BRPI0007487B1 - D-diphenyl ureas substituted with w-carboxy aryl as raf kinase inhibitors - Google Patents

Description

"Diphenyl-urea Substituted with Carboxy-Arylas as RAF Kinase Inhibitors" APPLICABLE PATENT APPLICATIONS

This report is a continuation-in-part of Serial Patent Application 09 / 257,266 filed February 15, 1999, and a continuation-in-part of Serial Patent Application No. 60 / 115,877 filed at January 13, 1999.

FIELD OF INVENTION

This invention relates to the use of a group of arylureas in the treatment of raf mediated diseases, and pharmaceutical compositions for use in such therapy.

BACKGROUND OF THE INVENTION p21ras oncogene is an important contributor to the development and progression of compact human cancers and mutates in 30% of all human cancers Bolton et al., Ann. Rep. Med. Chem. 1994, 29: 165-74; Bose. Cancer Res. 1989, 49: 4682-9). In its normal mutation-free form, ras protein is an important element of the growth factor receptor-driven signal transduction cascade in almost all tissues (Avruch et al., Trends Bioche. Sci. 1994, 19: 279-83 ). Biochemically, ras is a guanine nucleotide-binding protein, and recycling between a GTP-joined activated form and a GDP-inactivated form is strictly controlled by the activity of ras endogenous GTPase and other regulatory proteins. In ras mutants in cancer cells, endogenous GTPase activity is decreased, and thus the protein sends constitutive growth signals to downstream effectors such as the raf kinase enzyme. This leads to cancerous growth of cells carrying these mutants (Magnuson et al., Semin. Cancer Biol. 1994, 5: 247-53). By inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administering raf kinase-deactivating antibodies or by co-expression of dominant negative raf kinase or dominant negative MEK, the raf kinase substrate has been shown to inhibit the effect of ras. reversion of transformed cells to normal growth phenotype (see: Daum et al., Trends Biochem. Sci. 1994, 19: 474-80; Fridman et al., J.Biol. Chem. 1994, 269: 30105-8 Kolch et al. (Nature 1991, 349: 426-28) further indicated that inhibition of raf expression by RNA ■ "X Vx 4" “1. yi y \ Ύ" \ yi \ Jf "1 yx / γι * iy% “i ■ —xx" V ™ yx "1 Ί“ p * y \ * —x / x --x / x yx | y \ y Λ π π Ί —-x / - · y. wi λ νχ y yr yx yx y * dllLl ocll & c ÜXOCJlISXa dL pX.ÜXXX6IaÇdü QS CBXUXciS GIU Membrane-Associated OnCOgSIlGS Similarly, inhibition of raf kinase (by oligodeoxynucleotides) was correlated, in vitro and in vivo, with inhibition of in vivo, in vivo and in vivo growth.of human tumor types (Monia et al., Nat. Med. 1996, 2: 668-75).

SUMMARY OF THE INVENTION The present invention provides compounds that are raf kinase enzyme inhibitors. As the enzyme is a downstream effector, inhibitors are useful in pharmaceutical compositions for human or veterinary use, where inhibition of the raf kinase pathway is indicated, for example, in the treatment of tumors and / or cell growth. cancer mediated by raf kinase. In particular, the compounds are useful in the treatment of human or animal compact cancers, such as murine cancer, as the progression of these cancers is dependent on the ras protein signal transduction caste, and therefore susceptible to cascade disruption treatment, that is, by inhibiting raf kinase. Accordingly, the compounds of the invention are useful in the treatment of cancers, such as, for example, carcinomas (such as lung, pancreas, thyroid, bladder or colon), myeloid disorders (such as myeloid leukemia) or adenomas ( such as villous adenoma of the colon). The present invention therefore provides compounds generically described as arylureas, including aryl and heteroaryl analogs, which inhibit the raf kinase pathway. The invention also provides a method for treating a raf-mediated disease state in humans or mammals. Accordingly, the invention relates to compounds that inhibit the enzyme raf kinase and also compounds, compositions and methods for treating raf kinase-mediated cancer cell growth, wherein a compound of the following Formula I or a salt thereof for pharmaceutical use is where: D is -NH-C (O) -NH-, A is a substituted group having up to 40 carbon atoms of the formula: -L (M-L1) q, where L is a 5- or 6-membered cyclic structure bonded directly to D, L1 comprises a substituted cyclic group having at least 5 members, M is a bridging group that has at least one atom, q is an integer from 1 and 3; and each L and L1 cyclic structure contains 0 to 4 members of the nitrogen, oxygen and sulfur group, and B is a substituted or unsubstituted maximum tricyclic aryl or heteroaryl group having up to 30 carbon atoms with at least least one D-linked 6-membered cyclic structure containing 0 to 4 members of the nitrogen, oxygen and sulfur group, where L1 is substituted with at least one substituent selected from the group consisting of -SO2 Rx, -C (O ) Rjc and -C (NRy) Rz;

Ry is hydrogen or a carbon-based grouping of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O, and optionally halo-substituted, up to perhalo;

Rz is hydrogen or a carbon-based grouping of up to 30 carbon atoms, optionally containing heteroatoms selected from N, S and 0, and optionally substituted with halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S, O, and are optionally substituted with halogen;

Rx is Rz or NRaRb, where Ra and Rb are: a) independently hydrogen, a carbon-based grouping of up to 30 carbon atoms, optionally containing heteroatoms selected from N, S and O, and optionally substituted with halogen, hydroxy and substituents based on up to 24 carbon atoms which optionally contain heteroatoms selected from N, S and O and optionally substituted with halogen, or -OSi (Rf) 3 / where Rf is hydrogen or a carbon-based grouping of up to 24 atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted with halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms which optionally contain heteroatoms selected from N, S and 0 and optionally substituted with halogen; or b) Ra and Rb together form a 5- to 7-membered heterocyclic structure with 1 to 3 heteroatoms selected from N, S and 0, or a 5- to 7-membered heterocyclic structure with 1 to 3 heteroatoms selected from N, S and 0 halogen substituted, hydroxy or carbon-based substituents of up to 24 atoms, which optionally contain heteroatoms selected from N, S and 0, and optionally substituted with halogen; or c) one of Ra or Rb is -C (O) -, a divalent C 1 -C 5 alkylene group or a substituted C 3 -C 5 divalent alkylene group bonded to group L to form a cyclic structure of at least 5 members wherein the substituents of the substituted C1-C5 divalent alkylene group are selected from the group consisting of halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0, and are optionally substituted with halogen; where B is substituted, L is substituted or L1 is further substituted, the substituents being selected from the group consisting of halogen to perhalo, and Wn, where n is 0-3; where each W is independently selected from the group consisting of -CN, -CO 2 R 7, -C (0) NR 7 R 7, -C (0) -R 7, -N 2, -0 R 7, -SR 7, -NR 7 R 7, -NR 7 C (0) 0 R 7 , -NR 7 C (0) R 7, -Q-Ar, and carbon-based groups of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O, and optionally substituted with one or more substituents independently selected from the group consisting of of -CN, -CO 2 R 7, -C (0) NR 7 R 7, -C (0) -R 7, -N 2, -OR 7, -SR 7, -NR 7 R 7, -NR 7 C (0) R 7, -NR 7 C (0) 0 R 7, and halogen to perhalo; each R7 being independently selected from H or a carbon-based grouping of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O, optionally substituted with halogen, where Q is -O-, -S-, -N ( R7) -, - (CH2) m, -C (O) -, -CH (OH) -, - (CH2) m0-, - (CH2) mS-, - (CH2) mN (R7) -, -O (CH2) m-CXa, -CXa2-, -S- (CH2) m- and -N (R7) (CH2) m-, where m = 1-3, and Xa is halogen; and Ar is a 5- or 6-membered aromatic structure containing 0 to 2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted with halogen to perhalo and optionally substituted with Ζηχ where n1 is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO2 R7, -C (O) NR7 R7, -C (0) -R7, -no2 / -or7, -SR7, -NR7 R7, - NR7C (0) R7, NR7C (0) 0R7, and a carbon-based grouping of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0, optionally substituted with one or more substituents selected from the group consisting of - CN, -C 2 R 7, -C (0) NR 7 R v, -C (0) -R 7, -N 2, -OR 7, -SR 7, -NR 7 R 7, -NR 7 C (0) R 7, -NR 7 C (0) 0 R 7, where R 7 is as defined above.

Suitable Formula I heteroaryl groups include, but are not limited to, aromatic rings of 5 to 12 carbon atoms or ring systems containing 1 to 3 rings, at least one of which being aromatic, in which one or more carbon atoms are. carbon, for example 1 to 4, in one or more of the rings may be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3 to 7 atoms. For example, B may be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5 -isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2, 4-triazol-1-, -3 or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or 5 -ila, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl , 1,3,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7- indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3- , 4-, 5-, 6- or 7-benzopyrazyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 1-, 3 -, 4-, 5-, 6- or 7- benzothia zolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5 -, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or the optionally substituted following: phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc.

For example, B may be 4-methylphenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, 1-methyl-3-pyrryl, 1-methyl-3-pyrazolyl, 5-methyl-2-yl. thiazolyl or 5-methyl-1,2,4-thiadiazol-2-yl.

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

Aryl groups which do not contain heteroatoms include, for example, phenyl and 1- and 2-naphthyl. The term "cycloalkyl" as used herein refers to cyclic structures with or without alkyl substituents, such as, for example, "C4 cycloalkyl" includes methyl substituted cyclopropyl groups as well as cyclobutyl. The term "cycloalkyl" as used herein also includes saturated heterocyclic groups.

Suitable halogen groups include F, Cl, Br and / or I, from one to substitution (i.e. all H atoms in a group substituted by one halogen atom), possible when an alkyl group is substituted with halogen whereas mixed substitution of halogen atom types is also possible in a given grouping. The invention also relates to compounds of Formula I itself. The present invention also relates to pharmaceutical salts of the compound of Formula I. Suitable pharmaceutical 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, benzene sulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid , malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenyl acetic acid, and mandelic acid. In addition, salts of pharmaceutical use include inorganic acid base salts, such as salts containing alkaline cations (such as Li +, Na + or K +), alkaline earth metal cations (such as Mg2 +, Ca2 + or Ba2 +), ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium cation, and quaternary ammonium cations, such as those resulting from the protonation or peralkylation of triethylamine, N, N-diethyl- amine, N, N-dicyclohexylamine, lysine, pyridine, N, N-dimethylamino pyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] -undec-7ene (DBU).

Numerous compounds of Formula I have asymmetric carbons and may therefore exist in racemic and optically active forms. Methods for separating enanciomeric and diastereoisomeric mixtures are well known to those skilled in these techniques. The present invention encompasses any isolated or optically active isolated racemic form of compounds described in Formula I which have inhibitory activity.

GENERAL PREPARATION METHODS

The compounds of Formula I may be prepared by use of known chemical reactions and procedures, some from commercially available starting materials. However, generic preparation methods are provided below to assist those skilled in these techniques to synthesize these compounds, and detailed examples are provided in the following section of experiments.

Substituted anilines can be generated using standard methods (in March, "Advanced Organic Chemistry", 3rd Edition, John Wiley, New York (1985); Larock, "Comprehensive Transformations", VCH Publishers, New York (1989)). As indicated in Scheme I, aryl amines are commonly synthesized by reducing nitro aryls 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, United Kingdom (1985)). Nitroaryls can also be reduced directly by using a strong hydride source such as LiAlH4 (Seyden-Penne, "Reductions by Alumino and Borohydrides in Organic Synthesis", VCH Publishers, New York (1991)), or by using a metal. with zero valence, such as Fe, Sn or Ca, often in acidic medium. There are many methods for synthesizing nitroaryl (March, "Advanced Organic Chemistry", 3rd Edition, John Wiley, New York (1985); Larock, "Comprehensive Transformations", VCH Publishers, New York (1989)).

Scheme I

Reduction of Nitro-Aryls to Aryl-Amines Nitro-aryls are commonly formed by electrophilic aromatic nitration using HNO3 or an alternative source of N02A. Nitro-aryls can be made even before reduction. Therefore, nitroaryls substituted with potential leaving groups (such as F, Cl, Br, etc.) may undergo substitution reactions in treatment with nucleophiles such as thiolate (exemplified in Scheme II) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme II).

Scheme II

Select Nucleophilic Aromatic Substitution Using Nitro-Aryls Nitro-aryls may also undergo transition metal-mediated cross-coupling reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo palladium-mediated cross-coupling reactions with aryl nucleophiles such as aryl boronic acids (Suzuki reactions, exemplified below). ), aryl tin (Stille reaction) or aryl zinc (Negishi reaction) to produce biaryl (5).

Nitroaryls or anilines may be converted to the corresponding arenesulfonyl chloride (7) in the treatment with chlorosulfonic acid. The reaction of sulfonyl chloride with a fluoride source, such as KF, then produces sulfonyl fluoride (8). The reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source such as tris (dimethylamino) sulfonium difluor trimethyl silicate (TASF) leads to trifluoromethyl sulfone ( 9) corresponding. Alternatively, sulfonyl chloride 7 may be reduced to arenothiol (10) with, for example, zinc amalgam. Reaction of thiol 10 with CHC1F2, in the presence of a base, gives difluoromethyl mercaptan (11), which can be oxidized to sulfone (12) with any of a number of oxidants, including Cr03-acetic anhydride (Sedova). et al., Zh. Org. Khim. 1970, 6 (568).

Select Methods of Synthesis of Fluorinated Aryl Sulfones As indicated in Scheme IV, asymmetric urea formation may involve the reaction of an aryl isocyanate (14) with an aryl amine (13). Heteroaryl isocyanate may be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent such as trichloromethyl chloro-formate (diphosgene), bis (trichloromethyl) carbonate (triphosgene), or N, N'-carbonyl diimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius type rearrangement. Thus, the reaction of acid derivative 16 with an azide source, followed by rearrangement, produces the isocyanate. The corresponding carboxylic acid (17) may also be subjected to Curtius-type rearrangements using diphenyl phosphoryl azide (DPPA) or a similar reagent.

Select Methods Asymmetric Urea Formation Methods Finally, urea can still be manipulated using methods familiar to those skilled in these techniques. The invention also includes pharmaceutical compositions comprising a compound of Formula I and a pharmaceutical carrier.

The compounds may be administered orally, topically, parenterally, by inhalation or spray, or rectally, in unit dose formulations. The term "injection administration" includes intravenous, intramuscular, subcutaneous injections, as well as the use of infusion techniques. One or more compounds may be present in association with one or more non-toxic pharmaceutical carriers, and if desired, other active ingredients.

Compositions intended for oral use may be prepared according to any appropriate method known in the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, vaporizing agents, coloring agents and preservatives to provide palatable preparations. The tablets contain the active ingredient in admixture with non-toxic pharmaceutical excipients which are suitable for tablet manufacture. Such excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating or disintegrating agents such as maize starch or alginic acid; and binding agents, such as magnesium stearate, stearic acid or talc. The tablets may not be coated or they may be coated by known techniques to retard disintegration and adsorption in the gastrointestinal tract, and thereby provide prolonged action over a longer period. For example, a retarding material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds can also be prepared in rapidly released solid form.

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

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, poly (vinyl pyrrolidone), gum tragacanth and acacia gum; Dispersing or wetting agents may be a naturally occurring phosphatide, such as lecithin, or products of the condensation of an alkylene oxide with fatty acids, such as polyoxyethylene stearate, or products of the condensation of ethylene oxide with alcohols. long chain aliphatics such as heptadecaethylene oxyethanol, or ethylene oxide condensation products with fatty acid and hexitol derived esters, such as polyoxyethylene sorbitol monooleate, or ethyl ester oxide condensation products with partial esters fatty acid derivatives and hexitol anhydrides, such as polyethylene sorbitan monoleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more sodifying agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients may also be present, such as sweetening, sodifying and coloring agents.

The compounds may also be in the form of non-aqueous liquid formulations, such as suspensions in oils, which may be formulated by suspending the active ingredients in vegetable oil, such as peanut oil, olive oil, sesame, or in a mineral oil, such as liquid paraffin. Oily suspensions may contain a thickening agent, such as beeswax, heavy paraffin or cetyl alcohol. Sweetening agents, such as those mentioned above, and sodifying agents may be added to provide palatable oral preparations. Such compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the form of oil in water emulsions. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as for fine liquid, or mixtures thereof. Suitable emulsifying agents may be naturally occurring gums such as acacia or tragacanth gum, naturally occurring phosphatides such as soybean lecithin and partial esters or esters derived from fatty acids and hexitol anhydrides such as , sorbitan monooleate, and products of the condensation of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening and sodifying agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerin, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and coloring and sizing agents.

The compounds may also be administered as suppositories for rectal administration of the medicament. Such compositions may be prepared by mixing the drug with an appropriate non-irritating excipient which is solid at normal temperatures but liquid at the rectal temperature, and therefore will melt into the rectum to release the drug. These materials include cocoa butter and polyethylene glycols.

In all of the regimens of use described herein for the compounds of Formula I, the daily oral dosage regimen should preferably be between 0.01 and 200 mg / kg of total body weight. The daily dosage for injection administration, including intravenous, intramuscular, subcutaneous and parenteral injections, and the use of infusion techniques should preferably be between 0.01 and 200 mg / kg of total body weight. The daily rectal dosage schedule should preferably be between 0.01 and 200 mg / kg of total body weight. The daily topical dosage schedule should preferably be between 0.1 and 200 mg to be administered one to four times daily. The daily inhalation dosage schedule should preferably be between 0.01 and 10 mg / kg of the total body weight.

Those skilled in such techniques should appreciate that the specific method of administration will depend on a number of factors, all of which are routinely considered when administering therapy. Those skilled in these techniques should also appreciate that the specific dose level for a given patient depends on a number of factors, including the specific activity of the compound administered, age, body weight, health, gender, diet, time and route of administration, speed excretion, etc. It should further be appreciated by those skilled in these techniques that the optimal course of treatment, that is, the mode of treatment and the daily number of doses of a compound of Formula I or its pharmaceutical salt, for a defined number of days, can be determined by those skilled in these techniques using conventional treatment tests.

It should be understood, however, that the specific dose level for any particular patient will depend on a number of factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, via of administration, and rate of excretion, drug combination and the severity of the condition being treated.

All inclusion of all patent applications, patents, and publications cited above and below is incorporated herein by reference, including provisional patent application No. 60 / 115,877, filed January 13, 199, and patent application no. Provisional Order No. 09 / 257,266, filed February 25, 1999.

The compounds may be produced from known compounds (or from starting materials which, in turn, may be produced from known compounds), such as the generic preparation methods given below. The activity of a given compound to inhibit raf kinase can be routinely tested, for example according to the procedures described below. The following examples are provided by way of illustration only and are not intended and should not be construed as limiting the invention in any way.

EXAMPLES

All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were magnetically stirred unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula and introduced into the reaction vessels through rubber stoppers. Unless otherwise stated the term "concentration under reduced pressure" refers to the use of a Buchi rotary evaporator at approximately 15 mm Hg. Unless otherwise stated, the term "under high vacuum" refers to a vacuum of 0.4-1.0 mm Hg.

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

Industrial grade reagents and solvent were used without further purification. N-Cyclohexyl-N '- (methyl polystyrene) carbodiimide was purchased from Calbiochem-Novabiochem Corp. 3-tert-Butyl aniline, 5-tert-Butyl-2-methoxy aniline, 4-bromo-3- (trifluoromethyl) aniline, 4-chloro-3- (trifluoromethyl) aniline, 2 -methoxy-5- (trifluoromethyl) -aniline, 4-tert-butyl2-nitro-aniline, 3-amino-2-naphthol, ethyl 4-isocyanate-benzoate, N-acetyl-4-chloro-2 -methoxy-5- (trifluoromethyl) aniline and 4-chloro-3- (trifluoromethyl) phenyl isocyanate were purchased and used without further purification. The syntheses of 3-amino-2-methoxy-quinoline (E. Cho et al., WO 98/00402; A. Cordi et al. EP 542609; IBID Bioorg. Med. Chem. 1995, 3 : 129), 4- (3-carbamoyl-phenoxy) -1-nitro-benzene (K. Ikawa, Yakugaku Zasshi 1959, 79: 760; Chem.übstr. 1959, 53: 12761b), 3-tert-butyl enyl isocyanate (O. Rohr et al., DE No. 2,436,108), and 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (K. Inukai, JP No. 42,025,067; IBID Kogyo Kagaku Zasshi 1967, 70: 491) have been described previously. Thin film chromatography (TLC) was performed using Whatman® 60 F-254 250 µl pre-coated glass-bottom silica gel plates. Plates were visualized by one or more of the following techniques: (a) ultraviolet illumination, (b) iodine vapor exposure, (c) immersion of the plaque in a 10% phospho-molybdic acid solution in ethanol, followed by (d) immersion of the plate in an acidic ethanol solution of 2,4-dinitro-phenylhydrazine, followed by heating. Column chromatography (flame chromatography) was performed using 0.063-0.037 mm (230-400 mesh) EM Science® silica gel.

Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automatic melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton nuclear magnetic resonance (NMR) spectra (ΧΗ) were measured with a General Electric GN-Omega 300 (300 MHz) spectrophotometer with Me4Si (δ 0.00) or protonated residual solvent (CHC13 δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. Carbon (13C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) solvent spectrophotometer (CDC13 δ 77.0; MeOD-d3, * δ 49.0; DMSO-de δ 39.5 ) as default. Low resolution mass spectra (MS) and high resolution mass spectra (HEMS) were obtained as electron impact mass spectra (EI) or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacuometric Desorption Chemical Ionization Probe for sample introduction. The ion source was kept at 250 ° C. Electron impact ionization was performed with 70 eV electron energy and a 300 μΑ capture current. Liquid cesium secondary ion mass spectra (FAB-MS), an updated version of the fast atom bombardment were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS Machine (5989A) with methane or ammonia as a reactant gas (IxlCT4 torr at 2.5x10-4 torr). The direct insertion desorption chemical ionization probe (DCI) (Vaccumetrics, Inc.) was scaled between 0-11.5 amps in 10 s and maintained at 10 amps until all traces of the sample disappeared (~ 1-2 min). Spectra were scanned at 50-800 amu at 2 s per scan. HPLC electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a capture mass spectrometer Finnigan LCQ ions with electrospray ionization. Spectra were scanned at 120-800 amu using a time-varying ionic time according to the number of source ions. Gas chromatography - ion selective mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicon column (0.33 mM coating; 25 mx 0.2 mm ) and a Hewlett Packard Selective Mass Detector 5971 (70 eV ionization energy). Elemental analyzes were conducted by Robertson Microlit Labs of Madison, NJ, USA.

All compounds showed NMR spectra, LRMS and elemental analysis or HRMS consistent with the designated structures.

List of Abbreviations and Acronyms: AcOH anhydrous acetic acid at atmosphere BOC tert-butoxycarbonyl CDI 1,1'-carbonyl diimidazole conc concentrate decomposition day (s) DMAC N, N-dimethyl acetamide DMPU 1 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone DMF N, N-dimethylformamide DMSO dimethyl sulfoxide DPPA diphenyl phosphoryl azide EDCI 1- (3-dimethylamino -propyl) -3-ethylcarboimimide EtOAc ethyl acetate EtOH ethanol (100%) Et20 diethyl ether EtsN triethylamine hour (s) HOBT 1-hydroxy-benzotriazole m-CPBA 3-chloro-peroxybenzoic acid MeOH methanol ether e.g. petroleum ether (boiling range. 30-60 ° C) temp temperature THF tetrahydrofuran TFA trifluoro-AcOH

Tf trifluoromethanesulfonyl A. Generic Methods of Synthesis of Substituted Anilines Al. Generic Method of Arylamine Formation via Ether Formation, Following Ester Saponification, Curtius Rearrangement, and Carbamate Deprotection. Synthesis of 2-Amino-3-methoxy-naphthalene.

Step 1. Methyl 3-methoxy-2-naphthoate A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 nutiol) and K2 CO3 (7.96 g, 57.6 mmol) in DMF (200 ml) 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 concentrated NaCl solution (100 mL), dried (MgSO4), concentrated under reduced pressure (approximately 0.4 mm Hg overnight) to give methyl 3-methoxy-2-naphthoate. as an amber oil (10.30 g): 1H-NMR (DMSO-dg) δ 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J = 8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J = 8.09 Hz, 1H), 7.84 (d, J = 8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).

Step 2. 3-Methoxy-2-naphthoic acid A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room temperature was treated with 1 N NaOH solution (33.4 mL, 33.4 mmol). The mixture was heated to reflux temperature for 3 h, cooled to room temperature, and made acidic with a 10% citric acid solution. The resulting solution was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated under reduced pressure. The residue was triturated with hexane and then washed with hexane several times to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): 1 H-NMR (DMSO-de) δ 3 , 88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d, J = 8.09 Hz, 1H), 7.91 (d, J = 8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (br s, 1H).

Step 3. 2- (N- (Carbobenzyloxy) amino-3-methoxy-naphthalene A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et 3 N (2.59 mL) , 18.6 mmol) in anhydrous toluene (70 mL) was stirred at room temperature for 15 min, and then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mLO) via The resulting mixture was heated to 80 ° C for 2 h After cooling the mixture to room temperature, benzyl alcohol (2.06 ml, 20 mmol) was added via syringe.

The mixture was then heated to 80 ° C overnight. The resulting mixture was cooled to room temperature, quenched with a 10% citric acid solution, extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with 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-methoxy naphthalene as a light yellow oil (5.1 g, 100%): 1H-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).

Step 4. 2-Amino-3-methoxy-naphthalene A slurry of 2- (N- (Carbobenzyloxy) -amino-3-methoxy-naphthalene (5.0 g, 16.3 mmol) and 10% Pd / C ( 0.5 g) in EtOAc (70 ml) was kept under an atmosphere of H2 (balloon) at room temperature overnight The resulting mixture was filtered through Celite® and concentrated under reduced pressure to give 2-amino -3-methoxy-naphthalene as a light pink powder (2.40 g, 85%): 1H-NMR (DMSO-d6) δ 3.86 (s, 3H), 6.86 (s, 2H), 7 , 04-7.16 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H); EI-MS m / z 173 (M +) A2 Synthesis of ω-Carbamyl anilines via Formation of a Carbamyl pyridine, Followed by Nucleophilic Coupling with an Aryl Amine Synthesis of 4- (2-N-Methyl-carbamyl-4-pyridyloxy )-aniline.

Step there. Synthesis of 4-Chloro-N-methyl-2-pyridine carboxamide via Menisci Reaction Caution: This is a highly hazardous, potentially explosive reaction. Concentrated H2 SO4 (3.55 ml) was added to a solution of 4-chloro-pyridine (10.0 g) and N-methylformamide (250 ml) at room temperature while stirring to generate an exothermic process. To this mixture was added HO.-. (30% wt in ΗΗΗ, 17 ml), followed by FeSO4 «7H2 O (0.56 g) to generate another exothermic process. The resulting mixture was stirred in the dark at room temperature for 1h, and then slowly warmed for 4h to 45 ° C. When bubbling subsided, the reaction was heated to 60 ° C for 16 h. The resulting opaque brown solution was diluted with H2 O (700 mL), followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with a saturated NaCl solution (3 x 150 mL), and then they were combined, dried (MgSO4) and filtered through a silica gel bed with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient between 50% EtOAc / 50% hexane and 80% EtOAc / 20% hexane). The resulting yellow oil crystallized at 0 ° C for 72 h to give 4-chloro-N-methyl-2-pyridine carboxamide (0.61 g, 5.3%). TLC (50% EtOAc / 50% hexane) Rf 0.50; 1H-1SIMR (CDCl3) δ 3.04 (d, J = 5.1 Hz, 3H), 7.43 (dd, J = 5.4, 2.4 Ηζ, 1Η), 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J = 5.1 δ, 1H); CI-MS m / z 171 ((M + H) +).

Step 1b. Synthesis of 4-Chloro-pyridine-2-carbonyl Hydrochloride via Pieolinic Acid Anhydrous DMF (6.0 mL) was slowly added to SOCl 2 (180 mL) between 40 ° C and 50 ° C. The solution was stirred at this temperature range for 10 min, and then pieolinic acid (60.0 g, 487 mmol) was added portionwise over 30 min. The resulting solution was heated to 72 ° C (intense evolution of SO 2) for 16 h to give a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. Toluene / concentration addition process was repeated twice.The resulting nearly dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and dried under high vacuum for 4 h to yield 4-chloro-pyridine hydrochloride. -2-carbonyl as a yellow-orange solid (92.0 g, 89%).

Step 2. Synthesis of Methyl 4-Chloro-pyridine-2-carboxylate Hydrochloride Anhydrous DMF (10.0 mL) was slowly added to SOCl (300 mL) between 40 ° C and 48 ° C. The solution was stirred at this temperature range for 10 min, and then picolinic acid (100.0 g, 812 mmol) was added portionwise over 30 min. The resulting solution was heated to 72 ° C (intense evolution of SO2) for 16 h to give a yellow solid. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition / concentration process was repeated twice. The resulting nearly dry residue was filtered and the solids were washed with toluene (50 mL) and dried under high vacuum for 4 h to afford 4-chloro-pyridine-2-carbonyl hydrochloride as an off-white solid (27.2 g, 16%). This material has been saved. The red filtrate was added to MeOH (200 mL) at a rate that kept the internal temperature below 55 ° C. The contents were stirred at room temperature for 45 min, cooled to 5 ° C and treated with Et 2 O (200 ml) dropwise.

The resulting solids were filtered, washed with Et 2 O (200 mL) and dried under reduced pressure at 35 ° C to afford methyl 4-chloro-pyridine-2-carboxylate hydrochloride as a white solid (110 g, 65%). mp 108-112 ° C. 1H-NMR (DMSO-d6) δ 3.88 (s, 3H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 8.08 (d, J = 2.2 Hz , 1H), 8.68 (d, J = 5.5 Hz, 1H), 10.68 (br s, 1H); HPLC ES-MS m / z 172 ((M + H) +).

Step 3a. Synthesis of Methyl 4-Chloro-N-methyl-2-pyridine carboxamide From Methyl 4-Chloro-pyridine-2-carboxylate A suspension of methyl 4-chloro-pyridine-2-carboxylate hydrochloride (89.0 g , 428 mmol) in MeOH (75 mL) at 0 ° C was treated with a solution of 2.0 M methylamine in THF (1 liter) 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 liter) and filtered. The filtrate was washed with saturated NaCl solution (500 mL), dried (Na 2 SO 4) and concentrated under reduced pressure to afford 4-chloro-N-methyl-2-pyridine carboxamide as light yellow crystals (71.2 g 97%), mp 41-43 ° C. 1 H NMR (DMS0-d6) δ 2.81 (s, 3H), 7.74 (dd, J = 5.1, 2.2 Hz, 1H), 8.00 (d, J = 2, 2.61 (d, J = 5.1 Hz, 1H), 8.85 (br d, 1H); CI-MS m / z 171 ((M + H) +).

Step 3b. Synthesis of 4-Chloro-N-methyl-2-pyridine carboxamide From 4-Chloro-pyridine-2-carbonyl chloride 4-Chloro-pyridine-2-carbonyl hydrochloride (7.0 g, 32 g) was added. , 95 mmol) in portions to a mixture of a solution of 2.0 M 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 nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate was washed with saturated NaCl solution (2 x 100 mL), dried (Na 2 SO 4) and concentrated under reduced pressure to afford 4-chloro-N-methyl-2-pyridine carboxamide as a yellow crystalline solid ( 4.95 g, 88%), mp 37-40 ° C.

Step 4 Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline A solution of 4-amino-phenol (9.60 g, 88.0 mmol) in anhydrous DMF (150 mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at room temperature for 2 h. The contents were treated with 4-chloro-N-methyl-2-pyridine carboxamide (15.0 g, 87.9 mmol) and K 2 CO 3 (6.50 g, 47.0 mmol) and then heated to 80 ° C for 8 h. The mixture was cooled to room temperature and partitioned between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was back extracted with EtOAc (300 mL). The combined organic layers were washed with saturated NaCl solution (4 x 1,000 mL), dried (Na 2 SO 4) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 ° C for 3 h to yield 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline as a light brown solid (17.9 g, 84 %). 1H-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (ΑΑ'ΒΒ 'quartet, J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 8.44 (d , J = 5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m / z 244 ((M + H) +). Α3. Generic Method for Synthesis of Anilines by Nucleophilic Aromatic Addition, Followed by Nitro-Arene Reduction. Synthesis of 5- (4-Amino-phenoxy) -isoindoline-1,3-dione Step 1. Synthesis of 5-hydroxy-isoindoline-1,3-dione 4-Hydroxyphthalic acid (5.0 g) was slowly added , 27.45 mmol) to a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in concentrated AcOH (25 mL). The resulting mixture was heated to 120 ° C for 45 min, and then the intense light yellow mixture was heated to 160 ° C for 2 h. The resulting mixture was kept at 160 ° C and was concentrated to approximately 15 ml, then cooled to room temperature, and adjusted to pH 10 with 1 N NaOH solution. This mixture was cooled to 0 ° C and slowly acidified to pH 5 using 1 N HCl solution. The resulting precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a light yellow powder (3.24 g, 72%). 1H-NMR (DMSO-d6) δ 7.00-7.03 (m, 2H), 7.56 (d, J = 9.3 Hz, 1H).

Step 2. Synthesis of 5- (4-nitro-phenoxy) -isoindoline-1,3-dione A solution of 5-hydroxy-isoindoline-1,3-dione (3.2 g, 19.6 ml) was added. mmol) in DMF (40 mL) dropwise to a slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 ° C with stirring. The intense yellow-green mixture was allowed to return to room temperature, and was stirred for 1 h, and then 1-fluoro-4-nitro-benzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated to 70 ° C overnight, then cooled to room temperature, slowly diluted with water (150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (MgSO4), and concentrated under reduced pressure to give 5- (4-nitro-phenoxy) -isoindoline-1,3-dione as a yellow solid (3.3 g, 62%). TLC (30% EtOAc / 70% hexane). Rf 0.28; 1H-MMR (DMSO-d6) δ 7.32 (d, J = 12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J = 7.8 Hz, 1H ), 8.29 (d, J = 9Hz, 2H), 11.43 (br s, 1H); CI-MS m / z 285 ((M + H) +, 100%).

Step 3. Synthesis of 5- (4-Amino-phenoxy) -isoindoline-1,3-dione A solution of 5- (4-nitro-phenoxy) -isoindoline-1,3-dione (0.6 g, 2.11 mmol) in concentrated AcOH (12 mL) and water (0.1 mL) was stirred under a stream of argon while slowly adding iron powder (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-amino-phenoxy) -isoindoline-1,3-dione as a brownish solid (0.4 g, 75%). TLC (50% EtOAc / 50% hexane) Rf 0.27; 1H-NMR (DMSO-d6) δ 5.14 (br s, 2H), 6.62 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H) , 7.03 (d, J = 2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J = 8.4 Hz, 1H), 11.02 (s, 1H) ; HPLC ES-MS m / z 255 ((M + H) +, 100%). A4 Generic Method for Synthesis of Pyrrolyl Anilines.Synthesis of 5-tert-Butyl-2- (2,5-dimethyl-pyrrolyl) -aniline Step 1. Synthesis of 1- (4-tert-Butyl-2-nitro-phenyl) ) -2,5-dimethyl pyrrole AcOH (0.1 ml) and acetonyl acetone (0.299 g, 2.63 mmol) were added via syringe to a solution of 2-nitro-4 tert-butyl aniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) with stirring. The reaction mixture was heated to 120 ° C for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temperature, diluted with CH 2 Cl 2 (10 mL) and sequentially washed with 1 N HCl solution (15 mL), 1 N NaOH solution (15 mL) and saturated NaCl solution ( 15 ml), dried (MgSO4) and concentrated under reduced pressure.

The brown-orange solids were purified by column chromatography (60 g SiO 2; gradient between 6% EtOAc / 94% hexane and 25% EtOAc / 75% hexane) to give 1- (4- tert-butyl-2-nitro-phenyl) -2,5-dimethyl-pyrrole as a yellow-orange solid (0.34 g, 49%). TLC (15% EtOAc / 85% hexane) Rf 0.67; 1 H NMR (CDCl3) 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%).

Step 2. Synthesis of 5-tert-But-11-2- (2,5-dimethyl-pyrrolyl) -aniline A 1- (4-tert-Butyl-1-2-nitro-phenyl) -2,5-dimethyl-1-slurry Pyrrole (0.341 g, 1.25 mmol), 10% Pd / C (0.056 g) and EtOAc (50 mL) under a H 2 atmosphere (balloon) was stirred for 72 h, and then filtered through a mattress. from Celite®. The filtrate was concentrated under reduced pressure to give 5- tert-butyl-2- (2,5-dimethyl-pyrrolyl) -aniline as yellowish solids (0.30 g, 99%): TLC (10% EtOAc / 90% hexane) Rf 0.43; 1H-NMR (CDCl3) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H ), 7.28 (br s, 1H). A5 Generic Method for Synthesis of Anilines from Anilines by Nucleophilic Aromatic Substitution. Synthesis of 4- (2- (N-Methyl-carbamoyl) -4-pyridyloxy) -2-methyl-aniline Hydrochloride A solution of 4-amino-3-methylphenol (5.45 g, 4 4.25 mmol ) in anhydrous dimethyl acetamide (75 ml) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol), and the black mixture was stirred at room temperature until the flask reached room temperature. The contents were then treated with 4-chloro-N-methyl-2-pyridine carboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 ° C for 8 h. The mixture was cooled to room temperature and diluted with water (75 ml). The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with saturated NaCl solution (200 mL), dried (MgSO4), and concentrated under reduced pressure. The residual black oil was treated with Et 2 O (50 mL) and sonified. The solution was then treated with HCl (1 M in Et 2 O, 100 mL) and stirred at room temperature for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration of the solution and stored under anaerobic conditions at 0 ° C prior to use. 1H-NMR (DMSO-d6) 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. Generic Method for Synthesis of Anilines from Hydroxyanilines by N-Protection, Nucleophilic Aromatic Substitution and Deprotection. Synthesis of 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline Step 1. Synthesis of 3-Chloro-4- (2,2,2-trifluoroacetylamino) - phenol Iron (3.24 g, 58.00 mmol) was added to TFA (200 mL) while stirring. To this slurry was added 2-chloro-4-nitro-phenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 mL). This gray slurry was stirred at room temperature for 6 d. The iron was filtered from the solution and the remaining material was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). Saturated NaHCCb solution was added to the resulting yellow solution. The precipitated solid from the solution was removed. The filtrate was slowly quenched with sodium bicarbonate solution until the product visibly separated from the solution (determined using an elaborate mini-flask). The slightly cloudy yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with saturated NaCl solution (125 mL), dried (MgSO4) and concentrated under reduced pressure. 1H NMR (DMSO-d6) indicated a 1: 1 ratio of nitro-phenolic starting material to the desired product, 3-chloro-4- (2,2,2-trifluoro-acetyl-amino) -phenol. The crude material was washed to the next step without further purification.

Step 2. Synthesis of 4- (2- (N-Methyl-carbamoyl) -4-pyridyloxy) -2-chloro-phenyl- (2,2,2-trifluor) -acetamide A solution of 3-chloro-4- ( Crude 2,2,2-trifluoroacetamino) phenol in anhydrous dimethyl acetamide (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 vial had cooled to room temperature. The resulting mixture was treated with 4-chloro-N-methyl-2-pyridine carboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated to 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 (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by column chromatography (gradient between 20% EtOAc / petroleum ether and 40% EtOAc / petroleum ether) to yield 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) - 2-chlorophenyl- (222-trifluoro) acetamide as a yellow solid (8.59 g, 23.0 mmol).

Step 3. Synthesis of 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline A solution of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) Crude 2-chlorophenyl- (222-trifluoro) acetamide (8.59 g, 23.0 mmol) in anhydrous 4-dioxane (20 mL) was treated with 1 N NaOH solution (20 mL). This brown solution was allowed to stir 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 afford 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline as a green oil which solidified on standing (2.86 g, 10.30 mmol). 1H-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J = 8.5, 2.6 Hz , 1H), 6.76 (d, J = 2.6 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 7.07 (dd, J = 5.5, 2, 6 Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.75 (q, J = 4.8, 1H). A7 Generic Method for the Unprotection of an Acylated Aniline. Synthesis of 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline A suspension of 3-chloro-6- (N-acetyl) -4- (trifluoromethyl) anisole (4.00 g, 14 , 95 mmol) in a 6 M HCl solution (24 mL) was heated at reflux temperature for 1 h. The resulting solution was allowed to cool to room temperature, and during that time it solidified slightly. The resulting mixture was diluted with water (20 mL), and then treated with a combination of solid NaOH and saturated NaHCO3 solution until the solution was basic. The organic layer was extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to yield 4-chloro-2-methoxy-5- (trifluoromethyl) aniline as a brown oil (3.20 g, 14.2 mmol). 1H-NMR (DMSO-d6) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H). A8 Generic Method for Synthesis of (o-Alkoxycarboxyoxyphenylanilines) Synthesis of 4- (3- (N-Methylcarbamoyl) -4-methoxyphenoxy) -aniline Step 1. 4- (3- Methoxycarbonyl-4-methoxyphenoxy) -1-nitro-benzene S0C12 K2 CO: (5 g) and dimethyl sulfate (3.5 ml) were added to a solution of 4- (3-carboxy-4- hydroxyphenoxy) -1-nitro-benzene (prepared from dihydroxy-benzoic acid in a manner analogous to that described in Method A13, Step 1; 12 mmol) in acetone (50 mL). The resulting mixture was heated to at reflux temperature overnight, then cooled to room temperature, and filtered through a pad of Celite® The resulting solution was concentrated under reduced pressure, absorbed over Si 2 O, and purified by column chromatography (50% EtOAc / 50% hexane) to give 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitro-benzene as a yellow powder (3 g); mp 115-118 ° C.

Step 2. 4- (3-Carboxy-4-methoxy-phenoxy) -1-nitro-benzene A mixture of 4- (3-methoxy-carbonyl-4-methoxy-phenoxy) -1-nitro-benzene (1,2 g), KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temperature overnight, and then warmed to reflux temperature for 4 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50 ml), and the aqueous mixture was made acidic with 1 N HCl solution. 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-methoxy-phenoxy) -1-nitro-benzene (1.04 g).

Step 3. 4- (3- (N-Methyl-carbamoyl) -4-methoxy-phenoxy) -1-nitro-benzene SOCl 2 (0.64 ml, 8.77 mmol) was added portionwise to a solution of 4 - (3-carboxy-4-methoxy-phenoxy) -1-nitro-benzene (0.50 g, 1.75 mmol) in CH 2 Cl 2 (12 mL). The resulting solution was heated to reflux temperature for 18 h, cooled to room temperature, and concentrated under reduced pressure. The resulting yellow solids were dissolved in CH 2 Cl 2 (3 mL), and then the resulting solution was treated with a methyl amine solution (2.0 M in THF; 3.5 mL, 7.02 mmol) in portions (CAUTION: evolution of gas), and stirred at room temperature for 4 h. The resulting mixture was treated with 1 N NaOH solution, and then extracted with CH 2 Cl 2 (25 mL). The organic layer was dried (Na2 SO4) and concentrated under reduced pressure to give 4- (3- (N-methylcarbamoyl) -4-methoxy-phenoxy) -1-nitro-benzene as a yellow solid (0.50 g , 95%).

Step 4. 4- (3- (N-Methylcarbamoyl) -4-methoxyphenoxy) aniline A 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) -1-nitro Benzene (0.78 g, 2.60 mmol) and 10% Pd / C (0.20 g) in EtOH (55 mL) was stirred under 1 atm H2 (balloon) for 2.5 d, and then filtered. through a Celite® mattress. The resulting solution was concentrated under reduced pressure to afford 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline as an off-white solid (0.68 g, 96%). TLC (0.1% Et 3 N / 99.9% EtOAc) Rf 0.36. A9 Generic Method for Preparation of Anilines Containing ω-Alkyl Phthalimides. Synthesis of 5- (4-Aminophenoxy) -2-methyl-isoindoline-1,3-dione Step 1. Synthesis of 5- (4-Nitro-phenoxy) -2-methyl-isoindoline-1,3-dione One 5- (4-nitro-phenoxy) -isoindoline-1,3-dione slurry (A3, Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF HCl (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 was stirred at room temperature overnight, then cooled to 0 ° C, and treated with water (10 ml). The resulting solids were collected and dried under reduced pressure to give 5- (4-nitro-phenoxy) -2-methyl-isoindoline-1,3-dione as an intense yellow solid (0.87 g, 83%). TLC (35% EtOAc / 65% hexane) Rf 0.61.

Step 2. Synthesis of 5- (4-Amino-phenoxy) -2-methyl-isoindoline-1,3-dione A slurry of 5- (4-nitro-phenoxy) -2-methyl-isoindoline-1,3 -dione (0.87 g, 2.78 mmol) and 10% Pd / C (0.10 g) in MeOH was stirred under 1 atm H2 (balloon) overnight. The resulting mixture was filtered through a pad of Celite®, and concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) and filtered through a Si02 plug (60% EtOAc / 40% hexane) to afford 5- (4-amino-phenoxy) -2-methyl-isoindolin-2-one. 1,3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc / 60% hexane) Rf 0.27.

Al. Generic Method for Synthesis of o-Carbamoyl-Aryl-Anilines by Reaction of ω-Alkoxy-Carbonyl-Aryl Precursors with Amines. Synthesis of 4- (2- (N- (2-morpholin-4-yl-ethyl) -carbamoyl) -pyridyloxy) -aniline Step 1. Synthesis of 4-Chloro-2- (N- (2-morpholin-4- 4- (2-Amino-ethyl) -morpholine (2.55 ml, 19.4 mmol) dropwise was added to a solution of 4-chloro-pyridine-2-hydrochloride. methyl carboxylate (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL), and the resulting solution was heated to 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 (MgSO4) and concentrated under reduced pressure to afford 4-chloro-2- (N- (2-morpholin-4-yl-ethyl) carbamoyl) -pyridine as a yellow oil (1.25 g 95%): TLC (10% MeOH / 90% EtOAc) Rf 0.50.

Step 2. Synthesis of 4- (2- (N- (2-Morpholin-4-yl-ethyl) -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 sequentially treated with 4-chloro- (N- (2-morpholin-4-yl). (ethyl) carbamoyl) pyridine (1.22 g, 4.52 mmol) and K 2 CO 3 (0.31 g, 2.26 mmol). The resulting mixture was heated to 75 ° C overnight, cooled to room temperature, and partitioned between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were washed with saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure. The resulting brown solids were purified by column chromatography (58 g; gradient between 100% EtOAc and 25% MeOH / 75% EtOAc) to afford 4- (2- (N- (2-morpholin-4-yl (ethyl) carbamoyl) pyridyloxy) aniline (1.0 g, 65%): TLC (10% MeOH / 90% EtOAc) Rf 0.32.

All. Generic Method for Reduction of Nitroenes to Arylamines. Synthesis of 4- (3-Carboxy-phenoxy) -aniline A slurry of 4- (3-carboxy-phenoxy) -1-nitro-benzene (5.38 g, 20.7 mmol) and 10% Pd / C (0 50 g) in MeOH (120 ml) was stirred under an atmosphere of H2 (balloon) for 2 d. The resulting mixture was filtered through a bed of Celite®, and then concentrated under reduced pressure to afford 4- (3-carboxy-phenoxy) -aniline as a brown solid (2.26 g, 48%): TLC (10 % MeOH / 90% CH 2 Cl 2) Rf 0.44 (tracer).

Al 2. Generic Method for Synthesis of Anilines Containing Isoindolinones. Synthesis of 4- (1-0xoisoindolin-5-yloxy) -aniline Step 1. Synthesis of 5-Hydroxy-isoindolln-1-one Zinc powder (47.6 g, 729 mmol) was slowly added portionwise to a solution. 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL), and then the mixture was heated to reflux temperature 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 SiCk; gradient between 60% EtOAc / 40% hexane and 25% MeOH / 75% EtOAc) to give 5- hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) Rf 0.17; HPLC ES-MS m / z 150 ((M + H) +).

Step 2. Synthesis of 4- (1-Isoindolinon-5-yloxy) -1-nitro-benzene 5-Hydroxy-isoindolin-1-one (2.0 g, 13.4 mmol) was added portionwise to a slurry. NaH (0.39 g, 16.1 mmol) in DMF at 0 ° C. The resulting slurry was allowed to warm to room temperature and was stirred for 45 min, then 4-fluoro-1-nitro-benzene was added, and then the mixture was heated to 70 ° C for 3 h. The mixture was cooled to 0 ° C and treated with water droplets until a precipitate formed.

The resulting solids were collected to give 4- (1-isoindolinon-5-yloxy) -1-nitro-benzene as a dark yellow solid (3.23 q, 89%): TLC (100% EtOAc) Rf 0, 35

Step 3. Synthesis of 4- (1-Oxoisoindolin-5-yloxy) -aniline A 4- (1-Isoindolinon-5-yloxy) -1-nitro-benzene slurry (2.12 g, 7.8 mmol) and 10% Pd / C (0.20 g) in EtOH (50 mL) was stirred under an atmosphere of H2 (balloon) for 4, and then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford 4- (1-oxoavidindolin-5-yloxy) aniline as a dark yellow solid: TLC (100% EtOAc) Rf 0.15.

Al3. Generic Method for Synthesis of ω-Carbamoyl-anilines via EDCI-Mediated Amide Formation, Followed by Nitro-Arene Reduction. Synthesis of 4- (3-N-Methylcarbamoyl-phenoxy) -aniline Step 1. Synthesis of 4- (3-ethoxy-carbonyl-phenoxy) -1-nitro-benzene A mixture of 4-fluoro-1-nitro- benzene (16 mL, 150 mmol), methyl 3-hydroxy benzoate (25 g, 150 mmol) and K 2 CO 3 (41 g, 300 mmol) in DMF (125 mL) was heated to reflux temperature overnight, cooled to room temperature and treated with water (250 ml). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were washed sequentially with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na 2 SO 4) and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc / 90% hexane) to afford 4- (3-ethoxy-carbonyl-phenoxy) -1-nitro-benzene as an oil (38 g).

Step 2. Synthesis of 4- (3-carboxy-phenoxy) -1-nitro-benzene A solution of LiOH · H2 O (1.50 g, 35.8 mmol) in water (36 mL) was added under intense stirring to a mixture of 4- (3-ethoxycarbonyl-phenoxy) -1-nitro-benzene (5.14 g, 17.9 mmol) in a 3: 1 solution of THF water (75 mL). The resulting mixture was heated to 50 ° C overnight, cooled to room temperature, concentrated under reduced pressure, and adjusted to pH 2 with 1 M HCl solution. The resulting intense yellow solids were removed by filtration and washed with hexane to give 4- (3-carboxy-phenoxy) -1-nitro-benzene (4.40 g, 95%).

Step 3. Synthesis of 4- (3- (N-methylcarbamoyl) phenoxy) -1-nitro-benzene A mixture of 4- (3-carboxyphenoxy) -1-nitro-benzene (3.72 g, 14.4 mmol), EDCI * HCl (3.63 g, 18.6 mmol), N-methyl morpholine (1.6 mL, 14.5 mmol) and methyl amine (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 reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with 1 M HCl solution (50 mL). The aqueous layer was back extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with saturated NaCl solution (50 mL), dried (Na 2 SO 4), and concentrated under reduced pressure to give 4- (3- (N-methylcarbamoyl) -phenoxy) -1-nitro- benzene as an oil (1.89 g).

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

Al4. Generic Method for Synthesis of ω-Carbamoyl-anilines via EDCI-Mediated Amide Formation, Followed by Nitro-Arene Reduction. Synthesis of 4-3- (5-Methylcarbamoyl) -pyridyloxy) -aniline Step 1. Synthesis of 4- (3- (5-iaethoxycarbonyl) -pyridyloxy) -1-nitro-benzene A solution of Methyl 5-hydroxy nicotinate (2.0 g, 13.1 mmol) in DMF (10 mL) to a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL). The resulting mixture was added to a solution of 4-fluoro-nitro-benzene (1.4 mL, 13.1 mmol) in DMF (10 mL), and the resulting mixture was heated to 70 ° C overnight, cooled. to room temperature and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc / 70% hexane) to afford 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitro-benzene (0.60 g).

Step 2 Synthesis of 4-3- (5-Methoxy-carbonyl) -pyridyloxy) -aniline A 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -1-nitro-benzene slurry (0.60 g, 2.20 mmol) and 10% Pd / C in MeOH / EtOAc were stirred under a H 2 atmosphere (balloon) for 72 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient between 10% EtOAc / 90% hexane and 30% EtOAc / 70% hexane to 50% EtOAc / 50% hexane) to afford 4- (3- (5-methoxycarbonyl) -pyridyloxy) aniline (0.28 g, 60%): 1H-NMR (CDCl3) δ 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7 73 (d, 1H), 8.51 (d, 1H), 8.87 (d, 1H).

Al5. Synthesis of an Aniline via Electrophilic Nitration, followed by Reduction. Synthesis of 4- (3-Methylsulfamoylphenoxy) -aniline Step 1. Synthesis of N-Methyl-3-bromo-benzenesulfonamide Methylamine (2.0 M in THF; 28 mL, 56 mmol) to a solution of bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0 ° C. The resulting solution was allowed to warm to room temperature and was stirred at room temperature overnight. The resulting mixture was partitioned between EtOAc (25 mL) and 1 M HCl solution (25 mL). The aqueous phase was back extracted with EtOAc (2 x 25 mL). The combined organic phases were washed sequentially with water (2 x 25 mL) and a saturated NaCl solution (25 mL), dried (MgSO4) and concentrated under reduced pressure to give N-methyl-3-bromo-benzenesulfonamide as a white solid (2.8 g, 99%).

Step 2. Synthesis of 4- (3- (N-Methylsulfamoyl) -phenyloxy) -benzene N-Methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol) was added to a slurry of phenol (1.9 g, 20 mmol), K 2 CO 3 (6.0 g, 40 mmol) and Cul (4 g, 20 mmol) in DMF (25 mL), and the resulting mixture was stirred to room temperature. reflux overnight, cooled to room temperature, and partitioned between EtOAc (50 mL) and 1 N HCl solution (50 mL). The aqueous layer was back extracted with EtOAc (2 x 50 mL). The combined organic phases were washed sequentially 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).

Step 3. Synthesis of 4- (3- (N-Methylsulfamoyl) -phenyloxy) -1-nitro-benzene NaNO2 (0.097 g, 1.14 mmol) was added portionwise to a solution of 4- ( 3- (N-methylsulfamoyl) phenyloxy) benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10 ° C for 5 min. The resulting solution was stirred at -10 ° C for 1 h, then allowed to warm to room temperature, and concentrated under reduced pressure. The residue was partitioned between EtOAc (10 mL) and water (10 mL). The organic phase was washed sequentially with water (10 mL) and a saturated NaCl solution (10 mL), dried (MgSO4) and concentrated under reduced pressure to give 4- (3- (N-methylsulfamoyl) phenyloxy) Nitro-benzene (0.20 g). This material was carried to the next step without further purification.

Step 4. Synthesis of 4- (3- (N-Methylsulfamoyl) -phenyloxy) -aniline A 4- (3- (N-methylsulfamoyl) -phenyloxy) -1-nitro-benzene slurry (0 30 g) and 10% Pd / C (0.030 g) in EtOAc (20 ml) was stirred under a H 2 atmosphere (balloon) overnight. The resulting mixture was filtered through a Celite® mattress. 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).

Hello. Modification of ω-ketones. Synthesis of 4- (4- (1- (N-methoxy) imino-ethyl) -phenoxy-aniline hydrochloride O-methylhydroxylamine hydrochloride (0.65 g, 7.78 mmol, 2.0 equiv.) to a 4- (4-acetyl-phenoxy) -aniline hydrochloride slurry (prepared in a similar manner to Method A13, Step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH ( 10 ml) and pyridine (1.0 ml) The resulting solution was heated to 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 4- (4- (1- (N-methoxy) imino-ethyl) -phenoxy-aniline hydrochloride as a yellow solid (0.85 g): TLC (50% EtOAc / 50% ether Rf 0.78; 1H-NMR (DMSO-d6) δ 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m / z 257 ((M + H) +) .

Al7. Synthesis of N- (o -Silyloxyalkyl) amides. Synthesis of 4- (4- (2- (N- (2-Triisopropyl-silyloxy) -ethylcarbamoyl) -pyridyloxy.-aniline Step 1. 4-Chloro-N- (2-triisopropyl-silyloxy) ) -ethylpyridine-2-carboxamide Triisopropyl silyl chloride (1.59 g, 8.2 mmol, 1.1 equiv) and imidazole (1.12 g, 16.4 mmol, 2.2 mmol) were added. equiv.) to a solution of 4-chloro-N- (2-hydroxyethyl) pyridine-2-carboxamide (prepared in a manner analogous to that of Method A2, Step 3b; 1.5 g, 7.4 mmol) in anhydrous DMF (7 mL) The resulting yellow solution was stirred for 3 h at room temperature and then concentrated under reduced pressure The residue was partitioned between water (10 mL) and EtOAc (10 mL). extracted with EtOAc (3 x 10 mL) The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to yield 4-chloro-2- (N- (2-triisopropylsilyloxy) ethyl) pyridine carboxamide as an orange oil (2.32 g, 88%) This material was used in the next step without further purification.

Step 2. 4- (4- (2- (N- (2-Triisopropyl-silyloxy) -ethyl-carbamoyl) -pyridyloxy-aniline) Potassium tert-butoxide (0.67 g, 6.0 mmol, 1 mL) was added. 0.01 equiv.) In one portion to a solution of 4-hydroxy aniline (0.70 g, 6.0 mmol) in anhydrous DMF (8 mL), causing an exothermic process.When this mixture had cooled to room temperature , a solution of 4-chloro-2- (N- (2-triisopropylsilyloxy) ethyl) pyridine carboxamide (2.32 g, 6 mmol, 1 equiv) in DMF (4 mL) was added, followed by K 2 CO 3 (0.42 g, 3.0 mmol, 0.50 equiv.) The resulting mixture was heated to 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 (approximately 1 ml) was slowly added dropwise. The organic layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with saturated NaCl solution (20 mL), dried (MgSO4) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (Si02; 30% EtOAc / 70% petroleum ether) to yield 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) - pyridyloxy aniline as a clear light brown oil (0.99 g, 38%).

Al8. Synthesis of 2-Pyridine Carboxylate Esters via Oxidation of 2-Methyl Pyridines. Synthesis of 4- (5- (2-Methoxycarbonyl) -pyridyloxy) -aniline Step 1. 4- (5- (2-Methyl) -pyridyloxy) -1-nitro-benzene A mixture of 5-hydroxy- 2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-nitro-benzene (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 overnight. The resulting resinous mixture is at room temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed sequentially with water (2 x 100 mL) and saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure to give 4- (5- (2-Methyl) -pyridyloxy ) -1-nitro-benzene as a brown solid (12.3 g).

Step 2. Synthesis of 4- (5- (2-Methoxy-carbonyl) -pyridyloxy) -1-nitro-benzene A mixture of 4- (5- (2-Methyl) -pyridyloxy) -1-nitro-benzene (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 slurry was filtered, and then concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The solution was treated with a concentrated HCl solution (7 mL), and then heated to reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (50 mL) and a 1 N NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed sequentially with water (2 x 50 mL) and saturated NaCl solution (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (Si (> 50% EtOAc / 50% hexane) to afford 4- (5- (2-methoxycarbonyl) pyridyloxy) -J.-nitro-benzene (0.70 g).

Step 3. Synthesis of 4- (5- (2-Methoxycarbonyl) pyridyloxy) aniline A 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitro-benzene slurry (0 50 g) and 10% Pd / C (0.050 g) in a mixture of EtOAc (20 ml) and MeOH (5 ml) were placed under a H 2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite®, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2; 70% EtOAc / 30% hexane) to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline (0.40 g).

Al9. Synthesis of ω-Sulphonyl-phenyl anilines. Synthesis of 4- (4-Methylsulfonyl-phenoxy) -aniline Step 1. 4- (4-Methylsulfonyl-phenoxy) -1-nitrosobenzene m-CPBA (57-86%, 4.0 g) to a solution of 4- (4-methylthio-phenoxy) -1-nitro-benzene (2.0 g, 7.7 mmol) in CH 2 Cl 2 (75 mL) at 0 ° C, and the mixture of The reaction was stirred at room temperature for 5 h. The reaction mixture was treated with 1 N HCl solution (25 mL). The organic layer was washed sequentially with 1 N NaOH solution (25 mL), water (25 mL) and saturated NaCl solution (25 mL), dried (MgSO 4), and concentrated under reduced pressure to give 4- ( 4-methylsulfonyl-phenoxy) -1-nitro-benzene as a solid (2.1 g).

Step 2. 4- (4-Methylsulfonyl-phenoxy) -aniline 4- (4-Methylsulfonyl-phenoxy) -1-nitro-benzene was reduced to aniline in a manner analogous to that described in Method A18, Step 3. B. Urea Precursor Synthesis BI. Generic Method for Synthesis of Isocyanates from Anilines Using CPI. Synthesis of 4-Bromo-3- (trifluoromethyl) phenyl isocyanate Step 1. Synthesis of 4-Bromo-3- (trifluoromethyl) -aniline Hydrochloride A solution of HCl (1 M in Et 2 O) was added. 300 ml) droplets to a solution of 4-bromo-3- (trifluoromethyl) aniline (64 g, 267 mmol) in Et 2 O (500 ml) and the resulting mixture was stirred at room temperature for 16 h. The white-pink precipitate was filtered off and washed with Et 2 O (50 mL) to afford 4-bromo-3- (trifluoromethyl) aniline hydrochloride (73 g, 98%).

Step 2. Synthesis of 4-Bromo-3- (trifluoromethyl) phenyl isocyanate A suspension of 4-bromo-3- (trifluoromethyl) aniline hydrochloride (36.8 g, 133 mmol) in toluene ( 278 ml) was treated with trichloromethyl chloro-formate 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 CH 2 Cl 2 / concentration treatment protocol was repeated and the resulting amber oil was stored at -20 ° C for 16 h to yield 4-Bromo-3- (trifluoromethyl) phenyl isocyanate as a tan solid (35%). 1 g, 86%). GC-MS m / z 265 (M +). C. Urea Formation Methods Cia. Generic method for urea synthesis by reacting an isocyanate with an aniline. Synthesis of N- (4-Chloro-3- (trifluoromethyl) -phenyl) -Ν '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl) -urea A solution of 4 -chloro-3- (trifluoromethyl) phenyl isocyanate (14.60 g, 65.90 mmol) in CH 2 Cl 2 (35 mL) was added dropwise to a suspension of 4- (2- (N-methyl carbamoyl). ) -4-pyridyloxy) aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in ClbCl 2 (35 ml) at 0 ° C. The resulting mixture was stirred at room temperature for 22 h. The resulting yellow solids were removed by filtration, and then washed with CH 2 Cl 2 (2 x 30 mL) and dried under reduced pressure (approximately 1 mm Hg) to yield 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; 1H -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); MS m / z 465 ((M + H) +).

Clb. Generic Method for Urea Synthesis by Reaction of an Isocyanate with an Aniline. Synthesis of N- (4-Bromo-3- (trifluoromethyl) phenyl) -Nf- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea A solution of 4- bromo-3- (trifluoromethyl) phenyl isocyanate (Method B1, Step 2; 8.0 g, 30.1 mmol) in CH 2 Cl 2 (80 mL) was added dropwise to a suspension 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 removed by filtration, and then washed with CH 2 Cl 2 (2 x 50 mL) and dried under reduced pressure (approximately 1 mm Hg) at 40 ° C to yield N- (4-bromo-3- (trifluoro). -methyl) phenyl-N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as a light yellow solid (13.2 g, 90%); -205 ° C 1H-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J = 2.5 Hz, lh), 7.58 (m, 3H), 7.77 (d, J = 8.8 Hz, lh), 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); ES-MS HPLC m / z 509 (( M + H) +).

Clc. Generic Method for Urea Synthesis by Reaction of an Isocyanate with an Aniline. Synthesis of N- (4-Chloro-3- (trifluoromethyl) -phenyl) -α '- (2-methyl-4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl) -urea A solution of 2-methyl-4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (Method A5; 0.11 g, 0.45 mmol) in CH 2 Cl 2 (1 mL) was treated with Et 2 N (0.16 ml) and 4-chloro-3- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temperature for 6 d, and then treated with water (5 ml). The aqueous layer was back extracted with EtOAc (3 x 5 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield N- (4-chloro-3- (trifluoromethyl) phenyl) -Ν '- (2-methyl-4-4- (2- (N -methyl-carbamoyl) - (4-pyridyloxy)) -phenyl) -urea as a brown oil (0.11 g, 0.22 mmol). 1H-NMR (DMSO-d6) δ 2.27 (s, 3H), 2.77 (d, J = 4.8 Hz, 3H), 7.03 (dd, J = 8.5, 2.6 Hz , 1H), 7.11 (d, J = 2.9 Hz, 1H), 7.15 (dd, J = 5.5, 2.6 Hz, 1H), 7.38 (d, J = 2, 6 Hz, 1H), 7.62 (app d, J = 2.6 Hz, 2H), 7.84 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 8, 17 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.78 (q, J = 5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m / z 479 ((M + H) +).

Cld. Generic Method for Urea Synthesis by Reaction of an Isocyanate with an Aniline. Synthesis of N- (4-Chloro-3- (trifluoromethyl) -phenyl) -N '- (4-amino-phenyl) -urea p-Phenylene diamine (3.32 g, 30.7 mmol) was added. ) in one portion to a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (2.27 g, 10.3 mmol) in CH 2 Cl 2 (100 mL). 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 0.05 N HCl solution. The organic layer was concentrated under reduced pressure to afford impure N- (4-chloro-3- (trifluoromethyl) phenyl) - '' (4-amino-phenyl) urea (3.3 g): TLC (100% EtOAc) Rf 0.72.

Cie Generic Method for Synthesis of Urea by Reaction of an Isocyanate with an Aniline. Synthesis of N- (4-Chloro-3- (trifluoromethyl) -phenyl) -Ν '- (4-ethoxycarbonyl-phenyl) -urea 4-Chloro-3- (trifluoromethyl) -aniline was added (3.21 g, 16.4 mmol) to a solution of ethyl 4-isocyanate benzoate (3.14 g, 16.4 mmol) in CH 2 Cl 2 (30 mL) and the solution was stirred at room temperature throughout. night. The resulting slurry was diluted with CH 2 Cl 2 (50 mL) and filtered to yield N- (4-chloro-3- (trifluoromethyl) phenyl) - '' (4-ethoxycarbonylphenyl) urea as a white solid (5.93 g, 97%). TLC (40% EtOAc / 60% hexane) Rf 0.44.

Clf. Generic Method for Urea Synthesis by Reaction of an Isocyanate with an Aniline. Synthesis of N- (4-Chloro-3- (trifluoromethyl) -phenyl) -N '- (3-carboxy-phenyl) -urea 4- (3- (Carboxy-phenoxy) -aniline (Method Ά11) 0.81 g, 5.76 mmol) to a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (1.21 g, 5.46 mmol) in CH 2 Cl 2 (8 mL), and a The resulting mixture was stirred at room temperature overnight, then treated with MeOH (8 mL) and stirred for a further 2 hrs. The resulting mixture was concentrated under reduced pressure. The resulting brown solids were triturated with a 1: 1 solution of EtOAc: hexane to give N- (4-chloro-3- (trifluoromethyl) phenyl) r '- (3-carboxyphenyl) urea as an off-white solid (1.21 g, 76%) Generic Method for Urea Synthesis by Reaction of an Aniline with N, N'-Carbonyl Diimidazole, Followed by Addition of a Second Aniline N- (2-Methoxy-5- (trifluoromethyl) - phenyl) -Nf- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea CDI (0.13 g) was added to a solution of 2-methoxy-5- ( trifluoromethyl) aniline (0.15 g) in anhydrous CH 2 Cl 2 (15 ml) at 0 ° C. The resulting solution was allowed to warm to room temperature over 1h, stirred at room temperature for 16h, 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 water (125 ml). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with saturated NaCl solution (100 mL), dried (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 33% EtOAc / 67% hexane to 50% EtOAc / 50% hexane to 100% EtOAc) to give N- (2-Methoxy). 5- (trifluoromethyl) phenyl) - '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as a light tan solid (0.098 g, 30 %): TLC (100% EtOAc) Rf 0.62. 1H-NMR (DMSO-d6) 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. Generic Method for Urea Synthesis by Reaction of an Aniline with N, N'-Carbonyl Diimidazole, Following Addition of a Second Aniline. Symmetrical Ureas as Byproducts of a Reaction Procedure with N, N'-Carbonyl diimidazole. Synthesis of Bis- (4- (2- (N-Methyl-carbamoyl) -4-pyridyloxy) -phenyl) -urea CDI (0.13 g) was added to a solution of 3-amino-2-methoxy-quinoline (0.14 g) in anhydrous CH 2 Cl 2 (15 mL) at 0 ° C. The resulting solution was allowed to warm to room temperature over 1h, and stirred at room temperature for 16h. 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 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) Rf 0.50. 1H-NMR (DMSO-d6) 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. Generic Method for Urea Synthesis by Reaction of an Isocyanate with an Aniline. Synthesis of N- (2-Methoxy-5- (trifluoromethyl) -phenyl) -Nf- (4- (1,3-dioxoisoindolin-5-yloxy) -phenyl) -urea 5- (4-amino) -phenoxy) -isoindoline-1,3-dione (Method A3, Step 3; 0.12 g, 0.47 mmol) in one portion to a solution of 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.47 mmol) in CH 2 Cl 2 (1.5 mL) while stirring. 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 sequentially with 1 N HCl solution (15 mL) and saturated NaCl solution (15 mL), dried (MgSO 4) and concentrated under reduced pressure to yield N- (2-methoxy-5- ( trifluoro-methyl) -phenyl)-1,3 '- (4- (1,3-dioxoisoindolin-5-yloxy) -phenyl) -urea as a white solid (0.2 g, 96%): TLC (70% EtOAc / 30% hexane) Rf 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. Generic Method for Urea Synthesis by Reaction of an Aniline with N, N '-Carbonyl diimidazole, Following Addition of a Second Aniline. Synthesis of N- (5- (tert-Butyl) -2- (2,5-dimethyl-pyrrolyl) -phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy ) -phenyl urea 5- (tert-Butyl) -2- (2,5-dimethyl-pyrrophyl) -aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) was added in one portion to a solution of CDI (0.21 g, 1.30 mmol) in CH 2 Cl 2 (2 mL) while stirring.The resulting mixture was stirred at room temperature for 4 h, and then 4- {2- (N Methyl carbamoyl) -4-pyridyloxy) aniline (0.065 g, 0.267 mmol) in one portion. The resulting mixture was heated to 36 ° C overnight, then cooled to room temperature, and diluted with EtOAc (5 mL). The resulting mixture was washed sequentially with water (5 mL) and 1 N HCl solution (15 mL), dried (MgSO 4), and filtered through a silica gel pad (50 g) to yield N - (5- (tert-Butyl) -2- (2,5-dimethyl-pyrrolyl) -phenyl) -Ν '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl -urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc / 60% hexane) Rf 0.24 1 H-NMR (acetone-ds) δ 1.37 (s, 9H), 1 89 (s, 6H), 2.89 (d, J = 4.8Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 ( dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J = 5.4 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 Diphenyl Urea Synthesis Using Triphosgene One of the anilines to be coupled was dissolved in dichloro (0.10 M) This solution (0.5 ml) was added to an 8 ml flask containing dichlorethane (1 ml) To this was added a bis (trichloromethyl) carbonate solution (0.12 M in dichloroethane; 0.2 ml, 0.4 equiv.), Followed by diisopropyl ethyl amine (0.35 M in dichlorethane; 0.2 ml, 1.2 equiv.). The flask was capped and heated to 80 ° C for 5 h, and then allowed to cool to room temperature for approximately 10 h. The second aniline was added (0.10 M in dichlorethane; 0.5 ml, 1.0 equiv), followed by diisopropyl ethyl amine (0.35 M in dichlorethane; 0.2 ml, 1 ml). , 2 equiv.) · The resulting mixture was heated to 80 ° C for 4 h, then allowed to cool to room temperature, and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC. C4. Generic Method for Urea Synthesis by Reaction of a Phosgene Aniline, Following Addition of a Second Aniline. Synthesis of N- (2-Methoxy-5-trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl urea Anhydrous pyridine ( 0.32 ml) followed by 2-methoxy-5- (trifluoromethyl) aniline (0.75 g) to a phosgene solution (1.9 M in toluene; 2.07 ml, 0.21 g, 1.30 mmol) in CH 2 Cl 2 (20 mL) at 0 ° C under stirring The yellow solution was allowed to warm to room temperature during which time a precipitate formed The yellow mixture was stirred for 1 h and then concentrated under reduced pressure The resulting solids were treated with anhydrous toluene (20 ml), followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (prepared as described in Method A2; 0.30 g), and the resulting suspension was heated to 80 ° C for 20 h, then allowed to cool to room temperature, the resulting mixture was diluted with water (100 ml), and then made basic with a saturated NaHCO 3 solution (2 -3 ml) The basic solution was extracted with EtOAc (2 x 25 The organic layers were washed separately with a saturated NaCl solution, combined, dried (MgSO4), and concentrated under reduced pressure. The resulting pinkish brown residue was dissolved in MeOH and adsorbed on Si02 (100 g). Column chromatography (300 g SiO 2; gradient between 1% Et 3 N / 33% EtOAc / 66% hexane and 1% Et 3 N / 99% EtOAc to 1% Et 3 N / 20% MeOH / 79% EtOAc) followed by concentration under reduced pressure at 45 ° C, it gave a concentrated solution in hot EtOAc, which was treated with hexane (10 ml), to slowly form crystals of N- (2-methoxy-5-trifluoromethyl) phenyl) -Ν '- (4 - (2- (N-Methylcarbamoyl) -4-pyr (Ldyloxy) phenyl urea (0.44 g): TLC (1% Et 3 N / 99% EtOAc) Rf 0.40 D. Urea Interconversion Day. Conversion of ω-Amino-phenyl ureas to ta (Aroyl-amino) -phenyl ureas Synthesis of N- (4-Chloro-3 - ((trifluoromethyl) -phenyl) -N '- (4- ( 3-Methoxy-carbonyl-phenyl) -carboxy-amino-phenyl) -urea EDCI-HCl (0.29 g, 1.52 mmol) was added to a solution of N- (4-chloro-3- ( (trifluoro-methyl) -phenyl) -α- (4-amino-phenyl) -urea (Method Cld; 0.050 g, 1.52 mmol), mono methyl isophthalate (0.25 g, 1.38 mmol) (0.41 g, 3.03 mmol) and N-methyl morpholine (0.33 mL, 3.03 mmol) in DMF (8 mL). The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a saturated NaHCO 3 solution (25 mL). The organic layer was dried (Na 2 SO 4) and concentrated under reduced pressure. The resulting solids were triturated with a solution of EtOAc (80% EtOAc / 20% hexane) to give N- (4-Chloro-3 - ((trifluoromethyl) phenyl) -Ν '- (4- (3- methoxy-carbonyl-phenyl) -carboxy-amino-phenyl) -urea (0.27 g, 43%), mp 121-122 ° C: TLC (80% EtOAc / 20% hexane) Rf 0.75.

DLB Conversion of ω-Amino-phenyl ureas to ω ~ (Aryl carbamoyl) -phenyl ureas. Synthesis of N- (4-Chloro-3 - ((trifluoromethyl) phenyl) -il '- (4- (3-methylcarbamoyl-phenyl) -carbamoyl-phenyl) -urea EDCI * HCl (0.10 g, 0.53 mmol) to a solution of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4-methylcarbamoyl-phenyl) -carboxy amino-phenyl) -urea (0.14 g, 0.48 mmol), 3-methylcarbamoyl aniline (0.080 g, 0.53 mmol), Η0ΒΤ · Η20 (0.14 g, 1.07 mmol), and N-methyl morpholine (0.5 mL, 1.07 mmol) in DMF (3 mL) at 0 ° C. The resulting mixture was allowed to warm to room temperature and stirred overnight. 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 silica gel pad ( 17 g, gradient between 70% EtOAc / 30% hexane and 10% MeOH / 90% EtOAc) to give N- (4-Chloro-3 - ((trifluoromethyl) phenyl) -Ν '- (4- ( 3-methylcarbamoyl-phenyl) -carbamoyl-phenyl) -urea as a white solid (0.097 g, 41%), mp 225-229 ° C: TLC (100% EtOAc) Rf 0.23.

Dlc. Combinatorial Approach for the Conversion of <a-Carboxy-phenyl ureas to ω- (Aryl carbamoyl) -phenyl ureas. Synthesis of N- (4-Chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (N- (3- (N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) -phenyl) -urea A mixture of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -Ν '- (3-carboxy-phenyl) -urea (Method Clf; 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-amino pyridine in CH 2 Cl 2 (1 M (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 to 36 ° C overnight.

The cloudy reactions were then treated with THF (1 ml) and heating continued for 18 h. The resulting mixtures were treated with poly (4- (isocyanate-methyl) 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 silica gel plug (1 g). Concentration under reduced pressure yielded N- (4-Chloro-3 - ((trifluoromethyl) phenyl) -il '- (4- (N- (3- (N- (3-pyridyl) carbamoyl) phenyl) ) -carbamoyl) -phenyl) -urea (0.024 g, 59%): TLC (70% EtOAc / 30% hexane) Rf 0.12 D2 Conversion of ω-Carboalkoxy-aryl ureas to t-Carbamoyl-aryl Synthesis of N- (4-Chloro-3 - ((trifluoromethyl) phenyl) -Nf- (4- (3-methylcarbamoyl-phenyl) -carboxy-amino-phenyl) -urea Methyl was added (2 M in THF; 1 mL, 1.7 mmol) to a sample of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-carbomethoxy) phenyl) -carboxy-amino-phenyl) -urea (0.17 g, 0.34 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) carboxyaminophenyl) urea as a white solid: mp 247 ° C; (100% EtOAc) Rf 0.35 D3 Conversion of ω-Carboalkoxy aryl ureas to co-Carboxy aryl ureas Synthesis of N- (4-Chloro-3 - ((t Rifluoromethyl) phenyl) -N '- (4-carboxyphenyl) urea Aqueous KOH solution (2.5 N; 10 ml, 23 mmol) to a slurry of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -4 '- (4-ethoxycarbonylphenyl) urea (Method Cie; 5.93 15.3 mmol) in MeOH (75 mL) The resulting mixture was heated to 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 1 N HCl solution to adjust the pH to 2 to 3. The resulting solids were collected and dried under reduced pressure to give N- (4-Chloro-3 - ((trifluoromethyl) - phenyl) -Ν '- (4-carboxy-phenyl) -urea as a white solid (5.05 g, 92%) D4.Generic Method for the Conversion of ω-Alkoxy Esters to ω-Alkyl Amides Synthesis N- (4-Chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3- (5- (2-dimethyl-amino-ethyl) carbamoyl) -pyridyl) -oxyphenyl) -acetamide urea Step 1. Synthesis of N- (4-Chloro-3 - ((trifluoromethyl) phenyl) -N '- ((4- (3- (5-carboxy-pyridyl) -oxyphenyl) -urea N- ( 4-Chloro-3 - ((trifluoromethyl) phenyl) - '' ((4- (3- (5-methoxy I-carbonyl-pyridyl) -oxyphenyl) -urea was synthesized from 4-chloro-3- (trifluoromethyl) -phenyl and 4- (3- (5-methoxy-carbonyl-pyridyl) -oxyaniline isocyanate (Method A14, Step 2) in a manner analogous to that of Method C. A suspension of N- (4-Chloro-3 - ((trifluoromethyl) phenyl) -N '- ((4- (3- (5-methoxy -carbonyl-pyridyl) -oxyphenyl) -urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL ), and was stirred at room temperature for 1 h. The resulting mixture was adjusted to pH 5 with 1 N HCl solution. The resulting precipitate was filtered off and washed with water. The resulting solids were dissolved in EtOH (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-carboxy-pyridyl) - oxyphenyl) urea (0.18 g, 71%).

Step 2. Synthesis of N- (4-Chloro-3 - ((trifluoromethyl) phenyl) -N '- ((4- (3- (5- (2-dimethyl-amino-ethyl) carbamoyl) -pyr) - dil) -oxyphenyl) -urea A mixture of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -Ν '- ((4- (3- (5-carboxy-pyridyl) -oxyphenyl) -urea (0.050 g, 0.011 mmol), N, N-dimethylethylene diamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N-methyl morpholine (0.035 g 0.28 mmol), and EDCI * HCl (0.032 g, 0.17 mmol) in DMF (2.5 mL) were stirred at room temperature overnight The resulting solution was partitioned between EtOAc (50 mL ) and water (50 ml) The organic phase was washed with water (35 ml), dried (MgSO4 and concentrated under reduced pressure.) The residue was dissolved in a minimum amount of CH2 Cl2 (approximately 2 ml). was treated with dropwise Et 2 O to give N- (4-Chloro-3 - ((trifluoromethyl) phenyl) -4 '- ((4- (3- (5- (2-dimethylamino-ethyl)) carbamoyl) pyridyl) oxyphenyl) urea as a white precipitate (0.48 g, 84%). 1H NMR (DMSO-d6) 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. Generic Method for the Unprotection of N- (o-Silyloxy-alkyl) -amldas. Synthesis of N- (4-Chioro-3 - ((trifluoromethyl) phenyl) -N '- (4- (4- (2- (N- (2-hydroxy) ethylcarbaxoyl) pyridyloxy) tetrabutyl 1-argonium fluoride (1.0 M in THF; 2 ml) was added to a solution of N- (4-chloro-3- ((trifluoromethyl) phenyl) -Ν ' - (4- (4- (2- (N- (2-triisopropyl-silyloxy) -ethylcarbamoyl) -pyridyloxy-phenyl) -urea (prepared in a similar manner to that of Method Cia; 0.25 g, 0, 37 mmol) in anhydrous 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). dried (MgSO4) and concentrated under reduced pressure The residue was purified by column chromatography (Si02; gradient between 100% hexane and 40% EtOAc / 60% hexane) to give N- (4-Chloro-3 - (( trifluoromethyl) phenyl) -4- (4- (4- (2- (N- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).

Listed below are the compounds listed in the Tables below which have been synthesized according to the Detailed Experimental Procedures provided above: EXAMPLES OF COMPOUND SYNTHESIS (See Tables for Compound Characterization) Item 1: 4- (3-N-Methyl) carbamoyl phenoxy) aniline according to Method A13. According to Method C3, 3-tert-butyl aniline was reacted with bis (trichloromethyl) carbonate, followed by 4- (3-N-methyl carbamoyl phenoxy) aniline to produce urea .

Item 2: 4-Fluoro-1-nitro-benzene was reacted with p-hydroxy-acetophenone according to Method A13, Step 1 to yield 4- (4-acetyl-phenoxy) -1-nitro-benzene. 4- (4-Acetylphenoxy) -1-nitro-benzene was reduced according to Method Al3, Step 4 to yield 4- (4-acetylphenoxy) aniline. According to Method C3, 3-tert-butyl aniline was reacted with bis (trichloromethyl) carbonate, followed by 4- (4-acetylphenoxy) aniline to produce urea.

Item 3: According to Method C2d, 3-tert-butyl aniline was treated with GDI, followed by 4- (3-N-methylcarbamoyl) -4-methoxy-phenoxy) -aniline, which had been prepared from according to Method A8 to produce urea.

Item 4: 5-tert-Butyl-2-methoxy aniline was converted to 5-tert-Butyl-2-methoxy-phenyl isocyanate according to Method B. 4- (3-N-Methyl) was reacted. -carbamoyl-phenoxy) -aniline, prepared according to Method A13, with isocyanate according to Method Cia to produce urea.

Item 5: According to Method C2d, 5-tert-Butyl-2-methoxy aniline was reacted with GDI, followed by 4- (3-N-methylcarbamoyl) -4-methoxyphenoxy) aniline, which had been prepared according to Method A8 to produce urea.

Item 6: 5- (4-Amino-phenoxy) -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-amino-phenoxy) -isoindoline-1,3-dione to produce urea.

Item 7: 4- (1- 0xoisoindolin-5-yloxy) aniline was synthesized according to Method A12. According to Method 2d, 5-tert-Butyl-2-methoxy aniline was reacted with CDI, followed by 4- (1-oxoisoindolin-5-yloxy) aniline to produce urea.

Item 8: 4- (3-N-Methylcarbamoylphenoxy) aniline was synthesized according to Method A12. According to Method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI, followed by 4- (3-N-methylcarbamoylphenoxy) aniline to produce urea.

Item 9: 4-Hydroxyacetophenone was reacted with 2-chloro-5-nitro-pyridine to give 4- (4-acetyl-phenoxy) -5-nitro-pyridine according to Method A3, Step 2. According to Method A8, Step 4, 4- (4-acetyl-phenoxy) -5-nitro-pyridine was reduced to 4- (4-acetyl-phenoxy) -5-amino-pyridine. 2-Methoxy-5- (trifluoromethyl) aniline was converted to 2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method Bl. The isocyanate was reacted with 4- (4) - acetyl phenoxy) -5-amino pyridine according to Method Cl to produce urea.

Item 10: 4-Fluoro-1-nitro-benzene was reacted with p-hydroxy-acetophenone according to Method A13, Step 1 to yield 4- (4-acetyl-phenoxy) -1-nitro-benzene . 4- (4-Acetylphenoxy) -1-nitro-benzene was reduced according to Method Al3, Step 4, to yield 4- (4-acetylphenoxy) -aniline. According to Method C3 5- (trifluoromethyl) -2-methoxybutyl aniline was reacted with bis (trichloromethyl) carbonate followed by 4- (4-acetylphenoxy) aniline, to produce urea.

Item 11: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was prepared according to Method A2, Step 3a, was reacted with 3-aminophen 1 according to Method A2, Step 4, using DMAC in place 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 produce urea.

Item 12: 4-Chloro-pyridine-2-carbonyl hydrochloride was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridine carboxamide.

4-Chloro-2-pyridine carboxamide was reacted with 3-amino phenol according to Method A2, Step 4 using DMAC in place of DMF to give 3- (2-carbamoyl-4-pyridyloxy) -aniline.

According to Method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene, followed by 3- (2-carbamoyl-4-pyridyloxy) aniline to produce urea.

Item 13: 4-Chloro-N-methyl-2-pyridine carboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridine carboxamide was reacted with 4-amino phenol according to Method A2, Step 4 using DMAC in place 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 produce the urea.

Item 14: 4-Chloro-pyridine-2-carbonyl hydrochloride was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridylcarboxamide. 4-Chloro-2-pyridine carboxamide was reacted with 4-amino-phenol according to Method A2, Step 4 using DMAC in place of DMF to give 4- (2-carbamoyl-4-pyridyloxy) -aniline. According to Method C4, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene, followed by 4- (2-carbamoyl-4-pyridyloxy) aniline to yield urea.

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

Item 16: 4- (2- (N-Methyl-carbamoyl) -4-pyridyloxy) -2-methyl-aniline was synthesized according to Method A5.

5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. Isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline according to Method Clc to produce urea.

Item 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 B. 5- (Trifluoromethyl) was reacted. 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline -2-methoxy-phenyl isocyanate according to Method Cia to produce urea.

Item 18: According to Method A2, Step 4, 5-Amino-2-methyl-phenol was reacted with 4-chloro-N-methyl-2-pyridine carboxamide, 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- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B. 5- (Trifluoromethyl) was reacted. 3- (2- (Dimethyl-carbamoyl} -4-pyridyloxy) -4-methylaniline -2-methoxy-phenyl isocyanate according to Method Cia to produce urea.

Item 19: 4-Chloro-pyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridine carboxamide was reacted with 4-amino phenol according to Method A2, Step 4 to give 4- (2- (N-ethyl carbamoyl) - 4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B. 5- (Trifluoromethyl) was reacted. 2- (Methoxy-phenylisocyanate) with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) -aniline according to Method Cia to produce urea.

Item 20: According to Method A2, Step 4, 4-Amino-2-chloro-phenol was reacted with 4-chloro-N-methyl-2-pyridine carboxamide, 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- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B. 5- (Trifluoromethyl) was reacted. methyl) -2-methoxy-phenyl isocyanate with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline according to Method Cia to give urea.

Item 21: 4- (4-Methylthiophenoxy) -1-nitro-benzene was oxidized according to Method A19, Step 1 to give 4- (4-methylsulfonyl-phenoxy) -1-nitro-benzene. Nitro-benzene was reduced according to Method Al9, Step 2 to give 4- (4-methylsulfonylphenoxy) -1-aniline. According to Method Cia 5- (trifluoromethyl) -2-methoxy-phenylisocyanate was reacted with 4- (4-methylsulfonyl-phenoxy) -1-aniline to yield urea.

Item 22: 4- (3-Carbamoyl-phenoxy) -1-nitro-benzene was reduced to 4- (3-Carbamoyl-phenoxy) -aniline according to Method A15, Step 4. According to Method Cia, 5- (trifluoromethyl) -2-methoxy-phenyl isocyanate was reacted with 4- (3-carbamoyl-phenoxy) -aniline to produce urea.

Item 23: 5- (4-Amino-phenoxy) -isoindoline-1,3-diine was synthesized according to Method A3. 5- (Trifluoromethyl) -2-methoxy aniline was converted to 5- (trifluoromethyl) -2-methoxy phenyl isocyanate according to Method B1.

5- (Trifluoromethyl) -2-methoxy-phenyl-isocyanate was reacted with 5- (4-amino-phenoxy) -isoindoline-1,3-dione to produce urea.

Item 24: 4-Chloro-pyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. 4-Chloro-N, N-dimethyl-2-pyridinecarboxamide was reacted with 4-amino phenol according to Method A2, Step 4 to give 4- (2- (Ν, Ν-dimethyl carbamoyl) -4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxy aniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B. 5- (Trifluoromethyl) was reacted. 2- (Methoxy-phenyl isocyanate with 4- (2- ((, Ν-dimethylcarbamoyl) -4-pyridyloxy) -aniline according to Method Cia to produce urea.

Item 25: 4- (1-Oxoisoindolin-5-yloxy) aniline was synthesized according to Method A12. 5- (Trifluoromethyl) -2-methoxy aniline was treated with CDI, followed by 4- (1-oxoisoindolin-5-yloxy) aniline according to Method C2d to produce urea.

Item 26: 4-Hydroxyacetophenone was reacted with 4-fluoro-nitro-benzene according to Method A13, Step 1 to give 4- (4-acetyl-phenoxy) -nitro-benzene. Nitro-benzene was reduced according to Method A13, Step 4, to yield 4- (4-acetylphenoxy) -aniline, which was converted to 4- (4- (1- (N-methoxy) hydrochloride). imino-ethyl) phenoxy aniline according to Method A 16. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline hydrochloride). according to the Cia Method to produce urea.

Item 27: 4-Chloro-N-methyl-pyridine carboxamide 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. (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B. 5- (Trifluoromethyl) -2- methoxy phenyl isocyanate with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline according to Method Cia) to produce urea.

Item 28: 5- (4-Amino-phenoxy) -2-methyl-isoindoline-1,3-dione was synthesized according to Method A9. 5- (Trifluoromethyl) -2-methoxy aniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B. 5- (Trifluoromethyl) was reacted. 2- (Methoxy-phenyl-isocyanate) with 5- (4-amino-phenoxy) -2-methyl-isoindoline-1,3-dione according to Method Cia to produce urea.

Item 29: 4-Chloro-N-methyl-pyridine carboxamide 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. (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B. 5- (Trifluoromethyl) -2- methoxy phenyl isocyanate with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline according to Method Cia) to produce urea.

Item 30: 4-Chloro-pyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. 4-Chloro-N-isopropyl-2-pyridine carboxamide was reacted with 4-amino phenol according to Method A2, Step 4 to give 4- (2- (N-isopropyl carbamoyl) -4 -pyridyloxy) -aniline. 5- (Trifluoromethyl) -2-methoxy aniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B. 5- (Trifluoromethyl) was reacted. 2- (Methoxy-phenyl isocyanate with 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) -aniline according to Method Cia to produce urea.

Item 31: 4- (3- (5-Methoxy-carbonyl) -pyridyloxy) -aniline was synthesized according to Method Al4. 5- (Trifluoromethyl) -2-methoxy aniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B. 5- (Trifluoromethyl) was reacted. 2- (Methoxy-phenylisocyanate) with 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -aniline according to Method Cia to produce urea. N- (5- (trifluoromethyl) -2-methoxy-phenyl) -N '- (4- (3- (5-methoxy-carbonyl-pyridyl) -oxy) -phenyl) -urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4- (2-amino-ethyl) -morpholine, to produce the amide according to Method D4, Step 2.

Item 32: 4- (3- (5-Methoxy-carbonyl) -pyridyloxy) -aniline was synthesized according to Method A14. 5- (Trifluoromethyl) -2-methoxy aniline was converted to 5- (trifluoromethyl) -2-methoxy phenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxy-phenylisocyanate was reacted with 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -aniline according to Method Cia to produce urea. N- (5- (Trifluoromethyl) -2-methoxy-phenyl) -Ν '- (4- (3- (5-methoxy-carbonyl-pyridyl) -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 produce the amide.

Item 33: 4- (3- (5-Methoxy-carbonyl) -pyridyloxy) -aniline was synthesized according to Method Al4. 5- (Trifluoromethyl) -2-methoxy aniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B. 5- (Trifluoromethyl) was reacted. 2- (Methoxy-phenylisocyanate) with 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -aniline according to Method Cia to produce urea. N- (5- (trifluoromethyl) -2-methoxy-phenyl) -N '- (4- (3- (5-methoxy-carbonyl-pyridyl) -oxy) -phenyl) -urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with N, N-dimethylethylene diamine according to Method D4, Step 2, to produce the amide.

Item 34: 4- (3- (Carboxy-phenoxy) -aniline was synthesized according to All Method. 5- (Trifluoromethyl) -2-methoxy-aniline was converted to 5- (trifluoromethyl). ) -2-Methoxy-phenyl isocyanate according to Method B. 5- (Trifluoromethyl) -2-methoxy-phenyl isocyanate was reacted with 4- (3- (carboxy-phenoxy) -aniline). according to Method Clf to produce N- (5- (trifluoromethyl) -2-methoxy-phenyl) -Ν '- (3-carboxy-phenyl) -urea which was coupled to the 3-amino-pyridine of according to Method Dlc.

Item 35: 4- (3- (Carboxy-phenoxy) -aniline was synthesized according to Method All. 5- (Trifluoromethyl) -2-methoxy-aniline was converted to 5- (trifluoromethyl). ) -2-Methoxy-phenyl isocyanate according to Method B-5- (Trifluoromethyl) -2-methoxy-phenyl isocyanate was reacted with 4- (3- (carboxy-phenoxy) -aniline). according to Method Clf, to produce N- (5- (trifluoromethyl) -2-methoxy-phenyl) -Ν '- (3-carboxy-phenyl) -urea, which was coupled to N- (4-fluorine). -phenyl) piperazine according to Method Dlc.

Item 36: 4- (3- (Carboxy-phenoxy) -aniline was synthesized according to All Method. 5- (Trifluoromethyl) -2-methoxy-aniline was converted to 5- (trifluoromethyl) - 2-methoxy phenyl isocyanate according to Method B1.

5- (Trifluoromethyl) -2-methoxy-phenylisocyanate was reacted with 4- (3- (carboxy-phenoxy) -aniline according to Method Clf) to yield N- (5- (trifluoromethane) -methyl) -2-methoxy-phenyl) -N '- (3-carboxy-phenyl) -urea, which was coupled to 4-fluoraniline according to Method Dlc.

Item 37: 4- (3- (Carboxy-phenoxy) -aniline was synthesized according to All Method. 5- (Trifluoromethyl) -2-methoxy-aniline was converted to 5- (trifluoromethyl). ) -2-Methoxy-phenyl isocyanate according to Method B. 5- (Trifluoromethyl) -2-methoxy-phenyl isocyanate was reacted with 4- (3- (carboxy-phenoxy) -aniline). according to Method Clf to produce the N- (5- (trifluoromethyl) -2-methoxy-phenyl) -Ν '- (3-carboxy-phenyl) -urea which was coupled to 4- (dimethyl-amino). ) - aniline according to Method Dlc.

Item 38: 4- (3- (Carboxy-phenoxy) -aniline was synthesized according to All Method. 5- (Trifluoromethyl) -2-methoxy-aniline was converted to 5- (trifluoromethyl) - 2-methoxy phenyl isocyanate according to Method B1.

5- (Trifluoromethyl) -2-methoxy-phenylisocyanate was reacted with 4- (3- (carboxy-phenoxy) -aniline according to Method Clf) to yield N- (5- (trifluoromethane) -methyl) -2-methoxy-phenyl) -N '- (3-carboxy-phenyl) -urea, which was coupled to 5-amino-2-methoxypyridine according to Method Dlc.

Item 39: 4- (3- (Carboxy-phenoxy) -aniline was synthesized according to All Method. 5- (Trifluoromethyl) -2-methoxy-aniline was converted to 5- (trifluoromethyl) - 2-methoxy phenyl isocyanate according to Method B1.

5- (Trifluoromethyl) -2-methoxy-phenylisocyanate was reacted with 4- (3- (carboxy-phenoxy) -aniline according to Method Clf) to yield N- (5- (trifluoromethane) -methyl) -2-methoxy-phenyl) -Ν '- (3-carboxy-phenyl) -urea, which was coupled to 4-morpholine aniline according to Method Dlc.

Item 40: 4- (3- (Carboxy-phenoxy) -aniline was synthesized according to All Method. 5- (Trifluoromethyl) -2-methoxy-aniline was converted to 5- (trifluoromethyl) - 2-methoxy phenyl isocyanate according to Method B1.

5- (Trifluoromethyl) -2-methoxy-phenylisocyanate was reacted with 4- (3- (carboxy-phenoxy) -aniline according to Method Clf) to yield N- (5- (trifluoromethane) -methyl) -2-methoxy-phenyl) -N '- (3-carboxy-phenyl) -urea, which was coupled to N- (2-pyridyl) -piperazine according to Method Dlc.

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

Item 42: 4- (2-N-Methyl-carbamyl-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 Cia to produce urea.

Item 43: 4-Chloro-pyridine-2-carbonyl hydrochloride was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridine carboxamide.

4-Chloro-2-pyridine carboxamide was reacted with 4-amino phenol according to Method A2, Step 4 to form 4- (2-carbamoyl-4-pyridyloxy) aniline. According to Method Cia, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2-carbamoyl-4-pyridyloxy) aniline to yield urea.

Item 44: 4-Chloropyridine-2-carbonyl hydrochloride was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pididine carboxamide.

4-Chloro-2-pyridine carboxamide was reacted with 3-amino phenol according to Method A2, Step 4 to form 3- (2-carbamoyl-4-pyridyloxy) aniline. According to Method Cia, 3- (2-carbamoyl-4-pyridyloxy) aniline was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate to produce urea.

Item 45: 4-Chloro-N-methyl-2-pyridinecarboxamity, which was synthesized according to Method A2, Step 3a, was reacted with 3 amino phenol according to Method A2, Step 4, to form 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. According to Method Cia, 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate to produce urea.

Item 46: 5- (4-Amino-phenoxy) -isoindoline-1,3-diine was synthesized according to Method A3. According to Method Cia, 4-chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 5- (4-amino-phenoxy) -isoindoline-1,3-dione to produce urea.

Item 47: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was synthesized according to Method A5.

According to Method Clc, 4-chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 5- (4-amino-phenoxy) -isoindoline-1,3-dione to produce urea.

Item 48: 4- (3- (N-Methyl-sulfamoyl) -4-phenyloxy) -aniline was synthesized according to Method A15. According to Method Cia, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N-methylsulfamoyl) -4-phenyloxy) aniline to produce the urea.

Item 49: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6.

According to Method Cia, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloro -aniline, to produce urea.

Item 50: According to Method A2, Step 4, 5-amino-2-methyl-phenol was reacted with 4-chloro-N-methyl-2-pyridine carboxamide, which had been synthesized according to Method A2. Step 3b to give 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. According to Method Cia, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methyl aniline, to produce urea.

Item 51: 4-Chloro-pyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridine carboxamide was reacted with 4-amino phenol according to Method A2, Step 4 to give 4- (2- (N-ethyl carbamoyl) - 4-pyridyloxy) aniline. According to Method Cia 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline to produce the urea.

Item 52: According to Method A2, Step 4, 4-amino-2-chloro-phenol was reacted with 4-chloro-N-methyl-2-pyridine carboxamide, which had been synthesized according to Method A2. Step 3b to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. According to Method Cia 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline to produce urea .

Item 53: 4- (4-Methylthiophenoxy) -1-nitro-benzene was oxidized according to Method A19, Step 1 to give 4- (4-methylsulfonyl-phenoxy) -1-nitro-benzene. Nitro-benzene was reduced according to method Al9, Step 2, to give 4- (4-methylsulfonyl-phenoxy) -1-aniline. According to Method Cia, 4-chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (2- (N-methylsulfonyl-phenoxy) -1-aniline to yield urea.

Item 54: 4-Brortto-benzenesulfonyl was reacted with methylamine according to Method Al 5, Step 1 to yield N-methyl-4-bromo-benzenesulfonamide. N-Methyl-4-bromo-benzenesulfonamide was coupled to phenol according to Method A15, Step 2 to yield 4- (4- (N-methylsulfamoyl) -phenoxy) -benzene. 4- (4- (N-methylsulfamoyl) phenoxy) benzene was converted to 4- (4- (N-methylsulfamoyl) phenoxy) -1-nitro-benzene according to Method Al5, Step 3. 4- (4- (N-Methylsulfamoyl) -phenoxy) -1-nitro-benzene was reduced to 4- (4- (N-methylsulfamoyl) -phenyloxy) -aniline according to Method A15, Step 4. According to Method Cia, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (N-methylsulfamoyl) phenyloxy) aniline, to produce urea.

Item 55: 5-Hydroxy-2-methylpyridine was coupled to 1-fluoro-4-nitro-benzene according to Method A18 Step 1 to give 4- (5- (2-methyl)) -pyridyloxy) -1-nitro-benzene. Methylpyridine was oxidized to carboxylic acid, and then it was esterified according to Method Al8, Step 2, to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitro-benzene. Nitro-benzene 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 Cia to produce urea.

Item 56: 5-Hydroxy-2-methylpyridine was coupled to 1-fluoro-4-nitro-benzene according to Method Al8 Step 1 to give 4- (5- (2-methyl)) -pyridyloxy) -1-nitro-benzene. Methyl pyridine was oxidized to carboxylic acid, and then it was esterified according to Method Al 8, Step 2, to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitro-benzene. Nitro-benzene 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 Cia to give N- (4-chloro-3- (trifluoromethyl) phenyl) -Ν '- (4- (2- (Methoxycarbonyl) -5-pyridyloxy) phenyl) urea. The methyl ester was reacted with methylamine according to Method D2 to yield N- (4-chloro-3- (trifluoromethyl) phenyl) -Ν '- (4- (2- (N- methyl carbamoyl) -5-pyridyloxy) phenyl) urea.

Item 57: N- (4-Chloro-3- (trifluoromethyl) phenyl-β '- (4-amino-phenyl) -urea was prepared according to Method Cld. 3- (Trifluoromethyl) -phenyl-N '- (4-amino-phenyl) -urea was coupled to mono-methyl isophthalate according to Method D1 to produce urea.

Item 58: N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4-amino-phenyl) -urea was prepared according to Method Cld. 3- (trifluoromethyl) phenyl-β '- (4-amino-phenyl) -urea was coupled to xenon-methyl isophthalate according to Method D1 to produce N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4- (3-methoxycarbonyl-phenyl) -carboxy-amino-phenyl) -urea According to Method D2, N- (4 -chloro-3- (trifluoromethyl) phenyl-N '- (4- (3-methoxycarbonyl-phenyl) -carboxy-amino-phenyl) -urea with methylamine to produce the corresponding methylamide.

Item 59: 4-Chloro-pyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N, N-dimethyl-2-pyridine carboxamide was reacted with 4-amino-phenol according to Method A2, Step 4 to give 4- (2- (N, N-dimethyl carbamoyl) -4-pyridyloxy) aniline. According to Method Cia 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N, N-dimethyl carbamoyl) -4-pyridyloxy) aniline to produce the urea.

Item 60: 4-Hydroxyacetophenone was reacted with 4-fluoro-nitro-benzene according to Method 13, Step 1, to give 4- (4-acetyl-phenoxy) -nitro-benzene. Nitro-benzene was reduced according to Method A13, Step 4 to yield 4- (4-acetylphenoxy) aniline, which was converted to 4- (4- (1- (N-methoxy) imino) hydrochloride 4-chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (4-acetylphenoxy) according to Method Al6. ) -aniline, to produce urea.

Item 61: 4- (3-Carboxy-phenoxy) -1-nitro-benzene was synthesized according to Method A13, Step 2. 4- (3-Carboxy-phenoxy) -1-nitro-benzene was coupled to 4- (2-amino-ethyl) -morpholine according to Method A13, Step 3 to give 4- (3- (N- (2-morpholinyl-ethyl) -carbamoyl) -phenoxy) -1-nitro- benzene. According to Method A13, Step 4, 4- (3- (N- (2-morpholinyl-ethyl) -carbamoyl) -phenoxy) -1-nitro-benzene was reduced to 4- (3- (N - (2-morpholinyl-ethyl) -carbamoyl) -phenoxy) -aniline. According to Method Cia 4-chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (3- (N- (2-morpholinyl-ethyl) -carbamoyl) -phenoxy) -aniline, to produce urea.

Item 62: 0 4- (3-Carboxy-phenoxy) -1-nitro-benzene was synthesized according to Method A13, Step 2. 4- (3-Carboxy-phenoxy) -1-nitro-benzene was coupled to 1- (2-Amino-ethyl) -piperidine according to Method Al3, Step 3 to give 4- (3- (N- (2-piperidyl-ethyl) -carbamoyl) -phenoxy) -1-nitro- benzene. According to Method A13, Step 4, 4- (3- (N- (2-piperidylethyl) carbamoyl) -phenoxy) -1-nitro-benzene was reduced to 4- (3- (N - (2-piperidyl-ethyl) -carbamoyl) -phenoxy) -aniline. According to Method Cia 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N- (2-piperidylethyl) carbamoyl) phenoxy) -aniline, to produce urea.

Item 63: 4- (3-Carboxy-phenoxy) -1-nitro-benzene was synthesized according to Method A13, Step 2. 4- (3-Carboxy-phenoxy) -1-nitro-benzene was coupled to tetrahydrofururyl amine according to Method A13 Step 3 to give 4- (3- (N- (tetrahydrofurfuryl-methyl) carbamoyl) -phenoxy) -1-nitro-benzene. According to Method A13, Step 4, 4- (3- (N- (tetrahydrofurfuryl-methyl) carbamoyl) -phenoxy) -1-nitro-benzene was reduced to 4- (3- (N- (tetrahydrofurfuryl) methyl) carbamoyl) phenoxy) aniline. According to Method Cia, 4-chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (3- (N- (tetrahydrofurfuryl-methyl) -carbamoyl) -phenoxy) -aniline to produce urea.

Item 64: 0 4- (3-Carboxy-phenoxy) -1-nitro-benzene was synthesized according to Method Ά13, Step 2. 4- (3-Carboxy-phenoxy) -1-nitro-benzene was coupled to 2-Amino-ethyl-1-ethyl-pyrrolidine according to Method A13, Step 3 to give 4- (3- (N - ((1-methyl-pyrrolidinyl) methyl) carbamoyl) phenoxy) - 1-nitro-benzene. According to Method Al3, Step 4, 4- (3- (N - ((1-methyl-pyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitro-benzene was reduced to 4- (3- (N - ((1-Methyl-pyrrolidinyl-methyl) -carbamoyl) -phenoxy) -aniline According to Method Cia, 4-chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4 - (3- (N - ((1-methyl-pyrrolidinyl-methyl) -carbamoyl) -phenoxy) -aniline, to produce urea.

Item 65: 4-Chloro-N-methyl-pyridine carboxamide was synthesized according to 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. Method Cia 4-Chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (4- (2- (N-methylcarbamoyl) -phenylthio) -aniline to produce urea.

Item 66: 4-Chloro-pyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridine carboxamide was reacted with 4-amino phenol according to Method A2, Step 4 to give 4- (2- (N-isopropyl carbamoyl) - 4-pyridyloxy) aniline. According to Method Cia 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline to produce urea .

Item 67: N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4-ethoxy-carbonyl-phenyl) -urea was synthesized according to Method Cie. chloro-3- (trifluoromethyl) phenyl-N'- (4-ethoxycarbonylphenyl) urea was saponified according to Method D3 to give N- (4-chloro-3- (trifluoromethyl) ) - phenyl-N '- (4-carboxy-phenyl) -urea, N- (4-chloro-3- (trifluoromethyl) -phenyl-N' - (4-carboxy-phenyl) -urea was coupled to 3-methylcarbamoyl aniline according to Method Dlb to give N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4- (3-methylcarbamoylphenyl) - urea.

Item 68: 5- (4-Amino-phenoxy) -2-methyl-isoindoline-1,3-dione was synthesized according to Method A9. According to Method Cia, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-amino-phenoxy) -2-methyl-isoindoline-1,3-dione to produce the urea.

Item 69: 4-Chloro-N-methyl-pyridine carboxamide 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. Method Cia 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline to produce urea.

Item 70: 4- (2- (N- (2-Morpholin-4-yl-ethyl) carbamoyl) -pyridyloxy) -aniline was synthesized according to Method A10. According to Method Cia 4-chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (2- (N- (2-morpholin-4-yl-ethyl) -carbamoyl) -pyridyloxy ) -aniline, to produce urea.

Item 71: 4- (3- (5-Methoxy-carbonyl) -pyridyloxy) -aniline was synthesized according to Method A14. 4-Chloro-3- (trifluoromethyl) -2-methoxy-phenyl isocyanate was reacted with 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -aniline to produce Method Cia. the urea. N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4- (3- (5-methoxycarbonyl-pyridyl) oxy) -phenylurea was saponified according to Method D4, Step 1, and the corresponding acid was coupled to 4- (2-amino-ethyl) -morpholine to yield the amide.

Item 72: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14. 4-Chloro-3- (trifluoromethyl) -2-methoxy-phenyl isocyanate was reacted with 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -aniline to produce Method Cia. the urea. N- (5-trifluoromethyl) -2-methoxy-phenyl-N '- (4- (3- (5-methoxy-carbonyl-pyridyl) -oxy) -phenyl urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled to the methylamine according to Method D4, Step 2, to produce the amide.

Item 73: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14. 4-Chloro-3- (trifluoromethyl) -2-methoxy-phenyl isocyanate was reacted with 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -aniline to produce Method Cia. the urea. N- (5-trifluoromethyl) -2-methoxy-phenyl-N '- (4- (3- (5-methoxy-carbonyl-pyridyl) -oxy) -phenylurea was saponified according to Method D4, Step 1, and the corresponding acid was coupled to N, N-dimethylethylene diamine according to Method D4, Step 2, to produce the amide.

Item 74: 4-Chloro-pyridine-2-carbonyl hydrochloride was reacted with 2-hydroxyethylamine according to Method Ά2, Step 3b to form 4-chloro-N- (2-triisopropyl). silyloxy) ethyl pyridine-2-carboxamide. 4-Chloro-N- (2-trisopropyl-silyloxy) -ethyl-pyridine-2-carboxamide was reacted with triisopropyl-silyl chloride, followed by 4-amino-phenol according to Method Al7 to form 4 - (4- (2- (N- (2-Triisopropyl-silyloxy) -ethylcarbamoyl) -pyridyloxy aniline) According to Method Cia, 4-chloro-3- (trifluoromethyl) -phenyl was reacted. (4- (2- (N- (2-Triisopropylsilyloxy) -ethylcarbamoyl) -pyridyloxy-aniline) -isocyanate to yield N- (4-chloro-3 - ((trifluoromethyl) -phenyl) -Ν '- (4- (4- (2- (N-triisopropyl-silyloxy) -ethyl-carbamoyl) -pyridyloxy-phenyl) -urea.

Item 75: 4- (3-Carboxy-phenoxy) -aniline was synthesized according to All Method. 4-Chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (3- (5 (methoxycarbonyl) pyridyloxy) aniline according to Method Clf to produce urea which was coupled to 3-amino pyridine according to Method Dlc.

Item 76: 4- (3-Carboxy-phenoxy) -aniline was synthesized according to All Method. 4-Chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (3- carboxyphenoxy) aniline according to Method Clf to produce urea which was coupled to N- (4-acetylphenyl) piperazine according to Method Dlc.

Item 77: 4- (3-Carboxy-phenoxy) -aniline was synthesized according to All Method. 4-Chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (3- carboxy-phenoxy) -aniline according to Method Clf to produce urea which was coupled to 4-fluorine aniline according to Method Dlc.

Item 78: 4- (3-Carboxy-phenoxy) -aniline was synthesized according to All Method. 4-Chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (3- carboxy-phenoxy) -aniline according to Method Clf to produce urea which was coupled to 4- (dimethylamino) aniline according to Method Dlc.

Item 79: 4- (3-Carboxy-phenoxy) -aniline was synthesized according to All Method. 4-Chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (3- carboxyphenoxy) aniline according to Method Clf to produce urea which was coupled to N-phenylethylene diamine according to Method Dlc.

Item 80: 4- (3-Carboxy-phenoxy) -aniline was synthesized according to All Method. 4-Chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (3- carboxyphenoxy) aniline according to Method Clf to produce urea which was coupled to 2-methoxyethyl amine according to Method Dlc.

4- (3-Carboxy-phenoxy) -aniline was synthesized according to the All Method. 4-Chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (3- carboxy-phenoxy) -aniline according to Method Clf to produce urea which was coupled to 5-amino-2-methoxypyridine according to Method Dlc.

Item 82: 4- (3-Carboxy-phenoxy) -aniline was synthesized according to the All Method. 4-Chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (3- carboxy-phenoxy) -aniline according to Method Clf to produce urea which was coupled to 4-morpholine aniline according to Method Dlc.

Item 83: 4- (3-Carboxy-phenoxy) -aniline was synthesized according to All Method. 4-Chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (3- carboxyphenoxy) aniline according to Method Clf to produce urea which was coupled to N- (2-pyridyl) piperazine according to Method Dlc.

Item 84: 4-Chloro-pyrinine-2-carbonyl hydrochloride was reacted with 2-hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N- (2- triisopropylsilyloxy) ethyl pyridine-2-carboxamide. 4-Chloro-N- (2-triisopropyl-silyloxy) -ethyl-pyridine-2-carboxamide was reacted with triisopropyl-silyl chloride followed by 4-amino-phenol according to Method A17 to form 4 - (4- (2- (N-2-triisopropyl-silyloxy) -ethylcarbamoyl) -pyridyloxy-aniline.

According to Method Cia 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxy aniline, to yield N- (4-chloro-3 - ((trifluoromethyl) phenyl) -Nf- (4- (4- (2- (N- (2-trisopropylsilyloxy) ethyl) carbamoyl) pyridyloxyphenyl) urea Urea was deprotected according to Method 5 to produce N- (4-chloro-3 - ((trifluoromethyl) phenyl)-) '- (4- (4- (4- (2- (N- (2-hydroxy) ethylcarbamoyl) -pyridyloxy-phenyl) -urea.

Item 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. 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to produce urea.

Item 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. 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to produce urea.

Item 87: According to Method A2, Step 4, 4-Amino-2-chloro-phenol was reacted with 4-Chloro-N-methyl-2-pyridine carboxamide, 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. 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to produce urea.

Item 88: 4-Chloro-pyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridine carboxamide was reacted with 4-amino phenol according to Method A2, Step 4 to give 4- (2- (N-ethyl carbamoyl) - 4-pyridyloxy) aniline. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline to produce urea.

Item 89: 4-Chloro-N-methyl-2-pyridine carboxamide, which had been synthesized according to Method A2, Step 3a, was reacted with 3-amino-phenol according to Method A2, Step 4 to give 3- (2- (N-ethyl carbamoyl) -4-pyridyloxy) aniline. 4-Bromo-3- (trifluoromethyl) -aniline was converted to 4-bromo-3- (trifluoromethyl) -phenyl isocyanate according to Method B1. 4-Bromo-3- (trifluoromethyl) phenyl isocyanate with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to produce urea.

Item 90: According to Method A2, Step 4, 5-Amino-2-methyl-phenol was reacted with 4-chloro-N-methyl-2-pyridine carboxamide, 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 Bl. 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to produce urea.

Item 91; 4-Chloro-pyridine-2-carbonyl chloride was reacted with dimethyl-amine according to Method A2, Step 3b. The resulting 4-chloro-N, N-dimethyl-2-pyridine carboxamide was reacted with 4-amino-phenol according to Method A2, Step 4 to give 4- (2- (N, N-dimethyl carbamoyl) -4-pyridyloxy) aniline. 4-Bromo-3- (trifluoromethyl) -aniline was converted to 4-bromo-3- (trifluoromethyl) -phenyl isocyanate according to Method B1. 4-Bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline to produce urea.

Item 92: 4-Chloro-N-methyl-pyridine carboxamide was synthesized according to 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. bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method Cia, 4- bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline) to produce urea.

Item 93: 4-Chloro-N-methyl-pyridine carboxamide was synthesized according to 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. bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method Cia, 4- bromo-3- (trifluoromethyl) phenyl isocyanate with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline) to produce urea.

Item 94: 4- (2- (N- (2-Morpholin-4-yl-ethyl) 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. 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (2- (N- (2-morpholin-4-yl-ethyl) -carbamoyl) -pyridyloxy) -aniline to produce urea .

Item 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 Cia, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) - aniline, to produce urea.

Item 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 Cia, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) - 2-chloro-aniline, to produce urea.

Item 97: According to Method A2, Step 4, 4-amino-2-chloro-phenol was reacted with 4-chloro-N-methyl-2-pyridine carboxamide, 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. 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 Cia, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3- chlorine aniline, to produce urea.

Item 98: 4-Chloro-N-methyl-pyridine carboxamide was synthesized according to Method A2, Step 3a. Chloro-pyridine was reacted with 3-amino-phenol 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 Cia, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) - aniline to produce urea.

Item 99: 4-Chloro-pyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridine carboxamide was reacted with 4-amino-phenol 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 Bl. method Cia, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-ethyl carbamoyl) -4-pyridyloxy) aniline , to produce urea.

Item 100: 4-Chloro-pyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N, N-dimethyl-2-pyridine carboxamide was reacted with 4-amino-phenol according to Method A2, Step 4 to give 4- (2- (N, N-dimethyl carbamoyl) -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. With method Cia 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline, to produce urea.

Item 101: 4-Chloro-N-methyl-2-pyridine carboxamide was synthesized according to Method A2, Step 3a. Chloro-pyridine was reacted with 3-amino-phenol according to Method A2, Step 4 to form 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -aniline. 2-Amino-3-methoxy-naphthalene was synthesized according to Method A1. According to Method C3, 2-amino-3-methoxy-naphthalene was reacted with bis (trichloromethyl) carbonate followed by 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to form urea.

Item 102: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to Method A2. 5-tert-Butyl-2- (2,5-dimethyl-pyrrolyl) -aniline was synthesized according to Method A4. 5-Lerc-Butyl-2- (2,5-dimethyl-pyrrolyl) -aniline was reacted with CDI, followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -aniline according to with Method C2d to produce urea.

Item 103: 4-Chloro-N-methyl-2-pyridine carboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridine carboxamide was reacted with 4-amino phenol according to Method A2, Step 4 using DMAC in place of DMF to give 4- (2- (N (methylcarbamoyl) -4-pyridyloxy) aniline. According to Method C2b, reaction of 3-amino-2-methoxy-quinoline with CDI, followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -aniline afforded bis- (4 - (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea.

Listed in the tables below are compounds that have been synthesized according to the Detailed Experimental Procedures provided above.

TABLES

The compounds listed in Tables 1-6 below have been synthesized according to the generic methods provided above, and the more detailed exemplary procedures are in the listings of the above, and the characterizations are in the tables.

The foregoing examples may be repeated with similar success by substituting the reagents and / or operating conditions used in the preceding examples for those of this invention, described generically or specifically herein. From the foregoing description, those skilled in the art can readily appreciate the essential features of this invention and, without departing from the spirit and scope thereof, may make various changes and modifications to the invention to suit various uses and conditions.

Claims (10)

1. Compound, characterized in that it is selected from the group consisting of: - 4-chloro-3- (trifluoromethyl) phenyl urea: N- (4-chloro-3- (trifluoromethyl) - phenyl-N '- (3- (2-carbamoyl-4-pyridyloxy) -phenyl) -urea, N- (4-chloro-3- (trifluoromethyl) -phenyl) -Ν' - (3- (2- (N-Methyl-carbamoyl) -4-pyridyloxy) -phenyl) -urea, N- (4-chloro-3- (trifluoromethyl) -phenyl) -Ν '- (4- (2-carbamoyl-4-pyridyloxy) ) -phenyl) -urea, N- (4-chloro-3- (trifluoromethyl) -phenyl) -Ν '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl) - Urea, and N- (4-chloro-3- (trifluoromethyl) phenyl) -Ν '- (2-chloro-4- (2- (N-methylcarbamoyl) - (4-pyrylidoxy)) phenyl 4-bromo-3- (trifluoromethyl) phenyl urea: N- (4-bromo-3- (trifluoromethyl) phenyl-N '- (3- (2- (N- methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl-N '- (4- (2- (N-methylcarbamoyl) -4) (pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl-4-pyridylthio) phenyl) -urea, N- (4-brorno-3- (trifluoromethyl) phenyl) -N '- (2-cl oro- 4- (2- (N-methylcarbamoyl) - (4-pyridyloxy)) phenyl) urea, and N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- ( 3-chloro-4- (2- (N-methylcarbamoyl) - (4-pyridyloxy)) phenyl) urea; and 2-methoxy-4-chloro-5- (trifluoromethyl) phenyl urea: N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N'- (4- (2- (N-Methyl-carbamoyl) -4-pyridyloxy) -phenyl) -urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) -phenyl) -Ν '- (2-chloro -4- (2- (N-methylcarbamoyl) - (4-pyridyloxy)) phenyl) urea, or a pharmaceutically acceptable salt thereof. A compound according to claim 1, characterized in that it is a pharmaceutically acceptable salt of a compound of formula I, selected from the group consisting of: a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzene sulfonic acid, p-toluenesulfonic acid (tosylate salt), 1-naphthalenesulfonic acid sulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenyl acid acetic, and mandelic acid; and (b) acid salts of organic bases and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. Pharmaceutical composition, characterized in that it comprises a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. A compound according to claim 1, characterized in that it is selected from the group consisting of: N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2 - (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4- pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) - (4-pyridyloxy) ) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl-N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) -urea, N - (2-Methoxy-4-chloro-5- (trifluoromethyl) phenyl) -1 '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2 -methoxy-4-chloro-5- (trifluoromethyl) phenyl) -Ν '- (2-chloro-4- (2- (N-methylcarbamoyl) - (4-pyridyloxy)) phenyl) -urea or a pharmaceutically acceptable salt thereof. A compound according to claim 4, characterized in that it is a pharmaceutically acceptable salt of a compound of formula I, selected from the group consisting of: a) basic salts of organic acids and inorganic acids selected from the group. consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzene sulfonic acid, p-toluenesulfonic acid (tosylate salt), 1-naphthalene acid sulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenyl- acetic, and mandelic acid; and (b) acid salts of organic bases and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. Pharmaceutical composition, characterized in that it comprises a compound as defined in claim 4 or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. A compound according to claim 1, characterized in that it is N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) - phenyl) -urea. A compound according to claim 1, characterized in that it is N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl)) -4-pyridyloxy) phenyl) urea. 9. Pharmaceutical composition, characterized in that it comprises N- (4-chloro-3- (trifluoromethyl) phenyl) -N'- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier. 10. Pharmaceutical composition, characterized in that it comprises N- (4-chloro-3- (trifluoromethyl) phenyl) -N'- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) - phenyl) urea or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier.