 4- (4- (1- (Nmethoxy) iminoethyl) phenoxyaniline).

To a suspension of 4- (4-acetylphenoxy) aniline HCl salt (prepared in a manner analogous to method A 13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 ml) and pyridine (1 , 0 ml) was added O-methylhydroxylamine HCl (0.65 g, 7.78 mmol, 2.0 eq). The resulting solution was heated at reflux for 30 min, cooled to room temperature, and concentrated under reduced pressure. The resulting solids were triturated with water (10 ml) and washed with water to give the (4- (1- (N-methoxy) iminoethyl) phenoxyaniline) 4-HCl salt as a yellow solid (0.85 g ): TLC (50% EtOAc / 50% petroleum ether) R _f 0.78; Ή-NMR (DMSO-d _s ) delta 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MSm / z 257 ((M + H) ⁺ ) ·

A17. Synthesis of N (omega-silyloxyalkyl) amides.

Synthesis of 4- (4- (2-L1- (2-triisopropylsilyloxy) ethyl-carbamoyl) pyridyloxyaniline.

Step L 4-Chloro-No (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide

To a solution of 4-chloro-N (2-hydroxyethyl) pyridine-2-carboxamide, prepared in a manner analogous to method A2, step 3 b; (1.5 g, 7.4 mmol) in anhydrous DMF (7 ml) was added triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 eq) and

65945 B1 imidazole (1.12 g, 16.4 mmol, 2.2 eq). The resulting yellow solution was stirred for 3 h 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-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide as an orange oil (2.32 g, 88%). This product is used in the next step without further purification.

Step 2.4- (4- (2-N (2-triisopropylsilyloxy) ethylcarbamoyl) -pyridyloxyaniline

To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in DMF (8 ml) was added potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 eq) in one portion to give caused an exothermic reaction. When this mixture was cooled to room temperature, a solution of 4-chloro-2 (N- (2-triisopropylyloxy) ethyl) -pyridinecarboxamide (2.32 g, 6 mmol, 1 eq) in DMF (4 ml) was added, and then K ₂ CO ₃ (0.42 g, 3.0 mmol, 0.50 eq) was added. The resulting mixture was heated at 80 ° C overnight. An additional portion of potassium tert-butoxide (0.34 g, 3 mmol, 0.5 eq) was then added, and the mixture was stirred at 80 ° C for a further 4 h. The mixture was cooled to 0 ° C in an ice / water bath, then water (approximately 1 ml) was added dropwise slowly. The organic layer was extracted with EtOAc (3x10 ml). The combined organic layers were washed with saturated NaCl solution (20 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The brown residual oil was purified by column chromatography (SiO ₂ ; 30% EtOAc / 70% petroleum ether) to give 4- (4- (2- (N (2-triisopropyl-silyloxy) ethylcarbamoyl) pyridyloxyaniline) as a clear light brown oil (0.99 g, 38%).

A18. Synthesis of 2-pyridinecarboxylate esters by oxidation of 2-methylpyridines.

Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline

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

A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-nitrobenzene (9.8 g,

91.6 mmol), K2CO3 (25 g, 183 mmol, 2.0 eq) in DMF (100 ml) was heated at reflux overnight. The resulting mixture was cooled to room temperature, treated with water (200 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed successively with water (2 x 100 ml) and saturated NaCl solution (100 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to give 4 (5- (2-methyl) ) pyridyloxy) -1-nitrobenzene as a brown solid (12.3 g).

Fr.

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

A mixture of 4- (5- (2-methylethyl) pyridyloxy) 1-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3 eq), in pyridine, ( 20 ml) is heated at reflux for 5 hours, then cooled to room temperature. The resulting suspension was filtered, then 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 h, 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 sequentially with water (2 x 50 ml) and saturated NaCl solution (50 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ; 50% EtOAc / 50% hexane) to give 4- (5- (2-methoxycarbonyl) pyridyloxy) 1-nitrobenzene (0.70 g).

65945 Bl

Ο

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

A suspension of 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.50 g) and 10% Pd / C (0.050 ml) in a mixture of EtOAc (20 ml) and MeOH (5 ml) was added in an atmosphere of H ₂ (balloon) overnight. The resulting mixture was filtered through a pad of Celite (R), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ; 70% EtOAc / 30% hexane) to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline (0.40 g).

A19. Synthesis of omega-sulfonylphenyl anilines.

Synthesis of 4- (4-methylsulfonylphenoxy) aniline.

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

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

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

4- (4-Methylsulfonylphenoxy) -1-nitrobenzene is reduced to aniline in a manner analogous to that described in method A 18, step 3.

C. Synthesis of urea precursors

B1. General method for the synthesis of anilines isocyanates using CDI.

Synthesis of 4-bromo-3- (trifluoromethyl) phenylisocyanate

Step 1. Synthesis of the HCl salt of 4-bromo-3 (trifluoromethyl) 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 (1M in Et ₂ O; 300 ml), and the resulting mixture was added. stirred at room temperature for 16 h. The resulting pink-white precipitate was filtered off and washed with Et ₂ O (50 ml) to give the HCl salt of 4-bromo-3- (trifluoromethyl) aniline (73 g, 98%).

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

A suspension of the HCl salt of 4-bromo-3- (trifluoromethyl) aniline (36.8 g, 133 mmol) in toluene (278 ml) was treated dropwise with trichloromethyl chloroformate and the resulting mixture was heated at reflux in for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 ml), then concentrated under reduced pressure. The residue was treated with CH ₂ Cl ₂ (500 ml), then concentrated under reduced pressure. Treatment with CH ₂ Cl ₂ / concentration under reduced pressure was repeated and the resulting amber oil was kept at -20 ° C for 16 h to give 4-bromo-3- (trifluoromethyl) phenyl isocyanate as a reddish-brown solid (35.1 g, 86%): GC-MS m / z 265 (M ⁺ ).

C. Methods for urea formation

C1a. General method for the synthesis of ureas by the reaction of isocyanate with aniline.

Synthesis of No. (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (methylmethylcarbamoyl) -4-pyridyloxy) phenyl) urea

A solution of 4-chloro-3- (trifluoromethyl) 21

65 945 Bl phenyl isocyanate (14,60 g, 65,90 mmol) in CH ₂ C1 ₂ (35 ml) was added dropwise to a suspension of (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (Method A2, step 4; 16.0 g, 65.77 mmol) in CH ₂ Cl ₂ (35 ml) at 0 ° C, the resulting mixture was stirred at room temperature for 22 hours. The yellow solid obtained was separated by filtration, then washed with CR, C1 ₂ (2 x 30 ml) and dried under reduced pressure (1.332.10 ² Pa (mm Hg)) to give N- (4-chloro-3- (trifluoromethyl) phenyl N - (4- (2 (L-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as an off-white solid (28.5 g, 93%): mp 207 - 209 ° C; Ή NMR (DMSO d ₆ ) delta 2.77 (d,> 4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d,> 2.5 Hz, 1H), 7.62 (m, 4H) ), 8.11 (d,> 2.5 Hz, 1H), 8.49 (d,> 5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H) , 9.21 (s, 1H); HPLC ES - MS m / z 465 ((M + H) ⁺ ) ·

Clb. General method for the synthesis of ureas by the reaction of isocyanate with aniline.

Synthesis of N- (4-bromo-3- (trifluoromethyl) phenyl) -H '(4- (1- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea.

A solution of 4-bromo-3- (trifluoromethyl) phenyl isocyanate (method B1, step 2; 8.0 g, 30.1 mmol) in CH ₂ Cl ₂ (80 ml) was added dropwise to a solution of (4- ( 2- (L-methylcarbamoyl) -4-pyridyloxy) aniline (Method A2, step 4; 7.0 g, 28.8 mmol) in CH ₂ Cl ₂ (40 ml) at 0 ° C. The resulting mixture was stirred at room temperature. The yellow solids obtained were filtered off, then washed with CH ₂ Cl ₂ (2 x 50 ml) and dried under reduced pressure (1.332.10 ² Pa (mm Hg)) at 40 ° C to give N- (4-bromo-3- (trifluoromethyl) phenyl) -N- (4- (2- (L-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, ca. o a pale yellow solid (13,2 g, 90%); mp 203-205 ° C; Ή - NMR (DMSO - d ₆₎ delta 2,77 (d, J = 4,8 Hz , 3H), 7.16 (m, 3H), 7.37 (d,> 2.5 Hz, 1H), 7.58 (m, 3H), 7.77 (d,> 8.8 Hz, 1H), 8. 11 (d, J = 2.5 Hz, 1H), 8.49 (d,> 5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9. 21 (s, 1H); HPLC ES-MS m / z 509 ((M + H) ⁺ ).

Clc. General method for the synthesis of ureas by the interaction of isocyanate with aniline.

Synthesis of N- (4-χπορο-3 (trifluoromethyl) phenyl) -N (2-methyl-4- (2- (Lmethylcarbamoyl) (4-pyridyloxy)) phenyl) urea

A solution of 2-methyl-4- (2- (TM-methylcarbamoyl) (4-pyridyloxy) aniline isocyanate (method A5; 0.11 g, 0.45 mmol) in CH ₂ Cl ₂ (1 ml) was treated with Et ₃ N (0.16 ml) and 4-chloro-3- (trifluoromethyl) phenyl) isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temperature for 6 h, then treated with water (5 ml). The aqueous layer was re-extracted with EtOAc (3x5 ml). The combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (2-methyl-4- (2- (methylmethylcarbamoyl) (4pyridyloxy) phenyl) urea as a brown oil (0.11 g, 0.22 mmol): Ή-NMR (DMSO-d ₆ ) δ 2.27 (s, 3H), 2.77 (d, > 4.8 Hz, 3H), 7.03 (dd,> 8.5, 2.6 Hz, 1H), 7.11 (d,> 2.9 Hz, 1H), 7.15 (dd,> 5 , 5, 2.6 Hz, 1H), 7.38 (d,> 2.6 Hz, 1H), 7.62 (approximately d,> 2.6 Hz, 2H), 7.84 (d,> 8 , 8 Hz, 1H), 8.17 (s, 1H), 8.50 (d,> 5.5 Hz, 1H), 8.78 (q,> 5.2 Hz, 1H), 9.52 ( s, 1H); HPLC ES - MS m / z 479 ((M + H) ⁺ ) ·

Cid. General method for the synthesis of ureas by the interaction of isocyanate with aniline.

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

To a solution of 4-chloro-3- (trifluoromethyl) phenyl) isocyanate (2.27 g, 10.3 mmol) in CH ₂ Cl ₂ (308 ml) was added p-phenylenediamine (3.32 g, 30.7) at once. mmol). The resulting mixture was stirred at room temperature for 1 h, then treated with CH ₂ Cl ₂ (100 ml) and concentrated under reduced pressure. The pink solids obtained were dissolved in a mixture of EtOAc (3x5 ml) and MeOH (15 ml) and the clear solution was washed with 0.05 N HCl solution. The organic layer was concentrated under reduced pressure to give an impure

65945 Bl

N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (4aminophenyl) urea (3.3 g): TLC (100% EtOAc) R _f 0.72.

Cle. General method for the synthesis of ureas by the interaction of isocyanate with aniline.

Synthesis of 14- (4-chloro-3- (trifluoromethyl) phenyl) -H '(4-ethoxycarbonylphenyl) urea.

To a solution of ethyl 4-isocyanatobenzoate (3.13 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 The resulting suspension was diluted with CH ₂ Cl ₂ (50 ml) and filtered to give N- (4-χπορο3- (trifluoromethyl) phenyl) -N- (4- ethoxycarbonylphenyl) urea as a white solid (5.93 g, 97%): TLC (40% EtOAc 160% hexane) R _f 0.44.

Clf. General method for the synthesis of ureas by the interaction 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 Cl ₂ (8 ml) was added 4- (3-carboxyphenoxy) aniline (method All; 0, 81 g, 5.76 mmol), and the resulting mixture was stirred at room temperature overnight, then treated with MeOH (8 ml) and stirred for an additional 2 h. The resulting mixture was concentrated under reduced pressure. The brown solid obtained was triturated with 1: 1 EtOAc / hexane to give N (4-chloro-3- (trifluoromethyl) -phenyl) -L-3 (trifluoromethyl) phenyl) -N- (3-carboxyphenyl) urea as a dirty white solid (1.21 g, 76%).

C2a. General method for the synthesis of urea by the interaction of aniline with Ν, Ν′-carbonyl diimidazole, followed by the addition of second aniline.

Synthesis of 14- (2-methoxy-5- (trifluoromethyl) phenyl) -N- (4- (2- (14-methylcarbamoyl) -4-pyridyloxy) phenyl) urea.

To a solution of 2-methoxy-5- (trifluoromethyl) aniline (0.15 g) in anhydrous CH ₂ Cl ₂ (15 ml) at 0 ° C was added CDI (0.13 g). The resulting solution was allowed to warm to room temperature for 1 hour, stirred at room temperature for 16 hours, then treated with 4- (2- (N-methylcarbamoyl) 4-pyridyloxy) aniline (O, 18 g). The resulting yellow solution was stirred at room temperature for 72 h, then treated with H ₂ O (125 ml). The resulting aqueous mixture was extracted with EtOAc (2 x 150 ml). The combined organics were washed with saturated NaCl solution (100 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was triturated (90% EtOAc / 10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil was purified by column chromatography (gradient 33% EtOAc / 67% hexane, up to 50% EtOAc / 50% hexane, up to 100% EtOAc) to give N- (2-methoxy- 5 (Trifluoromethyl) phenyl) -N- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.098 g, 30%) as a light red solid: TLC (100% EtOAc) R _f 0, 62; Ή NMR (DMSO d) δ 2.76 (d, J = 4.8 Hz, 3H), 3.96 (s, 3H), 7.1 -

7.6 and 8.4 - 8.6 (m, 1H), 8.75 (d,> 4.8 Hz, 1H), 9.55 (s, 1H); FAB - MS m / z 461 ((M + H) &lt; ⁺ & gt ^; ).

C2b. General method for the synthesis of urea by the interaction of aniline with Ν, Ν′-carbonyl diimidazole, followed by the addition of second aniline. Symmetrical ureas as by-products of the рата'carbonyl diimidazole reaction procedure.

Synthesis of bis (4- (2- (1-methylcarbamoyl) 4-pyridyloxy) phenyl) urea. (The compound is not according to the invention).

65945 Bl

To a stirred solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH ₂ Cl ₂ (15 ml) at 0 ° C was added CDI (0.13 g). The resulting solution was allowed to warm to room temperature for 1 h, then stirred at room temperature for 16 h. The resulting mixture was treated with 4- (2 () N-methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 72 h, then treated with water (125 ml). The resulting aqueous mixture was extracted with EtOAc (2 x 150 ml). The combined organic phases were washed with saturated NaCl solution (100 ml), dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was triturated (90% EtOAc / 10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis (4- (2- (L-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) R _f 0.50; Ή-NMR (DMSO-d ₆ ) δ 2.76 (d, J = 5, 1 Hz, 6H), 3.96 (s, 3H), 7.1 - 7.6 (m, 12H), 8, 48 (d, J = 5.4 Hz, 1H), 8.75 (d, J = 4.8 Hz, 2H), 8.86 (s, 2H), 9.55 (s, 1H); HPLC ES - MS m / z 513 ((M + H) ⁺ ).

C2c. General method for the synthesis of ureas by the interaction of isocyanate with aniline.

Synthesis of N- (2-Methoxy-5- (trifluoromethyl) phenyl-L '(4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea (The compound is not according to the invention).

To a stirred solution of 2-methoxy-5 (trifluoromethyl) phenyl isocyanate (0.10 g, 0.47 mmol) in CH ₂ Cl ₂ (1.5 ml) was added at once 5 (4-aminophenoxy) isoindoline-1,3 -dione (method A3, step 3; 0.12 g, 0.47 mmol). The resulting mixture was stirred for 12 h, then treated with CH ₂ Cl ₂ (10 ml) and MeOH (3 ml). The resulting mixture was washed sequentially with 1N HCl solution (15 ml) and saturated NaCl solution (15 ml), dried (MgSO ₄ ) and concentrated under reduced pressure to give No. (2-methoxy-5- (trifluoromethyl) phenyl) -N (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea as a white solid (0.2 g, 96%): TLC (70% EtOAc / 30% hexane) R _f 0.50; Ή NMR (DMSO-d ₆ ) δ 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J = 9.3 Hz, 2H), 7, 80 (d, J = 8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS m / z 472.0 ((M + H) ⁺ , 100%.

C2d. General method for the synthesis of ureas by the interaction of aniline with Ν, Ν′-carbonyl diimidazole, followed by the addition of second aniline.

Synthesis of N- (5- (tert-butyl) -2- (2,8 dimethylpyrrolyl) phenyl) -N- (4- (2- (L-methylcarbamoyl) -4-pyridyloxy) phenyl) urea. (The compound is not according to the invention)

To a stirred solution of CDI (0.21 g, 1.39 mmol) in CH ₂ Cl ₂ (2 ml) was added at once 5- (tert-butyl) -2- (2,5-dimethyl-pyrrolyl) aniline (method A4, step 2; 0.30 g, 1.24 mmol). The resulting mixture was stirred at room temperature for 4 h, then 4- (2- (L-methyl-carbamoyl) -4-pyridyloxy) aniline (0.065 g, 0.267 mmol) was added at once. The resulting mixture was heated at 36 ° C overnight, then cooled to room temperature and diluted with EtOAc (5 ml). The resulting mixture was washed successively with water (15 ml) and with 1 N HCl solution (15 ml), dried (MgSO ₄ ) and filtered through a pad of silica gel (50 ml) to give No. (5-tert) -butyl) -2- (2,5-dimethylpyrrolyl) phenyl) -N- (4- (2- (N-methylcarbamoyl) -4- (pyridyloxy) phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40 % EtOAc / 60% hexane) R _f 0.24; NMR (acetone - d ₆ ) delta 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), 7.117 (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 m / z 515 ((M + H ⁺ ), 100%).

NW. Combined method for the synthesis of diphenyl ureas using triphosgene.

One of the anilines to be attached was dissolved in dichloroethane (0.10 M). This solution was added to an 8 ml vial (0.5 ml) containing dichloroethane (1 ml). To this was added a solution of bis (trichloromethyl) carbonate

65945 B1 (0.12 M in dichloroethane, 0.2 ml, 0.4 eq), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 ml, 1.2 eq). The vial was closed and heated at 80 ° C for 5 h, then allowed to cool to room temperature for 10 h. Second aniline was added (0.10 M in dichloroethane, 0.5 ml, 1.0 eq), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 ml, 1.2 eq). The resulting mixture was heated at 80 ° C for 4 h, cooled to room temperature and treated with MeOH (0.5 ml). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.

C4. General method for the synthesis of urea by the interaction of aniline with phosgene, followed by the addition of second aniline.

Synthesis of L1- (2-methoxy-5- (trifluoromethyl) phenyl) -N- (4- (2- (L-methylcarbamoyl) -4-pyridyloxy) phenyl) urea.

To a stirred solution of phosgene (1.9 M in toluene; 2.07 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 h, then concentrated under reduced pressure. The resulting solids were treated with anhydrous toluene (20 ml), then with 4- (2- (L-methylcarbamoyl) 4-pyridyloxy) aniline (prepared according to method A2; 0.30 g) and the resulting suspension heated at 80 ° C for 20 h, then allowed to cool to room temperature. The resulting mixture was diluted with water (100 ml), then basified with saturated NaHCO ₃ solution (2-3 ml). The alkaline 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-brown residue was dissolved in MeOH and absorbed in SiO ₂ (100 g). After purification by column chromatography (300 g SiO ₂ ; gradient from 1% Et ₃ N / 33% EtOAc / 66% hexane, to 1% Et ₃ N / 99% EtOAc, to 1% Et ₃ N / 20% MeOH / 79 ^Λ EtOAc), followed by concentration under reduced pressure at 45 ° C to give a hot concentrated solution in EtOAc, which is treated with hexane (10 ml) to slightly form crystals of N- (2-methoxy5- (trifluoromethyl) phenyl ) -N- (4- (2- (N-methylcarbamoyl) -4- (pyridyloxy) phenyl) urea (0.44 g); TLC (1% Et ₃ N / 99% EtOAc) R _f 0.40.

D. Mutual conversion of ureas

D1 a. Conversion of omega-aminophenyl ureas to omega (aroylamino) phenyl ureas.

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

(The compound is not in accordance with the invention).

To a solution of N- (4-χπορο-3 ((trifluoromethyl) phenyl) -N- (4-aminophenyl) urea (Cid method; 0.050 g, 1.52 mmol), monomethyl isophthalate (0.25 g, 1.3 , 8 mmol), HOB ₂ H ₂ O (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 ml, 3.03 mmol) in DMF (8 ml) were added EDC1.HC1 (0, 29 g, 1.52 mmol) The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (25 ml) and washed sequentially with water (25 ml) and saturated HaNaHCO ₃ solution (25 ml). The organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting solids were triturated with a solution of EtOAc (80% EtOAc / 20% hexane) to give Ν- (4-χπορο-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 omega-carboxyphenyl ureas to omega- (arylcarbamoyl) phenyl ureas.

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

To a solution of N- (4-chloro-3 - ((triflu

65945 Bromomethyl) phenyl) -L1 '- (4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), NEW (0, 14 g, 1.07 mmol) and Nmethylmorpholine (0.5 ml, 1.07 mmol) in DMF (3 ml) at 0 ° C was added EDC1.HC1 (0.10 g, 0.53 mmol). The resulting mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was treated with water (10 ml) and extracted with EtOAc (25 ml). The organic phase was concentrated under reduced pressure. The yellow solids obtained were dissolved in EtOAc (3 ml), then filtered through a pad of silica gel (17 g, gradient from 70% EtOAc / 30% hexane, to 10% MeOH / 90% EtOAc) to give Ν - (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4- (3-methylcarbamoylphenyl) -carbamoylphenyl) urea as a white solid (0.097 g, 41%); mp 225229 ° C; TLC (100 % EtOAc) R _f 0.23.

Die. Combined conversion of omega-carboxyphenyl ureas into omega- (arylcarbamoyl) phenyl ureas.

Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -14 '- (4- (L1- (3- (N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea.

(The compound is not in accordance with the present invention).

Mixture of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -BP- (3-carboxyphenyl) urea (Clf method; (0.030 g, 0.67 mmol) and N-cyclohexyl-N (methylpolystyrene) carbodiimide ( 55 mg) in 1,2 dichloroethane (1 ml) was treated with a solution of 3aminopyridine in CH ₂ Cl ₂ , (1 M; 0.074 ml, 0.074 mmol). (In the case of insolubility or turbidity, a small amount was also added The resulting mixture was heated at 36 [deg.] C. overnight, then the THF (1 ml) was treated with stirring and the heating continued for 18 h. The resulting mixture was treated with poly (4-isocyanatemethyl) styrene (0.040 g ) and the resulting mixture was stirred at 36 ° C After 72 h, it was then cooled to room temperature and filtered, and the resulting solution was filtered through a pad of silica gel (1 g).

Concentration under reduced pressure gave L- (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4- (N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea (0.024 g, 59 %): TLC (70% EtOAc / 30% hexane) R _f 0.12.

D2. Conversion of omega-carboalkoxyaryl ureas to omega-carbamoylaryl ureas.

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

(The compound is not in accordance with the present invention).

To a sample of L1- (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4 (3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (1 Mb THF; 1 ml, 1.7 mmol) and the resulting mixture was stirred at room temperature overnight, then concentrated under reduced pressure to give T4- (4-chloro-3 - ((trifluoromethyl) -phenyl) -N '- (4- (3-methylcarbamoylphenyl) -carboxyaminophenyl) urea as a white solid; mp 247; TLC (100% EtOAc) R _f 0.35.

D3. Conversion of omega-carboalkoxyaryl ureas to omega-carboxyaryl ureas.

Synthesis of N- (4-chloro-3 ((trifluoromethyl) phenyl) -N- (4-carboxyphenyl) urea.

To a suspension of b1- (4-chloro-3- (trifluoromethyl) phenyl) -N (4-ethoxycarbonylphenyl) urea (method C1 e; 5.93 g, 15.3 mmol) in MeOH (75 ml) was added an aqueous solution on KOH (2.5 N, 10 ml, 23 mmol). The resulting mixture was heated at reflux for 12 h, cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (50 ml), then treated with 1N HCl solution to pH 2 to 3. The resulting solids were collected and dried under reduced pressure to give N (4-chloro-3 - ( (trifluoromethyl) phenyl) -H '- (4

65945 B1 carboxyphenyl) urea as a white solid (5.05 g, 92%).

D4. General method for the conversion of omega-alkoxy esters into omega-alkyl amides.

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

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

B1- (4-chloro-3- (trifluoromethyl) phenyl) N '- ((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea is synthesized from 4-chloro-3- (trifluoromethyl) phenyl isocyanate and 4- ( 3- (5-methoxycarbonyl-pyridyl) oxyaniline (method A14, step 2) in a manner analogous to method C1a. A suspension of 14- (4-chloro-3- (trifluoromethyl) phenyl) -NG ((4- (3 - (5-methoxycarbonylpyridyl) oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 ml) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 ml) and was stirred at room temperature for 1 h. The resulting mixture was adjusted to pH 5 with a 1 N HCl solution. rubbing and washing with water. The solids obtained were dissolved in EtOH (10 ml) and the resulting solution concentrated under reduced pressure. The dissolution procedure in EtOH / concentration was repeated twice to give Ν- (4-χπορο -

3- (Trifluoromethyl) phenyl) -N - ((4- (3- (5-carboxypyridyl) -oxyphenyl) urea (0.18 g, 71%).

Η Η ”

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

Mixture of N- (4-chloro-3- (trifluoromethyl) phenyl) -N - ((4- (3- (5-carboxypyridyl) oxyphenyl) urea (0.050 g, 0.011 mmol), N, N-dimethylethylenediamine (0, 22 g, 0.17 mmol), HOBT (0.028 g, 0.17 mmol) and N-methylmorpholine (0.035 ml, 0.28 mmol) and EDC1.HC1 (0.10 g, 0.53 mmol) in DMF ( 2.5 ml) was stirred at room temperature overnight The resulting solution was partitioned between EtOAc (50 ml) and water (50 ml) The organic phase was washed with water (35 ml), dried (MgSO ₄ ). and concentrated under reduced pressure. The residue was dissolved in CH ₂ C1 ₂ (approximately 2 ml). The resulting solution was treated with Et ₂ O dropwise to give Y1- (4-chloro-3- (trifluoromethyl Trifluoromethyl) phenyl) -N '((4- (3- (5- (2dimetilaminoetil) carbamoyl) pyridyl) oxyphenyl) urea (0,48 g, 84% Ή - NMR (DMSO - d ₆₎ delta 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 / e. with 522 ((M + H) ⁺ ).

D5. General method for deprotection of N- (omega-silyloxyalkyl) amides.

Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (4- (1- (2- (hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea).

To a solution of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4-4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea (prepared in a manner analogous to method Cl a; 0.25 g, 0.37 mmol), in anhydrous THF (2 ml), tetrabutylammonium fluoride (1.0 M in THF; 2 ml) was added The mixture was stirred at room temperature for 5 min after this was treated with water (10 ml) The aqueous mixture was extracted with EtOAc (3x10 ml) The combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure The residue was purified by column chromatography (SiO ₂ ; gradient of 100 % hexane to 40% E YuAc / 60% hexane) to give N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4- (2- (N- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea as white solid (0.019 g, 10%).

The following are the compounds listed in the tables below that have been synthesized according to the detailed experimental procedures given above:

Synthesis of Example Compounds (See Compound Characterization Tables)

Description 1: 4- (3-L-methylcarbamoyl)

65945 Bloxy) aniline was prepared according to method A13. According to method C3, 3-tert-butyl-aniline is reacted with bis (trichloromethyl) carbonate, followed by 4- (3-X-methylcarbamoylphenoxy) aniline to give urea.

Description 2: 4-fluoro-1-nitrobenzene and hydroxy-acetophenone are reacted according to method A13, step 1, to give 4- (4-acetylphenoxy) -1-nitrobenzene. 4- (4-Acetylphenoxy) -1-nitrobenzene was reduced according to method A13, step 4 to give 4- (4-acetylphenoxy) aniline. According to method C3, 3-tert-butylaniline is reacted with bis (trichloromethyl) carbonate, followed by 4- (4-acetylphenoxy) aniline to give urea.

Description 3: According to method C2d, 3-tert-butylaniline was reacted with CDI, followed by 4- (3-N-methylcarbamoyl) 4-methoxyphenoxy) aniline, which was obtained according to method A8 to give urea.

Description 4: 5-tert-Butyl-2-methoxyaniline is converted to 5-tert-butyl-2-methoxyphenyl isocyanate according to method B1. 4- (3-Nmethylcarbamoylphenoxy) aniline prepared according to method A13 is reacted with isocyanate according to method C1a to give urea.

Description 5: According to method C2d, 5-tertbutyl-2-methoxy-aniline was reacted with CDI, followed by 4- (3-N-methyl-carbamoyl) -4-methoxyphenoxy) aniline, which was obtained according to method A8 to give urea.

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

Description 7: 4- (1-Oxoisoindolin-5-yloxy) aniline was synthesized according to method A12. According to method 2d, 5-tert-butyl-2-methoxyaniline is reacted with CDI followed by 4- (1-oxo-isoindolin-5-yloxy) aniline to give urea.

Description 8: 4- (3-N-methylcarbamoylphenoxy) aniline was synthesized according to method A13. According to method C2a, 2-methoxy-5- (trifluoromethyl) aniline is reacted with CDI followed by 4- (3-14-methylcarbamoylphenoxy) aniline to give urea.

Description 9: 4-Hydroxyacetophenone is reacted with 2-chloro-5-nitropyridine to give 4- (4-acetylphenoxy) -5-nitropyridine according to method A3, step 2. According to method A8, step 4.4- (4 -acetylphenoxy) -5-nitropyridine is reduced to 4- (4-acetylphenoxy) -5-aminopyridine. 2-Megoxy-5- (trifluoromethyl) -aniline was converted to 2-methoxy-5- (trifluoromethyl) -phenyl isocyanate according to method B1. The isocyanate was reacted with 4- (4-acetylphenoxy) -5-aminopyridine according to method C1a to give urea.

Description 10: 4-fluoro-1-nitrobenzene and p-hydroxyacetophenone are reacted according to method A13, step 1, to give 4- (4acetylphenoxy) -1-nitrobenzene. 4- (4-acetylphenoxy) -1-nitrobenzene was 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.

Description 11: 4-chloro-N-methyl-2-pyridinecarboxamide, which is synthesized according to method A2, step 3a, is reacted with 3-aminophenol according to method A2, step 4, using DMAC instead of DMF to give 3- (2 - (Nmethylcarbamoyl) -4-pyridyloxy) aniline. According to method C4,2-methoxy-5- (trifluoromethyl) aniline is reacted with phosgene followed by 3 - (- 2- (N- [methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 12: HCl salt of 4-chloropyridine-

2-carbonyl chloride is reacted with ammonia according to method A2, step 3b, to give 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to method A2, step 4, using DMAC instead of DMF to give 3- (2-carbamoyl-

4-pyridyloxy) aniline. According to method C2a, 2methoxy-5- (trifluoromethyl) aniline is reacted with phosgene followed by 3- (2-carbamoyl) -4-pyridyloxy) -aniline to give urea.

Description 13: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to method A2, step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, using DMAC instead of DMF to give 4 - (- 2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. According to the method

65945 Bl

C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI followed by 4- (2- (Nmethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 14: HCl salt of 4-chloropyridine-

2-carbonyl chloride is reacted with ammonia according to method A2, step 3b, to give 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, using DMAC instead of DMF to give 4- (2-carbamoyl-

4- pyridyloxy) aniline. According to method C4, 2methoxy-5- (trifluoromethyl) aniline is reacted with phosgene followed by 4- (2-carbamoyl) -4-pyridyloxy) aniline to give urea.

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

Description 16: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was synthesized according to method A5.5- (trifluoromethyl) -2-methoxyaniline converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate, according to method B1. The isocyanate is reacted with 4- (2- (Nmethylcarbamoyl) -4-pyridyloxy) -2methylaniline according to method C1c to give urea.

Description 17: 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to method A6.5- (trifluoromethyl) -2-methoxyaniline converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate, according to method B1. 5 (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (L-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline according to method C1a to give urea.

Description 18: According to method A2, step 4,

5- Amino-2-methylphenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to method A2, step 3b, to give 3- (2- (1M-methylcarbamoyl) -4-pyridyloxy) -4 -methylaniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5 (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1.5- (trifluoromethyl) -2-methoxyphenyl isocyanate by reaction with 3- (2- (Nmethylcarbamoyl) -4-pyridyloxy ) -4-methylaniline according to method C1a, to give urea.

Description 19: 4-Chloropyridine-2-carbonyl chloride is reacted with ethylamine according to method A2, step 3b. The resulting 4-chloro-L-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-methoxyphenyl isocyanate according to method B1. 5 (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline according to method C 1a to give urea.

Description 20: According to method A2, step 4,

4- Amino-2-chlorophenol was reacted with 4-chloro-1-methyl-2-pyridinecarboxamide, which was synthesized according to method A2, step 3b, to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3 -chloroaniline. 5- (Trifluoromethyl) -2-methoxy-aniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (L-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline according to method C1a to give urea.

Description 21: 4- (4-Methylthiophenoxy) -1nitrobenzene is oxidized according to method A19, step 1 to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. Nitrobenzene was reduced according to method A19, step 1 to give 4- (4-methylsulfonylphenoxy) -1-aniline. According to method C1a, 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (4methylsulfonylphenoxy) -1-aniline to give urea.

Description 22: 4- (3-Carbamoylphenoxy) -1nitrobenzene is reduced to 4- (3-carbamoylphenoxy) aniline according to method A15, step 4. According to method C 1a, 5- (trifluoromethyl) -2-methoxy-phenyl isocyanate is reacted with 4- (3carbamoylphenoxy) aniline to give urea.

Description 23: 5- (4-Aminophenoxy) isoindoline-1,3-dione was synthesized according to method A3.

5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione according to method C1a to give urea.

65945 Bl

Description 24: 4-Chloropyridine-2-carbonyl chloride is reacted with dimethylamine according to method A2, step 3b. The resulting 4-χπορο-Ν, dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4 to give 4- (2- (R, N-dimethylcarbamoyl) -4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) 2-methoxyphenyl isocyanate according to method B1. 5- (Trifluoromethyl) -2-methoxyphenylisocyanate was reacted with 4- (2- (N, N-dimethylcarbamoyl) 4-pyridyloxy) aniline according to method C1a to give urea.

Description 25: 4- (1-Oxoisoindolin-5yloxy) aniline was synthesized according to method A12. 5- (Trifluoromethyl) -2-methoxyaniline was treated with CDI followed by 4- (1-oxoisoindolin-5-yloxy) aniline according to method C2d to give urea.

Description 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to method A13, Step 1 to give 4- (4acetylphenoxy) nitrobenzene. Nitrobenzene is reduced according to method A13, Step 4 to give 4- (4-acetylphenoxy) aniline, which is converted to the 4- (4- (1- (Νmethoxy) iminoethyl) phenoxyaniline) HCl salt according to method A16. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1, 5 (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with the 4- (4- (1- ( Тоmethoxy) iminoethyl) phenoxyaniline according to method C 1a to give urea.

Description 27: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in method A2, step 3b. Chloropyridine is reacted with 4-aminothiophenol according to method A2, step 4 to give 4- (4- (2- (Nmethylcarbamoyl) phenylthio) aniline. 5- (trifluoromethyl) -2-methoxyaniline is converted to 5 (trifluoromethyl) -2 -methoxyphenyl isocyanate according to method B1.5- (trifluoromethyl) -2-methoxyphenylisocyanate is reacted with 4- (4- (2OH-methylcarbamoyl) -phenylthio) aniline according to method C1a to give urea.

Description 28: 5- (4-Aminophenoxy) -2-methylisoindoline-1,3-dione is synthesized according to method A9.5- (trifluoromethyl) -2-methoxyaniline converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate, according to method B1. 5 (Trifluoromethyl) -2-methoxyphenylisocyanate was reacted with 5- (4-aminophenoxy) -2-methyl zoindoline-1,3-dione according to method C1a to give urea.

Description 29: 4-Chloro-N-methylpyridinecarboxamide was synthesized according to the description of method A2, step 3b. Chloropyridine is reacted with 3-aminothiophenol according to method A2, step 4 to give 3- (4- (2- (N-methylcarbamoyl) phenylgio) aniline. 5- (trifluoromethyl) 2-methoxyaniline is converted to 5- (trifluoromethyl) -2-Methoxyphenyl isocyanate according to method B. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 3- (4- (2- (Nmethylcarbamoyl) phenylthio) aniline according to method C1a to give urea.

Description 30: 2-Chloropyridine-2-carbonyl chloride is reacted with isopropylamine according to method A2, step 3b. The resulting 4-chloro-L1-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, to give 4- (2- (L1-isopropylcarbamoyl) 4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (N-H3-propylcarbamoyl) -4-pyridyloxy) aniline according to method C1a to give urea.

Description 31: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to method A14. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 5 (Trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method C1a to give urea. B [- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to method D4, step 1 and the corresponding acid was linked to 4- ( 2-aminoethyl) -morpholine to give the amide according to method D4, step 2.

Description 32: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to method A14. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 5 (Trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method C1a to give urea. B1- (5- (Trifluoromethyl) -2-methoxyphenyl) -N- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to method D4, step 1, and the corresponding acid was

65945 B1 binds to methylamine to give the amide according to method D4, step 2.

Description 33: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to method A14.5- (trifluoromethyl) -2-methoxyaniline converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1.5 (Trifluoromethyl) -2-methoxyphenylisocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method C1a to give urea. 1M- (5- (trifluoromethyl) -

2-Methoxyphenyl) -N-4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to method D4, step 1 and the corresponding acid was coupled to N, N-dimethylethylenediamine according to method D4, step 2, to give the amide.

Description 34: 4- (3-Carboxyphenoxy) aniline was synthesized according to method All. 5 (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1.4- (3-carboxyphenoxy) aniline by reaction with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method Clf to give b1- (5- (trifluoromethyl) -2-methoxyphenyl) -N- (3-carboxyphenyl) urea which binds to 3-aminopyridine according to method Die.

Description 36: 4- (3-Carboxyphenoxy) aniline was synthesized according to method All. 5 (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1.4- (3-carboxyphenoxy) aniline reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method Clf to give b1- (5- (trifluoromethyl) -2-methoxyphenyl) -N- (3-carboxyphenyl) urea, which binds to b1- (4-fluorophenyl) piperazine according to method Die.

Description 37: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method All. 5 (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1.4- (3-carboxyphenoxy) aniline by reaction with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method Clf to give b1- (5- (trifluoromethyl) -2-methoxyphenyl) -N- (3-carboxyphenyl) urea which binds to 4-fluoroaniline according to method Die.

Description 38: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method All. 5 (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1.4- (3-carboxyphenoxy) aniline by reaction with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method Clf to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N- (3-carboxyphenyl) urea, bind to 5-amino-2-methoxypyridine according to method Die.

Description 39: 4- (3-Carboxyphenoxy) aniline was synthesized according to method All. 5 (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1.4- (3-carboxyphenoxy) aniline reacted with 5 (trifluoromethyl) -2-methoxyphenyl isocyanate according to method Clf to give N- (5 (trifluoromethyl) -2-methoxyphenyl) -N- (3carboxyphenyl) urea which binds to 4morpholinoaniline according to method Die.

Description 40: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method All. 5 (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1.4- (3-carboxyphenoxy) aniline reacted with 5 (trifluoromethyl) -2-methoxyphenyl isocyanate according to method Clf to give N- (5 (trifluoromethyl) -2-methoxyphenyl) -N- (3carboxyphenyl) urea which binds with N- (2-pyridyl) piperazine according to method Die.

Description 41: 4- (3- (L-Methylcarbamoyl) phenoxy) aniline was synthesized according to method A13. According to method C3, 4-chloro-3- (trifluoromethyl) aniline is converted to isocyanate, then reacted with 4- (3- (L-methylcarbamoyl) phenoxy) aniline to give the urea.

Description 42: 4- (2-L (-methylcarbamoyl-4-pyridyloxy) aniline is synthesized according to the description of method A2. 4-Chloro-3- (trifluoromethyl) -phenyl isocyanate is reacted with 4- (2-methylcarbamoyl-4-pyridyloxy) aniline according to the Cla method, to give urea.

Description 43: The 4-chloropyridine-2-carbonyl chloride HCl salt is reacted with ammonia according to method A2, step 3b, to give 4chloro-2-pyridinecarboxamide. The 4-chloro-2-pyridinecarboxamide is reacted with 4aminophenol according to method A2, step 4 to give 4- (2-carbamoyl) -4-pyridyloxy) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2carbamoyl) -4-pyridyloxy) aniline to give urea.

Description 44: 4-Chloropyridine-2-carbonyl

65945 B1 chloride HCl salt is reacted with ammonia according to method A2, step 3b, to give 4chloro-2-pyridinecarboxamide. The 4-chloro-2-pyridinecarboxamide is reacted with 3aminothiophenol according to method A2, step 4 to give 3- (2-carbamoyl) -4-pyridyloxy) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 3 (2-carbamoyl) -4-pyridyloxy) aniline to give urea.

Description 45: 4-Chloro-N-methyl-2-pyridinecarboxamide to be synthesized according to method A2, step 3 For reacting with 3-aminothiophenol according to method A2, step 4 to give 3- (2- (14-methylcarbamoyl) ) -4-pyridyloxy) aniline. According to method C1a, 4-chloro-3 (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (L1-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 46: 5- (4-Aminophenoxy) -2-isoindoline-1,3-dione was synthesized according to method A3. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 5- (4aminophenoxy) -2-isoindoline-1,3-dione to give urea.

Description 47: 4- (2- (L-Methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was synthesized according to the description of method A5. According to method C1c, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to give urea.

Description 48: 4- (3-Methylsulfamoyl) phenyloxy) aniline was synthesized according to the description of method A15. According to method C 1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-1M-methylsulfamoyl) phenyloxy) aniline to give urea.

Description 49: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to the description of method A6. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (L1-methylcarbamoyl) -

4- pyridyloxy) -2-chloroaniline to give urea.

Description 50: According to method A2, step 4,

5- Amino-2-methylphenol is reacted with 4-chloro-N-2-pyridinecarboxamide, which is synthesized according to method A2, step 3b, to give 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4 -methyl-aniline. According to method Cla, 4chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to give urea.

Description 51: 4-Chloropyridine-2-carbonyl chloride is reacted with ethylamine according to method A2, step 3b. The resulting 4-chloro-L1-ethyl-

2-Pyridinecarboxamide is reacted with 4aminophenol according to method A2, step 4 to give 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. According to method C1a, 4-chloro-3 (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (L-ethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 52: According to method A2, step 4, 4-amino-2-chlorophenol is reacted with 4-chlopo-N-2-pyridinecarboxamide, which is synthesized according to method A2, step 3b, to give 4- (2- (M- methylcarbamoyl) -4-pyridyloxy) -3 chloroaniline. According to method C1a, 4-chloro-3 (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (L1-methylcarbamoyl) -4-pyridyloxy) -

3- chloroaniline to give urea.

Description 53: 4- (4-Methylthiophenoxy) -1nitrobenzene was oxidized according to method A19, step 1 to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. Nitrobenzene was reduced according to method A19, step 2 to give 4- (4-methylsulfonylphenoxy) -1-aniline. According to method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4methylsulfonylphenoxy) -1-aniline to give urea.

Description 54: 4-Bromobenzenesulfonyl chloride is reacted with methylamine according to method A15, step 1 to give L1-methyl-4bromobenzenesulfonamide. The N-methyl-4-bromobenzenesulfonamide was coupled with phenol according to method A 15, step 2 to give 4- (4- (N-methylsulfamoyl) phenoxy) benzene. 4- (4- (1'-methylsulfamoyl) phenoxy) benzene is converted to

4- (4- (N-methylsulfamoyl) -phenoxy) -1-nitrobenzene according to method A15, step 3. 4- (4 (N-methylsulfamoyl) -phenoxy) -1-nitrobenzene is reduced to 4- (4-N-methylsulfamoyl) phenoxy ) aniline according to method A15, step 4. According to method Cla, 4-chloro-

3- (Trifluoromethyl) phenyl isocyanate is reacted with 4- (4-N-methylsulfamoyl) phenoxy) aniline to give urea.

Description 55: 5-Hydroxy-2-methylpyridine is coupled to 1-fluoro-4-nitrobenzene according to method A18, step 1 to give 4- (5- (2methyl) pyridyloxy) -1-nitrobenzene. Methylpyridine is oxidized carboxylic acid, then esterified according to method A18,

65945 B1 step 2 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene. Nitrobenzene was reduced according to method A18 step 3 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline. Aniline was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to method C 1a to give urea.

Description 56: 5-Hydroxy-2-methylpyridine is coupled to 1-fluoro-4-nitrobenzene according to method A18, step 1 to give 4- (5- (2methyl) -pyridyloxy) -1-nitrobenzene. The methylpyridine is oxidized to carboxylic acid, then esterified according to method A18, step 2 to give 4- (5- (2methoxycarbonyl) pyridyloxy) -1-nitrobenzene. Nitrobenzene was 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 the Cla method to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N (4- (2- (methoxycarbonyl) -5- pyridyloxy) phenyl) urea. The methyl ester was reacted with methylaniline according to method D2 to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N (4- (2- (L-methylcarbamoyl) -5-pyridyloxy) phenyl) urea.

Description 57: N- (4-Chloro-3- (trifluoromethyl) phenyl-N- (4-aminophenyl) urea is prepared according to method Cid. N- (4-chloro-3- (trifluoromethyl) phenyl-N- (4 -aminophenyl) urea is coupled to monomethyl isophthalate according to method Dla to give urea.

Description 58: N- (4-chloro-3- (trifluoromethyl) phenyl-L- (4-aminophenyl) urea is prepared according to the method Cid. L 1- (4-chloro-3- (trifluoromethyl) phenyl-N- (4 -aminophenyl) urea is coupled to monomethyl isophthalate according to method Dla to give N- (4-chloro-3- (trifluoromethyl) phenyl-N- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl urea. According to method D2, M- (4-Chloro-3- (trifluoromethyl) phenyl-N- (4- (3methoxycarbonylphenyl) -carboxyaminophenyl urea) is reacted with methylamine to give the corresponding methylamide.

Description 59: 4-Chloropyridine-2-carbonyl chloride is reacted with diethylamine according to method A2, step 3b. The resulting 4-chloro-N, N-diethyl-2-pyridinecarboxamide was reacted with 4aminophenol according to method A2, step 4 to give 4- (2- (N, 1-diethylcarbamoyl) -4-pyridyloxy) aniline. According to method C1a, 4 chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N, L-diethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 60: 4-Hydroxyacetophenone is reacted with 4-fluoronitrobenzene according to method A13, step 1 to give 4- (4acetylphenoxy) nitrobenzene. Nitrobenzene is reduced according to method A13, step 4 to give 4- (4-acetylphenoxy) aniline, which is converted to the HCl salt of 4- (4- (1- (Νmethoxy) iminoethyl) phenoxyaniline, according to method A16. method C1a, 4-chloro-3 (trifluoromethyl) phenyl isocyanate was reacted with 4- (4-acetylphenoxy) aniline to give urea.

Description 61: 4- (3-Carboxyphenoxy) -1nitrobenzene is synthesized according to method A13, step 2.4- (3-carboxyphenoxy) -1-nitrobenzene binds to 4- (2-aminoethyl) morpholine according to method A13, step 3, to give 4- (3-N- (2-morpholinylethyl) carbamoyl) phenoxy) -1nitrobenzene. According to method A13, step 4,4- (3 N- (2-morpholinyl-ethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3-N (2-morpholinylethyl) carbamoyl) phenoxy) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl) -isocyanate is reacted with 4- (3M- (2-morpholinylethyl) -carbamoyl) phenoxy) aniline to give urea.

Description 62: 4- (3-Carboxyphenoxy) -1nitrobenzene is synthesized according to method A13, step 2.4- (3-carboxyphenoxy) -1-nitrobenzene is coupled with 1- (2-aminoethyl) piperidine according to method A13, step 3, to give 4- (3- (N- (2-piperidylethyl) carbamoyl) phenoxy) -1nitrobenzene. According to method A13, step 4,4- (3 (N (2-piperidyl-ethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (N- (2-piperidylethyl) carbamoyl) phenoxy) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl) isocyanate is reacted with 4- (3- (N (2-piperidylethyl) carbamoyl) phenoxy) aniline to give urea.

Description 63: 4- (3-Carboxyphenoxy) -1nitrobenzene is synthesized according to method A13, step 2.4- (3-carboxyphenoxy) -1-nitrobenzene is coupled with tetrahydrofurfurylamine according to method A13, step 3 to give 4- (3 - (N (tetrahydrofurylmethyl) carbamoyl) phenoxy) -1nitrobenzene. According to method A13, step 4,4- (3 (b [- (tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4 (3- (M- (tetrahydrofurylmethyl) carbamoyl))

65945 B1 phenoxy) -aniline. According to method Cl a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (N- (tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline to give urea.

Description 64: 4- (3-Carboxyphenoxy) -1nitrobenzene is synthesized according to method A13, step 2.4- (3-carboxyphenoxy) -1-nitrobenzene is coupled to 2-aminomethyl-1-ethylpyrrolidine according to method A13, step 3, as 4- (3 (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene is obtained. According to method A13, step 4, 4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (b1 - ((1-methylpyrrolidinyl) methyl) carbamoyl) -phenoxy) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (N ((1-methyl-pyrrolidinyl) methyl) carbamoyl) phenoxy) aniline to give urea.

Description 65: 4-Chloro-L1-methylpyridinecarboxamide was synthesized as described in method A2, step 3b. Chloropyridine is reacted with 4-aminophenol according to method A2, step 4, to give 4- (4- (2- (L-methylcarbamoyl) phenylthio) -aniline. According to method C 1a,

4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- (1-methylcarbamoyl) phenylthio) aniline to give urea.

Description 66: 4-Chloropyridine-2-carbonyl chloride is reacted with isopropylamine according to method A2, step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to method A2, step 4 to give 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-3- (propylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 67: N1- (4-chloro-3- (trifluoromethyl) phenyl-L- (4-ethoxycarbonylphenyl) urea was synthesized according to the method Cle. Ν- (4-χπορο-3 (trifluoromethyl) phenyl-L- (4- ethoxycarbonylphenyl) urea was saponified according to method D3 to give N- (4-chloro-3- (trifluoromethyl) phenyl-E- (4-carboxyphenyl) urea. N- (4-chloro-3- (trifluoromethyl) phenyl-N- (4carboxyphenyl) urea was coupled to methylcarbamoylaniline according to method D1b to give b1- (4-chloro-3- (trifluoromethyl) phenyl-N- (4- (3-methylcarbamoylphenyl) carbamoylphenyl urea).

Description 68: 5- (4-Aminophenoxy) -2-methylisoindoline-1,3-dione is synthesized according to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 5- (4-aminophenoxy) -

2-methylisoindoline-1,3-dione to give urea.

Description 69: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in method A2, step 3b. Chloropyridine is reacted with 3-aminophenol according to method A2, step 4 to give 4- (4- (2- (1M-methylcarbamoyl) phenylthio) aniline According to method C1a, 4-chloro-3 (trifluoromethyl) phenyl isocyanate is reacted with 3 - (4- (2- (N-methylcarbamoyl) phenylthio) aniline, urea is obtained.

Description 70: 4- (2- (b1- (2-morpholin-4ylethyl) carbamoyl) was synthesized as described in method A10. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to give urea.

Description 71: 4- (3- (5methoxycarbonyl) pyridyloxy) -aniline was synthesized according to method A14. 4-Chloro-3 (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5methoxycarbonyl) pyridyloxy) aniline according to method C1a to give urea. N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl urea was saponified according to method D4, step 1 and the corresponding acid was linked to 4- ( 2aminoethyl) morpholine to give amide.

Description 72: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to method A14.4-chloro-3- (trifluoromethyl) phenyl isocyanate by reaction with 4- (3- (5methoxycarbonyl) -pyridyloxy) aniline according to method C1a to give urea. N- (5 (trifluoromethyl) -2-methoxyphenyl) -1H- (4- (3- (5methoxycarbonylpyridyl) oxy) phenyl urea was saponified according to method D4, step 1 and the corresponding acid was linked to methylamine according to method D4 , step 2 to give amide.

Description 73: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to method A14. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5methoxycarbonyl) -pyridyloxy) aniline according to method C1a to give urea. N- (5 (trifluoromethyl) -2-methoxyphenyl) -N- (4- (3- (5

65945 B1 methoxycarbonylpyridyl) oxy) phenyl urea was saponified according to method D4, step 1, and the corresponding acid was coupled to Ν, dimethylethylenediamine according to method D4, step 2 to give the amide.

Description 74: HCl salt of 4-chloropyridine-

2- Carbonyl chloride is reacted with 2hydroxyethylamine according to method A2, step 3b, to give 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide. 4-Chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to method A17 to give 4- (4- (2- (Ν (2-triisopropylsilyloxy) ethylcarbonyldiaryl) According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (b1- (2-triisopropylsilyloxy) -ethylcarbamoyl) pyridyloxyaniline) to give 14- (4-chloro-3 - ((trifluoromethyl) phenyl-N- (4- (4- (2 - (> 1- (2-methylsulfonyl) ethyl) urea).

Description 75: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method All. 4-chloro-

3- (Trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method Clf to give urea which binds to 3-aminopyridine according to method Die.

Description 76: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method All. 4-chloro-

3- (Trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to method Clf to give urea which binds to N- (4-acetylphenyl) piperazine according to method Die.

Description 77: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method All. 4-chloro-

3- (Trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to the Clf method to give urea which binds to 4-fluoroaniline according to the Die method.

Description 78: 4- (3-Carboxyphenoxy) aniline was synthesized according to method Al 1.4-chloro-

3- (Trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to the Clf method to give urea which binds to 4- (dimethylamino) aniline according to the Die method.

Description 79: 4- (3-Carboxyphenoxy) aniline was synthesized according to method All. 4-Chloro 3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to the Clf method to give urea which binds to N-phenylethylenediamine according to the Die method.

Description 80: 4- (3-Carboxyphenoxy) aniline was synthesized according to method All. 4-Chloro 3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to the Clf method to give urea, which binds to 2-methoxyethylamine according to the Die method.

Description 81: 4- (3-Carboxyphenoxy) aniline was synthesized according to method All. 4-Chloro 3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to method Clf to give urea, which binds to 5-amino-2-methoxypyridine according to method Die.

Description 82: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method All. 4-Chloro 3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to the Clf method to give the urea which is bound to 4-morpholinoaniline according to the Die method.

Description 83: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method All. 4-Chloro 3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to the Clf method to give urea which binds with L 2 -pyridyl) piperazine according to the Die method.

Description 84: The 4-chloropyridine-2-carbonyl chloride HCl salt is reacted with 2hydroxyethylamine according to method A2, step 3b, to give 4-chloro-N- (2-triisopropylyloxy) ethylpyridine-2-carboxamide. The 4-chloro- (2-triisopropylsilyloxy) ethylpyridine-2carboxamide was reacted with triisopropylsilyl chloride followed by 4-aminophenol according to method A17 to give 4- (4- (2 (N- (2-triisopropylsilyloxy) ethylcarbonyldiaryl) carbonyldiarylaryldaryl. According to Method C 1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline) to give N- (4-χπορο-3 ( (trifluoromethyl) phenyl) -K ['- (4- (4- (2- (b1- (2-trifluoromethyl) pyrrolidinyl) urea)] urea. The urea protection is removed according to method D5 to give Ν- ( 4- πορο-3 ((trifluoromethyl) phenyl) -YG- (4- (4- (2- (1CH- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea.

65945 Bl

Description 85: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -aniline was synthesized according to method A2.4-bromo-3- (trifluoromethyl) aniline converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate, according to method B1. According to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (14-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 86: 4- (2- (14-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to method A6. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2 (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 87: According to method A2, step 4,

4-Amino-2-chlorophenol is reacted with 4-chloro-methyl-2-pyridine-carboxamide, which is synthesized according to method A2, step 3b to give 4- (2- (14-methylcarbamoyl) -4-pyridyloxy) -3-Chloroaniline-4-bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (Nmethylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to give urea.

Description 88: 4-Chloropyridine-2-carbonyl chloride is reacted with ethylamine according to method A2, step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to method A2, step 4, to give 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-ethylcarbamoyl) -

4-pyridyloxy) aniline to give urea.

Description 89: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to method A2, step 3a, reacted with 3-aminophenol according to method A2, step 4 to give 3- (2- (N-methylcarbamoyl) -4 4-bromo-3- (trifluoromethyl) aniline is converted to 4bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-bromo3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -aniline to give urea.

Description 90: According to method A2, step 4,

5-Amino-2-chlorophenol was reacted with 4-chloro-methyl-2-pyridinecarboxamide synthesized according to method A2, step 3b, to give 3 (2- (14-methylcarbamoyl) -4-pyridyloxy) -3methylaniline. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to give urea.

Description 91: 4-Chloropyridine-2-carbonyl chloride is reacted with dimethylamine according to method A2, step 3b. The resulting 4-chloro-HH-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4 to give 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline. 4bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (b [, b [-dimethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 92: 4-Chloro-T4-methylpyridinecarboxamide was synthesized as described in method A2, step 3b. Chloropyridine is reacted with 3-aminophenol according to method A2, step 4 to give 4- (4- (2- (b [-methylcarbamoyl) phenylthio) aniline. 4-bromo-3- (trifluoromethyl) -aniline is converted to 4 -bromo-3- (trifluoromethyl) phenyl isocyanate according to method B. According to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2 (T4-methylcarbamoyl) phenylthio) aniline to give urea .

Description 93: 4-Chloro-L1-methylpyridinecarboxamide was synthesized as described in method A2, step 3b. Chloropyridine is reacted with 3-aminophenol 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 B. According to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (4- (2 (14-methylcarbamoyl) -phenylthio) aniline, such as urea is obtained.

Description 94: 4- (2- (bT-2-morpholin-4ylethyl) carbamoyl) -pyridyloxy) aniline was synthesized according to method A10. 4-bromo-3 (trifluoromethyl) aniline is converted to 4-bromo

65945 B1-10- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-bromo-3 (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to give urea.

Description 95: 4- (2- (L-methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to method A2.4-chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to method A7.4-chloro-2 -methoxy-5- (trifluoromethyl) aniline is converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-chloro-2-methoxy-5 (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (14-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 96: 4- (2- (L-Methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to method A6,4-chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to method A7.4-chloro-2 -methoxy-5- (trifluoromethyl) aniline is converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-chloro-2-methoxy-5 (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (L-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to give urea.

Description 97: According to method A2, step 4,

4-Amino-2-chlorophenol is reacted with 4-chloro-methyl-2-pyridinecarboxamide, which is synthesized according to method A2, step 3b, to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3- chloraniline. 4-Chloro-2-methoxy-5 (trifluoromethyl) aniline was synthesized according to method A7.4-chloro-2-methoxy-5- (trifluoromethyl) aniline converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to give urea.

Description 98: 4-Chloro-L [-methyl-2-pyridinecarboxamide, which is synthesized according to method A2, step 3a, is reacted with 3-aminophenol according to method A2, step 4 to give 3 (2- (b1- methylcarbamoyl) -4-pyridyloxy) aniline.

4-Chloro-2-methoxy-5- (trifluoromethyl) -aniline was synthesized according to method A7.4-chloro-2-methoxy-5- (trifluoromethyl) -aniline to be converted to 4-chloro-3-methoxy-5- ( trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-chloro-3-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (Nmethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

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

Description 100: 4-Chloropyrcidine-2-carbonyl chloride is reacted with dimethylamine according to method A2, step 3b. The resulting 4-chloro-dimethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to method A2, step 4 to give 4- (2- (N, L-dimethylcarbamoyl) -4-pyridyloxy) -aniline. 4-Chloro-2-methoxy-5 (trifluoromethyl) aniline was synthesized according to method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (HT4-dimethylcarbamoyl) 4-pyridyloxy) aniline to give urea.

Description 101: 4-Chloro-L-methyl-2-pyridinecarboxamide, which is synthesized according to method A2, step 3a, is reacted with 3-aminophenol according to method A2, step 4 to give 3- (2- (N-methylcarbamoyl) ) -4-pyridyloxy) aniline. 2-Amino-3-methoxynaphthalene was synthesized according to method A1. According to method C3, 2-amino-3-methoxynaphthalene is reacted with bis (trichloromethyl) carbonate followed by 3- (2 (L-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 102: 4- (2- (N-methylcarbamoyl) 4-pyridyloxy) aniline was synthesized according to method A2.5-tert-butyl-2- (2,5-dimethylpyrrolyl) aniline was synthesized according to method A4.5-tert-butyl -2- (2,5-dimethylpyrrolyl) aniline was reacted with CDI, followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline according to method

65945 Bl

C2d to give urea.

Description 103: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to method A2, step 3b. 4-Chloro-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, using DMAC instead of DMF to give 4- (2- (1H-methylcarbamoyl) -4-pyridyloxy) aniline . According to method C2b, the reaction of 3-amino-2-methoxyquinoline with CDI followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline results in θ yielding 4- (2 - (> 1-methyl-carbamoyl) -4-pyridyloxy) phenyl urea.

Compounds listed in the tables below have been synthesized according to the detailed experimental procedures given above:

Tables

The compounds listed in Tables 1-6 below are synthesized according to the general methods shown above, and more detailed exemplary procedures are in the descriptions listed above and the characteristics are listed in the Tables.

* Compounds marked with an asterisk are not protected by the invention.

Table 1.

3-tert-butylphenyl urea

n

Description: we R M.P. <'C) HPLC (min.) TLC Rf ' TLC Solution System Mac -Speggt (Source) Synthet. method 1 _θ_ο o ' ^m ' 0.22 50% EtOAc / 50% hexane 418 (M + H) + (HPLC ES-MS) A13 NW

2 * Me 0.58 50% EtOAc / 50% hexane 403 (M + H) + (HPLC ES-MS A13 NW 3 0 V-NH 133- 135 0.68 100% EtOAc 448 (M + H) + (FAB) A8 C2d

Table 2.

5-tert-butyl-2-methoxyphenyl ureas

65945 Bl

Description; we R M.P. SS) HPLC (mln.) TLC Rr TLC System Razta. Mac Spec. (source) Synthet. Method 4 0 5.93 448 (M + H) + (HPLC ES-MS) A13 B1 C1a 5 0 V-NH —2 — θ — A l — OMe 120- 122 0.67 100% EtOAc 478 (M + H) + (FAB) A8 C2d

6 * ν ^ΝΗ 0.40 50% EtOAc / 50% hexane 460 (MH) + (HPLC ES-MS) AZ C2d 7 λ 4> ° -Qy ^c 0.79 50% EtOAc / 50% hexane 446 (M + H) + (HPLC ES-MS) A12 C2d

Table 3

5- (Trifluoromethyl) -2-methoxyphenyl ureas

65945 Bl

Cia 10 * -OYH ° M 0.33 50% EtOAC / 50% petr. ether 445 (M + H) + (HPLC ES-MS A13 C3 11 * - £) Vnh ^{X ==} \ / = / Me 'HJ' ¹ 0.20 2% Et3N / 98% EtOAc 461 (M + H) + (HPLC ES-MS A2 C4 12 / - <o - / 3 in », 0.27 2% Et3N / 98% EtOAc 447 (M + H) + (HPLC ES-MS A2 C4 13 0 V-NH - / 3-0- / 4 '* 0.62 100% EtOAc 461 (M + H) + (FAB) A2 C2a 14 0 V-NH3 114- 117 0.40 1% Et3N / 99% EtOAc 447 (M + H) + (FAB) A2 C4 1b 0 OM 232- 235 0.54 100% EtOAc 447 (M + H) + (FAB) A8 C2d

65945 Bl

16 0 Me V-NH 210- 213 0.29 5%. MeOH / 45% EtOAc / 50% petr. ether 475 (M + H) + (HPLC ES-MS A5 B1 C1c 17 ^C \ Y-NH -θ-ο-θ ”· 187- 188 0.17 50% EtOAc / 50% petr. ether 495 (M + H) + (HPLC ES-MS A6 B1 C1a 18 / - \ ° \ —V-Me NH ₂ 0.48 100% EtOAc 475 (M + H) + (HPLC ES-MS A2 stage 4, B1, C1a 19 Oh V-NH 194- 196 0.31 5% MeOH / 45% EtOAc / 50% petr. ether 475 (M + H) + (HPLC ES-MS A2 B1, C1a 20 o Cl V-NH 214- 216 0.25 v 5% MEOH / 45% EtOAc / 50% pet ether 495 (M + H) + (HPLC ES-MS A2 C1a 21 * 208- 210 0.30 50% EtOAc / 50% hexane 481 (M + H) + (HPLC ES-MS) A19 C2a 22 and NH ₂ 188190 0.30 70% EtOAc / 50% hexane 447 (M + H) + (HPLC ES-MS) A15 step4 C1a

65945 Bl

23 * -θ-c ^ - Qy ° r 0.50 70% EtOAc / 30% hexane 472 (M + H) + (FAB) A3 B1 C1a 24 Me / = / V 203- 205 0.13 100% EtOAc 479 (M + H) + (HPLC ES-MS A2 B1 C1a 25 * -Q-o- 0.09 75% EtOAc / 25% hexane 4458 (M + H) + (HPLC ES-MS A12 C2d 26 & MeO Me 169- 171 0.67 50% EtOAc / 50% petr. ether 474 (M + H) + (HPLC ES-MS A13 step 1, A13 step4 A16, B1, C1a 27 - / Λ-S- 0 V-NH / = / Me 218- 219 0.40 50% EtOAc / 50% petr. ether 477 (M + H) + (HPLC ES-MS A9 B1, C1a 28 * _ £ y_o_ Q / X ^ NMe r 212- 214 0.30 40% EtOAc / 60% hexane A2 C4 29 ~ i ^Xs ~ A 0 NH = / Me _ / 0.33 50% EtOAc / 50% petr. ether 474 (M + H) + (HPLC ES-MS A2 step 3b, A2 step4 B1, C1a

65945 Bl

30 0 V-NH _ ^ ~~ 'λ θ / —Pr-i 210- 211 A2 B1 C1a 31 V-NH 210- 204 0.43 10% MeOH / CH ₂ CI ₂ A14 B1 C1a d ₄ 32 0 y-M4 247- 249 0.57 10% MeOH / CH ₂ Cl ₂ A14 B1 C1a d ₄ 33 217- 219 0.07 10% MeOH / CH ₂ CI ₂ A14 B1 C1a d ₄ 34 0.11 70% EtOAc / 30% hexane A11 B1 Cif D1c 35 * F 0 0 0.38 70% EtOAc / 30% hexane A11 B1 C1f Die

65945 Bl

36 j ——— Ch F— ¢ / 0.77 70% EtOAc / 30% hexane A11 B1 C1f D1c 37 m / 0.58 70% EtOAc / 30% hexane A11 B1 C1f D1C 38 0.58 70% EtOAc / 30% hexane A11 B1 Clf D1c 39 0.17 70% EtOAc / 30% hexane A11 B1 C1f D1c 40 0.21 Ύθ% EtOAc / 30% hexane A11 B1 C1f D1c

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

F

F. JF

65945 Bl

Description: we R M.P. fC) HPLC (min.) TLC Rf TLC Solution System Mass Spectrum. (source) Synthet. method 41 —— ° 0 Y-ΝΗ -ο ^Μβ 163- 165 0.08 50% EtOAc / 50% petr. ether 464 (M + H) + (HPLC ES-MS A13 NW 42 -O- ' 0 V-ΝΗ / = / Me 215 0.06 50% EtOAc / 50% petr. ether 465 (M + H) + (HPLC ES-MS A2 C1a 43 0 '' Oh 0.10 50% EtOAc / 50% petr. ether 451 (M + H) + (HPLC ES-MS A2 C1a 44 Λ. o 0.25 30% EtOAc / 70% petr. ether 451 (M + H) + (HPLC ES-MS A2 C1a 45 # A 0 B-NH / = (Me w 0.31 30% EtOAc / 70% petr. ether 465 (M + H) + (HPLC ES-MS A2 C1a 46 * -θ-ο . R 176- 179 0.23 40% EtOAc / 60% hexane 476 (M + H) + (FAB) A3 C1a

65945 Bl

47 Me 0 y — NH No 0.29 A% MeOH / 45% EtOAc / 50% petr. ether 465 (M + H) + (HPLC ES-MS A5 C1c 48 * % /? ^X S-NH 206- 209 A15 C1a 49 Cl 0 V-NH 7 = / Me 147- 151 0.22 50% EtOAc / 50% petr. ether 499 (M + H) + (HPLC ES-MS A6 C1a 50 o> -. y »7 = \ ^-Me w 0.54 100% EtOAc / 479 (M + H) + (HPLC ES-MS A2 C1a 51 _ £ y_ ( 0 y ~ NH 187- 189 0.33 5% MeOH / 45% EtOAc / 50% Petr. ether 479 (M + H) + (HPLC ES-MS A2 C1a 52 Cl 0 V-NH ί— (Me Hl # ¹ 219 0.18 50% EtOAc / 50% hexane 485 (M + H) + (HPLC ES-MS A19 C1a 53 * 246- 248 0.30 50% EtOAc / 50% hexane 485 (M + H) + (HPLC ES-MS A19 C1a

65945 Bl

54 * Me 196- 200 0.30 50% EtOAc / 50% hexane 502 (M + H) + (HPLC ES-MS A15 C1a 55 * 0 V_o 228- 230 0.30 30% EtOAc / 70% CH ₂ CI ₂ 466 (M + H) + (HPLC ES-MS 56 Me ^Z 57 Λ 221- 222 0.75 80% EtOAc / 20% hexane 492 (M + H) + (HPLC ES-MS C1d 01 a 58 * 247 0.35 100% EtOAc C1d D1a D2 59 ^ Me 198- 200 0.09 100% EtOAc 479 (M + H) + (HPLC ES-MS A2 C1a 60 * MeO <UHF Me 158- 160 0.64 50% EtOAc / 50% petr. ether 61 0 V-NH - Oh 195- 197 0.39 10% MeOH / CH ₂ CI ₂ - A13 C1a

65945 Bl

62 0 V-NH 170- 172 0.52 10% MeOH / CH ₂ C1 ₂ A13 C1a O Chl 63 o- Ό 168- 171 0.39 10% MeOH / CH ₂ CI ₂ A13 C1a 64 - # V-o- Et S-NH N—. V # 176- 177 0.35 10% MeOH / CH ₂ CI ₂ A13 C1a 65 0 V- NH / = / Me ^S \ _ / 130133 487 (M + H) + (HPLC ES-MS A2 B1 C1a 66 _ # y_ ₍ o V ™ r— / Pr-i 155 A2 C1a 67 Λ uT- 225- 229 0.23 100% EtOAc - C1e 03 D1b 68 * -O- · '-Qv ⁰ ^ yNMe 234- 236 0.29 40% ESAS / 60% hexane A9 C1a 69 0 μ / = / Me V / 0.48 50% EtOAc / 50% petr. ether 481 (M + H) + (HPLC ES-MS

65945 Bl

70 -------------- g V-NH 0.46 c% MeOH / 95% CH ₂ CI ₂ 564 (M + H) + (HPLC ES-MS A10 C1a 71 199- 201 0.50 10% MeOH / CH ₂ CI ₂ A14 C1a D4 72 235- 237 0.55 10% MeOH / CH ₂ Cl ₂ A14 C1a D4 73 0 ——o— (1 'Χ-Λ'Ά / _M ' 200- 201 0.21 50% MeOH / CH ₂ CI ₂ A14 C1a D4 74 A 145- 148 75 <r 0.12 70% EtOAc / 30% hexane 527 (M + H) + (HPLC ES-MS A11 C1f D1c

65945 Bl

76 * Q 0.18 70% EtOAc / 30% hexane A11 C1f D1c 77 0.74 70% EtOAc / 30% hexane A11 C1f D1c 78 0.58 70% EtOAc / 30% hexane A11 Clf D1c 79 6 0.47 70% EtOAc / 30% hexane 569 (M + H) + {HPLC ES-MS A11 C1f D1c 80 Oh - ^ Λ — θ — 4 ~ ”S 'oms 0.18 70% EtOAc / 30% hexane is it? (M + H) + (HPLC ES-MS A11 Clf Die 81 MeO— 0.58 70% EtOAc / 30% hexane 557 (M + H) + (HPLC ES-MS A11 Clf Die

65945 Bl

82 0.37 70% EtOAc / 30% hexane 611 (M + H) + (HPLC ES-MS A11 Clf D1c 83 * ο Ν · · χ \ «- fyj 0.19 70% EtOAc / 30% hexane A11 Clf D1C 84 Λ ^ -ΝΗ -0—0 179- 183 ..... A2 A17 C1a D5

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

n

We are intoxicated R f.T. SS) HPLC (min.) ILC Rf TLC Solution System Mac Speck. (source) Synthet. method 8b o V-NH 186- 187 0.13 50% EtOAc / 50% petr. ether 509 (M + H) + (HPLC ES-MS A2 C1 C1a

65945 Bl

86 Cl -Η- · 0 y-NH / = / Me ISO152 0.31 50% EtOAc / 50% petr. ether N, 4H (M + H) + (HPLC ES-MS A6 B1 C1a 87 Cl 0 y — NH / - / Me 217- 219 0.16 50% EtOAc / 50% petr. ether ςχκ (M + H) + (HPLC ES-MS A2 B1 C1a 88 O-NH / = / ^Et 183- 184 0.31 50% EtOAc / 50% petr. ether 525 (M + H) + (HPLC ES-MS A2 B1 C1a 89 _ / A o y-NH / == / 'Mb V / 0.21 50% EtOAc / 50% petr. ether 511 (M + H) + (HPLC ES-MS A2 B1 C1a 90 __ / ah, 0 * y-NH / = / Me w 0.28 50% EtOAc / 50% petr. ether 525 (M + H) + (HPLC ES-MS A2 B1 C1a 91 V * -A ¹ 214- 216 0.28 50% EtOAc / 50% petr. ether 522 (M + H) + (HPLC ES-MS A2 B1 C1a 92 ~ Ό ~ · 0 V-NH Z = / Me ⁱ ~ w ^N 0.47 50% EtOAc / 50% petr. ether 527 (M + H) + (HPLC ES-MS A2step 3b, A2step 4, B1

65945 Bl

C1a 93 -Q Dx 0.47 50% EtOAc / 50% petr. ether 477 (M + H) + (HPLC ES-MS A2et3b, A2et4, B1 C1a 94 0 y- NH -O- ° -0 ^ b> 145- 150 0.41 5% MeOH / 95% CH ₂ Cl ₂ A10 B1 C1a

Table 6 5- (Trifluoromethyl) -4-chloro-methoxyphenyl ureas

Opium us R M.P. him HPLC (min.) TLC R ₍ ; TLC Solution System Mass Speck. (source Synthet. method 95 0 y —NH 140- 144 0.29 4 MeOH / 45% EtOAc / 50% petr. ether 495 (M + H) + (HPLC ES-MS A2 A7 B1 C1a 96 ^Cl \ NH-b — o 244- 245 0.39 5% MeOH / 45% EtOAc / 50% petr. ether 47Q (M + H) + (HPLC ES-MS A6 A7 B1 C1a

65945 Bl

97 ο Cl V- NH SS " 220- 221 0.25 5% MeOH / 45% EtOAc / 50% petr. ether 529 (M + H) + (HPLC ES-MS A2 A7 B1 C1a 98 ° -Ο * 0.27 5% MeOH / 45% EtOAc / 50% petr. ether 4Q5 (M + H) + (HPLC ES-MS A2 A7 B1 C1a 99 I -o-o ^B 180- 181 0.52 5% MeOH / 45% EtOAc / 50% petr. ether 509 (M + H) + (HPLC ES-MS A2 A7 B1 C1a 100 162- 165 A2 A7 B1 C1a

Try it R M.P. ('C) HPLC (min.) TLC Rt TLC Solution System Mac Speck. (source) Synthet. method 101 * Cl ί T. Η Η ο 162- 165 A1 A2 NW

65945 Bl

102 * Fr. T Η Η “-Φ * 0.10 50% EtOAc / 50% hexane 442 (M + H) + (HPLC ES-MS A2 A4 C2d 103 * ΗΝ '^' ΝΗ Ο w Ο Me-Μ · Me-ΝΗ 125- 130 0.24 40% EtOAc / 60% hexane 512 (M + H) + (FAB A2 C2b

The above examples can be repeated with similar success by substituting the common or specifically described reagents and / or operating conditions of this invention for those used in the foregoing examples.

Claims (3)

Claims Use of a compound of formula I: A-D-B (I) or a pharmaceutically acceptable salt thereof, wherein D is -NH-C (O) -NH-, A is a substituted moiety of up to 40 carbon atoms of formula -L- (ML ') q, where L is a substituted or unsubstituted phenyl or pyridyl moiety directly attached to D, L ¹ contains a substituted phenyl or pyridyl moiety, M is a bridging group having at least one atom, q is an integer from 1 to 3; and B is a substituted or unsubstituted phenyl group directly attached to D, where L ¹ is substituted by C (O) R _x ; where R _x is NRy and R _a and R _b are independently hydrogen and a carbon-based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon-based substituents to 24 carbon atoms which optionally contain heteroatoms selected from N, S and O and optionally substituted by halogen; wherein the substituents on B and L and the additional substituents on L ¹ are selected from the group consisting of C 1 -C ₁₀ alkyl to perhalo substituted C 1 -C ₁₀ alkyl, CN, OH, halogen, alkoxy and to perhalo substituted C 1 -C ₁₀ alkoxy and wherein M is a bridging group selected from the group consisting of -O- or -S-; for the manufacture of a medicament for the treatment of cancer cell growth mediated by raf kinase. The use according to claim 1, wherein the pharmaceutically acceptable salt of a compound of formula I is selected from the group consisting of: a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonyl (p-toluenesulfonyl) naphthalic sulfonic acid, 2-naphthalic sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, mal eic acid, benzoic acid, salicylic 65945 B1 acid, phenylacetic acid and almond acid; 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. Use according to claim 1 or 2, where the growth of a cancer cell mediated by raf kinase is lung cancer, 5 pancreas, thyroid, bladder or colon, myeloid leukemia or colon colon adenoma. Publication of the Patent Office of the Republic of Bulgaria 1797 Sofia, 52-B Dr. GM Dimitrov Blvd. Expert: B. Shikalanova Cf. № 65948 Circulation: 40 VC