ES2272203T3 - USE OF DIFENIL-UREAS REPLACED WITH OMEGA-CARBOXIARILO AS INHIBITORS OF THE QUINASA RAF. - Google Patents

Abstract

A compound of Formula I: A-D-B (I) or a pharmaceutically acceptable salt thereof, in which D is -NH-C (O) -NH-, A is a substituted moiety of up to 40 carbon atoms of the formula: -L- (ML 1) q, where L is a 5 or 6-member cyclic structure linked directly to D, L1 comprises a substituted cyclic moiety having at least 5 members, M is a bridge forming group having at least one atom, q is an integer from 1 to 3; and each cyclic structure of L and L1 contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and B is a substituted or unsubstituted aryl or heteroaryl moiety, up to tricyclic having up to 30 carbon atoms with at least one cyclic structure 6-member directly linked to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, where L1 is substituted with at least one substituent selected from the group consisting of -SO2Rx, -C (O) Rx and -C (NRy) Rz, Ry is hydrogen or a carbon-based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, until per-halo, Rz is hydrogen or a carbon-based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted with halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, containing option Highly heteroatoms selected from N, S and O and are optionally substituted with halogen.

Description

Use of substituted diphenyl ureas with? -carboxaryl as inhibitors of raf kinase

Field of the Invention

The use of a group of aryl ureas in the treatment of diseases raf mediated, and pharmaceutical compositions for use in said therapy.

Background of the invention

The p21 ras oncogene is an important contributor to the development and progression of solid human cancers and is mutated in 30% of all human cancers (Bolton et al . Ann. Rep. Med. Chem. 1994 , 29 , 165-74; Bos. Cancer Res . 1989 , 99 , 4682-9). In its normal, non-mutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avruch et al . Trends Biochem. Sci. 1994 , 19 , 279- 83). Biochemically, ras is a guanine nucleotide binding protein, and the cyclization between an activated form combined with GTP and an inactive form combined with GDP is strictly controlled by the activity of the endogenous GTPase of ras and other regulatory proteins. In ras mutants in cancer cells, the activity of endogenous GTPase is attenuated and, for this reason, the protein supplies constitutive growth signals to downstream effectors such as the raf kinase enzyme. This leads to the cancerous growth of the carrier cells of these mutants (Magnuson et al . Semin. Cancer Biol. 1994 , 5 , 247-53). It has been shown that the inhibition of the active ras effect by inhibition of the raf kinase signaling pathway by administration of deactivating antibodies to the raf kinase or by co-expression of negative dominant raf kinase or negative dominant MEK, the kinase substrate raf, leads to the reversal of transformed cells to the normal growth phenotype (see: Daum et al . Trends Biochem. Sci. 1994 , 19 , 474-80; Fridman et al . J. Biol. Chem. 1994 , 269 , 30105 -8.Kolch et al . ( Nature 1991 , 349 , 426-28) have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes. Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with the inhibition of the growth of a variety of human tumor types (Monia et al ., Nat. Med. 1996 , 2 , 668-75).

Summary of the invention

The present invention provides compounds that they are inhibitors of the enzyme kinase raf. Since the enzyme is a effector downstream of p21 ras, inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway, e.g., in the treatment of tumors and / or growth of cancer cells raf kinase mediated. In particular, the compounds are useful in the treatment of solid cancers of humans or animals, e.g., murine cancer, since the progression of these cancers depends on the signal transduction cascade of the ras protein and is therefore susceptible to interruption treatment of the cascade, that is, by inhibition of the kinase raf. From accordingly, the compounds of the invention are useful in the treatment of cancers, which include solid cancers, such as, for example, carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders (e.g. myeloid leukemia) or adenomas (e.g. villous colon adenoma).

The present invention therefore provides the use of a compound of Formula I:

(I) A-D-B

or a pharmaceutically salt acceptable of it, in where

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

A is a rest substituted of up to 40 carbon atoms of the formula: -L- (M-L 1) q, where L is a residue substituted or unsubstituted phenyl or pyridyl attached directly to D, L1 comprises a phenyl or substituted pyridyl moiety, M is a bridge forming group that has at least one atom, q is a number 1-3 integer; Y

B is a group substituted or unsubstituted phenyl attached directly to D, wherein L 1 is substituted by C (O) R x;

where R_ {x} is NR_ {a} R_ {b}, and R_ {a} and R b are independently hydrogen and a residue based on carbon of up to 30 carbon atoms that optionally contains heteroatoms selected from N, S and O and is substituted optionally with substituents based on halogen, hydroxy and carbon of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are substituted optionally with halogen;

where the substituents for B and L and the additional substituents for L1, are selected from the group consisting of C 1 -C 10 alkyl up to C 1 -C 10 alkyl per-halosubstituted, CN, OH, halogen, C 1 -C 10 alkoxy and up C 1 -C 10 alkoxy per-replaced, and

where M is a bridge forming group selected from the group consisting of -O- or -S-;

for the manufacture of a medicine for treatment of cancer cell growth mediated by raf kinase

Suitable alkyl groups and alkyl portions of groups, eg, alkoxy, etc., throughout this specification, include methyl, ethyl, propyl, butyl, etc., including all linear and branched chain isomers such as isopropyl, isobutyl, sec- butyl, tert- butyl, etc.

Suitable halogen groups include F, Cl, Br, and / or I, being possible from a single substitution to per-substitution (that is, all the H atoms of a group are replaced by a halogen atom) when a group alkyl is substituted with halogen, also being possible mixed substitution of halogen atom types in a residue dice.

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, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, oxic acid , fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. Additionally, pharmaceutically acceptable salts include acidic salts of inorganic bases, such as salts containing alkali cations (eg, Li +, Na + or K +), alkaline earth cations (eg, Mg ^ {+2, Ca +2 or Ba +2), the ammonium cation, as well as acid salts of organic bases, which include ammonium with aliphatic and aromatic substituents, and quaternary ammonium cations, such as those originate from protonation or peralkylation of triethylamine, N, N- diethylamine, N, N- dicyclohexylamine, lysine, pyridine, N, N- dimethylaminopyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1 , 5-diazabicyclo [4.3.0] non-5-eno (DBN) and 1,8-diazabicyclo [5.4.0] undec-7-eno (DBU).

Certain number of the compounds of Formula I they have asymmetric carbons and can therefore exist in forms racemic and optically active. Mix separation methods enantiomers and diastereoisomers are well known to experts in the art. The present invention encompasses any form racemic or optically active isolates of the compounds described in Formula I that possess raf inhibitory activity.

General Preparation Methods

The compounds of Formula I can be prepare for the use of chemical reactions and procedures known, some from raw materials that are commercially available. However, they will be provided to then general methods of preparation to help experts in the art in the synthesis of these compounds, providing more detailed examples in the experimental section Whats Next.

Substituted anilines can be generated using standard methods (March, Advanced Organic Chemistry , 3rd edition; John Wiley: New York (1985). Larock, Comprehensive Organic Transformations ; VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines are generally synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander, Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls can also be directly reduced using a potent hydride source, such as LiAlH4 (Seyden-Penne, Reductions by the Alumino- and Borohydrides in Organic Synthesis ; VCH Publishers: New York (1991)), or using a metal of zero valence, such as Fe, Sn or Ca, often in acidic media. There are many methods for nitroaryl synthesis (March, Advanced Organic Chemistry , 3rd edition; John Wiley: New York (1985). Larock, Comprehensive Organic Transformations ; VCH Publishers: New York (1989)).

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Scheme I

Nitroaryl reduction to Aril-Amines

one

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Nitroaryls are usually formed by electrophilic nitration of aromatic compounds using HNO3,  or an alternative source of NO_ {2} -. Nitroaryls can be elaborated further before reduction. So, the nitroaryls substituted with

2

potentially labile groups (e.g. F, Cl, Br, etc.) may undergo substitution reactions by nucleophilic treatment, such as thiolate (illustrated in Scheme II) or phenoxide. Nitroaryls may also suffer Ullmann type coupling reactions (Scheme II).

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Scheme II

Aromatic Nucleophilic Substitution Selected using Nitroaryls

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3

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Nitroaryls may also suffer reactions of cross coupling mediated by transition metals. By example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, suffer Palladium-mediated cross-coupling reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reactions, illustrated below), Arilestaños (Stille reactions) or arilcincs (Negishi reaction) to provide the biaryl (5).

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4

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

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Scheme III

Selected Methods of Synthesis of Aryl-Sulfones Fluoridated

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5

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As shown in Scheme IV, the formation of asymmetric ureas may involve the reaction of an aryl isocyanate (14) with an aryl amine (13). The heteroaryl isocyanate can be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene), or N, N'- carbonyldiimidazole ( CDI). The isocyanate can also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius type transposition. Thus, the reaction of the acid derivative 16 with an azide source, followed by transposition, provides the isocyanate. The corresponding carboxylic acid (17) can also be subjected to Curtius type transpositions using diphenylphosphoryl azide (DPPA) or a similar reagent.

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(Scheme turns to page next)

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Scheme IV

Selected Methods of Ureas Formation Asymmetric

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6

Finally, ureas can be manipulated subsequently using familiar methods for experts in the technique.

The invention also includes compositions pharmaceuticals that include a compound of Formula I and a vehicle physiologically acceptable, for the use indicated above.

The compounds can be administered via oral, topical, parenteral, by inhalation or spraying or by route rectal in unit dosage formulations. The term 'administration by injection' includes intravenous injections, intramuscular, subcutaneous and parenteral, as well as the use of infusion techniques One or more compounds may be present. in association with one or more pharmaceutically non-toxic vehicles acceptable and, if desired, other active ingredients.

Compositions intended for oral use may be prepared according to any suitable method known in the technique for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, agents flavorings, coloring agents and preservatives in order to provide pleasant preparations to the palate. The tablets contain the active ingredient in admixture with non-toxic excipients pharmaceutically acceptable that are suitable for manufacturing of tablets. These excipients may be, for example, diluents. inert, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrators, for example, corn starch, or alginic acid; Y binding agents, for example magnesium stearate, acid stearic or talc. The tablets may be uncoated or they may be coated by known techniques to retard the disintegration and adsorption in the gastrointestinal tract and thereby provide sustained action over a period dragged on. For example, a delay material can be used temporary such as glyceryl monostearate or distearate glyceryl These compounds can also be prepared in the form solid, which is released quickly.

Formulations for oral use may also present as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, by example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium, for example peanut, paraffin oil or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are thick suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example poly (oxyethylene stearate), or condensation products of ethylene oxide with aliphatic alcohols of long chain, for example heptadecaethylene-oxyethanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as poly (oxyethylene sorbitol) monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example poly (ethylene sorbitan) monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p -hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin.

Suitable dispersible powders and granules for preparing a thick aqueous suspension by adding water provide the active ingredient in admixture with an agent dispersant or humectant, thick suspending agent and one or more preservatives Dispersing or wetting agents and agents Suitable thick suspension are illustrated by those already mentioned previously. Excipients may also be present. additional, for example, sweetening, flavoring and dyes

The compounds can also be found in the form of non-aqueous liquid formulations, e.g. suspensions oils that can be formulated by thick suspension of active ingredients in a vegetable oil, for example peanut ("arachis oil"), olive oil, sesame oil or peanut oil, or in such a mineral oil as paraffin oil. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol Sweetening agents such as the above, and flavoring agents to provide oral preparations pleasant to the palate. These compositions can be preserved by adding an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention they can also be found in the form of oil emulsions in Water. The oily phase can be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example a paraffin oil or mixtures thereof. Agents Suitable emulsifiers can be naturally occurring gums, eg gum arabic or gum tragacanth, existing phosphatides naturally, for example soy, lecithin, and esters or esters partial derivatives of fatty acids and hexitol anhydrides, by example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example poly (oxyethylene sorbitan) monooleate. The emulsions may also contain sweetening agents and flavorings

Syrups and elixirs can be formulated with agents sweeteners, for example glycerol, propylene glycol, sorbitol or saccharose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

The compounds can 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 temperatures ordinary but liquid at rectal temperature, and therefore It will melt in the rectum to release the drug. Such materials They include cocoa butter and polyethylene glycols.

For all the use regimes described in this report for the compounds of Formula I, the regimen of Daily oral dosage will preferably be from 0.01 to 200 mg / kg. of total body weight. The daily dosage for administration by injection, including intravenous injections, intramuscular, subcutaneous and parenteral, and use of techniques infusion will preferably be from 0.01 to 200 mg / kg of weight total body The daily rectal dosing regimen will be preferably from 0.01 to 200 mg / kg of total body weight. He Topical daily dosage regimen will preferably be from 0.1 at 200 mg, administered 1 to 4 times a day. The regime of Daily dosage by inhalation will preferably be from 0.01 to 10 mg / kg total body weight.

It will be appreciated by those skilled in the art. that the particular method of administration will depend on a diversity of factors, all of which are considered routinely when therapeutic products are administered. Be also appreciated by one skilled in the art that the level Specific dose for a given patient depends on a diversity of factors, which include the specific activity of the compound administered, age, body weight, health, sex, diet, time and route of administration, excretion rate, etc. It will be further appreciated by those skilled in the art that the optimal course of treatment, that is, the mode of treatment and the daily dose number of a compound of Formula I or a pharmaceutically acceptable salt thereof during a defined number of days, can be determined by experts in the art using conventional treatment tests.

It will be understood, however, that the level Specific dose for any particular patient will depend on a variety of factors, which include the activity of the compound specific employee, age, body weight, general condition health, sex, diet, administration time, route of administration and excretion rate, the combination of drugs and the severity of the condition undergoing therapy.

Compounds can be produced from known compounds (or raw materials that, in turn, can produced from known compounds), e.g., by the methods General preparation shown below. Activity of a given compound to inhibit raf kinase can be tested routinely, e.g., according to procedures described further ahead. The following examples are provided only for illustrative purposes and are not intended, nor should they be considered as limiting the invention in any way, nor they must be interpreted in that sense.

Examples

All reactions were performed on material of flame dried or oven dried glass under pressure positive of dry argon or dry nitrogen, and stirred magnetically unless otherwise indicated. Liquids and Sensitive solutions were transferred by syringe or cannula, and were introduced into the reaction vessels through rubber membranes Unless otherwise indicated, the term "concentration under reduced pressure" refers to the use of a rotary evaporator Buchi at 15 • 1,332 • 10 2 Pa (mmHg). Unless otherwise indicated, the term "a high vacuum "refers to a vacuum of 0.4-1.0 \ cdot 1,332 • 10 Pa (mmHg) (sic).

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All temperatures are expressed in degrees Celsius (ºC) uncorrected. Unless otherwise indicated, all Parts and percentages are expressed by weight.

Commercial grade reagents and solvents were used without further purification. N -cyclohexyl- N ' - (methyl-
polystyrene) carbodiimide was purchased from Calbiochem-Novabiochem Corp. 3- tert -Butilaniline, 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, ethyl 3-amino-2-naphthol, 4-isocyanatobenzoate, N- acetyl-4-chloro-2-methoxy-5- (trifluoromethyl ) 4-Chloro-3- (trifluoromethyl) phenyl aniline and isocyanate were purchased and used without further purification. The syntheses of 3-amino-2-methoxyquinoline (E. Cho et al ., WO 98/00402; A. Cordi et al ., EP 542,609; IBID Bioorg. Med. Chem. , 3 , 1995 , 129), 4- (3-carbamoylphenoxy) -1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79 , 1959 , 760; Chem. Abstr. 53 , 1959 , 12761b), 3- tert -butylphenyl isocyanate (O. Rohr et al ., DE 2,436. 108) and 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (K. Inukai et al ., JP 42.025.067; IBID Kogyo Kagaku Zasshi 70 , 1967 , 491) have been previously described.

Thin layer chromatography (TLC) is performed using Whatman® 250 µm silica gel plates 60A F-254 with glass and coated back previously. The plates were visualized by one or more of the following techniques: (a) ultraviolet lighting, (b) iodine vapor exposure, (c) immersion of the plate in a 10% solution of phosphomolibic acid in ethanol followed by heating, (d) immersion of the plate in a sulfate solution of cerium followed by heating, and / or (e) immersion of the plate in  an ethanolic acid solution of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using EM Science® mesh silica gel 230-400

Melting points (mp) were determined using a melting point apparatus Thomas-Hoover or an automatic knitting device Mettler FP66 fusion, and are uncorrected. Infrared spectra according to the Fourier transform they were obtained using a Mattson 4020 Galaxy Series spectrophotometer. The spectra of Nuclear magnetic resonance imaging (NMR) of the proton (1 H) was measured with a General Electric GN-Omega 300 spectrometer (300 MHz) with Me 4 Si (δ 0.00) or residual solvent protonized (CHCl 3, δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. NMR spectra of carbon (13 C) were measured with a General Electric spectrometer GN-Omega 300 (75 MHz) with solvent (CDCl3) δ 77.0; MeOD-d 3; δ 49.0; DMSO-d_ {6} δ 39.5) as standard. The Low resolution mass spectra (MS) and mass spectra High resolution (HRMS) were obtained as mass spectra with electron impact (EI) or as mass spectra with bombardment of fast atoms (FAB). Mass spectra with impact of electrons (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer, equipped with a Probe  of Chemical Ionization by Desorption Vaccumetrics for introduction of the sample. The ion source was maintained at 250 ° C. Ionization Electron impact was performed with 70 electronic energy eV and a capture current of 300 µA. Mass spectra of secondary ion with liquid cesium (FAB-MS), a updated version of rapid atom bombardment, were obtained using a Kratos Concept 1-H spectrometer. The mass spectra by chemical ionization (CI-MS) are obtained using a Hewlett Packard instrument MS-Engine (5989A) with methane or ammonia as the gas reagent (1 x 10-4 · 1332 • 10 Pa (torr) a 2.5 x 10 -4 - 1,332 · 10 2 Pa (torr) at 2.5 x 10-4? 1,332? 10 Pa (torr) (sic). Probe chemical ionization with direct insertion desorption (DCI) (Vaccumetrics, Inc.) intensified from 0 to 1.5 amps in 10 s and it kept at 10 amps until the traces of the sample (~ 1-2 min). The spectra are They scanned from 50 to 800 amu at 2 s per scan. The spectra of HPLC masses-electronic spray (HPLC ES-MS) were obtained using an instrument Hewlett-Packard 1100 HPLC equipped with a pump quaternary, a variable wavelength detector, a column C-18, and a mass spectrometer by capture of Finnigan LCQ ions with electronic spray ionization. The spectra were scanned from 120 to 800 amu using a variable ionization time according to the number of ions in the fountain. Mass spectra with gas chromatography of Selective ions (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with a column HP-1 methyl silicone (0.33 mM coating; 25 m x 0.2 mm) and a Selective Detector Hewlett Packard 5971 masses (ionization energy 70 eV). The Elemental analyzes were performed by Robertson Microlit Labs, Madison, NJ

All compounds exhibited NMR spectra, LRMS and elementary analysis or HRMS consistent with the structures assigned.

List of abbreviations and acronyms

AcOH

acetic acid

anh

Anhydrous atm atmosphere (s)

BOC

tert -butoxycarbonyl

CDI

1,1'-carbonyl diimidazole

conc

Concentrated

d

days)

desc

decomposition

DMAC

N, N- dimethylacetamide

DMPU

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

DMF

N, N- dimethylformamide

DMSO

Dimethylsulfoxide

DPPA

diphenylphosphoryl azide

EDCI

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

EtOAc

ethyl acetate

EtOH

ethanol (100%)

Et 2 O

diethyl ether

Et 3 N

Triethylamine

h

hours)

HOBT

1-hydroxybenzotriazole

m -CPBA

acid 3-chloroperoxybenzoic

MeOH

Methanol

pet ether

petroleum ether (boiling range 30-60ºC)

temp.

Temperature

THF

Tetrahydrofuran

TFA

trifluoroacetic acid

Tf

Trifluoromethanesulfonyl

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A. General Methods for Synthesis of Anilines Replaced A1. General Method for Training Aril-Aminas by the Way of Formation of Ether Followed by Saponification of Ester, Curtius Transposition and Carbamate deprotection. Synthesis of 2-Amino-3-methoxynaphthalene

7

He passed one

3-Methoxy-2-naphthoate of methyl

A thick suspension of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K 2 CO 3 (7.96 g, 57.6 mmol) in DMF (200 ml) it was stirred at room temperature for 15 min, and then treated with iodomethane (3.43 ml, 55.1 mmol). The mixture was allowed to stir at room temperature overnight, and then treated with water (200 ml). The resulting mixture was extracted with EtOAc (2 x 200 ml). The combined organic layers were washed with a saturated NaCl solution (100 ml), dried (MgSO 4), and concentrated under reduced pressure (0.4 · 1.332 • 10 Pa (0, 4 mmHg) overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10.30 g): 1 H-NMR (DMSO-d 6) δ 2.70 ( s, 3H), 2.85 (s, 3H), 7.38 (t app, J = 8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (t app, J = 8 , 09 Hz, 1H), 7.84 (d, J = 8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).

8

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He passed 2

Acid 3-methoxy-2-naphthoic

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A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 ml) in MeOH (100 ml) at room temperature was treated with a 1N solution of NaOH (33, 4 ml, 33.4 mmol). The mixture was heated at reflux temperature for 3 h, cooled to room temperature, and acidified with a 10% citric acid solution. The resulting solution was extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO4), and concentrated under reduced pressure. The residue was triturated with hexane and then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): 1 H-NMR (DMSO-d_ { 6}) δ 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d, J = 8, 09 Hz, 1H), 7.91 (d, J = 8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (br s, 1H).

9

He passed 3

2- ( N - (Carbobenzyloxy) amino-3-methoxynaphthalene

A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et 3 N (2.59 ml, 18.6 mmol) in toluene anh. (70 ml) was stirred at room temperature for 15 min, and 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 by syringe. The mixture was then heated at 80 ° C overnight. The resulting mixture was cooled to room temperature, quenched with a 10% citric acid solution, and extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc / 86% hexane) to give 2- ( N - (carbobenzyloxy) amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%): 1 } H-NMR (DMSO-d6) δ 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7 , 75 (m, 2H), 8.20 (s, 1H), 8.76 (s, 1H).

10

He passed 4

2-Amino-3-methoxynaphthalene

A thick suspension of 2- ( N - (carbobenzyloxy) amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd / C (0.5 g) in EtOAc (70 ml) was kept low an atm of H2 (balloon) at room temperature overnight. The resulting mixture was filtered through Celite® and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder. (2.40 g, 85%): 1 H-NMR (DMSO-d 6) δ 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7 , 16 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0, 1H); EI-MS m / z 173 (M ^ +}).

A2. Synthesis of?-Carbamil-Anilines by Formation of a Carbamilpiridine Followed by Nucleophilic Coupling with an Aryl-Amine. Synthesis of 4- (2- N- Methylcarbamil-4-pyridyloxy) aniline

eleven

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He passed 1st

Synthesis of 4-Chloro- N -methyl-2-pyridinecarboxamide by the Menisci reaction

Caution : This is a very dangerous, potentially explosive reaction. To a stirred solution of 4-chloropyridine (10.0 g) in N- methylformamide (250 ml) at room temperature, conc. H 2 SO 4 was added. (3.55 ml) to generate an exotherm. H2O2 (30% by weight in H2O, 17 ml) was added to this mixture followed by FeSO4 · 7H2O (0.56 g) to generate Another exotherm. The resulting mixture was stirred in the dark at room temperature for 1 h, and then slowly heated for 4 h at 45 ° C. When the bubbling had decreased, the reaction mixture was heated at 60 ° C for 16 h. The resulting opaque brown solution was diluted with H2O (700 ml) followed by a 10% NaOH solution (250 ml). The resulting mixture was extracted with EtOAc (3 x 500 ml). The organic phases were washed separately with a saturated solution of NaCl (3 x 150 ml), then combined, dried (MgSO 4) and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc / 50% hexane to 80% EtOAc / 20% hexane). The resulting yellow oil crystallized at 0 ° C for 72 h to give 4-chloro- N- methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc / 50% hexane) R f 0 ,fifty; 1 H-NMR (CDCl 3) δ 3.04 (d, J = 5.1 Hz, 3H), 7.43 (dd, J = 5.4, 2.4 Hz, 1H) , 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J = 5.1 Hz, 1H); CI-MS m / z 171 ((M + H) +).

12

He passed 1 B

Synthesis of the chloride salt of 4-chloropyridine-2-carbonyl.HCl via picolinic acid

Anhydrous DMF (6.0 ml) was added slowly to SOCl 2 (180 ml) between 40 ° and 50 ° C. The solution was stirred in said temperature range for 10 min, and then acid was added picolinic (60.0 g, 487 mmol) in portions for 30 min. The resulting solution was heated to 72 ° C (vigorous release of SO2) for 16 h to generate a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 ml. The addition process of toluene / concentration was repeated twice. The residue The resulting practically dry was filtered and the solids washed with toluene (2 x 200 ml) and dried under high vacuum for 4 h to provide the chloride salt of 4-chloropyridine-2-carbonyl.HCl  as a yellow-orange solid (92.0 g, 89%).

13

He passed 2

Salt Synthesis 4-chloropyridine-2-carboxylate methyl.HCl

DMF anh was added slowly. (10.0 ml) a SOCl 2 (300 ml) at 40-48 ° C. The solution was stirred. in said temperature range for 10 min, and then added picolinic acid (100 g, 812 mmol) for 30 min. The solution resulting was heated to 72 ° C (strong release of SO2) for 16 h to generate a yellow solid. The resulting mixture cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 ml. The process of adding Toluene / concentration was repeated twice. The residue practically The resulting dry was filtered, and the solids were washed with toluene (50 ml) and dried under high vacuum for 4 hours to provide the chloride salt 4-chloropyridine-2-carbonyl.HCl as an off-white solid (27.2 g, 16%). This material was left apart.

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 Et2O (200 ml) dropwise. The resulting solids were filtered, washed with Et2O (200 ml) and dried under reduced pressure at 35 ° C to provide the methyl 4-chloropyridine-2-carboxylate salt.HCl as a white solid (110 g, 65 %): mp 108-112 ° C; 1 H-NMR (DMSO-d 6) δ 3.88 (s, 3H); 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 5.5 Hz, 1H ); 10.63 (br s, 1 H); HPLC ES-MS m / z 172 ((M + H) +).

14

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He passed 3rd

Synthesis of methyl 4-chloro- N -methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carboxylate

A thick suspension of the methyl 4-chloropyridine-2-carboxylate salt. HCl (89.0 g, 428 mmol) in MeOH (75 mL) at 0 ° C was treated with a 2.0 M solution of methylamine in THF (1 L ) at a rate that kept the internal temperature below 5 ° C. The resulting mixture was stored at 3 ° C for 5 h, and then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500 ml), dried (Na2SO4) and concentrated under reduced pressure to provide 4-chloro- N- methyl-2-pyridinecarboxamide as colored crystals. pale yellow (71.2 g, 97%): mp 41-43 ° C; 1 H-NMR (DMSO-d 6) δ 2.81 (s, 3H), 7.74 (dd, J = 5.1, 2.2 Hz, 1H), 8.00 ( d, J = 2.2, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.85 (br d, 1H); CI-MS m / z 171 ((M + H) +).

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fifteen

He passed 3b

Synthesis of 4-chloro- N- methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carbonyl chloride

The salt of 4-chloropyridine-2-carbonyl chloride.HCl (7.0 g, 32.95 mmol) was added portionwise to a mixture of a 2.0 M solution of methylamine in THF (100 ml) and MeOH (20 ml) at 0 ° C. The resulting mixture was stored at 3 ° C for 4 h and then concentrated under reduced pressure. The resulting practically dry solids were suspended in EtOAc (100 ml) and filtered. The filtrate was washed with a saturated NaCl solution (2 x 100 ml), dried (Na2SO4) and concentrated under reduced pressure to provide 4-chloro- N- methyl-2-pyridinecarboxamide as a crystalline yellow solid (4.95 g, 88%): mp 37-40 ° C.

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16

He passed 4

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

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in DMF anh. (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 content was treated with 4-chloro- N- methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and K 2 CO 3 (6.50 g, 47.0 mmol) and heated then at 80 ° C for 8 h. The mixture was cooled to room temperature and separated between EtOAc (500 ml) and a saturated NaCl solution (500 ml). The aqueous phase was extracted again with EtOAc (300 ml). The combined organic layers were washed with a saturated NaCl solution (4 x 1000 ml), dried (Na2SO4) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 ° C for 3 h to provide 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline as a light brown solid (17.9 g, 84%): 1} H-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, 3H), 5.17 (br s, 2H), 6.64-6.86 (quartet AA'BB ', J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H) , 8.44 (d, J = 5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m / z 244 ((M + H) +).

A3. General Method for the Synthesis of Anilines by Aromatic Nucleophilic Addition Followed by Nitroarene Reduction. Synthesis of 5- (4-aminophenoxy) isoindoline-1,3-dione

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17

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He passed one

Synthesis of 5-hydroxyisoindoline-1,3-dione

To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH. (25 ml) 4-hydroxyxtalic acid (5.0 g, 27.45 mmol) was added slowly. The resulting mixture was heated at 120 ° C for 45 min, and then the clear bright yellow mixture was heated at 160 ° C for 2 h. The resulting mixture was maintained at 160 ° C and concentrated to 15 ml, then cooled to temp. ambient and adjusted to pH 10 with a 1N NaOH solution. This mixture was cooled to 0 ° C and slowly acidified to pH 5 using a 1N HCl solution. The resulting precipitate was collected by filtration and dried under reduced pressure to give 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%): 1 H-NMR (DMSO-d 6) δ 7.00-7.03 (m, 2H), 7.56 (d, J = 9.3 Hz, 1H).

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18

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He passed 2

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

To a thick suspension of NaH (1.1 g, 44.9 mmol) in DMF (40 ml) maintained under stirring at 0 ° C was added a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19, 6 mmol) in DMF (40 ml) dropwise. The bright yellow-green mixture was allowed to return to room temperature and stirred for 1 h, after which 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added by syringe in 3-4 servings The resulting mixture was heated at 70 ° C overnight, then cooled to temp. ambient and slowly diluted with water (150 ml), after which it was extracted with EtOAc (2 x 100 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 5- (4-nitrophenoxy) isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC ( 30% EtOAc / 70% hexane) R f 0.28; 1 H-NMR (DMSO-d 6) δ 7.32 (d, J = 12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 9 Hz, 2H), 11.43 (br s, 1H); CI-MS m / z 285 ((M + H) +, 100%).

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19

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He passed 3

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

A solution of 5- (4-nitrophenoxy) isoindoline-1,3-dione (0.6 g, 2.11 mmol) in conc. AcOH. (12 ml) and water (0.1 ml) was stirred under argon while slowly adding powdered iron (0.59 g, 55.9 mmol). 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 (MgSO4) and concentrated under reduced pressure to give 5- (4-aminophenoxy) isoindoline-1,3-dione as a brownish solid (0.4 g, 75%): TLC ( 50% EtOAc / 50% hexane) R f 0.27; 1 H-NMR (DMSO-d 6) δ 5.14 (br s, 2H), 6.62 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J = 8.4 Hz, 1H), 11.02 (s, 1 H); 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-dimethylpyrrolyl) aniline

twenty

He passed one

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

To a solution of 2-nitro-4- tert -butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 ml) maintained under stirring were 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 separation of volatile materials. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 (10 ml) and washed sequentially with a 1N solution of HCl (15 ml), a 1N solution of NaOH (15 ml) and a saturated solution of NaCl (15 ml), dried (MgSO4) and concentrated under reduced pressure. The resulting orange-brown solids were purified by column chromatography (60 g of SiO2; gradient from 6% EtOAc / 94% hexane to 25% EtOAc / 75% hexane) to give 1- (4- tert -butyl) -2-nitrophenyl) -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) δ 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 ( m, 1H), 7.62 (dd, 1H), 7.88 (d, J = 2.4 Hz, 1H); CI-MS m / z 273 ((M + H) +, 50%).

twenty-one

He passed 2

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

A thick suspension of 1- (4- tert -butyl-2-nitrophenyl) -2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10% Pd / C (0.056 g) and EtOAc (50 ml) in H 2 atmosphere (balloon) was stirred for 72 h, and then filtered through a plug of Celite®. The filtrate was concentrated under reduced pressure to give 5- tert -butyl-2- (2,5-dimethylpyrrolyl) aniline as yellowish solids (0.30 g, 99%): TLC (10% EtOAc / 90% hexane) R_ { f} 0.43; 1 H-NMR (CDCl 3) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73 -6.96 (m, 3H), 7.28 (br s, 1H).

TO 5. General Method for the Synthesis of Anilines from Anilines by Aromatic Nucleophilic Substitution. Synthesis of Salt 4- (2- ( N- Methylcarbamoyl) -4-pyridyloxy) -2-methylaniline. HCl

22

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 mixture The black color was stirred at room temperature until the flask had reached room temperature. The content was then treated with 4-chloro- N- methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 ° C for 8 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 a saturated NaCl solution (200 ml), dried (MgSO4) and concentrated under reduced pressure. The residual black oil was treated with Et2O (50 ml) and subjected to ultrasound. The solution was then treated with HCl (1 M in Et2O; 100 ml) and stirred at room temperature for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was filtered off the solution and stored under anaerobic conditions at 0 ° C before use: 1 H-NMR (DMSO-d 6 }) δ 2.41 (s, 3H), 2.78 (d, J = 4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J = 8.5 , 2.6 Hz, 1H), 7.23 (dd, J = 5.5, 2.6 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.55 (d , J = 2.6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 5.9 Hz, 1H), 8.99 (q, J = 4.8 Hz, 1H).

A6 General Method for the Synthesis of Anilines from Hydroxyanilines by N Protection, Nucleophilic Aromatic Substitution and Deprotection. Synthesis of 4- (2- ( N- Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline

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2. 3

He passed one

Synthesis of 3-Chloro-4- (2,2,2-trifluoroacetylamino) phenol

Iron (3.24 g, 58.00 mmol) was added to TFA kept under stirring (200 ml). They were added to this suspension thick 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 ml). This thick gray suspension was stirred at room temperature for 6 d. The iron was separated from the solution by filtration and the Remaining material was concentrated under reduced pressure. Gray solid The resulting was dissolved in water (20 ml). To the yellow solution resulting was added a saturated solution of NaHCO3 (50 ml). The solid that precipitated from the solution was separated. The filtrate is slowly extinguish with sodium bicarbonate solution until that the product visibly separated from the solution (which is determined using a mini-treatment vial). The slightly cloudy yellow solution was extracted with EtOAc (3 x 125 ml) The combined organic layers were washed with a solution saturated NaCl (125 ml), dried (MgSO4) and concentrated  under reduced pressure. 1 H-NMR (DMSO-d6) indicated a 1: 1 ratio of the material starting nitrophenol and the product 3-Chloro-4- (2,2,2-trifluoroacetylamino) phenol wanted. The raw material was taken to the next step without further purification.

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24

He passed 2

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

A solution of crude 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 ml) was treated with potassium tert -butoxide (5.16 g, 45.98 mmol) and the brownish black mixture was stirred at room temperature until the flask had cooled to room temperature. The resulting mixture was treated with 4-chloro- N- methyl-2-pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 ° C under argon for 4 d. The black reaction mixture was cooled to room temperature and then poured into cold water (100 ml). The mixture was extracted with EtOAc (3x75 ml) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was precipitated by column chromatography (gradient from 20% EtOAc / pet. Ether to 40% EtOAc / pet. Ether) to give 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl - (2,2,2-trifluoro) acetamide as a yellow solid (8.59 g, 23.0 mmol).

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25

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He passed 3

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

A solution of 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl- (2,2,2-trifluoro) acetamide crude (8.59 g, 23.0 mmol) in dry 4-dioxane (20 ml) was treated with a 1N solution of NaOH (20 ml). This brown solution was kept under stirring 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- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline as a green oil that solidified upon leaving. at rest (2.86 g, 10.30 mmol): 1 H-NMR (DMSO-d 6) δ 2.77 (d, J = 4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J = 8.5, 2.6 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 7.07 (dd, J = 5.5, 2.6 Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.75 (q, J = 4.8 Hz, 1H).

A7 General Method for the Deprotection of an Aniline Acylated Synthesis of 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline

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26

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A thick suspension of 3-chloro-6- ( N -acetyl) -4- (trifluoromethyl) anisole (4.00 g, 14.95 mmol) in a 6 M solution of HCl (24 ml) was heated to the temperature of reflux for 1 h. The resulting solution was allowed to cool to room temperature, during which time it solidified slightly. The resulting mixture was diluted with water (20 ml), and then treated with a combination of solid NaOH and a saturated NaHCO 3 solution until the solution became basic. The organic layer was extracted with CH2Cl2 (3 x 50 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 4-chloro-2-methoxy-5- (trifluoromethyl) aniline as a brown oil (3.20 g, 14.2 mmol): 1 H-NMR (DMSO-d 6) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

A8 General Method for the Synthesis of? -Alkoxy-? -Carboxyphenyl-Anilines. Synthesis of 4- (3- ( N- Methylcarbamoyl) -4-methoxyphenoxy) aniline

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27

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He passed one

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

To a solution of 4- (3-carboxy-4-hydroxyphenoxy) -1-nitrobenzene (prepared from 2,5-dihydroxybenzoic acid analogously to that described in method A13, Step 1, 12 mmol) in acetone (50 ml) K2CO3 (5 g) and sulfate were added dimethyl (3.5 ml). The resulting mixture was heated to the temperature of reflux overnight, then cooled to the temperature ambient and filtered through a plug of Celite®. The solution resulting was concentrated under reduced pressure, absorbed into SiO2, and was purified by column chromatography (50% EtOAc / 50% hexane) to give 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene as a yellow powder (3 g): mp. 115-118 ° C.

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28

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He passed 2

4- (3-Carboxy-4-methoxyphenoxy) -1-nitrobenzene

A mix of 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 ml) in MeOH (45 ml) was stirred at room temperature overnight and then heated to the reflux temperature for 4 h. The resulting mixture was cooled. at room temperature and concentrated under reduced pressure. He residue was dissolved in water (50 ml), and the aqueous mixture was acidified with a 1N solution of HCl. The resulting mixture was extracted with EtOAc (50 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (1.04 g).

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29

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He passed 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 SOCl2 (0.64 ml, 8.77 mmol) in portions. The resulting solution heated at reflux temperature for 18 h, cooled to room temperature and concentrated under reduced pressure. The solids resulting yellows were dissolved in CH2Cl2 (3 ml) and the resulting solution was then treated with a methylamine solution (2.0 M in THF, 3.5 ml, 7.02 mmol) in portions (Caution: gas evolution), and stirred at room temperature for 4 h. The resulting mixture was treated with a 1N solution of NaOH, and then extracted with CH2Cl2 (25 ml).

The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give 4- (3- ( N- methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene as a yellow solid (0.50 g, 95%).

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30

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He passed 4

4- (3- ( N- Methylcarbamoyl) -4-methoxyphenoxy) aniline

A thick suspension of 4- (3- ( N- methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd / C (0.20 g) in EtOH ( 55 ml) was stirred under 1 atm of H2 (balloon) for 2.5 d, and then filtered through a plug of Celite®. The resulting solution was concentrated under reduced pressure to provide 4- (3- ( N- methylcarbamoyl) -4-methoxyphenoxy) aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et3) N / 99.9% EtOAc) R f 0.36.

A9 General Method for Preparation of Anilines that They contain? -Alkylphthalimide. Synthesis of 5- (4-Aminophenoxy) -2-methylisoindoline-1,3-Dione

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31

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He passed one

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

A thick suspension of 5- (4-nitrophenoxy) isoindoline-1,3-dione (A3, Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 ml) was stirred at room temperature for 1 h, and then treated with methyl iodide (0.3 ml, 4.57 mmol). The resulting mixture is stirred at room temperature overnight, then cooled at 0 ° C and treated with water (10 ml). The resulting solids are collected and dried under reduced pressure to give 5- (4-nitrophenoxy) -2-methylisoindoline-1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc / 65% hexane) R f 0.61.

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32

He passed 2

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

A thick 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 under 1 atm of H2 (balloon) overnight. The resulting mixture is filtered through a plug of Celite® and concentrated under pressure reduced The resulting yellow solids were dissolved in EtOAc (3 ml) and filtered through a plug of SiO2 (60% EtOAc / 40% hexane) to provide 5- (4-Aminophenoxy) -2-methyl-isoindoline-1,3-dione  as a yellow solid (0.67 g, 86%): TLC (40% EtOAc / 60% hexane) R f 0.27.

A10 General Method for the Synthesis of [omega]-Carbamoylaryl-Anilines by Reaction of [Omega] -alkoxycarbonylaryl Precursors with Amines. Synthesis of 4- (2- ( N - (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline

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33

He passed one

Synthesis of 4-Chloro-2- ( N - (2-morpholin-4-ylethyl) carbamoyl) pyridine

To a solution of methyl 4-chloropyridine-2-carboxylate salt.HCl (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 ml) was added 4- (2-aminoethyl) morpholine ( 2.55 ml, 19.4 mmol) dropwise and the resulting solution was heated at reflux temperature for 20 h, cooled to room temperature, and treated with water (50 ml). The resulting mixture was extracted with EtOAc (50 ml). The organic layer was dried (MgSO 4) and concentrated under reduced pressure to provide 4-chloro-2- ( N - (2-morpholin-4-ylethyl) carbamoyl) pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH / 90 EtOAc) R f 0.50.

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3. 4

He passed 2

Synthesis of 4- (2- ( N - (2-Morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert -butoxide (0.53 g, 4.75 mmol) in DMF (8 ml) was stirred at room temperature for 2 h, and then treated successively with 4-chloro-2- ( N - (2-morpholin-4-ylethyl) carbamoyl) pyridine (1.22 g, 4.52 mmol) and K 2 CO 3 (0, 31 g, 2.26 mmol). The resulting mixture was heated at 75 overnight, cooled to room temperature, and separated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The aqueous layer was extracted again with EtOAc (25 ml). The combined organic layers were washed with a saturated NaCl solution (3 x 25 ml) and concentrated under reduced pressure. The resulting brown solids were purified by column chromatography (58 g; gradient from 100% EtOAc to 25% MeOH / 75% EtOAc) to provide 4- (2- ( N - (2-morpholin-4-ylethyl) carbamoyl ) pyridyloxy) aniline (1.0 g, 65%): TLC (10% MeOH / 90 EtOAc) R f 0.32.

A11 General Method for the Reduction of Nitroarenos a Arylamines Synthesis of 4- (3-Carboxyphenoxy) aniline

35

A thick suspension of 4- (3-carboxyphenoxy) -1-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd / C (0.50 g) in MeOH (120 ml) was stirred under H2 (balloon) for 2 d. Mix resulting was filtered through a plug of Celite®, and concentrated then under reduced pressure to provide 4- (3-carboxyphenoxy) aniline as a solid brown (2.26 g, 48%): TLC (10% MeOH / 90 CH 2 Cl 2) R f 0.44 (band formation).

A12 General Method for the Synthesis of Anilines that They contain Isoindolinone. Synthesis of 4- (1-Oxoisoindolin-5-yloxy) aniline

36

He passed one

Synthesis of 5-hydroxyisoindolin-1-one

To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 ml) zinc powder (47.6 g, 729 mmol) was added slowly in portions, and the mixture was then heated to the temperature of reflux for 40 min, filtered hot, and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 kg SiO2; gradient from 60% EtOAc / 40% hexane to 25% MeOH / 75% EtOAc) to give 5 -hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) R f 0.17; HPLC ES-MS m / z 150 ((M + H) +).

37

He passed 2

Synthesis of 4- (1-Isoindolinon-5-yloxy) -1-nitrobenzene

To a thick suspension of NaH (0.39 g, 16.1 mmol) in DMF at 0 ° C was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting thick suspension is let it warm to room temperature and stir for 45 min, was added later 4-fluoro-1-nitrobenzene and the mixture was then heated at 70 ° C for 3 h. It cooled mixture at 0 ° C and treated with water dropwise until a precipitate. The resulting solids were collected to give 4- (1-Isoindolinon-5-yloxy) -1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) R f 0.35.

38

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He passed 3

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

A thick suspension of 4- (1-Isoindolinon-5-yloxy) -1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd / C (0.20 g) in EtOH (50 ml) was stirred under H2 atmosphere (balloon) for 4 h and then filtered to through a wad of Celite®. The filtrate was concentrated under pressure. reduced to provide 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? -Carbamoyl-Anilines via the EDCI Mediated Amide Formation, Followed by Nitroarene Reduction. Synthesis of 4- (3- N -methylcarbamoylphenoxy) aniline

39

He passed one

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

A mix of 4-fluoro-1-nitrobenzene (16 ml, 150 mmol), ethyl 3-hydroxybenzoate (25 g, 150 mmol) and K 2 CO 3 (41 g, 300 mmol) in DMF (125 ml) is heated to reflux temperature overnight, cooled to room temperature and treated with water (250 ml). Mix The resulting was extracted with EtOAc (3 x 150 ml). Organic phases together they were washed successively with water (3 x 100 ml) and a saturated NaCl solution (2 x 100 ml), dried (Na2SO4) and concentrated under reduced pressure. The residue purified by column chromatography (10% EtOAc / 90% hexane) to provide 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene  as an oil (38 g).

40

He passed 2

Synthesis of 4- (3-carboxyphenoxy) -1-nitrobenzene

To a vigorously stirred mixture of 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene (5.14 g, 17.9 mmol) in a 3: 1 THF / water solution (75 ml) was added a solution of LiOH • O 2 (1.50 g, 35.8 mmol) in water (36 ml) The resulting mixture was heated at 50 overnight. then cooled to room temperature, concentrated under pressure reduced, and adjusted to pH 2 with a 1M solution of HCl. The solids resulting bright yellow filtered off and washed with hexane to give 4- (3-carboxyphenoxy) -1-nitrobenzene  (4.40 g, 95%).

41

He passed 3

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

A mixture of 4- (3-carboxyphenoxy) -1-nitrobenzene (3.72 g, 14.4 mmol), EDCI.HCl (3.63 g, 18.6 mmol), N- methylmorpholine (1.6 ml, 14.5 mmol) and methylamine (2.0 M in THF; 8 ml, 16 mmol) in CH 2 Cl 2 (45 ml) was stirred at room temperature for 3 d, and then concentrated under pressure reduced The residue was dissolved in EtOAc (50 ml) and the resulting mixture was extracted with a 1M solution of HCl (50 ml). The aqueous layer was extracted again with EtOAc (2 x 50 ml). The combined organic phases were washed with a saturated NaCl solution (50 ml), dried (Na2SO4), and concentrated under reduced pressure to give 4- (3- ( N- methylcarbamoyl) phenoxy) -1-nitrobenzene as an oil (1.89 g).

42

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He passed 4

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

A thick 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) It was stirred in an atmosphere of H2 (balloon) overnight. The resulting mixture was filtered through a plug of Celite® and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH / 95% CH2Cl2). The resulting oil was solidified under vacuum overnight to give 4- (3- ( N- methylcarbamoyl) phenoxy) aniline as a yellow solid (0.95 g, 56%).

A14 General Method for the Synthesis of ? -carbamoyl-anilines by the Formation of Amida Formation Mediated by EDCI Followed by Reduction Nitroarene. Synthesis of 4- (3- (5-Methylcarbamoyl) pyridyloxy) aniline

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43

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He passed one

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

To a thick suspension of NaH (0.63 g, 26.1 mmol) in DMF (20 ml) a solution of Methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 ml). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 ml, 13.1 mmol) in DMF (10 ml) and the resulting mixture was heated at 70 overnight, cooled to room temperature, and treated with MeOH (5 ml) followed by water (50 ml). The resulting mixture was extracted with EtOAc (100 ml). The organic phase was concentrated under reduced pressure. He residue was purified by column chromatography (30% EtOAc / 70% hexane) to provide 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.60 g).

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44

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He passed 2

Synthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline

A thick suspension of 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd / C in MeOH / EtOAc was stirred in atmosphere of H2 (balloon) for 72 h. The resulting mixture is filtered and the filtrate was concentrated under reduced pressure. The residue is purified by column chromatography (gradient from 10% EtOAC / 90% hexane to 30% EtOAc / 70% hexane to 50% EtOAc / 50% hexane) to provide 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline  (0.28 g, 60%): 1 H NMR (CDCl 3) δ 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H), 8.87 (d, 1H).

A15 Synthesis of an Aniline by Electrophilic Nitration Followed by Reduction. Synthesis of 4- (3-Methylsulfamoylphenoxy) aniline

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Four. Five

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He passed one

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 and stirred at room temperature overnight. The resulting mixture was separated between EtOAc (25 ml) and a 1M solution of HCl (25 ml). The aqueous phase was extracted again with EtOAc (2 x 25 ml). The combined organic phases were washed successively with water (2 x 25 ml) and a saturated NaCl solution (25 ml), dried (MgSO 4) and concentrated under reduced pressure to give N- methyl-3-bromobenzenesulfonamide as a white solid (2.8 g, 99%).

46

He passed 2

Synthesis of 4- (3- ( N- Methylsulfamoyl) phenyloxy) benzene

To a thick suspension of phenol (1.9 g, 20 mmol), K 2 CO 3 (6.0 g, 40 mmol), and CuI (4 g, 20 mmol) in DMF (25 ml) is N- methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol) was added, and the resulting mixture was stirred at reflux overnight, cooled to room temperature, and separated between EtOAc (50 mL) and a 1N solution of HCl (50 ml). The aqueous layer was extracted again with EtOAc (2 x 50 ml). The combined organic phases were washed successively with water (2 x 50 ml) and a saturated NaCl solution (50 ml), dried (MgSO4), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc / 70% hexane) to give 4- (3- ( N- methylsulfamoyl) phenyloxy) benzene (0.30 g).

47

He passed 3

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

To a solution of 4- (3- N -methylsulfamoyl) phenyloxy) benzene (0.30 g, 1.14 mmol) in TFA (6 ml) at -10 ° C was added NaNO2 (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 separated between EtOAc (10 ml) and water (10 ml). The organic phase was washed successively with water (10 ml) and a saturated NaCl solution (10 ml), dried (MgSO 4) and concentrated under reduced pressure to give 4- (3- ( N- methyl sulfamoyl) phenyloxy ) -1-nitrobenzene (0.20 g). This material was taken to the next step without further purification.

48

He passed 4

Synthesis of 4- (3- ( N- Methylsulfamoyl) phenyloxy) aniline

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

A16 Modification of ga-Ketones. Synthesis of salt 4- (4- (1- ( N -methoxy) iminoethyl) phenoxyaniline. HCl

49

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

A17 Synthesis of N - (ome-Sililoxyalkyl) amides. Synthesis of 4- (4- (2- ( N - (2-Triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline

fifty

He passed one

4-Chloro- N - (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide

To a solution of 4-chloro- N - (2-hydroxyethyl) pyridine-2-carboxamide (prepared in a manner analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in DMF anh. (7 ml) triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) And imidazole (1.12 g, 16.4 mmol, 2.2 equiv.) Were added. The resulting yellow solution was stirred for 3 h at room temperature, and then concentrated under reduced pressure. The residue was separated 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 provide 4-chloro-2- ( N - (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide as an orange oil (2.32 g, 88% ). This material was used in the next step without further purification.

51

He passed 2

4- (4- (2- ( N - (2-Triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline

To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in DMF anh. (8 ml) potassium tert -butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) Was added in a single portion causing an exotherm. When this mixture had cooled to room temperature, a solution of 4-chloro-2- ( N - (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) In DMF (4 ml), followed by K 2 CO 3 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was heated at 80 ° C overnight. An additional portion of potassium tert -butoxide (0.34 g, 3 mmol, 0.5 equiv.) Was then added and the mixture was stirred at 80 ° C for a further 4 h. The mixture was cooled to 0 ° C with an ice / water bath, and then water (approx. 1 ml) was added dropwise slowly. The organic layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with a saturated NaCl solution (20 ml), dried (MgSO4) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (SiO2; 30% EtOAc / 70% pet. Ether) to provide 4- (4- (2- ( N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline as an oil light brown transparent (0.99 g, 38%).

A18 Synthesis of the Esters of 2-Pyridinecarboxylate by Oxidation of 2-Methylpyridines. Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline

52

He passed one

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

A mix of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-nitrobenzene (9.8 ml, 91.6 mmol, 1.0 equiv.), K 2 CO 3 (25 g, 183 mmol, 2.0 equiv.) In DMF (100 ml) was heated to reflux temperature during one night The resulting mixture was cooled to temperature ambient, 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 a saturated solution of NaCl (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).

53

He passed 2

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

A mix of 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 ml) was heated to reflux temperature for 5 h, and then cooled to room temperature. The resulting thick suspension was filtered, and then concentrated to reduced pressure The residue was dissolved in MeOH (100 ml). The solution was treated with a concentrated solution of HCl (7 ml), then heated at reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure. He residue was separated between EtOAc (50 ml) and a 1N solution of NaOH (50 ml) The aqueous layer was extracted with EtOAc (2 x 50 ml). Layers The combined organics were washed successively with water (2 x 50 ml) and a saturated solution of NaCl (50 ml), dried (MgSO4) and dried concentrated under reduced pressure. The residue was purified by column chromatography (SiO2; 50% EtOAc / 50% hexane) to provide 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene  (0.70 g).

54

He passed 3

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

A thick suspension of 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.50 g) and 10% Pd / C (0.050 g) in a mixture of EtOAc (20 ml) and MeOH (5 ml) was placed under an atmosphere of H2 (balloon) during one night. The resulting mixture was filtered through a plug of Celite®, and the filtrate was concentrated under reduced pressure. The residue purified by column chromatography (SiO2; 70% EtOAc / 30% hexane) to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline  (0.40 g).

A19 Synthesis of ? -Sulfonylphenyl-Anilines. Synthesis of 4- (4-Methylsulfonylphenoxy) aniline

55

He passed one

4- (4-Methylsulfonylphenoxy) -1-nitrobenzene

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

He passed 2

4- (4-Methylsulfonylphenoxy) -1-aniline

The 4- (4-Methylsulfonylphenoxy) -1-nitrobenzene to aniline analogously to that described in Method A18, Step 3.

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B. Synthesis of Urea Precursors B1. General Method for Synthesis of Isocyanates a Starting from Anilines Using CDI. Synthesis of Isocyanate 4-Bromo-3- (trifluoromethyl) phenyl

56

He passed one

Salt Synthesis 4-Bromo-3- (trifluoromethyl) aniline.HCl

To a solution of 4-Bromo-3- (trifluoromethyl) aniline (64 g, 267 mmol) in Et2O (500 ml) a solution of HCl (1M in Et2O; 300 ml) dropwise and the resulting mixture is stirred at room temperature for 16 h. The precipitate resulting white-pink was filtered off and washed with Et2O (50 ml) to provide the salt 4-Bromo-3- (trifluoromethyl) aniline.HCl (73 g, 98%).

57

He passed 2

Synthesis of isocyanate from 4-Bromo-3- (trifluoromethyl) phenyl

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

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C. Ureas Formation Methods C1a. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N - (4-Chloro-3- (trifluoromethyl) phenyl) - N '- (4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) phenyl) urea

58

A solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (14.60 g, 65.90 mmol) in CH2Cl2 (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 h. The resulting yellow solids were filtered off, then washed with CH 2 Cl 2 (2 x 30 ml) and dried under reduced pressure (1 · 1,332 • 10 Pa (mm Hg) (sic) to provide N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - (4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) phenyl) urea as an off-white solid (28 , 5 g, 93%): mp 207-209 ° C; 1 H-NMR (DMSO-d 6) δ 2.77 (d, J = 4.8 Hz, 3H), 7.16 ( m, 3H), 7.37 (d, J = 2.5 Hz, 1H), 7.62 (m, 4H), 8.11 (d, J = 2.5 Hz, 1H), 8.49 ( d, J = 5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m / z 465 (( M + H) +).

C1b. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N - (4-Bromo-3- (trifluoromethyl) phenyl) - N '- (4- (2- N -methylcarbamoyl) -4-pyridyloxy) phenyl) -urea

59

A solution of 4-bromo-3- (trifluoromethyl) phenyl isocyanate (Method B1, Step 2; 8.0 g, 30.1 mmol) in CH 2 Cl 2 (80 ml) was added dropwise to a solution of 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH 2 Cl 2 (40 ml) at 0 ° C. The resulting mixture was stirred at room temperature for 16 h. The resulting yellow solids were filtered off, then washed with CH 2 Cl 2 (2 x 50 ml) and dried under reduced pressure (1 · 1,332 · 10 2 Pa ( mmHg) (sic) at 40 ° C to provide N - (4-bromo-3- (trifluoromethyl) phenyl) - N ' - (4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) phenyl-urea as a yellow solid pale (13.2 g, 90%): mp 203-205 ° C; 1 H-NMR (DMSO-d 6) δ 2.77 (d, J = 4.8 Hz, 3H), 7 , 16 (m, 3H), 7.37 (d, J = 2.5 Hz, 1H), 7.58 (m, 3H), 7.77 (d, J = 8.8 Hz, 1H), 8 , 11 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m / z 509 ((M + H) +).

C1c. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N - (4-Chloro-3- (trifluoromethyl) phenyl) - N '- (2-methyl-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea

60

A solution of 2-methyl-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) aniline (Method A5; 0.11 g, 0.45 mmol) in CH2Cl2 (1 ml ) was treated with Et3N (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 d, and then treated with water (5 ml). The aqueous layer was extracted again with EtOAc (3 x 5 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to provide N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - (2-methyl-4- (2- (N -methylcarbamoyl) (4-pyridyloxy)) phenyl) -urea as a brown oil (0.11 g, 0.22 mmol): 1 H-NMR (DMSO-d 6) δ 2.27 ( s, 3H), 2.77 (d, J = 4.8 Hz, 3H), 7.03 (dd, J = 8.5, 2.6 Hz, 1H), 7.11 (d, J = 2 , 9 Hz, 1H), 7.15 (dd, J = 5.5, 2.6 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H), 7.62 (d app, J = 2.6 Hz, 2H), 7.84 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.78 (q, J = 5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m / z 479 ((M + H) +).

C1d. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N - (4-Chloro-3- (trifluoromethyl) phenyl) - N '- (4-aminophenyl) -urea

61

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (2.27 g, 10.3 mmol) in CH 2 Cl 2 (308 ml) was added p- phenylenediamine (3.32 g , 30.7 mmol) in a single portion. The resulting mixture was stirred at room temperature for 1 h, treated with CH 2 Cl 2 (100 ml), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc (110 ml) and MeOH (15 ml), and the clear solution was washed with a 0.05 N solution of HCl. The organic layer was concentrated under reduced pressure to provide impure N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - (4-aminophenyl) -urea (3.3 g; TLC (100% EtOAc) R_ { f} 0.72.

C1e. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N - (4- (Chloro-3- (trifluoromethyl) phenyl) - N '- (4-ethoxycarbonylphenyl) -urea

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62

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

C1f. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N - (4-Chloro-3- (trifluoromethyl) phenyl) - N '- (3-carboxyphenyl) -urea

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63

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (1.21 g, 5.46 mmol) in CH 2 Cl 2 (8 ml) was added 4- (3-carboxyphenoxy) aniline (Method A11; 0.81 g, 5.76 mmol) and the resulting mixture was stirred at room temperature overnight, then treated with MeOH (8 ml), and stirred for a further 2 hours. The resulting mixture was concentrated under reduced pressure. The resulting brown solids were triturated with a 1: 1 EtOAc / hexane solution to give N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - (3-carboxyphenyl) -urea as an off-white solid (1 , 21 g, 76%).

C2a. General Method for the Synthesis of Ureas by Reaction of an Aniline with N , N '-Carbonyl-Diimidazole Followed by Addition of a Second Aniline. Synthesis of N - (2-Methoxy-5- (trifluoromethyl) phenyl) - N '- (4- (2- ( N- methylcarbamoyl) -4-piri-diloxy) phenyl) -urea

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64

To a solution of 2-methoxy-5- (trifluoromethyl) aniline (0.15 g) in CH2Cl2 anh. (15 ml) at 0 ° C CDI (0.13 g) was added. The resulting solution was allowed to warm to room temperature for 1 h, stirred at room temperature for 16 h, and then treated with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g ). The resulting yellow solution was stirred at room temperature for 72 h, and then treated with H2O (125 ml). The resulting aqueous mixture was extracted with EtOAc (2 x 150 ml). The combined organic phases were washed with a saturated NaCl solution (100 ml), dried (MgSO4) 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 from 33% EtOAc / 67% hexane to 50% EtOAC / 50% hexane to 100% EtOAc) to give N - (2-methoxy-5 - (trifluoromethyl) phenyl) - N ' - (4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) phenyl-urea as a light tan solid (0.098 g, 30%): TLC (100% EtOAc) R f 0.62; 1 H NMR (DMSO-d 6) δ 2.76 (d, J = 4.8 Hz, 3H), 3.96 (s, 3H), 7 , 1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, J = 4.8 Hz, 1H), 9.55 (s, 1H); FAB-MS m / z 461 ((M + H) +).

C2b General Method for the Synthesis of Ureas by Reaction of an Aniline with N , N '-Carbonyl-Diimidazole Followed by Addition of a Second Aniline. Symmetric Areas as Secondary Products of a Reaction Procedure with N , N '-Carbonyl-Diimidazole. Synthesis of Bis (4- (2- ( N- Methylcarbamoyl) -4-pyridyloxy) phenyl) -urea (Compound not according to the invention)

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65

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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 and 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, and 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 a saturated NaCl solution (100 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was triturated (90% EtOAc / 10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis (4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) R_ {f} 0.50; 1 H NMR (DMSO-d 6) δ 2.76 (d, J = 5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d , J = 5.4 Hz, 1H), 8.75 (d, J = 4.8 Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m / z 513 ((M + H) +).

C2c General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N - (2-Methoxy-5- (trifluoromethyl) phenyl- N '- (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) -urea (Compound not according to the invention)

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66

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To a solution under stirring of 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.47 mmol) in CH2Cl2 (1.5 mL) was added 5- ( 4-aminophenoxy) isoindoline-1,3-dione (Method A3, Step 3, 0.12 g, 0.47 mmol) in a single portion. The resulting mixture was stirred for 12 h, and then treated with CH 2 Cl 2 (10 ml) and MeOH (5 ml). The resulting mixture was washed successively with a 1N HCl solution (15 ml) and a saturated NaCl solution (15 ml), dried (MgSO 4) and concentrated under reduced pressure to provide N - (2-methoxy- 5- (trifluoromethyl) phenyl- N ' - (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) -urea as a white solid (0.2 g, 96%): TLC (70% EtOAc / 30% hexane) R f 0.50; 1 H NMR (DMSO-d 6) δ 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7, 57 (d, J = 9.3 Hz, 2H), 7.80 (d, J = 8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11 , 27 (br s, 1H); HPLC ES-MS 472.0 ((M + H) +, 100%).

C2d General Method for the Synthesis of Ureas by Reaction of an Aniline with N , N '-Carbonyl-Diimidazole Followed by Addition of a Second Aniline. Synthesis of N - (5- ( tert- Butyl) -2- (2,5-dimethylpyrrolyl) phenyl) - N '- (4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -phenyl) -urea ( compound not according to the invention)

67

To a stirred solution of CDI (0.21 g, 1.30 mmol) in CH 2 Cl 2 (2 ml) was added 5- ( tert -butyl) -2- (2,5-dimethylpyrrolyl ) aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in a single portion. The resulting mixture was stirred at room temperature for 4 h, and 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline (0.065 g, 0.267 mmol) was added in a single portion. 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 a 1N solution of HCl (15 ml), dried (MgSO 4), and filtered through a plug of silica gel (50 g) to provide N - (5- ( tert -butyl) -2- (2,5-dimethylpyrrolyl) phenyl) - N ' - (4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) phenyl) -urea as a solid yellowish (0.033 g, 24%): TLC (40% EtOAc / 60% hexane) R f 0.24; 1 H NMR (acetone-d 6) δ 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J = 4.8 Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J = 5.4 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M + H) +, 100%).

C3 Combinatorial Method for the Synthesis of Diphenyl Ureas Using Triphosgene

One of the anilines to be coupled dissolved in dichloroethane (0.10 M). This solution was added to an 8 ml vial. (0.5 ml) containing dichloroethane (1 ml). Added to this a bis (trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 ml, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 ml, 1.2 equiv.). The vial was covered and heated at 80 ° C for 5 h, after which it was allowed to cool to room temperature for 10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 ml, 1.0 equiv.), Followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 ml, 1.2 equiv.). The resulting mixture was heated at 80 ° C for 4 h, cooled to room temperature, and treated with MeOH (0.5 ml). Mix resulting was concentrated under reduced pressure and the products were purified by reverse phase HPLC.

C4 General Method for the Synthesis of Ureas by Reaction of an Aniline with Phosgene Followed by Addition of a Second Aniline. Synthesis of N - (2-Methoxy-5- (trifluoromethyl) phenyl) - N '- (4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) -urea

68

To a solution maintained under stirring phosgene (1.9 M in toluene; 2.07 ml, 0.21 g, 1.30 mmol) in CH2Cl2 (20 ml) at 0 ° C was added pyridine anh . (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 a precipitate formed. The yellow mixture was stirred for 1 h, and then concentrated under reduced pressure. The resulting solids were treated with toluene anh. (20 ml) followed by 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline (prepared as described in Method A2; 0.30 g) and the resulting thick suspension was heated at 80 ° C for 20 h, and then allowed to cool to room temperature. The resulting mixture was diluted with water (100 ml), and then made alkaline with a saturated solution of NaHCO3 (2-3 ml). The basic solution was extracted with EtOAc (2 x 250 ml). The organic layers were washed separately with a saturated NaCl solution, combined, dried (MgSO4), and concentrated under reduced pressure. The resulting brown-pink residue was dissolved in MeOH and absorbed on SiO2 (100 g). Column chromatography (300 g SiO 2; gradient from 1% Et 3 N / 33% EtOAc / 66% hexane to 1% Et 3 N / 99% EtOAc to 1% Et 3 N / 20% MeOH / 79% EtOAc) followed by concentration under reduced pressure at 45 ° C provided a hot concentrated solution in EtOAc, which was treated with hexane (10 ml) to slowly form crystals of N - (2-methoxy-5- (trifluoromethyl) phenyl) - N ' - (4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) -urea (0.44 g): TLC (1% Et 3 N / 99% EtOAc) R f } 0.40.

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D. Ureas Interconversion Day 1 Conversion of ome-Aminophenyl-Ureas into ome- (Aroylamino) Phenyl-Ureas. Synthesis of N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N '- (4- (3-methoxycarbonyl-phenyl) carboxylamino-phenyl) -urea (compound not according to the invention)

69

To a solution of N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N ' - (4-aminophenyl) -urea (Method C1d; 0.050 g, 1.52 mmol), mono- methyl isophthalate (0 , 25 g, 1.38 mmol), HOBT • H 2 O (0.41 g, 3.03 mmol) and N- methylmorpholine (0.33 ml, 3.03 mmol) in DMF (8 ml) is EDCI.HCl (0.29 g, 1.52 mmol) was added.The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (25 ml) and washed successively with water (25 ml) and a solution NaHCO 3 saturated (25 ml). The organic layer was dried (Na2SO4), and concentrated under reduced pressure. The resulting solids were triturated with EtOAc solution (80% EtOAc / 20 % hexane) to give N - (4-chloro-3 - ((trifluoromethyl) phenyl- N ' - (4- (3-methoxycarbonylphenyl) carboxylaminophenyl) -urea (0.27 g, 43%): mp 121-122; TLC (80% EtOAc / 20% hexane) R f 0.75.

D1b. Conversion of ga-Carboxyphenyl-Ureas into - (Arylcarbamoyl) phenyl-Ureas. Synthesis of N - (4-Chloro-3 - ((trifluoro-methyl) phenyl) - N '- (4- (3-methylcarbamoyl-phenyl) carbamoylphenyl) -urea

70

To a solution of N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N ' - (4- (3-methylcarbamoylphenyl) -carboxiaminophenyl) -urea
(0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBT • H2O (0.14 g, 1.07 mmol), and N- methylmorpho-
Line (0.5 ml, 1.07 mmol) in DMF (3 ml) at 0 ° C EDCI.HCl (0.10 g, 0.53 mmol) was added. The resulting mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was treated with water (10 ml), and extracted with EtOAc (25 ml). The organic phase was concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 ml), and then filtered through a plug of silica gel (17 g, gradient from 70% EtOAc / 30% hexane to 10% MeOH / 90% EtOAc) to give N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N ' - (4- (3-methylcarbamoylphenyl) carbamoyl-phenyl) -urea as a white solid (0.097 g, 41%): mp 225-229; TLC (100% EtOAc) R f 0.23.

D1c. Combinatorial Approach for the Conversion of? -Carboxyphenyl-Ureas into? -Arilcarbamoyl) phenyl-Ureas. Synthesis of N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N '- (4- (N- (3-N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) -urea (compound no according to the invention)

71

A mixture of N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N ' - (3-carboxyphenyl) -urea (Method C1f; 0.030 g, 0.067 mmol) and N -cyclohexyl- N' - (methyl polystyrene) Carbodiimide (55 mg) in 1,2-dichloroethane (1 ml) was treated with a solution of 3-aminopyridine in CH2Cl2 (1M; 0.074 ml, 0.074 mmol). (In cases of insolubility or turbidity , a small amount of DMSO was also added.) The resulting mixture was heated at 36 ° C overnight. The cloudy reaction mixtures were then treated with THF (1 ml) and heating was continued for 18 h. The resulting mixtures were treated. with poly (4- (isocyanatomethyl) styrene) (0.040 g) and the resulting mixture was stirred at 36 ° C for 72 h, then cooled to room temperature and filtered.The resulting solution was filtered through a plug of gel silica (1 g) Concentration under reduced pressure provided N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N ' - (4- (N- (3- (N- (3-pyridyl) carbamoyl)) phenyl) carbamoyl) phenyl) -urea (0.024 g, 59%): TLC (70% EtOAc / 30% hexane) R f 0.12.

D2 Conversion of ome-Carboalkoxyaryl-Ureas into ome-Carbamoylaryl-Ureas. Synthesis of N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N '- (4- (3-methylcarbamoylphenyl) -carboxiaminophenyl) -urea (compound not according to the invention)

72

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

D3 Conversion of \ omega-Carboalkoxyaryl-Ureas into \ omega-Carboxaryl-Ureas. Synthesis of N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N '- (4-carboxyphenyl) -urea

73

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

D4 General Method for the Conversion of ome-Alkoxy-Esters into Al-Alkyl-Amides. Synthesis of N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N '- ((4- (3- (5- (2-dimethylaminoethyl) -carbamoyl) pyridyl) oxyphenyl) -urea

74

He passed one

Synthesis of N - (4-Chloro-3- (trifluoromethyl) phenyl) - N '- ((4- (3- (5-carboxypyridyl) -oxyphenyl) -urea

N - (4-Chloro-3- (trifluoromethyl) phenyl) - N ' - ((4- (3- (5-methoxycarbonylpyridyl) -oxyphenyl) -urea was synthesized from 4-chloro-3- (trifluoromethyl isocyanate) ) phenyl and 4- (3- (5-methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a manner analogous to Method C1a. A suspension of N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - ((4- (3- (5-Methoxycarbonylpyridyl) oxyphenyl) -urea (0.26 g, 0.56 mmol) in MeOH (10 ml) was treated with a solution of KOH (0.14 g, 2, 5 mmol) in water (1 ml) and stirred at room temperature for 1 h The resulting mixture was adjusted to pH 5 with a 1N HCl solution.The resulting precipitate was filtered off and washed with water. The resulting were dissolved in EtOAc (10 ml) and the resulting solution was concentrated under reduced pressure The EtOH / concentration procedure was repeated twice to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N ' - ( (4- (3- (5-carboxypyridyl) oxyphenyl) -urea (0.18 g, 71%).

75

He passed 2

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

A mixture of N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - ((4- (3- (5- (carboxypyridyl) -oxyphenyl) -urea (0.050 g, 0.011
mmol), N, N- dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N- methylmorpholine (0.035 g, 0.28 mmol), and EDCI.HCl (0.032 g, 0.17 mmol) in DMF (2.5 ml) was stirred at room temperature overnight. The resulting solution was separated 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 a minimum amount of CH 2 Cl 2 (approximately 2 ml). The resulting solution was treated with Et2O dropwise to give N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - ((4- (3- (5- (2-dimethylaminoethyl)) carbamoyl ) pyridyl) oxyphenyl) -urea as a white precipitate (0.48 g, 84%): 1 H NMR (DMSO-d 6) δ 2.10 (s, 6H), 3.26 ( s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, 1H), 8.43 (s, 1H), 8.58 (t, 1H), 8.69 (s, 1H), 8.90 (s, 1H), 9.14 (s, 1H); HPLC ES-MS m / z 522 ((M + H) +).

D5 General Method for the Deprotection of N - (ome-Sililoxyalkyl) amides. Synthesis of N - (4-Chloro-3 - ((trifluoromethyl) phenyl) - N '- (4- (4- (2- ( N - (2-hydroxy) -ethylcarbamoyl) -pyridyloxyphenyl) -urea

76

To a solution of N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N ' - (4- (4- (2- ( N - (2-triisopropylsilyloxy) -ethylcarbamoyl) pyridyloxyphenyl) -urea (prepared from in a manner analogous to Method C1a; 0.25 g, 0.37 mmol) in anhydrous THF (2 ml) was (sic) tetrabutylammonium fluoride (1.0 M in THF; 2 ml) .The mixture was stirred at room temperature for 5 min, and then treated with water (10 ml) The aqueous mixture was extracted with EtOAc (3 x 10 ml) The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2; gradient from 100% hexane to 40% EtOAc / 60% hexane) to give N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N ' - ( 4- (4- (2- ( N - (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) -urea as a white solid (0.019 g, 10%).

Listed below are included compounds in the following Tables that have been synthesized according to the Detailed Experimental Procedures given above.

Synthesis of Compounds Cited as Examples

(See Tables for characterization of compounds)

Entry 1: 4- (3- N -methylcarbamoylphenoxy) aniline was prepared according to Method A13. According to Method C3, 3- tert -butylaniline was reacted with bis (trichloromethyl) carbonate followed by 4- (3- N -methylcarbamoyl-
phenoxy) aniline to provide urea.

Entry 2: 4-Fluoro-1-nitrobenzene and p- hydroxyacetophenone were reacted according to method A13, Step 1 to provide 4- (4-acetylphenoxy) -1-nitrobenzene. 4- (4-Acetoxyphenoxy) -1-nitrobenzene was reduced according to method A13, Step 4 to provide 4- (4-acetylphenoxy) aniline. According to method C3, 3- tert -butylaniline was reacted with bis (trichloromethyl) carbonate followed by 4- (4-acetylphenoxy) aniline to provide urea.

Entry 3: According to Method C2d, 3- tert -butylaniline was treated with CDI, followed by 4- (3- N -methylcarbamoyl) -4-methoxyphenoxy) aniline, which had been prepared according to method A8, for provide urea.

Entry 4: 5- tert -butyl-2-methoxyaniline was converted into 5- tert -butyl-2-methoxyphenyl isocyanate according to Method B1. 4- (3- N -methylcarbamoylphenoxy) aniline, prepared according to Method A13, was reacted with the isocyanate according to Method C1a to provide urea.

Entry 5: According to Method C2d, 5- tert -butyl-2-methoxyaniline was reacted with CDI followed by 4- (3- N -methylcarbamoyl) -4-methoxyphenoxy) aniline, which had been prepared according to Method A8, to provide urea.

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

Entry 7: 4- (1-Oxoindolin-5-yloxy) aniline was synthesized according to method A12. According to Method 2d, 5- tert -butyl-2-methoxyaniline was reacted with CDI followed by 4- (1-oxoisoindolin-5-yloxy) aniline to provide urea.

Entry 8: 4- (3- N -methylcarbamoylphenoxy) aniline was synthesized according to Method A13. According to Method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI followed by 4- (3- N -methylcarbamoylphenoxy) aniline to provide urea.

Entry 9: Reacted 4-hydroxyacetophenone with 2-chloro-5-nitropyridine to give 4- (4-acetylphenoxy) -5-nitropyridine  according to Method A3, Step 2. According to Method A8, Step 4, the 4- (4-acetylphenoxy) -5-nitropyridine  to 4- (4-acetylphenoxy) -5-aminopyridine. He turned 2-methoxy-5- (trifluoromethyl) aniline in isocyanate 2-methoxy-5- (trifluoromethyl) phenyl  according to Method B1. The isocyanate was reacted with 4- (4-acetylphenoxy) -5-aminopyridine according to Method C1a to provide urea.

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

Entry 11: 4- (Chloro- N -methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to give 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline According to Method C4, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene, followed by 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entry 12: The chloride salt of was reacted 4-chloropyridine-2-carbonyl.HCl with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. The 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, it was reacted 2-methoxy-5- (trifluoromethyl) aniline with phosgene followed by 3- (2-carbamoyl-4-pyridyloxyaniline to provide urea.

Entry 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 Method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI followed by 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entry 14: The chloride salt of was reacted 4-chloropyridine-2-carbonyl.HCl with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. He reacted the 4-chloro-2-pyridinecarboxamide  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, it was reacted 2-methoxy-5- (trifluoromethyl) aniline with phosgene followed by 4- (2-carbamoyl) -4-pyridyloxy) aniline to provide urea.

Entry 15: According to Method C2d, 5- (trifluoromethyl) -2-methoxyaniline was reacted with CDI followed by 4- (3- N -methylcarbamoyl) -4-methoxyphenoxy) aniline, which had been prepared according to Method A8, to provide urea.

Entry 16: 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was synthesized according to Method A5. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. The isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-methylaniline according to Method C1c to provide urea.

Entry 17: 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. 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- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline according to Method C1a to provide urea.

Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro- N -methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (tri-
fluoromethyl) -2-methoxyphenyl according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -4-methylaniline according to Method C1a to provide urea.

Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro- N- ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- ( N -ethylcarbamoyl) -4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- ( N- ethylcarbamoyl) -4-pyridyloxy) aniline according to Method C1a to provide urea.

Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro- N- methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (tri-
fluoromethyl) -2-methoxyphenyl according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline according to Method C1a to provide urea.

Entry 21: Rusted 4- (4-methylthiophenoxy) -1-nitrobenzene 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 C1a, the isocyanate of 5- (trifluoromethyl) -2-methoxyphenyl se he reacted with 4- (4-Methylsulfonylphenoxy) -1-aniline  to provide urea.

Entry 22: The 4- (3-carbamoylphenoxy) -1-nitrobenzene to 4- (3-carbamoylphenoxy) aniline according to  Method A15, Step 4. According to Method C1a, it was done react isocyanate from 5- (trifluoromethyl) -2-methoxyphenyl with 4- (3-carbamoylphenoxy) aniline for provide urea.

Entry 23: It was synthesized 5- (4- (aminophenoxy) isoindoline-1,3-dione according to Method A3. He turned 5- (trifluoromethyl) -2-methoxyaniline in isocyanate 5- (trifluoromethyl) -2-methoxyphenyl of according to Method B1. Isocyanate 5- (trifluoromethyl) -2-methoxyphenyl se he reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione  according to Method C1a to provide urea.

Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro- N, N- dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- ( N, N- dimethylcarbamoyl) -4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- ( N, N- dimethylcarbamoyl) -4-pyridyloxy) aniline according to Method C1a to provide urea.

Entry 25: 4- (1-Oxoisoindolin-5-yloxy) aniline was synthesized according to Method A12. It was treated 5- (trifluorome-
til) -2-methoxyaniline with CDI, followed by 4- (1-oxoisoindolin-5-yloxy) aniline according to Method C2d to provide urea.

Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4- (4-acetylphenoxy) nitrobenzene. Nitrobenzene was reduced according to Method A13, Step 4 to provide 4- (4-acetylphenoxy) aniline, which became the salt 4- (4- (1- ( N -methoxy) iminoethyl) phenoxy-aniline. HCl 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 salt 4- (4- (1- ( N -methoxy) imino-ethyl) phenoxyaniline.HCl according to Method C1a to provide the
urea.

Entry 27: 4-Chloro- N- methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. Chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline.) 5- (Trifluoromethyl) -2-methoxyaniline was converted to isocyanate of 5- (trifluoromethyl) -2-methoxyphenyl according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline according to Method C1a to provide urea.

Entry 28: It was synthesized 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione according to Method A9. He turned 5- (trifluoromethyl) -2-methoxyaniline in isocyanate 5- (trifluoromethyl) -2-methoxyphenyl of according to Method B1. The isocyanate was reacted from 5- (trifluoromethyl) -2-methoxyphenyl with 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione  according to Method C1a to provide urea.

Entry 29: 4-Chloro- N- methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. Chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline.) 5- (Trifluoromethyl) -2-methoxyaniline was converted to isocyanate 5- (trifluoromethyl) -2-methoxyphenyl according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 3- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline according to Method C1a to provide urea.

Entry 30: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropyl amine according to Method A2, Step 3b. The resulting 4-chloro- N- isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- ( N- isopropylcarbamoyl) -4-pyridyloxy) aniline. 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 -isopropylcarbamoyl) -4-pyridyloxy) aniline according to Method C1a to provide urea.

Entry 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. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to provide urea. N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - (4- (3- (5-methoxycarbonylpyridyl) -oxy) phenyl) -urea was saponified according to method D4, Step 1, and the acid corresponding was coupled with 4- (2-aminoethyl) morpholine to provide the amide according to Method D4, Step 2.

Entry 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. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyl-oxy) aniline according to Method C1a to provide urea. N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) -urea was saponified according to method D4, Step 1, and the corresponding acid It was coupled with methylamine according to Method D4, Step 2 to provide the amide.

Entry 33: 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. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to provide urea. N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - (4- (3- (5-methoxycarbonyl-pyridyl) oxy) phenyl) -urea was saponified according to method D4, Step 1, and the Corresponding acid was coupled with N, N- dimethylethylenediamine according to Method D4, Step 2 to provide the amide.

Entry 34: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to provide N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - (3 -carboxyphenyl) -urea, which was coupled with 3-aminopyridine according to Method D1c.

Entry 35: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to provide N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - (3 -carboxyphenyl) -urea, which was coupled with N - (4-fluorophenyl) piperazine according to Method D1c.

Entry 36: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with the 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to provide N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - ( 3-carboxyphenyl) -urea, which was coupled with 4-fluoroaniline according to Method D1c.

Entry 37: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with the 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to provide N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - ( 3-carboxyphenyl) -urea, which was coupled with 4- (dimethylamino) aniline according to Method D1c.

Entry 38: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with the 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to provide N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - ( 3-carboxyphenyl) -urea, which was coupled with 5-amino-2-methoxypyridine according to Method D1c.

Entry 39: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with the 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to provide N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - ( 3-carboxyphenyl) -urea, which was coupled with 4-morpholinoaniline according to Method D1c.

Entry 40: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with the 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to provide N - (5- (trifluoromethyl) -2-methoxyphenyl) - N ' - ( 3-carboxyphenyl) -urea, which was coupled with N - (2-pyridyl) piperazine according to Method D1c.

Entry 41: 4- (3- N -methylcarbamoyl) phenoxy) aniline was synthesized according to Method A13. According to Method C3, 4-chloro-3- (trifluoromethyl) aniline was converted into the isocyanate, and then reacted with 4- (3- N -methylcarbamoyl) phenoxy) aniline to provide urea.

Entry 42: 4- (2- N -methylcarbamoyl-4-pyridyloxy) aniline was synthesized according to Method A2. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- N -methylcarbamyl-4-pyridyloxy) aniline according to Method C1a to provide urea.

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Entry 43: The chloride salt of was reacted 4-chloropyridine-2-carbonyl.HCl with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. He reacted the 4-chloro-2-pyridinecarboxamide  with 4-aminophenol according to Method A2, Step 4, to form 4- (2-carbamoyl-4-pyridyloxy) aniline. According to Method C1a, isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (2-carbamoyl-4-pyridyloxy) aniline  to provide urea.

Entry 44: The chloride salt of was reacted 4-chloropyridine-2-carbonyl.HCl with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. He reacted the 4-chloro-2-pyridinecarboxamide  with 3-aminophenol according to Method A2, Step 4 to form 3- (2-carbamoyl-4-pyridyloxy) aniline. According to Method C1a, isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 3- (2-carbamoyl-4-pyridyloxy) aniline  to provide urea.

Entry 45: 4-Chloro- N -methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3- (2 - N -methylcarbamoyl) -4-pyridyloxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- N -methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entry 46: It was synthesized 5- (4-aminophenoxy) isoindoline-1,3-dione according to Method A3. According to Method C1a, it was done react isocyanate from 4-chloro-3- (trifluoromethyl) phenyl with 5- (4-aminophenoxy) isoindoline-1,3-dione  to provide urea.

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

Entry 48: 4- (3- N- Methylsulfamoyl) -phenyloxy) aniline was synthesized according to Method A15. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- N -methylsulfam-oil) phenyloxy) aniline to provide urea.

Entry 49: 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcar-
bamoyl) -4-pyridyloxy) -2-chloroaniline to provide urea.

Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro- N -methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to provide urea.

Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro- N- ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- ( N -ethylcarbamoyl) -4-pyridyloxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- N -ethylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entry 52: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro- N- methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to provide urea.

Entry 53: Rusted 4- (4-methylthiophenoxy) -1-nitrobenzene 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 C1a, isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (4-Methylsulfonyl-phenoxy) -1-aniline  to provide urea.

Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to provide N- methyl-4-bromobenzenesulfonamide. The N- methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to provide 4- (4- ( N- methylsulfamoyl) phenoxy) benzene. 4- (4- ( N- Methylsulfamoyl) phenoxy) benzene was converted to 4- (4- ( N- methylsulfamoyl) phenoxy) -1-nitrobenzene according to Method A15, Step 3. 4- (4- ( N -methylsulfamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (4- N -methylsulfamoyl) phenyloxy) aniline according to Method A15, Step 4. According to Method C1a, 4-chloro isocyanate was reacted -3- (trifluoromethyl) phenyl with 4- (3- N -methylsulfamoyl) phenyloxy) aniline to provide urea.

Entry 55: Docked 5-hydroxy-2-methylpyridine with 1-fluoro-4-nitrobenzene According to Method A18, Step 1 to give 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid, and was then esterified according to Method A18, 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.  The aniline was reacted with isocyanate of 4-chloro-3- (trifluoromethyl) phenyl according to Method C1a to provide urea.

Entry 56: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid, and then esterified according to Method A18, 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. The aniline was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method C1a to give N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - (4- (2- (methoxycarbonyl) -5-pyridyloxy) phenyl) -urea. The methyl ester was reacted with methylamine according to Method D2 to provide N - (4-chloro-3- (trifluoromethyl) phenyl) - N ' - (4- (2- ( N' -methylcarbamoyl) -5-pyridyloxy ) phenyl) -urea.

Entry 57: N - (4-Chloro-3- (trifluoromethyl) phenyl) - N ' - (4-aminophenyl) -urea was prepared according to Method C1d. N - (4-Chloro-3- (trifluoromethyl) phenyl) - N ' - (4-aminophenyl) -urea was coupled with mono- methyl isophthalate according to Method D1a to provide urea.

Entry 58: N - (4-Chloro-3- (trifluoromethyl) phenyl- N ' - (4-aminophenyl) -urea was prepared according to Method C1d. N - (4-Chloro-3- (trifluoromethyl) was coupled phenyl) - N ' - (4-aminophenyl) -urea with mono- methyl isophthalate according to Method D1a to provide N - (4-chloro-3- (trifluoromethyl) phenyl- N' - (4- (3- Methoxycarbonyl-phenyl) carboxyminophenyl) -urea According to Method D2, N - (4-chloro-3- (trifluoromethyl) -phenyl- N ' - (4- (3-methoxycarbonylphenyl) carboxyminophenyl) -urea was reacted with methylamine to provide the corresponding methyl amide.

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

Entry 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4- (4-acetylphenoxy) nitrobenzene. Nitrobenzene was reduced according to Method 13, Step 4 to provide 4- (4-acetylphenoxy) aniline, which was converted to the salt 4- (4- (1- ( N -methoxy) iminoethyl) phenoxyaniline.HCl according with Method A 16. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4-acetylphenoxy) aniline to provide urea.

Entry 61: 4- (3-Carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with 4- (2-aminoethyl) morpholine according with Method A13, Step 3 to give 4- (3- ( N - (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene. -1-nitrobenzene 4- (3- (N - (2-morpholinylethyl) carbamoyl) - according to Method A13, Step 4, 4- ((2-morpholinylethyl) carbamoyl) phenoxy 3- (N) decreased phenoxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- ( N - (2-morpholinylethyl) carbamoyl) phenoxy) aniline to provide urea.

Entry 62: 4- (3-Carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with 1- (2-aminoethyl) piperidine according with Method A13, Step 3 to give 4- (3- ( N - (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene. According to Method A13, Step 4, 4- (3- ( N - (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (3- ( N - (2-piperidylethyl) carbamoyl) phenoxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- ( N - (2-piperidylethyl) carbamoyl) phenoxy) aniline to provide urea.

Entry 63: 4- (3-Carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4- (3- ( N - (tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene. According to Method A13, Step 4, 4- (3- ( N - (tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (3- ( N - (tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- ( N - (tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline to provide urea.

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

Entry 65: 4-Chloro- N- methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. Chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline. According to Method C1a, 4-isocyanate was reacted -chloro-3- (trifluoro-
methyl) phenyl with 4- (4- (2- ( N- methylcarbamoyl) -phenylthio) aniline to provide urea.

Entry 66: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro- N- isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- ( N- isopropylcarbamoyl) -4-pyridyloxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N -isopropylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

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

Entry 68: It was synthesized 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione according to Method A9. According to Method C1a, it was done react isocyanate from 4-chloro-3- (trifluoromethyl) phenyl with 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione  to provide urea.

Entry 69: 4-Chloro- N- methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. Chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline. According to Method C1a, 4-chloro was reacted -3- (trifluoromethyl) phenyl with 3- (4- (2- N -methylcarbamoyl) phenylthio) aniline to provide urea.

Entry 70: 4- (2- N - (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was synthesized according to 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 provide urea.

Entry 71: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14. 4-Chloro-3- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to provide 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 acid corresponding was coupled with 4- (2-aminoethyl) morpholine to provide the amide.

Entry 72: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to provide urea. N - (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 with methylamine according to Method D4, Step 2, to provide the amide.

Entry 73: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to provide urea. N - (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 with N, N- dimethylethylenediamine according to Method D4, Step 2, to provide the amide.

Entry 74: The salt of 4-chloropyridine-2-carbonyl chloride.HCl was reacted with 2-hydroxyethylamine according to Method A2, Step 3b to form 4-chloro- N - (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide . 4-Chloro- N - (2-triisopropylsilyloxy) -ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4- (4- (2- ( N - (2-Triisopropylsilyloxy) -ethylcarbamoyl) pyridyloxyaniline According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- ( N - (2-triisopropyl-silyloxy) ) ethylcarbamoyl) pyridyloxyaniline to provide N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N '- (4- (4- (2- ( N- ( 2 - triisopropylsilyloxy) -ethylcarbamoyl) pyridyloxyphenyl) -urea.

Entry 75: It was synthesized 4- (3-carboxyphenoxy) aniline according to the Method A11 Isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1f to provide urea, which is coupled with 3-aminopyridine according to the Method D1c.

Entry 76: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with N - (4-acetylphenyl) piperazine according to Method D1c.

Entry 77: It was synthesized 4- (3-carboxyphenoxy) aniline according to the Method A11 Isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with 4-fluoroaniline according to Method D1c.

Entry 78: It was synthesized 4- (3-carboxyphenoxy) aniline according to the Method A11 Isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with 4- (dimethylamino) aniline according to Method D1c.

Entry 79: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with N- phenylethylene diamine according to Method D1c.

Entry 80: It was synthesized 4- (3-carboxyphenoxy) aniline according to the Method A11 Isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with 2-methoxyethylamine according to Method D1c.

Entry 81: It was synthesized 4- (3-carboxyphenoxy) aniline according to the Method A11 Isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with 5-amino-2-methoxypyridine according to Method D1c.

Entry 82: It was synthesized 4- (3-carboxyphenoxy) aniline according to the Method A11 Isocyanate was reacted from 4-chloro-3- (trifluoromethyl) phenyl with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with 4-morpholinoaniline according to Method D1c.

Entry 83: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to provide urea, which was coupled with N - (2-pyridyl) piperazine according to Method D1c.

Entry 84: The salt of 4-chloropyridine-2-carbonyl chloride.HCl was reacted with 2-hydroxyethylamine according to Method A2, Step 3b to form 4-chloro- N - (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide . 4-Chloro- N - (2-triisopropylsilyloxy) -ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4- (4- (2- ( N - (2-Triisopropylsilyloxy) -ethylcarbamoyl) pyridyloxyaniline According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- ( N - (2-triisopropyl-silyloxy) ) ethylcarbamoyl) pyridyloxyaniline to give N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N ' - (4- (4- (2- ( N - (2-triiso-propylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) -urea Urea was deprotected according to Method D5 to provide N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N ' - (4- (4- (2- ( N - (2-hydroxy) ethylcarbamoyl) ) pyridyloxyphenyl) -urea.

Entry 85: 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to Method A2. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entry 86: 4- (2- ( N- 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 was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to provide urea.

Entry 87: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro- N- methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4- (2- ( N- 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, the 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to provide urea.

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

Entry 89: 4-Chloro- N -methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4, to form 3- ( 2- ( N- methylcarbamoyl) -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, the 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entry 90: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro- N -methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to provide urea.

Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro- N, N- dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4, to give 4- (2- ( N, N- dimethylcarbamoyl) -4-pyridyloxy )aniline. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N, N- dimethylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entry 92: 4-Chloro- N- methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. Chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-Bromo-3- isocyanate (trifluoro-
methyl) phenyl according to Method B1. According to Method C1a, the 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline to provide urea.

Entry 93: 4-Chloro- N- methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. Chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-Bromo-3- isocyanate (trifluoro-
methyl) phenyl according to Method B1. According to Method C1a, the isocyanate was reacted from
4-Bromo-3- (trifluoromethyl) phenyl with 3- (4- (2- ( N- methylcarbamoyl) phenylthio) aniline to provide urea.

Entry 94: 4- (2- ( N - (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was synthesized according to Method A10. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N - (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to provide the urea .

Entry 95: 4- (2- ( N- 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 was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entry 96: 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline 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 was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, the 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to provide the urea.

Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro- N- methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7. The 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, the 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to provide the urea.

Entry 98: 4-Chloro- N -methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3- (2 - ( N- methylcarbamoyl) -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, the 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro- N- ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4, to give 4- (2- ( N- ethylcarbamoyl) -4-pyridyloxy) aniline. 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, the 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N- ethylcarbamoyl) -4-pyridyloxy) aniline to provide urea.

Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro- N, N- dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4, to give 4- (2- ( N, N- dimethylcarbamoyl) -4-pyridyloxy )aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was 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, the 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N, N- dimethylcarbamoyl) -4-pyridyloxy) aniline to provide urea .

Entry 101: 4-Chloro- N- methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3- (2 - N -methylcarbamoyl) -4-pyridyloxy) -aniline. 2-Amino-3-methoxy-naphthalene was synthesized as described in Method A1. According to Method C3, 2-amino-3-methoxynaphthalene was reacted with bis (trichloromethyl) carbonate followed by 3- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline to form urea.

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Entry 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. The 5- tert -butyl-2- (2,5-dimethylpyrrolyl) aniline was reacted with CDI followed by 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline according to Method C2d to provide the urea .

Entry 103: 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 Method C2b, the reaction of 3-amino-2-methoxyquinoline with CDI followed by 4- (2- ( N- methylcarbamoyl) -4-pyridyloxy) aniline provided bis (4- (2- ( N- methylcarbamoyl)) -4-pyridyloxy) phenyl) urea.

Compounds are listed in the following Tables that have been synthesized according to the Procedures Detailed Experimental provided above:

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Boards

The compounds listed in the Tables 1-6 following were synthesized according to the general methods set forth above, and procedures More detailed illustrative are found in the listings of previous entry, indicating the characterizations in the boards.

Compounds designated with an asterisk do not They are subject matter of the invention.

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TABLE 1 3- tert -Butylphenyl-Ureas

77

TABLE 2 3- tert -Butyl-2-methoxyphenyl-Ureas

78

TABLE 3 5- (Trifluoromethyl) -2-methoxyphenyl-Ureas

79

80

81

82

TABLE 4 3- (Trifluoromethyl) -4-chlorophenyl-Ureas

83

84

85

86

87

TABLE 5 3- (Trifluoromethyl) -4-bromophenyl-Ureas

88

TABLE 6 5- (Trifluoromethyl) -4-chloro-2-methoxyphenyl-Ureas

89

TABLE 7 Additional areas

90

The preceding examples can be repeated with similar success using the reactants and / or the operating conditions of this invention described generically or specifically replacing those used in the examples that precede

Claims (3)

1. Use of a compound of Formula I: (I) A-D-B or a pharmaceutically salt acceptable of it, in where

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

A is a rest substituted of up to 40 carbon atoms of the formula: -L- (M-L 1) q, where L is a residue substituted or unsubstituted phenyl or pyridyl attached directly to D, L1 comprises a phenyl or substituted pyridyl moiety, M is a bridge forming group that has at least one atom, q is a number 1-3 integer; Y

B is a group substituted or unsubstituted phenyl attached directly to D, wherein L 1 is substituted by C (O) R x;

where R_ {x} is NR_ {a} R_ {b}, and R_ {a} and R b are independently hydrogen and a residue based on carbon of up to 30 carbon atoms that optionally contains heteroatoms selected from N, S and O and is substituted optionally with substituents based on halogen, hydroxy and carbon of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are substituted optionally with halogen; where the substituents for B and L and the additional substituents for L1, are selected from the group consisting of C 1 -C 10 alkyl up to C 1 -C 10 alkyl per-halosubstituted, CN, OH, halogen, C 1 -C 10 alkoxy and up C 1 -C 10 alkoxy per-replaced, and where M is a bridge forming group selected from the group consisting of -O- or -S-; for the manufacture of a medicine for treatment of cancer cell growth mediated by raf kinase 2. The use of a compound of the claim 1, wherein the pharmaceutically acceptable salt of a compound of Formula I is selected from the group consisting of:

to)

you go out Basic organic acids and inorganic acids selected from group consisting of hydrochloric acid, hydrobromic acid, acid sulfuric acid, phosphoric acid, methanesulfonic acid, acid trifluorosulfonic acid, benzenesulfonic acid, acid p-toluenesulfonic acid (tosylate salt), acid 1-naphthalenesulfonic acid 2-Naphthalenesulfonic acid, acetic acid, 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 mandelic acid; Y

b)

you go out acids from organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, ammonium cations with aliphatic substituents and ammonium cations with substituents aromatic

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3. The use of claim 1 or the claim 2, wherein the growth of cancer cells Raf-mediated kinase is a carcinoma of the lung, of the pancreas, thyroid, bladder or colon, myeloid leukemia or hairy adenoma of colon.