?-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors

DIFENILUREAS SUBSTITUTED WITH ω-CARBOXIARIL AS

RAF QUINASA t INHIBITORS t

Cross reference to related requests

This is a partial continuation of the US Patent Application. N °: 09 / 257,266, filed on February 25, 1999 and a partial continuation of US Patent Application. N °; 60 / 115,877 filed on January 13, 1999.

Field of the Invention

This invention relates to the use of a group of ariiureas in the treatment of diseases mediated by raf and pharmaceutical compositions for use in said therapy.

Background of the invention

The oncogen p21^flush It is one of the main contributors to the development and advancement of solid human cancers and presents 30% of all mutations of all types of cancer in humans (Boiton et ai. Ann. Rep. Med. Chem. 1994, 29 , 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, non-mutated form, the ras protein constitutes a key element of the signal transduction cascade directed at the receptors of growth factors in almost all tissues (Avruch et al. Trends Biochem. Sci. 1994, 19, 279-83). From a biochemical point of view, the ras protein is a guanine nucleotide binding protein and the interconversion between an activated GTP-linked form and a non-active GDP-linked form is strictly controlled by the endogenous GTPase activity of ras and other regulatory proteins. . In flush mutants of cancer cells, endogenous GTPase activity is decreased and, therefore, does the protein generate signals from?

constitutive growth towards subsequent effectors, such as the enzyme raf kinase. This leads to the cancerous growth of the cells that carry these mutants (Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). It has been shown that inhibition of the effect of active ras by inhibition of the signal pathway of raf kinase by the administration of deactivating antibodies against raf kinase or by coexpression of negative dominant raf kinase or negative dominant MEK, the substrate of the raf kinase, leads to the regression of transformed cells to the normal growth phenotype (see: Daum et al. Trends Biochem. Sci. 1994, 19, 47480; Fridman et al. J. Biol. Chem. 1994, 269, 30105-8). Kolch et al. {Nature 1991, 349, 426-28) have further described that inhibition of raf expression by antisense RNA blocks cell proliferation by membrane-associated oncogenes. Similarly, the inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with the inhibition of the growth of various types of human tumors (Monia et ai, Nat. Med. 1996,2,668-75).

Summary of the Invention

The present invention provides compounds that are inhibitors of the enzyme raf kinase. Since the enzyme is an effector located 3 'with respect to p21^flushInhibitors are useful in pharmaceutical compositions intended for use in humans and animals where inhibition of the raf kinase pathway is convenient, for example, in the treatment of tumor and / or cancer cell growth mediated by raf kinase In particular, the compounds are useful in the treatment of solid types of human or animal cancer, for example, of murine cancer, since the progress of these types of cancer depends on the signal transduction cascade of the ras protein and therefore it is susceptible to the treatment that comprises the interruption of the cascade, that is, by inhibition of the raf kinase. Accordingly, the compounds of the invention are useful in the treatment of cancers, including solid cancers, such as, for example, carcinomas (eg, lung, pancreas, thyroid, bladder or colon), disorders mleloldes (for example, myeloid leukemia) or adenomas (for example, coion villous adenoma).

The present invention therefore provides compounds that are generally described as arllureas, including both aryl and heteroaryl analogs, that inhibit the raffinase pathway. The invention also provides a method for the treatment of a raf-mediated disease state in humans or mammals. Accordingly, the invention relates to compounds that inhibit the enzyme raf kinase and also to compounds, compositions and methods for the treatment of cancer cell growth mediated by raf kinase, where a compound of Formula I or a salt acceptable for use is administered pharmacist thereof.

AD - Β (I)

In formula I, D is -NH-C (O) -NH-,

A is a substituted group of a maximum of 40 carbon atoms of formula: -L- (ML¹)_that, where L is a cyclic structure of 5 or 6 members directly attached to D, L¹ it comprises a substituted cyclic group that has at least 5 members, M is a bridge group that has at least one atom, q is an integer of 1-3: and each cyclic structure of L and L¹ contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and

B is an aryl or heteroaryl to tricyclic group of a maximum of 30 carbon atoms, substituted or unsubstituted, with at least one 6-membered cyclic structure directly attached to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur where L¹ it is substituted with at least one substituent selected from the group consisting of -SO₂R_X, -C (O) R_X and -C (NR_and) R₂,

R_and it is hydrogen or a carbon-based group of up to 24 carbon atoms that optionally contain heteroatoms selected from N, S and O and optionally halosubstltuids, until perhalo,

R₂ it is hydrogen or a carbon-based group of a maximum of 30 carbon atoms, which optionally contains heteroatoms selected from N, S and O and is optionally substituted by halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

R_x is R₂ or NR_toR_bwhere R_to and Rb are

a) independently hydrogen, a carbon-based group of a maximum of 30 carbon atoms, which optionally contains heteroatoms selected from N, S and O and is optionally substituted by halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, which they optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or

-OSi (Rf) 3, where R_F it is hydrogen or a carbon-based group of up to 24 carbon atoms, which optionally contains heteroatoms selected from N, S and O and is optionally substituted by halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or

b) R_to and R_b together they form a 5-7-membered heterocyclic structure, of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7-membered heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by nucleogen, hydroxy or carbon-based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or

c) one of R_to or R_b is -C (O) -, a divalent C alkylene group_rC₅ or a substituted CrC divalent alkylene group attached to the L portion to form a cyclic structure with at least 5 members, where 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 O and are optionally substituted by halogen;

where B is substituted, L is substituted or L¹ is further substituted, the substituents are selected from the group consisting of halogen, up to perhalo and Wn, where n is 0-3;

where each W is independently selected from the group consisting of -CN, -CO₂R⁷, -C (O) NR⁷R⁷, -C (O) -R⁷, -NO_2i -OR⁷, -MR⁷, -NR⁷R⁷, NR⁷C (O) OR⁷, -NR⁷C (O) R⁷, -Q-Ar and carbon-based groups of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by one or more substituents independently selected from the group consisting of -CN, -CO₂R⁷, -C (O) R⁷, -C (O) NR⁷R⁷, -OR⁷, -MR⁷, -NR⁷R⁷, -NO_2i -NR⁷C (O) R⁷, NR⁷C (O) OR⁷ and halogen until perhalo; where every R⁷ it is independently selected from H or a carbon-based group of up to 24 carbon atoms, which optionally contains heteroatoms selected from N, S and O and is optionally substituted by halogen, where Q is -O-, -S-, -N ( R⁷) -, - (CH2) „-, -C (O) -, -CH (OH) -, - (CH2)„ O-, - <CHz) mS-, - (CH2) mN (R⁷) -, -O (CH2)_m-CHX^to-, -CX^to2-, -S- (CH₂)_m- and -N (R⁷) (CH₂)_m-, where m =

1-3, and X^to it is halogen; and

Ar is a 5 or 6 member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, until perhalo, and optionally substituted by Z_ni, where the value of n1 is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO₂R⁷, -C (O) R⁷, C (O) NR⁷R⁷, -NO2, -OR⁷, - MR⁷ -NR⁷R⁷, -NR⁷C (O) OR⁷, -NR⁷C (O) R⁷ and a carbon-based group of up to 24 carbon atoms, which optionally contains heteroatoms selected from N, S and O and is optionally substituted by one or more substituents selected from the group consisting of -CN, -CO2R⁷, -COR⁷, -C (O) NR⁷R⁷, -OR⁷, -MR⁷, -NO₂, -NR⁷R⁷, -NR⁷C (O) R⁷, and -NR⁷C (O) OR⁷where R⁷ It is as defined above.

In formula I, suitable heteroaryl groups include, but are not limited to, rings or aromatic ring systems of 5-12 carbon atoms containing 1-3 rings, at least one of which is aromatic, in which one or Several, for example, 1-4 carbon atoms in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. For example, B can 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 5isoxazolyl, 2-, 4- or 5-thiazolyl, 3- , 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5o 6-pyrimidinyl, 1,2,3-triazoM-, -4- or —5-yl, 1,2 , 4-trizzol-1-, -3- or —5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5- ilo,

1.3.4- thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2Hthiopyranium, 2-, 3 - or 4-4H-t¡op¡ranyl, 3- or 4-plridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6th 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-benzopyrazolyl, 2-, 4, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5- , 6- or 7-benzothiazolyl, 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-quinoiini, or 1-, 3-, 4-, 5-, 6-, 7-, 8isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 5-, 7-, 8- or 9acridinyl or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or also phenyl, 2- or 3-thienyl,

1.3.4- thiadiazolyl, 3-pyrrile, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. optionally substituted. For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, 1-methyl-3-pyrrile, 1-methyl-3-pyrazolyl, 5-methyl-2- thiazolyl or

5- methyl-1,2,4-thiadiazol-2-yl.

Alkyl groups and portions of suitable alkyl groups, for example, alkoxy, etc. they always include methyl, ethyl, propyl, butyl, etc., including linear and branched chain isomers, such as isopropyl, isobutyl, sec-butyl, fer-butyl, etc.

Suitable aryl groups that 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 that, for example, "C₄ Cycloalkyl includes methyl substituted cyclopropyl groups, as well as cyclobutyl groups. The term "cycloalkyl", as used herein, also includes saturated heterocyclic groups.

Suitable halogen groups include F, Cl, Br and / or I, a single substitution being possible to a substitution (ie all H atoms of a group are replaced by a halogen atom), where the alkyl group is substituted by halogen, a mixed substitution of types of halogen atoms in a given group is also possible.

The invention also relates to compounds per se, of formula I.

The present invention also relates to salts acceptable for pharmaceutical use of formula I. Suitable salts acceptable for pharmaceutical use 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, trifiuoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 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, phenylacetic acid and mandelic acid . In addition, salts acceptable for pharmaceutical use include acid salts of inorganic bases, such as salts containing alkali cations (e.g., Li⁺ Na⁺ okay⁺), alkaline earth cations (for example, Mg⁺² , Ca *² or Ba *²), the ammonium cation, as well as acid salts of organic bases, including ammonium substituted with aliphatic and aromatic compounds, and quaternary ammonium cations, such as those that come from the protonation or peralkylation of triethylamine, N, N-diethylamine, N, N- dicyclohexyllamine, lysine, pyridine, Λ /, / V-dimethylaminpyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,5-diazabicc! or [4.3. 0] non-5eno (DBN) and 1,8-diazabic¡clo [5.4.0] undec-7-eno (DBU).

A quantity of the compounds of Formula I have asymmetric carbons and therefore can exist in racemic and optically active forms. The methods of separation of enantiomeric and diastereomeric mixtures are well known to those skilled in the art. The present invention encompasses any racemic or optically active form isolated from the compounds described in Formula I which exhibit raf inhibitory activity.

General Preparatory Methods

The compounds of Formula I can be prepared by the use of known chemical processes and reactions, some from starting materials that are commercially available. However, general preparative methods to assist the art specialist in the synthesis of these compounds are described below, with the provision of more detailed examples in the Experimental section below.

Substituted anilines can be generated using standard methods (March. Advanced Organic Chemistry, 3^to Ed .; John Wiley: New York (1985).

Larock Comprehensive Organic Transformations \ VCH Publishers: New

York (1989)). As shown in Scheme I, arylamines are usually synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd or Pt, and H₂ or a hydride transfer agent, such as formate, cyclohexadiene or a borohydride (Rilander. Hydrogenation Methods; Academic Press: London, United Kingdom (1985)). Nitroaryls can also be directly reduced using a strong hydride source, such as LiAIH₄ (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic Synthesis] VCH Publishers: New York (1991)), or a zero-valence metal, such as Fe, Sn or Ca, often in an acidic medium. There are many methods for nitroaryl synthesis (March. Advanced Organic Chemistry, 3 'Ed .; John Wiley: New York (1985). Larock. Comprehensive

Organic Transformations] VCH Publishers: New York (1989)).

H₂ / catalyst / (eg Ni, Pd, Pt)

Arno₂ -ttU-ArNH₂ \ M (Q) (eg Fe, Sn, Ca)

Scheme I Reduction of nitroaryls in arylamines

Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO3, or an alternative source of ΝΟ₂⁺. Nitroaryls can be subjected to additional treatments before reduction. Accordingly, nitroaryls substituted with potential leaving groups (eg F, Cl, Br, etc.) hno₃ > - ArNO₂

<img file="CU23213A3_D0001.tif" />

Ar-H may undergo substitution reactions after treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide. Nitroaryls can also undergo coupling reactions of the Ullman type (Scheme ll).

<img file="CU23213A3_D0002.tif" />

Scheme II Selected nucleophilic aromatic substitution using nltroarllos

The nitriles can also be subjected to cross-coupling reactions mediated by transition metals. For example, nitroaryl electrophiles, ta! as bromides, iodides or nitroaryl triflates, they undergo palladium-mediated cross-coupling reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reactions, exemplified below), arllestaños (Stille reactions) or arilzinc (Neglshi reaction) for Get the blarllo (5).

O? N,

ArB (ORj₂

Pd (0) or₇n.

<img file="CU23213A3_D0003.tif" />

Ar

Nitroaryls or anilines can be converted into the corresponding arenesulfonyl chloride (7) after treatment with chlorosulfonic acid. The reaction of sulfonyl chloride with a source of fluoride, ta! as KF, it allows to obtain sulfonyl fluoride (8). The reaction of sulfonyl fluoride with trimethylsilyltrifluoromethane in the presence of a source of fluoride, such as tris (dimethylamine) sulfonium difluorotrimethylsilconate (TASF), leads to the corresponding trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 can be reduced in arentiol (10), for example with zinc amalgam. The reaction of thiol 10 with CHCIF₂ in the presence of a base it allows to obtain difluoromethylmercaptane (11), which can be oxidized in the sulfone (12) with any of several oxidants, including CrO3-acetic anhydride (Sedova et al. Zh. Org. Khim. 1970, 6, (568 ).

<img file="CU23213A3_D0004.tif" />

[OR]

And so₂chf₂₁₂

Scheme III Selected methods of fluorinated arylsulfone synthesis

As shown in Scheme IV, the formation of non-symmetric urea may comprise the reaction of an arylisocyanate (14) with an arylamine (13). The heteroaryl isocyanate can be synthesized from a heteroarylamine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bi (trichloromethyl) carbonate (triphosgene) or N, N-carbonyldiimidazole (CDI). The isocyanate can also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius rearrangement. Consequently, the reaction of the acid derivative 16 with an azide source, followed by rearrangement allows the isocyanate to be obtained. The corresponding carboxylic acid (17) can also be subjected to rearrangements of type

Curtius using diphenylphosphorylazide (DPPA) or a similar reagent.

Ar¹-NH₂ 13

COCI₂₁ H₂NA °

Art-NCO -&gt; - ArVX ^ .Ar²

Ν N ^{H H} / v 15

N₃'7 Λ DPPA

O or aA ^ 'X Ar^1/^ OH

17

Scheme IV Selected methods of non-symmetric urea formation

Finally, ureas can be further manipulated using methods that are familiar to those skilled in the art.

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

The compounds can be administered orally, topically, parenterally, by inhalation or atomization or rectally in unit dosage formulations. The term 'administration by injection' includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as the use of infusion techniques. There may be one or more compounds present in association with one or more non-toxic vehicles, acceptable for pharmaceutical use and, if convenient, other active ingredients.

Compositions intended for oral use can be prepared according to any suitable method known in the art for the preparation of pharmaceutical compositions. Said compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide acceptable preparations for consumption. The tablets contain the active ingredient in a mixture with non-toxic excipients acceptable for pharmaceutical use that are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or can be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, a retarding material, such as glyceryl monostearate or glyceryl dlestearate, can be used. These compounds can also be prepared in a fast-release 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, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in a mixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, for example hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and acacia gum; dispersing or wetting agents may be a natural phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, chicken oxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaetiienoxlcetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example p16 ethyl hydroxybenzoate or n-propyl, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Powders and dispersible granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Dispersing or wetting agents and suitable suspending agents are exemplified by those already mentioned above. They may also contain other excipients, for example, sweetening, flavoring and coloring agents.

The compounds can also be found in the form of non-aqueous liquid formulations, for example, oily suspensions that can be formulated by suspending the active ingredients in a vegetable oil, for example peanut oil, olive oil, sesame oil or peanut oil. , or in a mineral oil such as liquid paraffin. The oil suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those mentioned above, and flavoring agents may be added in order to provide oral preparations acceptable for consumption. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

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

Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain an emollient, a preservative and flavoring and coloring agents.

The compounds can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperatures but liquid at the rectal temperature and that will therefore melt in the rectum releasing the drug. Such materials include cocoa butter and polyethylene glycols.

For all the use regimens described herein for the compounds of Formula I, the oral daily dosage regimen will preferably be from 0.01 to 200 mg / kg of total body weight. Daily dosing with administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and the use of infusion techniques will preferably be from 0.01 to 200 mg / kg of total body weight! The daily rectal dosing regimen will preferably be from 0.01 to 200 mg / kg of total body weight. The daily topical dosage regimen will preferably be 0.1 to 200 mg administered one to four times per day. The daily inhalation dosage regimen will preferably be 0.01 to 10 mg / kg of total body weight.

Specialists in the art will understand that the particular method of administration will depend on various factors, all of which are routinely taken into account when therapeutic products are administered. Those skilled in the art will also understand that the specific dose level for a given patient depends on various factors, including the specific activity of the compound administered, age, body weight, health, sex, diet, time and age. administration route, excretion rate, etc. Those skilled in the art will further understand that the optimal course of treatment, that is, the mode of treatment and the amount of daily doses of a compound of Formula I, or a salt acceptable for pharmaceutical use thereof, administered by a defined amount of Days can be determined by the art specialist using conventional treatment tests.

It should be borne in mind, however, that the specific dose level for any particular patient will depend on various factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet. , the time of administration, the route of administration and the rate of excretion, the combination of drugs and the severity of the condition being treated with therapy.

The full description of all applications, patents and publications cited above and below, is incorporated herein by way of reference, including the Patent Application

US Provisional N °: 60 / 115,877, filed on January 13, 1999 and the

U.S. Non-Provisional Patent Application N °: 09 / 257,266 filed on February, 1999.

The compounds can be produced from known compounds (or from Initial materials which, in turn, can be produced from known compounds), for example, by the general preparative methods shown below. The activity of a given compound to inhibit raf kinase can be routinely evaluated, for example according to the procedures described below. The following examples are offered for illustrative purposes only and are not intended to constitute or should be construed as limitations of the invention in any way.

EXAMPLES

All reactions were carried out with flame-dried glassware or in the oven under a positive pressure of dry argon or dry nitrogen and stirred magnetically unless otherwise indicated. The liquids and the sensitive solutions were transferred by means of a syringe or cannula and were introduced into the reaction vessels through a rubber septum. Unless otherwise indicated, the term 'concentration under reduced pressure' refers to the use of a Buchi rotary evaporator at approximately 15 mm Hg. Unless otherwise indicated, the term 'under high vacuum' refers to a vacuum of 0.4 - 1.0 mm Hg.

All temperatures are expressed in degrees Celsius (° C) not corrected. Unless stated otherwise, all parts and percentages are by weight.

Commercial grade reagents and solvents were used without further purification. The compound A / -cyclohexyl- / V '- (methylpolystren) carbodimide was purchased from Calbiochem-Novabiochem Corp. The compounds 3-tert-butylaniline, 5-tert-butyl-2 -methoxyaniline, 4-bromo-3- (trifluoromethyl) aniline, 4-chloro-3 (trifluoromethyl) aniline, 2-methoxy-5- (trifiuorometii) aniline, 4-ter-b.util-2-nitroan¡Iina ,

3-Amino-2-naphthol, ethyl 4-isocyanatobenzoate, A / -acetyl-4-chloro-2-methoxy-5 (trifluoromethyl) aniline and 4-chloro-3- (trifluoromethyl) phenoxyacnate were purchased and used without further purification. The synthesis of 3-am-2-methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem. 3, 1995, 129), 4 - (3-carbamoylfenox¡) -1-nitrobenzene (K. Ikawa

Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-tert-butylphenyl isocyanate (O. Rohr et al. DE 2,436,108) and 2-methoxy-5 (trifluoromethyl) phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491) have been described previously.

Thin layer chromatography- (TLC) was carried out using glass plates coated with Whatman® 60A F-254 silica gel 250 pm. The plates were visualized using one of the following techniques: (a) ultraviolet illumination, (b) iodine vapor exposure, (c) immersion of the plate in a 10% solution of phosphomolibed acid in ethanol followed heating, (d) immersion of the plate in a solution of cerium sulfate followed by heating and / or (e) immersion of the plate in a solution in acidic ethanol of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 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 not corrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton nuclear magnetic resonance spectra (¹H) (NMR) were performed with a General Electric GN-Omega 300 spectrometer (300 MHz) with Me4S¡ (5 0.00) or with a residual protonated solvent (CHCI3 δ 7.26; MeOH δ 3.30; DMSO δ 2 , 49) as standard. NMR carbon spectra (¹³C) were measured with a General Electric GNOmega 300 spectrometer (75 MHz) with a solvent (CDCI3 δ 77.0; MeOD-d3; δ 49.0; DMSOd5 δ 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were obtained as mass spectra by Electron Impact (El) or as mass spectra by rapid atom bombardment (FAB). Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vaccumetrics Desorption Chemical Ionization Probe to introduce the sample. The ion source was maintained at 250 ° C. Ionization by the impact of electrons was carried out with an electron acceleration energy of 70 eV and a pick-up current of 300 μΑ. The mass spectra by secondary ions of liquid cesium (FAB-MS), an updated version of the rapid atom bombardment, were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as a reactive gas (1x10 ~⁴ torr at 2.5x1Q '⁴ torr). Direct insertion of the chemical ionization probe by desorption (DCI) (Vaccumetrlcs, Inc.) was carried out by means of a 0-1.5 amp ramp in 10 sec and was maintained at 10 amp until all traces of sample (-1-2 min). The spectra were processed between 50-800 amu at a rate of 2 sec per scan. HPLC - electroatomization mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC kit with a quaternary pump, a variable wavelength detector, a C-18 column and a trap mass spectrometer for Ions Flnnigan LCQ with ionization by electroatomization. The spectra were processed between 120-800 amu using a variable ionization time according to the amount of ions in the source. The mass spectra of gas chromatography - ion selective mass spectroscopy (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methylsilicone column (0.33 mM coating; 25 mx 0.2 mm) and a selective Hewlett Packard 5971 mass detector (ionization energy 70 eV). Element analyzes were performed by Robertson Microlit Labs, Madison NJ.

All compounds showed NMR, LRMS and either element analysis or HRMS spectra consistent with the assigned structures.

List of abbreviations and acronyms:

AcOH acetic acid anh anhydrous atm atmosphere (s)

BOC fer-butoxycarbonllo

CDI 1,1'-carbonyldiimidazole conc concentrate

<td>d</td><td>days)</td>

<td>dec</td><td>decomposition</td>

<td>DMAC</td><td>/ V, / \ / - d¡met¡lacetamide</td>

<td>DMPU</td><td>1,3-dimethyl-3,4,5,6-tetrahyd ro-2 (1 H) -pyridinon a</td>

<td>DMF</td><td>N, W-dimethylformamide</td>

<td>DMSO</td><td>dimethylsulfoxide</td>

<td>DPPA</td><td>diphenylphosphorylazide</td>

<td>EDCI</td><td>1- (3-dimethylaminopropyl) -3-ethylcarbodiimide</td>

<td>EtOAc</td><td>ethyl acetate</td>

<td>EtOH</td><td>ethanol (100%)</td>

<td>Et₂OR</td><td>diethyl ether</td>

<td>Et₃N</td><td>triethylamine</td>

<td>h</td><td>hours)</td>

<td>HOBT</td><td>1-hydroxybenzotriazole</td>

<td>m-CPBA</td><td>3-chloroperoxybenzoic acid</td>

<td>MeOH</td><td>methanol</td>

<td>Pet ether.</td><td>petroleum ether (boiling range: 30-60 ° C)</td>

<td>temp.</td><td>temperature</td>

<td>THF</td><td>tetrahydrofuran</td>

<td>TFA</td><td>trifluoroAcOH</td>

<td>Tf</td><td>trifluoromethanesulfonyl</td>

A. General methods for the synthesis of substituted anilines

A1. General method for the formation of arylamine with ether formation followed by ester saponification, Curtius rearrangement and carbamate deprotection. Synthesis of 2-amn-3-methoxynaphthalene.

<img file="CU23213A3_D0005.tif" />

CQ2M6

OMe

Step 1. Methyl 3-methox-2-naphthoate

A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K2CO3 (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temperature for 15 min., Then treated with ¡odomethane (3.43 ml, 55.1 mmol). The mixture was left under stirring at room temperature overnight, then treated with water (200 ml). The resulting mixture was extracted with EtOAc (2 x 200 ml). The combined organic layers were washed with a saturated NaCl solution (100 ml), dried (MgSO₄), were concentrated under reduced pressure (approximately 0.4 mm Hg, overnight) to obtain

Methyl 3-methoxy-2-naphthoate as an amber oil (10.30 g): ¹HNMR (DMSO-d_s) δ 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (t app, J = 8.09 Hz, 1 Η), 7.44

<img file="CU23213A3_D0006.tif" />

8.21 (s, 1 H).

OMe

Step 2. Acid 3-Methox¡-2-Naphtho¡co

A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 ml) in MeOH (100 ml) was treated at room temperature with a solution of 1 N NaOH (33, 4 ml, 33.4 mmol). The mixture was heated at reflux temperature for 3 h, cooled to room temperature and acidified with a 10% citric acid solution. The resulting solution was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO &lt;) and concentrated under reduced pressure. The residue was triturated with hexane, then washed several times with hexane to obtain 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%):¹H-NMR (DMSO-d₆) 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 (brs, 1H).

<img file="CU23213A3_D0007.tif" />

Step 3.2 - (/ V- (carbobenzyloxy) amin-3-methoxynaphthalene

A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and ΕίβΝ (2.59 mL, 18.6 mmol) in toluene anh (70 mL) was stirred at room temperature for 15 min. ., then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 ml) by pipette. The resulting mixture was heated at 80 ° C for 2 h. After cooling the mixture to room temperature, benzyl alcohol (2.06 mL, 20 mmol) was added by syringe. The mixture was then heated at 80 ° C overnight. The resulting mixture was cooled to room temperature, neutralized with a 10% citric acid solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc / 86% hexane) to obtain 2 - (/ V- (carbobenclox) amin 3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%) ;¹H26

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), 8.75 (s, 1H).

<img file="CU23213A3_D0008.tif" />

OMe

Step 4. 2-am¡n-3-methoxynaphthalene

A slurry of 2 - (/ V- (carbobenzyloxy) am-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd / C (0.5 g) in EtOAc ( 70 mi) under H atmosphere₂(bell) at room temperature overnight. The resulting mixture was filtered through Celite® and concentrated under reduced pressure to obtain 2-amn-3-methoxynaphthalene as a pale 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-carbamylanilines by formation of a carbamyl pyridine followed by nucleophilic coupling with an aruamine.

Synthesis of 4- (2-A / -methylcarbamil-4-p¡rid¡lox¡) anil¡na O

Cl

NHMe

Passed it. Synthesis of 4-chloro- / V-methyl-2-pyridinecarboxamide by a Menísci reaction

Warning: this is a very dangerous, potentially explosive reaction.

To a stirred solution of 4-chloropyridine (10.0 g) in W-methylformamide (250 ml) at room temperature was added H₂SW₄ conc. (3.55 mi) to generate exotherm. To this mixture was added H₂OR₂ (30% by weight in H₂O, 17 ml) followed by FeSO₄* 7H₂Or (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temperature for 1 h, then slowly heated over a period of 4 h at 45 ° C. When the bubbling had ceased, the reaction was heated at 60 ° C for 16 h. The resulting opaque brown solution was diluted with H₂O (700 ml) followed by a 10% NaOH solution (250 ml). The resulting mixture was extracted with EtOAc (3 x 500 ml). The organic phases were washed separately with a saturated solution of NaCl (3 x 150 ml), then combined, dried (MgSO₄) and filtered through a bed of silica gel with the help of EtOAc. The resulting brown oil was purified by column chromatography (gradient of 50% EtOAc / 50% hexane to 80% EtOAc / 20% hexane). The resulting brown oil crystallized at 0 ° C over a period of 72 h to obtain 4-chloro- / V-methyl-2-pyridcarboxamide (0.61 g, 5.3%); TLC (50% EtOAc / 50% hexane) R_F 0,50; ¹H NMR (CDGI₃) δ 3.04 (d, J = 5.1 Hz, 3H), 7.43 (dd, J = 5.4, 2.4 Hz, 1H), 7.96 (brs, 1H), 8.21 (s, 1H), 8.44 (d, J = 5.1 Hz, 1 H); CI-MS m / z 171 ((M + H) J.

OR

<img file="CU23213A3_D0009.tif" />

Step 1b. Synthesis of 4-chloropyrin-2-carbonyl chloride, HCI salt by picolinic acid

Anhydrous DMF (6.0 ml) was added slowly to SOCI₂ (180 ml) between 40 ° and 50 ° C. The solution was stirred in said temperature range for 10 min., Then picolinic acid (60.0 g, 487 mmol) was added portionwise over a period of 30 min. The resulting solution was heated to 72 ° C (vigorous evolution of SO₂) for 16 h to generate a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 ml. The toluene addition / concentration process was repeated twice. The resulting almost dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and dried under high vacuum for 4 h to obtain 4-chloropridin-2-carbonyl chloride, HCI salt as an orange solid. yellow (92.0 g, 89%).

ci

OMe

HCI

Step 2. Synthesis of methyl 4-chlorcp! Rid¡n-2-carboxylate, HCI salt

DMF anh (10.0 mi) was slowly added to SOCI₂ (300 mi) at 40-48 'C. The solution was stirred in said temperature range for 10 min., Then picolinic acid (100 g, 812 mmol) was added over a period of 30 min. The resulting solution was heated to 72 'C (vigorous evolution of SO₂) for 16 h to generate a yellow solid. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to a volume of 200 ml. The toluene addition / concentration process was repeated twice. The resulting almost dry residue was filtered and the solids were washed with toluene (50 ml) and dried under high vacuum for 4 hours to obtain 4-chloropyridine-2-carbonyl chloride, HCI salt as an off-white solid (27.2 g, 16 %). This material was set aside.

The red filtrate was added to MeOH (200 ml) at a rate that maintained the Internal temperature below 55 'C. The contents were stirred at room temperature for 45 min., Cooled to 5 ° C and treated with Et₂Or (200 ml) per drops. The resulting solids were filtered, washed with Et₂O (200 ml) and dried under reduced pressure at 35 ° C to obtain methyl 4-chloropyridine-2-carboxylate, HCI salt as a white solid (110 g, 65%); mp 108-112 ° C; 'H-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 (brs,

1 HOUR); HPLC ES-MS m / z 172 ((M + H)⁺).

OR

NHMe

Step 3 Synthesis of 4-chloro- / V-methyl-2-pyridinecarboxamide from

Methyl 4-chloropridic-2-carboxylate

A suspension of methyl 4-chloropyridine-2-carboxylate, HCl salt (89.0 g, 428 mmol) in MeOH (75 mL) was treated at 0 ° C with a 2.0 M methylamine solution in THF (1 L ) at a speed that kept the internal temperature below 5 ° C. The resulting mixture was stored at 3 ° C for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500 ml), dried (Na₂SW₄) and concentrated under reduced pressure to obtain 4-chloro-N-mei-2-pyridyricarboxamide as pale yellow crystals (71.2 g, 97%); mp 41-43 ° C;¹H-NMR (DMSO-d_s) δ 2.81 (s, 3H), 7.74 (dd, J = 5.1, 2.2 Hz, 1H), 8.00 (d, J = 2.2, 1H), 8.61 ( d, J = 5.1 Hz, 1H), 8.85 (br d, 1H); CI-MS m / z 171 ((M + H)⁺).

OR

<img file="CU23213A3_D0010.tif" />

Step 3b. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carbonium chloride

4-Chloropyridin-2-carbonyl chloride, HCl salt (7.0 g, 32.95 mmol) was added portionwise to a mixture of a 2.0 M solution of methylamine in THF (100 ml) and MeOH ( 20 ml) at 0 ° C. The resulting mixture was stored at 3 'C for 4 h, then concentrated under reduced pressure. The resulting almost dry solids were suspended in EtOAc (100 ml) and filtered. The filtrate was washed with a saturated NaCl solution (2 x 100 mL), dried (Na₂SW₄) and concentrated under reduced pressure to obtain 4-cIoro-A / -methyl-2-pyridinecarboxamide as a yellow crystalline solid (4.95 g, 88%): mp 37-40 ° C.

or

<img file="CU23213A3_D0011.tif" />

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

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in DMF anh (150 mL) was treated with potassium ferrobutoxide (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-p¡r¡d¡ncarboxam¡da (15.0 g, 87.9 mmol) and K₂CO₃ (6.50 g, 47.0 mmol) and then heated at 80 ° C for 8 h. The mixture was cooled to room temperature and separated between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was reextracted with EtOAc (300 ml). The combined organic layers were washed with a saturated NaCl solution (4 x 1000 ml), dried (Na₂SW₄) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 ° C for 3 h to obtain 4- (2- (A / -methylcarbamoyl) -4-p¡r¡lox¡) anne as a solid light brown 17.9 g, 84%):¹ H-NMR (DMSO-d₆) δ 2.77 (d, J = 4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB '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 (brd, 1H); HPLC ES-MS m / z 244 ((M + H)⁺).

A3. General method for the synthesis of anilines by aromatic nucleophilic addition followed by nitroarenos reduction. Synthesis of 5- (4aminophenoxy) isoindolin-1,3-done

<img file="CU23213A3_D0012.tif" />

Step 1. Synthesis of 5-h¡drox¡iso¡ndolin-1,3-diona

To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH. (25 ml) 4-hydroxyxtalic acid (5.0 g, 27.45 mmol) was added slowly. The resulting mixture was heated at 120 ° C for 45 min., Then the clear bright yellow mixture was heated at 160 ° C for 2 h. The resulting mixture was maintained at 160 ° C and concentrated to approximately 15 ml, then cooled to room temperature and the pH value adjusted to 10 with a 1N NaOH solution. This mixture was cooled to 0 ° C and slowly acidified to pH 5 using a 1N HCl solution. The resulting precipitate was collected by filtration and dried under reduced pressure to give the

5-hydroxyisoindolin-1,3-dione as a pale yellow powder as product (3.24 g, 72%): ¹H NMR (DMSO-d_s) δ 7.00-7.03 (m, 2H), 7.56 (d, J = 9.3 Hz, 1H).

<img file="CU23213A3_D0013.tif" />

Step 2. Synthesis of 5- (4-nitrofenox) Sondolin-1,3-dione

To a stirred slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 ° C was added a solution of 5-hydroxisoisoolin-1,3-done (3, 2 g, 19.6 mmol) in DMF (40 ml) per drops. The bright yellow-green mixture was allowed to return to room temperature and stirred for 1 h, then 132 fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added by syringe in 3-4 portions. The resulting mixture was heated at 70 ° C overnight, then cooled to room temperature and 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 obtain 5 (4-n-trophenoxl) lsondolln-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc / 70% hexane) F% 0.28; ¹H NMR (DMSO-d_s) δ 7.32 (d, J = 12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J = 7.8 Hz, 1H), 8.29 (d , J = 9 Hz, 2H), 11.43 (br s, 1H); CI-MS m / z 285 ((M + H)⁺, 100%).

<img file="CU23213A3_D0014.tif" />

G

Step 3. Synthesis of 5- (4-amofenox¡) ¡sondoI¡n-1,3-diona

A solution of 5- (4-nitrophenoxy) isoindolin-1,3-dione (0.6 g, 2.11 mmol) in conc. AcOH was stirred. (12 ml) and water (0.1 ml) under a flow of argon while slowly filing iron (0.59 g, 55.9 mmol). This mixture was stirred at room temperature for 72 h, then diluted with water (25 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were dried (MgSO₄) and concentrated under reduced pressure to obtain 5- (4-aminophenoxy) isoindolin-1,3-done as a brown solid (0.4 g, 75%): TLC (50% EtOAc / 50% hexane) R / 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. General method for the synthesis of pyrrolylanilines. Synthesis of 5-terbutyl-2- (2,5-dimethylpyrrolyl) aniline

<img file="CU23213A3_D0015.tif" />

NO₂

Yr

Step 1. Synthesis of 1 - (4-ten-butyl-2-nitrophenyl) -2,5-dimethylpirro,

To a stirred solution of 2-nitro-4-tert-butylanine (0.5 g, 2.57 mmol) in cyclohexane (10 ml) was added AcOH (0.1 ml) and acetonylacetone (0.299 g, 2, 63 mmol) by syringe. The reaction mixture was heated at 120 ° C for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temperature, diluted with CH₂CI₂ (10 ml) and washed sequentially with a solution of 1N HCl (15 ml), a solution of 1N NaOH (15 ml) and a saturated solution of NaCl (15 ml), dried (MgSO₄) and concentrated under reduced pressure. The resulting brown-orange solids were purified by column chromatography (60 g SiO₂; EtOAc gradient

6% / hexane 94%

LLUnD 4-0 / 0 / I l “'- ¹ "· '75% exano) to obtain 1- (4-tert-butyl-2ntrophenol) -2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (EtOAc 15 % / hexane 85%) R, 0.67; ¹H NMR (CDCI₃) d 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H), 7.62 (dd, 1H) , 7.88 (d, J = 2.4 Hz, 1H); CI-MS m / z 273 ((M + H)⁺, 50%).

Step 2.

Synthesis of 5-tert-butyl-2- (2,5-d-methylprolrol) annna nh₂ \\ //

A slurry of 1- (4-tert-butyl-2-n-prophenyl) -2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10% Pd / C (0.056 g) was stirred ) and EtOAc (50 ml) under H atmosphere₂(bell) for 72 h, then filtered through a bed of Celite®. The filtrate was concentrated under reduced pressure to obtain 5-tert-butll-2- (2.5dlmethylpyrrolyljanillna as yellowish solids (0.30 g, 99%): TLC (10% EtOAc / 90% hexane) R_F 0,43; ¹H NMR (CDCI₃) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, 1H).

TO 5. General method for the synthesis of anilines from anilines by nucleophilic aromatic substitution. Synthesis of 4- (2 - (/ V-methylcarbamoyl) -4pyridyloxy) -2-methylaniline, HCI salt or

<img file="CU23213A3_D0016.tif" />

A solution of 4-amln-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 ml) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the mixture Black was stirred at room temperature until the vessel had reached room temperature. The contents were then treated with 4-chloro- / V-methyl-2-p¡r¡d¡ncarboxamlda (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 ° C for 8 h. The mixture was cooled to room temperature and diluted with water (75 ml). The organic layer was extracted with EtOAc (5 x 100 ml). The combined organic layers were washed with a saturated NaCl solution (200 ml), dried (MgSCU) and concentrated under reduced pressure. The residual black oil was treated with Et₂Or (50 ml) and sonicated. The solution was then treated with HCI (1 M in Et₂OR; 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 before use:¹H NMR (DMSOd₆) 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, 0 = 2.6 Hz, 1H), 7.55 (d, 0 = 2.6 Hz, 1H), 7.64 (d, 0 = 8.8 Hz, 1H), 8.55 (d, 0 = 5.9 Hz, 1H), 8.99 (q, 0 = 4 , 8 Hz, 1H).

A6 General method for the synthesis of anilines from hydroxyanilines by ^ -protection, nucleophilic aromatic substitution and deprotection. Synthesis of 4- (2 - (/ V-methylcarbamoyl) -4-pyridylox) -2-chloroaniline

<img file="CU23213A3_D0017.tif" />

Step 1: Synthesis of 3-Chloro-4- (2,2,2-Trifluoroacetlamine) Phenol

Iron (3.24 g, 58.00 mmol) was added to TFA under stirring (200 ml). To this slurry was added 2-chloro-4-nltrophenol (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). To the resulting yellow solution was added a saturated solution of NaHCOs (50 ml). The solid that precipitated from the solution was removed. The filtrate was slowly neutralized with the sodium bicarbonate solution until the product was visibly separated from the solution (determined with a mini-treatment by means of a vial). The slightly cloudy yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with a saturated NaCl solution (125 mL), dried (MgSO₄) and concentrated under reduced pressure. 'H NMR (DMSO-de) indicated a 1: 1 ratio between the nitrophenol starting material and the desired product 3-chloro-4- (2,2,2-trifluoroacetylamin) phenol. The crude material was taken to the next step without further purification.

<img file="CU23213A3_D0018.tif" />

NHMe

Step 2: Synthesis of 4- (2 - (/ V-methylcarbamoyl) -4-pyrloxy) -2-chlorophenyl (2,2,2-trifluoro) acetamide

A solution of crude 3-chloro-4- (2,2,2-trifluoroacetylamin) phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 ml) was treated with potassium tert-butoxide (5.16 g, 45.98 mmol) and the brown brown mixture was stirred at room temperature until the vessel had reached room temperature. The resulting mixture was treated with 4-chloro-A / -methyl-2-pyridinecarboxamide (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 of 20% EtOAc / pet ether. at 40% EtOAc / pet. ether to obtain 4- (2- (A / -methylcarbamoyl) -4-pyridylloxy) -2-chlorophenol (2,2,2-trifluoro) acetamide as a yellow solid (8.59 g, 23.0 mmol).

OR

<img file="CU23213A3_D0019.tif" />

Step 3. Synthesis of 4- (2 - (/ V-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline

A solution of the crude 4- (2 - (/ \ / - methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl (2,2,2-trifluoro) acetamide (8.59 g, 23.0 mmol) ) in dry 4-dioxane (20 ml) with a solution of 1N NaOH (20 ml). This brown solution was left under stirring for 8 h. To this solution was added EtOAc (40 ml). The green organic layer was extracted with EtOAc (3 x 40 mL) and the solvent was concentrated to obtain 4- (2 - (/ V-methylcarbamoyl) -4-p¡r¡dilox¡) -2-chloroanaline as a green oil that solidified with rest (2.86 g, 10.30 mmol): ¹H NMR (DMSO-dg) δ 2.77 (d, J = 4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J = 8.5, 2.6 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 7.07 (dd, J = 5.5, 2.6 , Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.75 (q, J = 4.8, 1 HOUR).

A7 General method for deprotection of an acylated aniline. Synthesis of 4-chloro-2-methoxy-5- (trfluoroomethyl) anine

<img file="CU23213A3_D0020.tif" />

OMe

A suspension of 3-chloro-6- (N-acetyl) -4- (trifluoromethyl) anisole (4.00 g, 14.95 mmol) in a solution of 6M HCl (24 mL) was heated at the reflux temperature for 1 h. The resulting solution was allowed to cool to room temperature during which time it solidified slightly. The resulting mixture was diluted with water (20 ml), then treated with a combination of solid NaOH and a saturated NaHCO solution.₃ until the solution had become alkaline. The organic layer was extracted with CH2CI2 (3 x 50 mL). The combined organics were dried (MgSO₄) and concentrated under reduced pressure to obtain 4-chloro-2-methoxy-5- (trfluoromethyl) anil as a brown oil (3.20 g, 14.2 mmol): Ή NMR (DMSO-dg) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

A8 General method for the synthesis of ro-alkoxy-o-carboxyphenylanilines.

Synthesis of 4- (3- (jV-methylcarbamoíI) -4-methoxyphenoxy) aniline.

O o₂n

<img file="CU23213A3_D0021.tif" />

or.

<img file="CU23213A3_D0022.tif" />

OMe

OMe

Step 1. 4- (3-methoxycarbonl-4-methoxyphenoxy) -1-n -benzene:

To a solution of 4- (3-carboxy-4-hydroxyphenoxy) -1-nitrobenzene (prepared from 2,5-dihydroxybenzole acid analogously to the description of Method A13, Step 1.12 mmol) in acetone (50 ml) K2CO3 (5 g) and dimethyl sulfate (3.5 ml) were added. The resulting mixture was heated at reflux temperature overnight, then cooled to room temperature and filtered through a bed of Celite®. The resulting solution was concentrated under reduced pressure, adsorbed on SiO₂, and purified by column chromatography (50% EtOAc / 50% hexane) to obtain 4- (3methoxycarbonyl-4-methoxyphenoxy) -1-n -benzene as a yellow powder (3 g):

<img file="CU23213A3_D0023.tif" />

Step 2. 4- (3-Carbox¡-4-Methox¡phenox¡) -1-Nitrobenzene.

A mixture of 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1 nitrobenzene (1.2 g), KOH (0.33 g) and water (5 ml) in MeOH (45 ml) was stirred at temperature room overnight and then heated at 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 acidified with a solution of

1N HCl The resulting mixture was extracted with EtOAc (50 ml). The organic layer was dried (MgSO₄) and concentrated under reduced pressure to obtain 4- (3-carboxy-4-methoxylfenox) -1-nitrobenzene (1.04 g).

OR

O, N

OR.

NHMe • ^ OMe

Step 3. 4- (3 - (/ V-methylcarbamoyl) -4-methoxyphenox) -1-nitrobenzene:

To a solution of 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (0.50 g,

1.75 mmol) in CH2CI2 (12 mL) SOCI was added₂ (0.64 ml, 8.77 mmol) in portions. The resulting solution was heated at reflux temperature for 18 h, cooled to room temperature and concentrated under reduced pressure. The resulting yellow solids were dissolved in CH2CI2 (3 ml), then the resulting solution was treated with a solution of methylamine (2.0 M in THF, 3.5 ml, 7.02 mmol) in portions (WARNING: evolution of gas ) and stirred at room temperature for 4 h. The resulting mixture was treated with a 1N NaOH solution, then extracted with CH₂CI₂ (25 mi). The organic layer was dried (Na₂SW₄) and concentrated under reduced pressure to obtain

4- (3 - (/ V-methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene as a yellow solid (0.50 g, 95%).

<img file="CU23213A3_D0024.tif" />

Step 4. 4- (3- (W-methylcarbamoyl) -4-methoxyphenoxy) aniline:

A slurry of 4- (3 - (/ V-methylcarbamoyl) -4-methoxyphenox) -1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd / C (0.20 g) was stirred in EtOH (55 ml) under 1 atm of H₂ (bell) for 2.5 d, then filtered through a bed of

Celite® The resulting solution was concentrated under reduced pressure to obtain

4- (3- (A / -methylcarbamoyl) -4-methoxyphenoxy) anine as an off-white solid (0.68 g, 96%); TLC (Et₃N 0.1% / EtOAc 99.9%) Rr0.36.

A9 General method for the preparation of anilines containing ωalkylphthalimide. Synthesis of 5- (4-aminophenox¡) -2-met¡l¡so¡ndol¡n-1,3-d¡ona

<img file="CU23213A3_D0025.tif" />

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

A slurry of 5- (4-nitrophenoxy) isoindolin-1,3-dione (A3, Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF was stirred (15 ml) at room temperature for 1 h, then treated with methyl uroide (0.3 ml, 4.57 mmol). The resulting mixture was stirred at room temperature overnight, then cooled to ° C and treated with water (10 ml). The resulting solids were collected and dried-under reduced pressure to obtain 5- (4-nltrofenox) -2-methylisolndolin-1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc / hexane 65%) Rr 0.61.

<img file="CU23213A3_D0026.tif" />

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

A slurry of n-tryophenox-2-methyl-sodandol-1,3-done (0.87 g, 2.78 mmol) and 10% Pd / C (0.10) was stirred g) in MeOH under 1 atm of H₂ (bell) throughout the night. The resulting mixture was filtered through a bed of Celite® and concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 ml) and filtered through a bed of SIO₂ (EtOAc

60% / 40% hexane) to obtain 5- (4-aminophenoxy) -2-methyl-soindole-1,3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc / hexane 60%) R / 0.27.

A10 General method for the synthesis of ω-carbamoylarylanilines by means of the reaction of ω-alkoxycarbonllaryl precursors with amines.

Synthesis of 4- (2 - (/ V- (2-morphol-4-ethyl) carbamoyl) p¡rid¡lox¡) anil¡na

OR

<img file="CU23213A3_D0027.tif" />

Step 1. Synthesis of 4-Chloro-2 - (/ V- (2-morphol-4-ilet¡l) carbamoyl) p¡r¡d¡na

To a solution of methyl 4-chloropyridin-2-carboxylate, HCI salt (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added 4- (2 aminoethyl). 1) morpholine (2.55 ml, 19.4 mmol) per drop and the resulting solution was heated at reflux temperature for 20 h, cooled to room temperature and treated with water (50 ml). The resulting mixture was extracted with EtOAc (50 ml). The organic layer was dried (MgSO₄) and concentrated under reduced pressure to obtain 4-c! gold-2 - (. M- (2-.morph! n-4 - !! et!!) carbamoí!) pi.rid! na as a brown oil (1.25 g, 95%): TLC (10% MeOH / 90% EtOAc) Rf 0.50.

or

<img file="CU23213A3_D0028.tif" />

Step 2. Synthesis of 4- (2- (W- (2-morpholin-4-ethyl) carbamoyl) pyridyloxy) aniline.

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium terbutoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temperature for 2 h, then treated sequentially with 4-chloro-2 - (/ V- (2-morpholln-4-ethyl) carbamoyl) pyrdine (1.22 g, 4.52 mmol) and K2CO3 (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 ° C overnight, cooled to room temperature and separated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The aqueous layer was reextracted with EtOAc (25 ml). The combined organic layers were washed with a saturated NaCl solution (3 x 25 ml) and concentrated under reduced pressure. The resulting brown solids were purified by column chromatography (58 g; gradient of 100% EtOAc to 25% MeOH / 75% EtOAc) to obtain 4- (2 - (/ V- (2-morpholin-4-methyl) carbamoyl) pyriloxy) anine (1.0 g, 65%): TLC (10% MeOH / 90% EtOAc) 0.32.

A11 General method for nitroarenos reduction in arylamines.

Synthesis of 4- (3-carboxyphenox) aniline.

OR

A slurry of 4- (3-carboxyphenoxy) -1-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd / C (0.50 g) in MeOH (120 mL) was stirred under H atmosphere₂

<img file="CU23213A3_D0029.tif" />

Celite® was then concentrated under reduced pressure to obtain 4- (3-carboxyphenoxyl) anine as a brown solid (2.26 g, 48%): TLC (10% MeOH / CH₂CI₂ 90%) R_F 0.44 (run).

A12 General method for the synthesis of anilines containing isoindolinone. Synthesis of 4- (1-oxo¡so¡ndolin-5-ilox¡) an¡I¡na.

NH

OR

Step 1. Synthesis of 5-h¡drox¡iso¡ndol¡n-1-one

To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 ml) zinc powder (47.6 g, 729 mmol) was added slowly in portions, then the mixture was heated to reflux temperature for 40 min., it was filtered hot and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 Kg SIO₂; gradient of 60% EtOAc / 40% hexane to 25% MeOH / 75% EtOAc) to obtain 5-hydroxyisoindolin-1 -one (3.77 g): TLC (100% EtOAc) Rf 0.17; HPLC ES-MS m / z 150 ((M + H) *).

<img file="CU23213A3_D0030.tif" />

OR

Step 2. Synthesis of 4- (1-isoindolin-5-lox¡) -1-n -trobenzene

To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 ° C was added 5hldroxyisolndolin-1 -one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to reach room temperature and stirred for 45 min., Then 4-fluoro-1-nitrobenzene was added and then the mixture was heated at 70 ° C for 3 h. The mixture was cooled to 0 'C and treated with water by drops until a precipitate formed. The resulting solids were collected to obtain 4- (1-isoindolinon-5-yloxy) -1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf 0.35.

<img file="CU23213A3_D0031.tif" />

OR

Step 3. Synthesis of 4- (1-oxo¡soindolin-5-ílox¡) aniIina

A slurry of 4- (1 -sondolinon-5-lox¡) -1-n -trobenzene (2.12 g, 7.8 mmol) and 10% Pd / C (0.20 g) was stirred in EtOH (50 ml) under H atmosphere₂ (bell) for 4 h; It was then filtered through a bed of Celite®. The filtrate was concentrated under reduced pressure to obtain 4- (1 -oxoisoindolin-5iloxyijaniiine as a dark yellow solid: TLC (100% EtOAc) Rf 0.15.

Α13. General method for the synthesis of ω-carbamoylanols with formation of an EDCI-mediated amide followed by nitroarenos reduction. Synthesis of 4- (3- / V-methylcarbamoylophenoxy) anna.

OR

<img file="CU23213A3_D0032.tif" />

Step 1. Synthesis of 4- (3-ethoxycarbonylphenoxl) -1-nltrobenzene

A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K2CO3 (41 g, 300 mmol) in DMF (125 mL) was heated at reflux temperature during overnight, it was cooled to room temperature and treated with water (250 ml). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were washed sequentially with water (3 x 100 mL) and a saturated solution of NaCl (2 x 100 mL), dried (Na₂SW₄) and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc / 90% hexane) to obtain 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene as an oil (38 g).

<img file="CU23213A3_D0033.tif" />

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

To a vigorously stirred mixture of 4- (3-ethoxycarbonylphenoxy) -1 nitrobenzene (5.14 g, 17.9 mmol) in a solution of THF / water 3: 1 (75 mL) was added a solution of LiOH '^ O (1.50 g, 35.8 mmol) in water (36 ml). The resulting mixture was heated at 50 ° C overnight, then cooled to room temperature, concentrated under reduced pressure and adjusted to pH 2 with a 1M HCl solution. The resulting bright yellow solids were removed by filtration and washed with hexane to obtain 445 (3-carboxyphenoxy) -1-nitrobenzene (4.40 g, 95%).

or

NHMe

OR₂n

Step 3. Synthesis of 4- (3 - (/ V-mefilcarbamoíl) phenoxy) -1-nitrobenzene

A mixture of 4- (3-carboxyphenoxy) -1-nitrobenzene (3.72 g, 14.4 mmol), EDCI'HCI (3.63 g, 18.6 mmol), W-methylmorpholine (1.6) was stirred. ml, 14.5 mmol) and methylamine (2.0 M in THF; 8 ml, 16 mmol) in CH2CI2 (45 ml) at room temperature for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 ml) and the resulting mixture was extracted with a solution of 1M HCl (50 ml). The aqueous layer was reextracted with EtOAc (2 x 50 mL). The combined organic phases were washed with a saturated NaCl solution (50 ml), dried (Na₂SW₄) and concentrated under reduced pressure to obtain 4- (3- (W-methylcarbamoyl) phenoxy) -1-nitrobenzene as an oil (1.89 g).

OR

<img file="CU23213A3_D0034.tif" />

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

A slurry of 4- (3 - (/ V-methylcarbamoyl) phenoxy) -1-n-benzene (1.89 g, 6.95 mmol) and Pd 5% / C (0.24 g) was stirred in EtOAc (20 mi) under H atmosphere₂(bell) throughout the night. The resulting mixture was filtered through a bed of Celite® and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH / CH₂CI₂ 95%) The resulting oil solidified under vacuum overnight to obtain 4- (3 - (/ Vmethylcarbamoi) phenoxy) aniline as a yellow solid (0.95 g, 56%).

A14 General method for the synthesis of ω-carbamoylanilines with EDCI-mediated amide formation followed by nitroarenos reduction. Synthesis of 4-3- (5-methacarbamoyl) pyridollox) anil O

<img file="CU23213A3_D0035.tif" />

Step 1. Synthesis of 4- (3- (5-methoxycarbonyl) p¡r¡dilox¡) -1-n¡trobenzene

To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 ml) was added a solution of methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 ml). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 ml, 13.1 mmol) in DMF (10 ml) and the resulting mixture was heated at 70 ° C overnight, cooled to room temperature and It was 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 obtain 4- (3- (5-methoxycarbonyl) pyriloxy) -1-nitrobenzene (0.60 g).

<img file="CU23213A3_D0036.tif" />

Step 2. Synthesis of 4- (3- (5-methoxycarbonyl) pylidloxy) anine

A slurry of 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd / C in MeOH / EtOAc was stirred under H atmosphere.₂(bell) for 72 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient of 10% EtOAc / 90% hexane to 30% EtOAc / 70% hexane to 50% EtOAc / 50% hexane) to obtain 4- (3- (5-methoxycarbonyl) pyridyloxy) aniiine (0.28 g, 60%):¹H NMR (CDCI₃) δ 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H), 8.87 ( d, 1H).

A15 Synthesis of an aniline by electrophilic nitration followed by reduction. Synthesis of 4- (3-methylsulfamoylfenox¡) aniIine.

^Br JHMe

<img file="CU23213A3_D0037.tif" />

Step 1. Synthesis of / V-methyl-3-bromobenzenesulfonamide

To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0 ° C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was allowed to reach room temperature and stirred at room temperature overnight. The resulting mixture was separated between EtOAc (25 mL) and a solution of 1 M HCl (25 mL). The aqueous phase was reextracted 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 obtain A / -methyl-3-bromobenzenesulfonamide as a white solid (2.8 g, 99%).

<img file="CU23213A3_D0038.tif" />

Step 2. Synthesis of 4- (3 - (/ V-methylsulfamoyl) fen¡Iox¡) benzene

To a slurry of phenol (1.9 g, 20 mmol), K2CO3 (6.0 g, 40 mmol) and Cul (4 g, 20 mmol) in DMF (25 mL) was added A / -methyl-3-bromobenzenesulfonam Da (2.5 g, 10 mmol) and the resulting mixture was stirred at reflux temperature overnight, cooled to room temperature and separated between EtOAc (50 mL) and a 1N HCl solution (50 my). The aqueous layer was reextracted 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 obtain 4- (3 - (/ V-methylsulfamoyl) phenyllox) benzene (0.30 g).

<img file="CU23213A3_D0039.tif" />

Step 3. Synthesis of 4- (3 - (/ V-methylsulfamoyl) fen¡lox¡) -1-nitrobenzene

To a solution of 4- (3 - (/ V-methylsulfamoyl) phenyloxy) benzene (0.30 g, 1.14 mmol) in TFA (6 ml) at -10 ° C was added NaNO₂ (0.097 g, 1.14 mmol) in portions over a period of 5 min. The resulting solution was stirred at -10 ° C for 1 h, then allowed to reach room temperature and concentrated under reduced pressure. The residue was separated 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 obtain 4- (3- (Á / -methylsulfamoyl) phenyloxy) -1-nitrobenzene (0.20 g). This material was taken to the next step without further purification.

<img file="CU23213A3_D0040.tif" />

Step 4. Synthesis of 4- (3 - (/ V-methylsulfamoi!) Phenoxy) anna

A slurry of 4- (3- (A / -methylsulfamoyl) phenyloxy) -1-nitrobenzene (0.30 g) and 10% Pd / C (0.030 g) in EtOAc (20 ml) was stirred under H atmosphere.₂(bell) throughout the night. The resulting mixture was filtered through a bed of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc / 70% hexane) to obtain 4- (3 - (/ V-methylsulfamoyl) phenyloxy) aniline (0.070 g).

A16 Modification of ω-ketones.

Synthesis of 4- (4- (1 - (/ V-methoxy) ¡m¡noet¡l) phenoxyanaline, HCL salt

<img file="CU23213A3_D0041.tif" />

To a slurry of 4- (4-acetylphenoxl) annel, HCI salt (prepared analogously to Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10-ml) and Pyridine (1.0 ml) O-methylhydrolamine, HCI salt (0.65 g, 7.78 mmol, 2.0 equiv.) was added. The resulting solution was heated at reflux temperature for 30 min, cooled to room temperature and concentrated under reduced pressure. The resulting solids were triturated with water (10 ml) and washed with water to obtain 4- (4- (1 - (A / -methox) iminoethyl) phenoxyanal, HCI salt as a yellow solid ( 0.85 g): TLC (50% EtOAc / 50% pet ether) Rf 0.78; ¹H NMR (DMSO-d_s) δ 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m / z 257 ((M + H)⁺).

A17 Synthesis of / V- (cú-silloxyalkyl) amides.

Synthesis of 4- (4- (2 - (/ V- (2-trisopropylsiloxy) etcarbamoyl) p¡r¡d¡lox¡an¡l¡na.

Step 1. 4-c parrot- / V- (2-triiso pro pi Is liloxi) ethyl pi rid i na-2-ca rb oxa mi da

To a solution of 4-chloro- / V- (2-hydroxyethyl) pyridine-2-carboxamide (prepared analogously to Method A2, Step 3b; 1.5 g, 7.4 mmol) in DMF anh (7 ml) trüsopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv.) were added. The resulting yellow solution was stirred for 3 h at room temperature, then concentrated under reduced pressure. The residue was separated between water (10 ml) and EtOAc (10 ml). The aqueous layer was extracted with EtOAc (3x10 ml). The combined organic phases were dried (MgSO₄) and concentrated under reduced pressure to obtain 4-chloro-2- (M- (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide as an orange oil (2.32 g, 88%). This material was used in the next step without further purification.

Step 2. 4- {4- (2- (A / - (2-trüsopropiIsiIiloxi) etílcarbamoíl) pyrilodianxyanil¡na

To a solution of 4-hldroxianlllna (0.70 g, 6.0 mmol) in DMF anh (8 mL) was added potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) In a portion thereby causing the generation of exotherm. When this mixture had been cooled to room temperature, a solution of 4-chloro2- (A7- (2-triisopropylslilox¡) et¡!) Pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) Was added. in DMF (4 mi) followed by K₂CO₃ (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was heated at .80 ° C overnight. Then an additional portion of potassium tert-butoxy (0.34 g, 3 mmol, 0.5 equiv.) Was added and the mixture was stirred at 80 ° C for another 4 h. The mixture was cooled to 0 'C with an ice / water bath, then water (approximately 1 ml) was slowly added by drops. The organic layer was extracted with EtOAc (3x10 ml). The combined organic layers were washed with a saturated NaCl solution (20 ml), dried (MgSO₄) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (30% EtOAc / 70% pet ether) to obtain 4- (4- (2- (A / - (2-tropropylsil) lox¡) et¡lcarbamoíl) p¡rid¡lox¡an¡l¡na as a light brown oil (0.99 g, 38%).

A18 Synthesis of 2-pyridincarboxylate esters by oxidation of 2-methylpyridines. Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline.

<img file="CU23213A3_D0042.tif" />

Step 1. 4- (5- (2-methyl) p¡r¡diIoxy) -1-nitrobenzene.

A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol) was heated,

1-fluoro-4-n-benzene (9.8 mi, 91.6 mmol, 1.0 equiv.), K2CO3 (25 g, 183 mmol, 2.0 equiv.) In DMF (100 mi) at the temperature of reflux all night. The resulting mixture was cooled to room temperature, treated with water (200 ml) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed sequentially with water (2 x 100 mL) and a saturated solution of NaCl ((100 mL), dried (MgSO₄) and concentrated under reduced pressure to obtain 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene as a brown solid (12.3 g).

OR_?N

<img file="CU23213A3_D0043.tif" />

OMe or

<img file="CU23213A3_D0044.tif" />

A mixture of 4- (5- (2-methy) pyridyloxy) -1-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0) was heated equiv.) in pyridine (20 ml) at reflux temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered, then concentrated under reduced pressure. The residue was dissolved in MeOH (100 ml). The solution was treated with a conc solution of HCl (7 mL), then heated at reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was separated between EtOAc (50 mL) and a solution of 1N NaOH (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 a saturated NaCl solution (50 ml), dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂;

50% EtOAc / 50% hexane) to obtain 4- (5- (2-methoxycarbonyl) pyripoxyl) -1 nitrobenzene (0.70 g).

<img file="CU23213A3_D0045.tif" />

or

Step 3. Synthesis of 4- (5- (2-methox¡carbon¡l) p¡rid¡lox¡) an¡l¡na.

A slurry of 4- (5- (2-methoxycarbonyl) pyridyllox) -1-nitrobenzene (0.50 g) and 10% Pd / C (0.050 g) was left in a mixture of EtOAc (20 ml ) and MeOH (5 ml) under H atmosphere₂ (bell) throughout the night. The resulting mixture was filtered through a bed of Celite®, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S¡O₂; 70% EtOAc / 30% hexane) to obtain 4- (5- (2-methoxycarbonyl) pyrloxyl) aniline (0.40 9)

A19 Synthesis of o) -sulfonIfen¡lan¡Linas. Synthesis of 4- (4-methylsulfonlfenoxy) aniline.

<img file="CU23213A3_D0046.tif" />

Step 1. 4- (4-Methylsulfon¡lfenox¡) -1-n¡trobenzene:

To a solution of 4- (4-methylthiophenoxy) -1-nitrobenzene (2.0 g, 7.7 mmoi) in CH₂CI₂ (75 ml) at 0 ° C m-CPBA (57-86%, 4.0 g) was added slowly and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a solution of 1N NaOH (25 ml). The organic layer was washed sequentially with a solution of 1N NaOH (25 ml), water (25 ml) and a saturated NaCl solution (25 ml), dried (MgSO₄) and concentrated under reduced pressure to obtain 4- (4-methylsulfonylphenoxy) -1-nitrobenzene as a solid (2.1 g).

Step 2. 4- (4-Methylsulfon-phenoxy) -1-aniline:

Compound 4- (4-methylsulfonlfenoxy) -1-nitrobenzene was reduced to aniline in a manner analogous to the description of Method A18, step 3.

B. Synthesis of urea precursors

B1. General method for the synthesis of socianates from anilines using CDI. Synthesis of 4-bromo-3- (trifluoromethyl) phenylisocyanate. cf₃

Bm X nh₂-hci

Step 1. Synthesis of 4-bromo-3- (trfluoromethyl) aniline, HCl salt

To a solution of 4-bromo-3- (trifluoromethyl) anine (64 g, 267 mmol) in Et₂O (500 ml) a solution of HCl (1 M in Et was added₂OR; 300 ml) per drop and the resulting mixture was stirred at room temperature for 16 h. The resulting white-pink precipitate was removed by filtration and washed with Et₂O (50 ml) and 4-bromo-3- (trifluoromethyl) aniline, HCl salt (73 g, 98%) was obtained.

<img file="CU23213A3_D0047.tif" />

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

A suspension of 4-bromo-3- (trifluoromethyl) aniiine, HCl salt (36.8 g, 133 mmol) in toluene (278 ml) was treated with trichloromethyl chloroformate by drops 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), then concentrated under reduced pressure. The residue was treated with CH₂CI₂ (500 ml), then concentrated under reduced pressure. The CH treatment protocol was repeated₂CI₂/ concentration and the resulting amber oil was stored at -20 ° C for 16 h, to obtain 4-bromo-3 (trifluoromethyl) phenylisocyanate as a tan solid (35.1 g, 86%):

GC-MS m / z 265 (M *).

C. Methods of urea C1a formation. General method for the synthesis of ureas by reaction of an isocyanate with an aniline. Synthesis of / V- (4-chloro-3- (trifluoromethyl) phenyl) A / '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

<img file="CU23213A3_D0048.tif" />

Η H

A solution of 4-chloro-3- (trifluoromethyl) phenylisocyanate (14.60 g, 65.90 mmol) in CH was added₂CI₂ (35 ml) per drop to a suspension of 4- (2 - (/ 7-methylcarbamoyl) -4-paryloxy) anine (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH₂CI₂ (35 ml) at 0 ° C. The resulting mixture was stirred at room temperature for 22 h. The resulting yellow solids were removed by filtration, then washed with CH₂CI₂ (2 x 30 ml) and dried under reduced pressure (approximately 1 mm Hg) to obtain / V- (4-chloro-3- (trfluoromethyl) fenll) -N '(4- (2 - (/ V-Methylcarbamoyl) -4-pyrilloxl) phenol) urea as an off-white solid (28.5 g, 93%): mp 207-209 ° 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, 1H), 7.62 (m, 4H ), 8.11 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m / z 465 ((M + H) *).

C1b. General method for the synthesis of ureas by reaction of an isocyanate with an aniline. Synthesis of tV- (4-bromo-3- (trifiuoromethyl) phenyl) / V '- (4. (2 - (/ V-methylcarbamoyl) -4-pyryloxy) phenyl) urea

<img file="CU23213A3_D0049.tif" />

NHMe

A solution of 4-bromo-3- (trifluoromethyl) phenyl isocyanate (Method B1, Step 2; 8.0 g, 30.1 mmol) in CH was added₂CI₂ (80 ml) by drops to a solution of 4- (2- (W-methylcarbamoyl) -4-pyridyloxy) anine (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH₂CI₂ (40 ml) at 0 ° C. The resulting mixture was stirred at room temperature for 16 h. The resulting yellow solids were removed by filtration, then washed with CH2CI2 (2 x 50 ml) and dried under reduced pressure (approximately 1 mm Hg) at 40 ° C to obtain A / - (4-bromo-3- (trifluoromethyl) ) phenyl) - / V '- (4- (2- (N-methylcarbamoyl) -4pyridyloxy) phenyl) urea as a pale yellow solid (13.2 g, 90%): mp 203-205 ° C;¹H-NMR (DMSO-d₅) δ 2.77 (d, J = 4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J = 2.5 Hz, 1H), 7.58 (m, 3H ), 7.77 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ESMS m / z 509 ((M + H) *).

C1c. General method for the synthesis of ureas by reaction of an isocyanate with an aniline. Synthesis of W- (4-Chloro-3- (trfluoromethyl) phenyl) / V '- (2-meti! -4- (2- (N-methycarbamoyl) (4-pyridyloxy)) feniI) or rea cf₃ or

Ck X - .0.

<img file="CU23213A3_D0050.tif" />

A solution of 2-methyl-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) aniline (Method A5; 0.11 g, 0.45 mmol) in CH2CI2 (1 mL) was treated with Et₂N (0.16 ml) and 4-chloro-3- (trifluoromethyl) phenylalsoate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temperature for 6 d, then treated with water (5 ml). The aqueous layer was reextracted with EtOAc (3x5 mL). The combined organic layers were dried (MgSO₄) and concentrated under reduced pressure to obtain A / - (4-chloro-3- (trifluoromethyl) phenyl) -A / '- (2-methyl4- (2- (N-methylcarbamoyl) (4 -pyridyl)) phenol) urea as a brown oil (0.11 g, 0.22 mmol): ¹H NMR (DMSO-d_s) 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, 7 = 2.6 Hz, 1H), 7.62 (app d, 7 = 2.6 Hz, 2H), 7.84 (d, 7 = 8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H) ; 8.50 (d, 7 = 5.5 Hz, 1H), 8.78 (q, 7 = 5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m / z 479 ((M + H)⁺).

C1d. General method for the synthesis of ureas by reaction of an isocyanate with an aniline. Synthesis of N- (4-chloro-3- (trifluoroomethyl) phenyl) / V '- (4-aminophenyl) urea

<img file="CU23213A3_D0051.tif" />

To a solution of 4-chloro-3- (trifluoromethyl) phenylalsocianate (2.27 g, 10.3 mmol) in CH2CY2 (308 mL) was added p-phenylenediamine (3.32 g, 30, 7 mmol) in one part. The resulting mixture was stirred at room temperature for 1 h, treated with CH2CI2 (100 mL) and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc (110 ml) and MeOH (15 ml) and the clear solution was washed with a solution of 0.05 N HCI. The organic layer was concentrated under reduced pressure to obtain W- (4-chloro-3 (trifluoromethyl) phenol) -A / '- (4-aminophenyl) impure urea (3.3 g): TLC ( 100% EtOAc) Rf 0.72.

C1e. General method for the synthesis of ureas by reaction of an isocyanate with an aniiine. Synthesis of A / - {4-chloro-3- (trifluoromethyl) phenyl) / V '- (4-ethoxycarbonylpheni) urea

<img file="CU23213A3_D0052.tif" />

To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH₂CÍ2 (30 ml) was added 4-chloro-3- (trifluoromethyl) anal (3.21 g, 16.4 mmol), and the solution was stirred at room temperature overnight. The resulting slurry was diluted with CH2CI2 (50 mL) and filtered to obtain A / - (4-chloro-3 (trifluoromethyl) phenyl) - / \ / '- (4-ethoxycarbonyl) urea as a white solid (5.93 g, 97%): TLC (40% EtOAc / 60% hexane) R_F 0,44.

C1f. General method for the synthesis of ureas by reaction of an isocyanate with an aniline. Synthesis of / V- (4-chloro-3- (trifluoroomethyl) phenol) W '- (3-carboxyphenyl) urea

<img file="CU23213A3_D0053.tif" />

To a solution of 4-chloro-3- (trifluoromethyl) phenoxsocnate (1.21 g, 5.46 mmol) in CH2CI2 (8 mL) 4- (3-carboxyphenox) was added ) Anin (Method A11; 0.81 g, 5.76 mmol) and the resulting mixture was stirred at room temperature overnight, then treated with MeOH (8 mL) and stirred another 2 h. The resulting mixture was concentrated under reduced pressure. The resulting brown solids were triturated with a 1: 1 EtOAc / hexane solution to obtain A / - (4-chloro-3- (trifluoromethyl) phenol) -W '- (3-carboxyphenyl) urea as a solid whitish (1.21 g, 76%).

C2a. General method for the synthesis of urea by reaction of an aniline with Ν, Λ / '-carbonyldmidazole followed by the addition of a second aniline.

Synthesis of / V- (2-methoxy-5- (trfluoromethyl) phenol) -W '- (4- (2 - (/ V-methylcarbamoyl) 4-pyridyllox)) phenol) urea

<img file="CU23213A3_D0054.tif" />

To a solution of 2-methoxy-5- (trlfluoromethyl) anlline (0.15 g) in CH₂CI₂anh (15 ml) at 0 ° C CDI (0.13 g) was added. The resulting solution was allowed to reach room temperature over a period of 1 h, stirred at room temperature for 16 h, then treated with 4- (2- (M-methylcarbamoyl) 4-pyrloxyl) aniiine ( 0.18 g). The resulting yellow solution was stirred at room temperature for 72 h, then treated with H₂Or (125 mi). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCl solution (100 ml), dried (MgSO₄) and concentrated under reduced pressure. The residue was triturated (90% EtOAc / 10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil was purified by column chromatography (gradient of 33% EtOAc / 67% hexane to 50% EtOAc / 50% hexane to 100% EtOAc) to obtain / V- (2-methox¡ -5- (trifluoromethyl) phenol) - / V '- (4- (2 - (/ V-methylcarbamoyl) -4pyridyloxy) phenyl) urea as a light tan solid (0.098 g, 30% ): TLC (100% EtOAc) R / 0.62; ¹H NMR (DMSO-d₅) 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, 0 = 4.8 Hz, 1H), 9.55 (s, 1 H); FAB-MS m / z 461 ((M + H)⁺).

C2b General method for the synthesis of urea by reaction of an aniline with Λ /, / V'-carbonyldiimidazole followed by the addition of a second aniline.

Symmetric areas as secondary products of a reaction procedure with iV, / V'-carbon¡ldiim¡dazol. Synthesis of bi (4- (2 - (/ Vmetlcarbamoyl) -4-pyriloxy) phenol) urea

<img file="CU23213A3_D0055.tif" />

To a stirred solution of 3-amin-2-methoxyquinoline (0.14 g) in anhydrous CH2CI2 (15 mL) at 0 ° C was added CDI (0.13 g). The resulting solution was allowed to reach room temperature over a period of 1 h, then stirred at room temperature for 16 h. The resulting mixture was treated with 4- (2- (A / -methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 72 h, then treated with water (125 ml). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with a saturated NaCl solution (100 ml), dried (MgSO₄) and concentrated under reduced pressure. The residue was triturated (90% EtOAc / 10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to obtain bi (-4- (2 - (/ Vmetylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.081 g, 44%): TLC (100% EtOAc ) Rf 0.50;¹H NMR (DMSO-d_s) δ 2.76 (d, J = 5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J = 5.4 Hz, 1H), 8.75 (d, J = 4.8 Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m / z 513 ((M + H)⁺).

C2c General method for the synthesis of ureas by reaction of an isocyanate with an aniline. Synthesis of A / - (2-methoxy-5- (trifluoromethyl) phenyl / V '- (4- (1,3-dioxo-soindole-5-yloxy) phenyl) urea

<img file="CU23213A3_D0056.tif" />

0'

OR

To a stirred solution of 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.47 mmoi) in CH₂CI₂ (1.5 ml) 5- (4-aminophenoxy) soindolin-1,3dione (Method A3, Step 3; 0.12 g, 0.47 mmol) was added in one portion. The resulting mixture was stirred for 12 h, then treated with CH₂CI₂ (10 ml) and MeOH (5 ml). The resulting mixture was washed sequentially with a 1N HCl solution (15 ml) and a saturated NaCl solution (15 ml), dried (MgSO₄) and concentrated under reduced pressure to obtain A / - (2-methoxy-5- (trifluoromethyl) phenylN - (4- (1,3-dioxoxsoindolin-5-yloxy) phenyl) urea as a solid white (0.2 g, 96%): TLC (70% EtOAc / 30% hexane) F% 0.50; ¹H NMR (DMSO-d_and) δ 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J = 9.3Hz, 2H), 7.80 (d, J = 8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27 (brs, 1H); HPLC ES-MS 472.0 ((M + H)⁺, 100%).

C2d General method for the synthesis of urea by reaction of an aniline with ty / V'-carbonyldiimidazole followed by the addition of a second aniline.

Synthesis of / V- (5- (fer-butyl) -2- (2,5-d¡met¡lp¡rrolÍI) fen¡l) - / V '- (4- (2 - (/ Vmethylcarbamoyl) -4 -pyridloxy) phenyl) urea

NHMe

N

<img file="CU23213A3_D0057.tif" />

To a stirred solution of CDI (0.21 g, 1.30 mmol) in CH₂CI₂ (2 ml) 5- (fer-butyl) -2- (2,5-d-methylpyrrole) anine (Method A4, Step 2; 0.30 g, 1.24 mmol) was added in a portion. The resulting mixture was stirred at room temperature for 4 h, then 4- (2 - (/ V-methylcarbamoyl) -4-pyridyloxy) aniline (0.065 g, 0.267 mmol) was added in one portion. The resulting mixture was heated at 36 ° C overnight, then cooled to room temperature and diluted with EtOAc (5 mL). The resulting mixture was washed sequentially with water (15 ml) and a solution of 1N HCI (15 ml), dried (MgSO₄) and filtered through a bed of silica gel (50 g) to obtain N (5- (fef-butyl) -2- (2,5-dti-methylpyrrolyl) phenyl) - / \ / '- (4 - (2 - (/ \ / - methylcarbamoyl) -4pyridyloxy) phenyl) urea as a yellowish solid (0.033 g, 24%); TLC (40% EtOAc / 60% hexane) R, 0.24;¹H NMR (acetone-d₆) 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), 7.517.58 (m, 3H), 8.43 (d, J = 5.4Hz, 1H), 8.57 (d, J = 2, 1Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M + Hf, 100%).

C3 Combined method for the synthesis of diphenylureas using triphosgene

One of the anilines to be collected was dissolved in dichloroethane (0.10 ívi). this solution was added an 8 ml vial (0.5 ml) containing dichloroethane (1 ml). To this was added a solution of bi (trichloromethyl) carbonate (0.12 M in dichloroethane, 0.2 ml, 0.4 equiv.), Followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 ml, 1 , 2 equiv.). The vial was capped and heated at 80 ° C for 5 h, then allowed to cool to room temperature for a period of approximately 10 h. The second aniline (0.10 M in dichloroethane, 0.5 ml, 1.0 equiv.) Was added, followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 ml, 1.2 equiv.). The resulting mixture was heated at 80 ° C for 4 h, cooled to room temperature and treated with MeOH (0.5 ml). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.

C4 Method generates! for the synthesis of urea by reaction of an aniline with phosgene followed by the addition of a second aniline. Synthesis of N- (2methoxy-5- (trifluoromethyl) phenol) -W^,- (4- (2 - (/ V-metlcarbamoyl) -4-

<img file="CU23213A3_D0058.tif" />

To a stirred solution of phosgene (1.9 M in toluene; 2.07 ml, 0.21 g, 1.30 mmol) in CH2CI2 (20 ml) at 0 ° C was added pyridine anh (0.32 ml) followed of 2-methoxy-5- (trifluoromethyl) aniline (0.75 g). The yellow solution was allowed to reach room temperature during which a precipitate formed. The yellow mixture was stirred for 1 h, then concentrated under reduced pressure. The resulting solids were treated with toluene anh (20 ml) followed by 4- (2 - (/ V-methylcarbamoyl) -4-pyridyloxy) anine (prepared as described in Method A2; 0.30 g) and the The resulting suspension was heated at 80 ° C for 20 h, then allowed to cool to room temperature. The resulting mixture was diluted with water (100 ml), then made alkaline with a saturated solution of NaHCO3 (2-3 ml). The alkaline solution was extracted with EtOAc (2 x 250 ml). The organic layers were washed separately with a saturated NaCl solution, combined, dried (MgSO₄) and concentrated under reduced pressure. The resulting pink-brown residue was dissolved in MeOH and adsorbed on SiO₂ (100 g) Column chromatography (300 g SiO2i gradient of EtjN 1% / EtOAc 33% / hexane 66% to Et3N% / EtOAc 99% to Et₃N 1% / MeOH 20% / EtOAc 79%) followed by concentration under reduced pressure at 45 ° C allowed to obtain a concentrated hot solution of EtOAc, which was treated with hexane (10 ml) to slowly form crystals of / V- ( 2-methoxy-5- (trfluoromethyl) phenol) - / V '- (4- (2 - (/ \ / - methylcarbamoyl) -4-pyridyloxy) fenii) urea (0.44 g) : TLC (Et₃N1% / EtOAc 99%) R_F-0,40.

D. urea interconversion

Day 1 Conversion of ω-aminophenylureas into o- (aroylamin) phenylureas. Synthesis of N- (4-chloro-3 - ((trifluoroomethyl) phenol) - / V '- (4- (3-methoxycarbonylphenyl) carboxiaminophenyl) urea

Cl

OMe

To a solution of / \ / - (4-chloro-3 - ((trifluorometI) phenol) - / V '- (4aminofenll) urea (Method C1d; 0.050 g, 1.52 mmol), softalate mono-methyl (0.25 g, 1.38 mmol), HOBT-H2O (0.41 g, 3.03 mmol) and W-methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) EDCI-HCI (0.29 g, 1.52 mmol) was added.The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (25 mL) and washed sequentially with water (25 mL) and a saturated NaHCO solution₃ (25 mi). The organic layer was dried (Na₂SW₄) and concentrated under reduced pressure. The resulting solids were triturated with a solution of EtOAc (80% EtOAc / 20% hexane) to obtain / V- (4-chloro-3 ((trifluoromethyl) phenol) -AF- (4- (3-methoxycarbonylfen) L) carboxyamophenol) urea (0.27 g, 43%): mp 121-122; TLC (80% EtOAc / 20% hexane) Ry 0.75.

D1b. Conversion of ω-carboxyphenylureas into o- (arylcarbamoyl) phenylureas.

Synthesis of N- (4-chloro-3 - ((trfluoromethyl) phenol) -W '- (4- (3_methylcarbamoylphenyl) carbamoylphthalene) urea

<img file="CU23213A3_D0059.tif" />

Η H

To a solution of A / - (4-Chloro-3 - ((trfluorometll) phenol) -A / - (4- (3-methylcarbamoyl) carboxyamophenol) urea (0.14 g , 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), ΗΟΒΤ · Η₂CH (0.14 g, 1.07 mmol) and A / -methylmorpholine (0.5 mL, 1.07 mmol) in DMF (3 mL) at 0 ° C EDCHHCI (0.10 g, 0 was added , 53 mmol). The resulting mixture was allowed to reach room temperature and stirred overnight. The resulting mixture was treated with water (10 ml) and extracted with EtOAc (25 ml). The organic phase was concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then filtered through a bed of silica gel (17 g, 70% EtOAc gradient / 30% hexane to 10% MeOH / 90% EtOAc) to obtain / V - (4-Chloro-3 - ((trfluoromethyl) phenyl) - / \ / '- (4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea as a white solid (0.097 g, 41%):

mp 225-229; TLC (100% EtOAc) R_r 0,23.

D1c. Combined approach to the conversion of ω-carboxyphenylureas into o- (arylcarbamoyl) phenols. Synthesis of / V- (4-Chloro-3 - ((trifluoromethyl) phenyl) / V '- (4- (N- (3- (N- (3-piles) carbamoyl) phenyl) carbamoyl) ) phenyl) urea

<img file="CU23213A3_D0060.tif" />

Η H

A mixture of / \ Z- (4-chloro-3 - ((trfluoromethyl) phenol) -A / - (3-carboxylfenll) urea (Method C1f; 0.030 g, 0.067 mmol) and / \ / -cyclohexyl-N '(methylpollestlrenjcarbodümlda (55 mg) in 1,2-dichloroethane (1 ml) with a solution of 3-aminplridlna in CH2CI2 (1 M; 0.074 ml, 0.074 mmol). (In cases of Insolubility or turbidity, a small amount of DMSQ was also added.) The resulting mixture was heated at 36 ° C overnight. The cloudy reactions were then treated with THF (1 ml) and heating was continued for 18 h. The resulting mixtures were treated with poly (4 (soclanatomethyl) 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 bed of silica gel (1 g). The concentration under reduced pressure allowed to obtain / V- (4-chloro-3 - ((trifIuorometl) fenll) - / \ / '- (4 (N- (3- (N- (3-p¡rld¡i ) carbamoí) fenll) carbamoí1) feniI) urea (0.024 g, 59%): TLC (70% EtOAc / 30% hexane) F% 0.12.

D2 Conversion of ω-carboalkoxylarylureas into ω-carbamoyllarylureas. Synthesis of A / - (4-cIoro-3 - ((trifluorometí!) Phenyl) - / V^,- (4- (3-methylcarbamoyl) l) carboxyiamophenyl) urea

Cl

NHMe

Η H

To a sample of A / - (4-chloro-3 - ((trifluoromethyl) fenll) -W '- (4- (3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2M in THF; 1 ml, 1.7 mmol) and the resulting mixture was stirred at room temperature overnight, then concentrated under reduced pressure to obtain / V- (4-chloro-3 - ((trifluoromet L) phenyl) - / V '- (4- (366 methylcarbamoylfenii) carboxyiamophenol) urea as a white solid: mp 247; TLC (100% EtOAc) RfO.35,

D3 Conversion of ω-carboalkoxyarylureas into ω-carboxycarylureas. Synthesis of N- (4-chloro-3 - ((trifIuoromethyl) phenyl) - / V '- (4-carboxyphenyl) urea

<img file="CU23213A3_D0061.tif" />

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

D4 General method for the conversion of ω-alkoxy esters into quilaalkylamides. Synthesis of / V- (4-chloro-3 - ((trfluoromethyl) phenol) - / V '- ((4- (3- (5- (2dimetlaminoethyl) carbamoyl) pyrid) I) ox¡fen¡l) urea

<img file="CU23213A3_D0062.tif" />

Pasol Synthesis of carboxypyridi) oxyphenyl) urea / V- (4-chloro-3- (trifluoromethyl) phenolic) - / V '- ((4- (3- (5 A / - was synthesized (4-Chloro-3- (trifluoromethyl) phenol) -N '- ((4- (3- (5-methoxycarbonyl pyridii) oxyphenyl) urea from 4-chloro-3- (trifluoromethyl) phenylisocyanate and 4- (3- (567 methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) analogously to Method C1a. A suspension of A / - (4-cIoro-3- (trifluoromethyl) phenol) - / V ((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea (0.26 g, 0,) was treated 56 mmol) in MeOH (10 mL) with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and stirred at room temperature for 1 h. The resulting mixture was adjusted to pH 5 with a solution of 1 N HCl. 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 obtain A / - (4-chloro-3 (trifluoromethyl) phenol) - / V '- ((4- (3- (5-carboxypyridyl) oxyphenyl) urea (0.18 g, 71%).

<img file="CU23213A3_D0063.tif" />

Step 2. Synthesis of / V- (4-chloro-3- (trifluoromethyl) phenyl) - / V '- ((4- (3- (5- (2d¡met¡laminoet¡l) carbamoyl) p¡r¡ d¡l) ox¡fen¡l) urea

A mixture of / V- (4-chloro-3- (trifluoromethyl) phenyl) - / V - ((4- (3- (5-carboxypyridyl) oxyphenyl) urea (0.050 g, 0.011 mmol), / V, was stirred W-dimethyletamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), AA methylmorpholine (0.035 g, 0.28 mmol) and EDCI'HCI (0.032 g, 0.17 mmol) in DMF (2.5 ml) at room temperature overnight The resulting solution was separated between EtOAc (50 ml) and water (50 ml) The organic phase was washed with water (35 mi), dried (MgSO₄) and concentrated under reduced pressure. The residue was dissolved in a minimum amount of CH2CI2 (approximately 2 ml). The resulting solution was treated with Et2Ü by drops to obtain A / - (4-chloro-3- (trifluoromethyl) phenol) - / V '- ((4 (3- (5- (2-d¡methylaminoet L) 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,

2Η), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, 1H), 8.43 (s, 1H), 8.58 (t, 1H), 8, 69 (s, 1H), 8.90 (s, 1H), 9.14 (s, 1H); HPLC ES-MS m / z 522 ((M + H)⁺).

D5 General method for the deprotection of / V- (ro-silloxyalkyl) amides.

Synthesis of / V- (4-chloro-3 - ((trifluoromethyl) phenol) - / V '- (4- (4- (2- (A / - (2hdroxy) ethylcarbamoyl) pyridyllox) Phenol) urea.

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To a solution of / V- (4-cIoro-3 - ((trifluorometiI) phenol) -A / '- (4- (4- (2- (AZ- (2tr¡soprop¡lsil¡loxi) et Carbamoyl) pyridyloxyphenyl) urea (prepared analogously to Method C1a; 0.25 g, 0.37 mmol) in THF anh (2 ml) tetrabutylammonium fluoride (1.0 M in THF) was added ; 2 ml.) The mixture was stirred at room temperature for 5 min, then treated with water (10 ml.) The aqueous mixture was extracted with EtOAc (3 x 10 ml). The combined organic layers were dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2; gradient from 100% hexane to 40% EtOAc / 60% hexane) to obtain / V- (4-chloro-3 ((trifluoromethyl) phenol) - / V '- ( 4- (4- (2- (A / - (2-hydrox)) etcarbamoyl) pyrloxyphenyl) urea as a white solid (0.019 g, 10%).

The compounds listed below are described below in the Tables that were synthesized in accordance with the detailed experimental procedures described above:

Synthesis of compound examples (see Tables for compound characterization)

Compound 1: 4- (3-A / -methylcarbamoylophenoxy) aniline was prepared according to Method A13. According to Method C3, it was reacted

3-tert-Butylaniline with bi (trichloromethyl) carbonate followed by 4- (3- / 7-methylcarbamoylphenoxyl) aniline to obtain urea.

Compound 2: 4-Fluoro-1-nitrobenzene and phydroxyacetophenone were reacted according to Method A13, Step 1 to obtain 4 (4-acetylphenoxy) -1-nitrobenzene. Compound 4- (4-acetylphenox) -1-nitrobenzene was reduced according to Method A13, Step 4 to obtain 4- (4-acetylphenoxine) anne. According to Method C3, 3-terbutylaniline was reacted with bi (trichloromethyl!) Carbonate followed by 4- (4-acetylphenoxyijaniline to obtain urea.

Compound 3: According to Method C2d, 3-tert-butllanillna was treated with CDI, followed by 4- (3- / 7-methylcarbamoyl) -4-methoxyphenoxy) anne, which had been prepared from according to Method A8, to obtain urea. Compound 4: 5-tert-butyl-2-methoxyanlline was converted to 5-tert-butyl-2-methoxylfenylsoclanate according to Method B1. 4- (3- / 7 meíücarbamoílfenoxijanilina, prepared according to Method Al 3, was reacted with the Isocyanate according to Method C1a to obtain urea.

Compound 5: According to Method C2d, 5-terbutyl-2-methoxyaniline was reacted with CDI followed by 4- (3- / 7-methylcarbamoyl) -4methoxyphenoxyijaniline, which had been prepared according to Method A8, to obtain urea .

Compound 6: 5- (4-amofenoxl) solndol-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-aminophenox!) Soindolin-1,3-dione to obtain urea.

ΊΟ

Compound 7: 4- (1 -oxo¡solndol¡n-5-loxl) an anl¡na was synthesized according to ei

Method A12 According to Method 2d, 5-tert-butyl-2-methoxylanilna was reacted with CDI followed by 4- (1-oxoisolndolin-5-ylox¡) aniline to obtain urea.

Compound 8: 4- (3- / 7-methicarbamoyllfenox) analogen was synthesized according to Method A13. According to Method C2a, 2-methox-5 (trifluorometlijanlllna was reacted with CDI followed by 4- (3-N-methylcarbamoylphenoxy) anlllna to obtain urea.

Compound 9: 4-Hydroxyacetophenone was reacted with 2-chloro-5nltropyridine to obtain 4- (4-acetyllfenox) -5-nitropyrnna according to Method A3, Step 2. According to Method A8, Step 4, 4- (4-acetylphenox) 5-nitropyridine was reduced in 4- (4-acetylphenoxy-5-aminpyridine). It became 2-methox-5 (trlfluorometlljanlllna in 2-methox¡- 5- (trifluoromethyl) fenllsoclanate according to Method B1. The isocyanate was reacted with 4- (4-acetllfenox) -5-aminopyridin according to the Cia Method to obtain urea.

Compound 10: 4-Fluoro-1-nitrobenzene and phydroxyacetophenone were reacted according to Method A13, Step 1 to obtain 4- (4-acetylphenoxy) -1-nitrobenzene. The 4- (4-acetylphenoxy) -1-nitrobenzene compound was reduced according to Method A13, Step 4 to obtain 4- (4-acetylphenoxyl) aniline. According to Method C3, 5- (trlfluoromethyl) -2-methoxybutylanlline was reacted with bi (tr! C! Oromethyl) carbonate followed by 4- (4acetylphenoxyijaninna to obtain urea.

Compound 11: 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted_l which was synthesized according to Method A2, Step 3a, with 3-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to obtain 3 - (- 271 (A / -methicarbamoyl) -4-pyridyloxy) aniiyria. According to Method C4, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene followed by 3 - (- 2- (Wmethylcarbamoyl) -4-pyridyloxy) aniline to obtain urea.

Compound 12: 4-Chloropyridin-2-carbonyl chloride, HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-amophenol according to Method A2, Step 4 using DMAC instead of DMF to obtain 3- (2-carbamoyl-4-pyrid). lox¡) an¡lin5. According to Method C2a, 2-methoxy-5- (trifluoromethyl) anine was reacted with phosgene followed by 3- (2-carbamoyl-4-pyridyloxy) anine to obtain urea.

Compound 13: 4-Chloro-N-methyl-2-pyridincarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro- / V-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to obtain 4- (2 - (/ V-methylcarbamoyl) -4-pyruxyijaniüna. with Method C2a, 2-methox5- (trifluoromethyl) aniline was reacted with CDI followed by 4- (2- (N-methylcarbamoyl) -4pyridyloxy) aniline to obtain urea.

Compound 14: 4-Chloropyrin-2-carbonyl chloride was reacted! HCl with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to obtain 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-pyrloxyl) anine to obtain urea.

Compound 15: According to Method C2d, 5 (triflourometl) -2-methoxyanaline was reacted with CDI followed by 4- (3-W-methylcarbamoyl) -4methox¡phenoxine) anine, which had been prepared according to Method A8, to obtain urea.

Compound 16: 4- (2 - (/ V-Methylcarbamoyl) -4-pyridyloxy) -2-methylanlline was synthesized according to Method A5. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenylsoanate according to Method B1. The Isocyanate was reacted with 4- (2 - (/ V-methylcarbamoyl) -4-pyridyllox) -2-methanol in accordance with Method C1c to obtain urea.

Compound 17: 4- (2 - (/ V-methylcarbamoyl) -4-pyrlox) -2-chloroaniline was synthesized according to Method A6. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trif! Uoromethyl) -2-methoxyphenolate soarate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenolisocyanate was reacted with 4 (2- (A / -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline according to Method C1a to obtain urea.

Compound 18: According to Method A2, Step 4, 5-amn-2-metllphenol was reacted with 4-chloro-A / -methyl-2-p¡r¡ncarboxamide, which had been synthesized according to Method A2, Step 3b, to obtain 3- (2- (Λ / methylcarbamoyl) -4-p¡r¡d¡loxÍ) -4-methylaniline. 5- (trifluoromethyl) -2methoxlanlline was converted to 5- (trifluoromethyl) -2-methoxyphenoisocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 3 (N mellli cnl'diih Ul) -I | Ίι l&gt; lil ·&gt; · Ι) Ί 11 loliltu illli ici ilo ρυιιαιιΙ ...... ol Mólinln i Hi to get urea.

Compound 19: 4-cIoropyridin-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro- / V-etll-273 pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to obtain 4- (2 - (/ V-ethylcarbamoyl) -4-pyridphioxy) aniiine. 5- (Trifluoromethyl) -2-methoxyaniiine was converted to 5 (trifluoromethyl) -2-methoxyphenoisocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyisoisocyanate was reacted with 4- (2- (A / -ethylcarbamoyl) 4-paryloxy) aniiine according to Method C1a to obtain urea.

Compound 20: According to Method A2, Step 4, 4-amin-2-chlorophenol was reacted with 4-chloro-, M-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to obtain 4- (2- (Λ / methylcarbamoyl) -4-pyridyloxy) -3-chloroanine. 5- (Trifluoromethyl) -2methoxyanilna was converted to 5- (trifluoromethyl) -2-methoxyphenochloroate according to Method B1. 5- (trlfluoromethyl) -2-methoxfen-socrate was reacted with 4 (2- (A / -methylcarbamoyl) -4-pyridium-Ioxy) -3-chloroanaline according with Method C1a to obtain urea.

Compound 21: 4- (4-Methythiophenoxy) -1-nitrobenzene was oxidized according to Method A19, Step 1 to obtain 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. Nitrobenzene was reduced according to Method A19, Step 2 to obtain 4- (4-methylsulfon¡lfenox¡) -1-aniline. According to Method C1a, 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (4-methylsulfoniofenox) -1-anine to obtain urea.

Compound 22: 4- (3-Carbamoylphenox) -1-n -benzene was reduced by 4- (3-carbamoylphenoxine) in accordance with Method A15, Step 4. According to Method C1 a, reacted 5- (trifluoromethyl) -2-methoxyphenoyl associanate with 4- (3-carbamoylphenoxy) aniline to obtain urea.

Compound 23: 5- (4-Aminophenox¡) soindolin-1,3-dione was synthesized according to Method A3. 5- (trifiuorometii) -2-methoxyaniline was converted to 5 (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenylsocnate was reacted with 5- (4-aminophenoxy) isoindolin-1,3-dione according to Method C1a to obtain urea.

Compound 24: 4-Chloropyrid-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-οΙογο-Λ /, Λ / dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to obtain 4- (2 - (/ V, A / -dimethylcarbamoyl) -4-pyridyloxyijaniiine 5- (trifluoromethyl) -2-methoxyaniline was converted to 5 (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2 - (/ V, / Vdimethylcarbamoyl) -4-pyridylloxy) aniline according to Method C1a to obtain urea.

Compound 25: 4- (1-Oxoisoindolin-5-lox¡) aniline was synthesized according to Method A12. 5- (Trifluoromethyl) -2-methoxyaniline with CDI was treated, followed by 4- (1-oxoisoindolin-5-yloxy) aniline according to Method C2d to obtain urea.

Compound 26: 4-Hydroxyacetophenone was reacted with 4fluoronitrobenzene according to Method A13, Step 1 to obtain 4- (4-Acetylphenoxy-Jnitrobenzene. Nitrobenzene was reduced according to Method A13, Step 4 to obtain 4- (4-Aceti! Phenoxy ) aniline, which became 4- (4 (1 - (/ V-methoxy) iminoethyl) phenoxyaniline, HCl salt, according to Method A16. It became 5- (trifluoromethyl) -2-methoxyaniline in 5- (trifluoromethyl) -275 methoxyphenyl isocyanate according to Method B1. 5 (Trifluoromethyl) -2-methoxyphenylsoccinate was reacted with 4- (4- (1- (Nmethox) iminoethyl) phenoxyaniline, HCl salt according to Method C1a to obtain urea.

Compound 27: 4-Chloro- / 7-methypyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-amylophenol according to Method A2, Step 4 to obtain 4- (4- (2 - (/ Vmetylcarbamoyl) phenylthio) aniline. It became 5- (trifiuoromet: l) -2- Methoxyanine in

5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (4- (2 - (/ 7-methylcarbamoyl) phenylthio) aniline according to Method C1a to obtain urea.

Compound 28: 5- (4-Aminophenox) -2-methylsoindolin-1,3dione was synthesized according to Method A9. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trubluoromethyl) -2-methoxylphenocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 5 (4-aminophenoxy) -2-methylisondolin-1,3-dione according to Method C1a to obtain urea.

Compound 29: 4-Chloro- / 7-Methylpyridincarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminophenol according to Method A2, Step 4 to obtain 3- (4- (2 - (/ 7-methylcarbamoyl) phenylthio) anne. It became 5- (trifluoromethyl) - 2-Methoxyannan in 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 3- (4- (2 - (/ 7/76 methylcarbamoyl) phenylthio) anne according to Method C1a for get urea.

Compound 30: 4-Chloropyridin-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-A / isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to obtain 4- (2 - (/ 7-isopropylcarbamoyl) -4-pyridyloxy) aniline. 5- (trifluoromethyl) -2methoxlanillna was converted to 5- (trifluorcmethyl) -2-methoxysphenolysamate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl¡soanate was reacted with 4 (2- (A / -isopropylcarbamoyl) -4-paryloxy) anine according to Method C1a to obtain the urea.

Compound 31: 4- (3- (5-Methoxcarbonll) pridridlox) was synthesized according to Method A14. 5- (Trifiuoromethyl) -2-methoxyaniline was converted to 5 (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifuoroi and ietl) -2-methoxyphenoisocyanate was reacted with

A i *) ÍC methoxycarbonii) pyridiioxy) aniline according to Method C1a to obtain urea. Saponified / 7- (5- (trifluoromethyl) -2-methoxyphenyl) - / 7- (4- (3- (5-methoxycarbonylpyridyl) oxy) fen¡!) Urea according to Method D4, Step 1, and the corresponding acid was coupled with 4- (2-amnoethyl) morpholine to obtain the amide according to Method D4, Step 2.

Compound 32: 4- (3- (5-Methoxcarbonll) pldrlox) was synthesized according to Method A14. 5- (trifiuoromethyl) -2-methoxyani! Ina was converted to 5 (trifiuoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) anine according to Method C1a to obtain urea. A / - (5- (trfluoromethyl) -2-methoxyphenyl) -A / '- (4- (3- (5-methoxycarbonyl) linear) oxy) phenolic) was saponified urea according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4,

Step 2, to get the amide.

Compound 33: 4- (3- (5-Methoxycarbonyl) pylidloxyl) aniline was synthesized according to Method A14. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5 (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyriloxy) anne according to Method C1a to obtain urea. A / - (5- (trifluoromethyl) -2-methoxyphenyl) -A / - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with A /, A / -dimethylethylenediamine according to Method D4, Step 2 to obtain the amide.

Compound 34: 4- (3-carboxyphenoxy) anne was synthesized according to the

All method. 5- (Virifluoromethyl) -2-n eHi o- (a iuui υι i icui; 2-methoxyphenyl isocyanate according to Method B1 was converted. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenylsocnate according to Method C1f to obtain W- (5- (trifluoromethyl) -2-methoxyphenyl) - / V '- (3-carboxyphenyl) urea, which was coupled with 3-aminpyridine according to the Method

D1c.

Compound 35: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyannan in 5- (trifluoromethyl) 2-methoxyphenyl isocyanate was converted according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to obtain / V- (5- (trifluoromethyl) -2-methoxyphenyl) -N ' - (378 carboxlienyl) urea, which was coupled with / 7- (4-fluorofenll) perazlna according to Method D1c.

Compound 36: 4- (3-Carboxyphenoxine) was synthesized according to Method A11. 5- (trifluorometll) -2-methoxyaniline was converted to 5- (trlfluorometll) 2-methoxlfenllisocyanate according to Method B1. 4- (3-carboxyphenoxl) analine was reacted with 5- (trfluoromethyl) -2-methoxfenphenatoate according to Method C1f to obtain A / - (5- (trfluoromet) l) -2-methoxyphenyl) - / V '- (3carbox: phenol) urea, which was coupled with 4-fluoroaniline according to Method D1c.

Compound 37: 4- (3-Carboxlfenoxl) anne was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) 2-methoxylfenylsoclanate according to Method B1. 4- (3-Carboxyphenoxy) anine was reacted with 5- (trifluoromethyl) -2-methoxyphenylsocnate according to Method C1f to obtain A / - (5- (trlfluoromethyl) -2 -methoxyphenyl) - / \ / '- (3-carboxyphenyl) urea, which was coupled with 4- (dlmethylamin) annna according to Method D1c.

Compound 38: 4- (3-Carboxlfenox) anne was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxyannan was converted to 5- (trifluoromethyl) 2-methoxylfenllolonate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trlfluorometll) -2-methoxyphenylsocnate according to Method C1f to obtain N- (5- (trifluoromethyl) -2-methoxfen. 1) -N '- (3-carboxyphenyl) urea, which was coupled with 5-amin-2-methoxypyridine according to Method D1c.

Compound 39: 4- (3-Carboxyphenoxy) anneline was synthesized according to Method A11. It became 5- (trlfluorometii) -2-methoxyanlline into 5- (trifluoromethyl) 79

2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniiine was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to obtain A / - (5- (trifluoromethyl) -2-methoxyphene) - / V '- (3-carboxyphel) urea, which was coupled with 4-morpholinaniline according to the

Method D1c.

Compound 40: 4- (3-carboxyphenoxine) analog was synthesized according to Method A11. 5- (Trifiuoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) 2-methoxyphenylsocnate in accordance with Method B1. 4- (3-Carboxyphenoxine) anne was reacted with 5- (trifluorometi!) -2-methoxyphenoisocyanate according to Method C1f to obtain A / - (5- (trifluoromethyl) -2-methox Phenol) -N '- (3-carboxyphenyl) urea, which was coupled with AA (2-p¡r¡l) p perazine according to Method D1c.

Compound 41: 4- (3- (N-Methyl carbamoyl) phenoxy) aniline was synthesized according to Method A13. According to Method C3, 4-chioro-3- (trfluoromethi) anine was converted into the isocyanate, then reacted with 4- (3 - (/ V-methylcarbamoyl) phenoxy) aniline to get urea.

Compound 42: 4- (2-A / -metiicarbamil-4-pyridiioxy) aniIine was synthesized according to Method A2. 4-Chloro-3 (trfluoromethyl) phenylisocyanate was reacted with 4- (2- / V-methylcarbamyl-4-pyridyloxy) aniline according to Method C1a to obtain urea.

Compound 43: 4-Chloropyridin-2-carbonyl chloride, HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. The compound 4-chloro-2-pridridcarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to form 4- (2-carbamoyl-4-pyridylxyl) aniline . According to Method C1a, 4-chloro-3- (trifluoromethyl) phenylisocyanate was reacted with 4- (2-carbamoyl-4-pyridyloxy) aniline to obtain urea.

Compound 44: 4-Chloropyridin-2-carbonyl chloride, HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. Compound 4-Chloro-2-plcardamcarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 to form

3- (2-carbamoyl-4-pyridyloxy) aniline. According to Method C1a, 4-Chloro-3- (trifluoromethyl) phenol: ar.ato was reacted with 3- (2-carbamoyl-4-pyridyloxy) aniline to obtain urea.

Compound 45: Compound 4 chloro-A / -methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3aminophenol according to Method A2, Step 4 to form 3- (-2- (Λ / methylcarbamoíI) -4-pir¡d¡! Ox¡) anil¡na. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenylisocyanate was reacted with 3- (2 - (/ V-methylcarbamoyl) 4- pyridium) an ina! To obtain to urea.

Compound 46: 5- (4-Aminophenoxy) isoindole-1,3-dione was synthesized according to Method A3. According to Method C1a, 4-chloro-3- (trifl or oromethyl) phenyl isocyanide was reacted with 5- (4-aminophenoxy) isondolin-1,3dione to obtain urea.

Compound 47: 4- (2- (N-methylcarbamoyl) -4-pyridyllox) -2-methianiline was synthesized according to Method A5. According to Method C1 c, 4-chloro-3- (trfluoromethyl) phenoxysocatoate was reacted with 5- (4-amnoenoxyl) lsolndol-1,3-dlone to obtain the urea.

Compound 48: 4- (3- / V-Methylsulfamoyl) phenyloxy) anne was synthesized according to Method A15. According to Method C1a, 4-chloro-3- (trfluoromethi) phenylisocyanate was reacted with 4- (3- / 7-methylsulfamoyl) phenyloxy) aniline to obtain urea.

Compound 49: 4- (2 - (/ 7-methylcarbamoyl) -4-pyrilodyl) -2-chloroariilin was synthesized according to Method A6. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenylisocyanate was reacted with 4- (2 - (/ 7-methylcarbamoyl) -4-pyridyl) -2-chloroaniline to obtain urea

Compound 50: According to Method A2, Step 4, 5-amin-2-methylphenol was reacted with 4-chloro- / 7-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b , to obtain 3- (2 - (/ 7-methylcarbamoyl) -4-pyridium-Ioxy) -4-methylaniline. According to Method C1a, the compound 4-chloro-3- (trifluoromethyl) phenylsocyanate was reacted with 3- (2 (/ 7-methylcarbamoyl) -4-pyridylloxy) -4 -methylanine to obtain urea.

Compound 51: 4-Chloropyridin-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro- / 7-etii-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to obtain 4- (2 - (/ 7-ethylcarbamoyl) -4-pyridyloxyijaniline. According to Method C1a , 4-Chloro-3 (trifluoromethyl) phenylisocyanate was reacted with 4- (2 - (/ 7-ethylcarbamoyl) -4-p¡r¡lox¡) anine to obtain urea.

Compound 52: According to Method A2, Step 4, 4-amin-2-chlorophenol was reacted with 4-chloro- / 7-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b , to obtain 4- (2 - (/ 7-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenylisocyanate was reacted with 4- (2 - (/ 7-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to obtain urea.

Compound 53: Compound 4- (4-methylthiophenox) -1-nitrobenzene was oxidized according to Method A19, Step 1 to obtain 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. Nitrobenzene was reduced according to Method A19, Step 2 to obtain 4- (4-methylsulfonylphenoxy) -1-aniline. According to Method C1a, 4-chloro-3 (trifluoromethyljphenyl isocyanate was reacted with 4- (4-methylsulfonylphenox) -1 -aniline to obtain urea.

Compound 54: Sulphonyl 4-bromobenzechloride was reacted with methylamine according to Method A15, Step 1 to obtain N-methyl-4-bromobenzenesulfonamide. The compound / V-methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to obtain 4- (4 (A / -methylsulfamoyl) phenoxy) benzene. 4- (4- (Λ / Methylsulfamoyl) phenoxy) benzene was converted to 4- (4- (N-methylsuIfamoyl) phenoxy) -1-nitrobenzene according to Method A15, Step 3. Compound 4- (4- (Nmetlsulfamoyl) phenoxy) -1-nitrobenzene was reduced by 4- (4- / V-methylsulfamoyl) phenyloxy) anne according to Method A15, Step 4. according to Method C1a, 4-chloro-3 (trifluoromethyl) phenylisocyanate was reacted with 4- (3-N-methylsulfamoyl) phenyloxy) aniline to obtain urea.

Compound 55: The 5-hydroxy-2-methylpyridine compound was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to obtain 4 (5- (2-methyl) pyridylox) -1-nitrobenzene. The methylpyridine was oxidized in the corresponding carboxylic acid, then esterified according to Method A18, Step 2 to obtain 4- (5- (2-methoxycarbonyl) pyridylox!) -1 nitrobenzene. The nitrobenzene was reduced according to Method A18, Step to obtain 4- (5- (2-methoxycarbonyl) p¡r¡loxl) annna. The aniline was reacted with 4-c! Gold-3- (trfluoromethyl) phenyl isocyanate according to the

Method C1 a to obtain urea.

Compound 56: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to obtain 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene. The methylpyridine was oxidized in the corresponding carboxylic acid, then esterified according to Method A18, Step 2 to obtain 4- (5- (2-methoxycarbonyl) pldyloxy) -1-nitrobenzene. Nitrobenzene was reduced according to Method A18, Step 3 to obtain 4- (5- (2methoxycarbonlljpiridlloxijanlllna. The aniline was reacted with 4-chloro-3 (trifluoromethyl) phenylisocyanate according to Method C1a to obtain N- (4-chloro-3- (trifluoromethyl) fen¡!) - A / '- (4- (2- (methoxycarbonyl) -5-pyridylloxy) phenoI) urea. The methyl ester was reacted with the methylamine according to Method D2 to obtain / V- (4-cioro-3- (trifluoromethyl) phenol) - / V '- (4- (2- (A / -met¡lcarbamoíl) -5InrGIf-wóíom 11 \ ¡»roo 11 lUIIVAI / IVI lliyUl MM.

Compound 57: The compound W- (4-chloro-3- (trifluorometii) fenll-N '- (4aminophenlljurea according to Method C1d. The A / - (4-chloro-3 (trfluoromethyl) fen¡ lA / '- (4-amophenol) urea was coupled with mono-metillsophthalate according to Method D1a to obtain urea.

Compound 58: The compound / V- (4-chloro-3- (trfluoromethyl) phenyl- / V '- (4 aminophenol) urea was prepared according to Method C1d. The A / - (4- Chloro-3 (trlfluoromethyl) phenol / '- (4-aminophenol) urea was coupled with mono-methylisphthalate according to Method D1a to obtain / V- (4-chloro-3- (trifluoromethyl) phenyl - / V '- (4 (3-methoxycarbonylphenol) carboxamofenll) urea. According to Method D2, / 7- (4-chloro-3- (trifluoromethyl) phenol / '- (4- (3react methoxycarbonylphenyl) carboxyminophenyl) urea was reacted with methylamine to obtain the corresponding methylamide.

Compound 59: 4-Chloropridin-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro- / 7, / 7-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to obtain 4- (2 - (/ 7, / 7-dimethylcarbamoyl) -4pyrid! loxi) an¡l¡na. In accordance with Method C1a, the compound 4-chloro-3 (trif! Uorcmetyl) phenylsocyanate was reacted with .4- (2 - (/ 7, / 7-dimethylcarbamoyl) -4-pyridylloxy) Andean to get urea.

Compound 50: The 4-hydroxyacetophenone compound was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to obtain 4- (4-acetylphenoxy) nitrobenzene. Nitrobenzene was reduced according to Method 13, Step 4 to obtain 4- (4-acetylphenoxy) aniline, which became 4- (4- (1 - (/ 7-methox) iminoethyl) phenoxy. Anine, HCI salt according to Method A16. The compound 4-chloro3- (trifluorometI) phenoxysocate with 4- (4-acetylphenoxy) anine was reacted according to Method C1 a to obtain urea.

Compound 61: 4- (3-carboxyphenox) -1-nitrobenzene was synthesized according to Method A13, Step 2. Compound 4- (3-carboxyphenoxy) -1 nitrobenzene was coupled with 4- (2-aminoethyl) morphol According to Method A13, Step 3 to obtain 4- (3 - (/ 7- (2-morpholiethyl) carbamoyl) phenoxy) -1 nitrobenzene. According to Method A13 Step 4, the compound 4- (3 - (/ 7- (2morpholiniletl) carbamoyl) phenoxy) -1-nitrobenzene was reduced by 4- (3 - (/ 7- (2morpholinyl) ) carbamol) phenoxy) aniline. According to Method C1a, 4-chloro-3- (trlfluoromethyl) phellisocyanate was reacted with 4- (3 - (/ 7- (2morpholletlet) carbamoyl) phenoxy) ring to obtain the urea.

Compound 62: 4- (3-Carboxenophene) -1-nitrobenzene was synthesized according to Method A13, Step 2. Compound 4- (3-Carboxlfenox) -1 nitrobenzene was coupled with 1- (2-amlnoetll ) Pérperna according to Method A13, Step 3 to obtain 4- (3 - (/ 7- (2-p¡periledi) carbamoyl) phenoxy) -1 nitrobenzene. According to Method A13 Step 4, the compound 4- (3 - (/ 7- (2p¡perld¡iet¡l) carbamoyl) phenoxy¡) -1-nitrobenzene was reduced by 4- (3 - (/ 7 - (2piperldiletil) carbamoí!) Fenox¡) anll¡na. According to Method C1a, 4-chloro-3- (trlfluoromethyl) phellisocyanate was reacted with 4- (3 - (/ 7- (2pperperd! Etll) carbamoyl) phenoxy)) Line to get urea.

Compound 63: 4- (3-Carboxlfenox¡) -1-nitrobenzene was synthesized according to Method A13, Step 2. Compound 4- (3-Carboxlfenox¡) -1nltrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to obtain 4- (3- (A / - (tetrah¡drofuriÍmetii) carbamoíí) phenoxy) -1nitrobenzene. According to Method A13 Step 4, compound 4- (3 - (/ 7 (tetrahydrofuryl) carbamoyl) phenoxy) -1-nitrobenzene was reduced by 4- (3 - (/ 7 ( tetrahydrophilicl) carbamoyl) phenoxyl) anine. In accordance with Method C1a, 4-chloro-3- (trfluoromethyl) phenyl-soarate was reacted with 4- (3 - (/ 7 (tetrahydrofurylmetll) carbamoyl) phenoxy) anine to obtain urea

Compound 64: 4- (3-Carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, Step 2. Compound 4- (3-carboxyphenoxine) -1-nitrobenzene was coupled with 2-aminomethyl. 1-ethylpyrrolidine according to Method A13, Step 3 to obtain 4- (3 - (/ 7 - ((1-methylprolroldlnl) methyl) carbamoyl) phenoxy) -1-nltrobenzene. According to Method A13 Step 4, 4- (3 - (/ 7 - ((1 86 methylpyrrolidin) l) methyl) carbamoyl) phenoxy) -1-nitrobenzene was reduced by 4- (3 - (/ 7 ((1-Methylprolrolin) l) Methyl) Carbamoyl) Phenoxyjaniline According to the Method

C1a, 4-c! Gold-3- (trfluoromethyl) phenylsocyanate was reacted with 4- (3 - (/ 7 - ((1-methylprolidinyl) methyl) carbamoyl) phenoxychanylna to get urea.

Compound 65: 4-Chloro- / 7-Methylplrn-Carboxamide was synthesized as described in Method A2, Step 3b. Chloroplridlna was reacted with 4-amylophenol according to Method A2, Step 4 to obtain 4- (4- (2 - (/ 7met! Carbamoyl) phenyl) anne.According to the Method C1 a, the compound 4-chloro-3- (trlfluoromethyl) phenylalsoate was reacted with 4- (4- (2 - (/ 7-methylcarbamoyl) phenylthio) ring to obtain urea.

Compound 66: 4-Chloropyridine-2-carbonyl chloride was reacted with sopropylamine according to Method A2, Step 3b. The resulting 4-chloro- / 7isopropyl-2-pyridinecarboxamide was reacted with 4-amophenol according to Method A2, Step 4 to obtain 4- (2 - (/ 7-sopropylcarbamoi) -4-p¡ r¡diiox¡) an¡I¡na. According to Method C1a, the compound 4-chloro-3- (trlfluoromethyl) phenosylsoate was reacted with 4- (2 (A / -sopropylcarbamoyl) -4-p¡r¡lox ¡) Anílina to obtain urea.

Compound 67: / 7- (4-Chloro-3- (trifluoromethyl) phenol- / 7 '- (4-ethoxycarbonyl) urea was synthesized according to Method C1e. The compound / 7- (4-chloro-3 - (trfluoromethyl) fen¡lA / '- (4-ethoxycarbonyl) urea was saponified according to Method D3 to obtain / 7- (4-chloro-3- (trifluoromethyl) phenyl- / 7 '- (4-carboxyphenyl) urea. / 7- (4-Chloro-3- (trifluoromethyl) phenyl- / 7 '- (4-carboxyphenyl) urea was coupled with 3-methylcarbamoyaniiine according to Method D1b to obtain / 7- (4 -chloro-3- (trfluoromethyl) phenol- / 7 '- (4- (3-methylcarbamoylphenyl) carbamoiiphenyl) urea.

Compound 68: 5- (4-Aminophenox) -2-methylisoindolin-1,3dione was synthesized according to Method A9. The compound 4-cIoro-3- (trifiuoromethyl) phenylisocyanate was reacted, according to Method C1a, with 5- (4aminophenoxy) -2-methylisoindolin-1,3-dione to obtain urea.

Compound 69: 4-Chloro-A / -methylpyrncarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-amlphenol according to Method A2, Step 4 to obtain 3- (4- (2 - (/ Vmetylcarbamoyl) phenyl) aniline According to Method Cia, the compound 4-chloro-3 - (trifluoromethyl) phenoxysocatoate was reacted with 3- (4- (2- (A / methylcarbamoyl) phenylthio) anine to obtain urea.

Compound 70: 4- (2 - (/ V- (2-morphol-4-iletl) carbamoyl) paryloxy) aniline was synthesized according to Method A10. 4-Chloro-3 (trifluoromethyl) phenytsocyanate was reacted according to Method C1a, with 4- (2- (A / - (2morpholin-4-ylethyl) carbamoyl) pyriloxyloxy aniline to obtain urea . L / IU IpUCÓlU / I.

He

Λ / O ZC + \ zi / '- λ rU \ / λ ι! \ I &lt;4 11rsvzt · I · &lt;4 / **&gt;

'· I iciUAiOai uui iiiyjjn lUiiuXi and anilina uc according to Method A14. The 4-chloro-3- (trifluoromethyl) -2-methoxyphenyl isocyanate compound was reacted with 4- (3- (5-methoxycarbonyl) pyridoxyoxy) anine according to Method C1a to obtain urea. The / V- (4-chloro-3- (trifluoromethyl) fen¡l) -N '- (4- (3- (5-methoxycarbon¡lp¡d¡l) ox¡) fen¡l) Urea was saponified, according to Method D4, Step 1, and the corresponding acid was coupled with 4- (2-aminoethyl) morpholine to obtain the amide.

Compound 72: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniiine was synthesized according to Method A14. 4-Chloro-3 (trifluoromethyl) phenoxsocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridylloxyl) aniline, according to the Cia Method, to obtain urea. The compound Λ / - (588 (trifluoromethyl) -2-methoxyphenyl) - / 7 '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenol) or area was saponified accordingly with Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to obtain the amide.

Compound 73: 4- (3- (5-Methoxycarbonyl) p¡r¡lox¡) anine was synthesized according to Method A14. The compound 4-chloro-3- (trifluoromethyl) phenylocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyriloxyloxy) aniline, according to Method C1 a, to obtain urea. The A / - (5- (trifluoromethyl) -2methoxyphenyl) - / V '- (4- (3- (5-methoxycarbon¡lp¡r¡d) ox¡) fen¡l) urea se saponified according to Method D4, Step 1, and the corresponding acid was coupled with Α /, / 7-dimethylethylenediamine according to Method D4, Step 2 to obtain the amide.

Compound 74: 4-Chloropyridin-2-carbonyl chloride, HCl salt was reacted with 2-hydroxyethylamine according to Method A2, Step 3b to form 4-chloro- / 7- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide . The compound

4-Cioro-A / - (2-triisopropylsiloxy) etlp¡ridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol, according to Method A17, to form 4- (4- (2- (A / - (2-tr¡soprop¡ls¡l¡lox¡) et¡lcarbamoíl) pir¡d¡lox¡an¡l¡na. In accordance with Method C1a, 4-chloro-3 (trfluoromethyl) phenylalsocianate was reacted with 4- (4- (2 - (/ 7- (2trophopylsilyloxy) ethylcarbamoyl) p Ridyloxyaniin to obtain / 7- (4-chloro-3 ((trfluoromethyl) phenyl) - / 7 '- (4- (4- (2- (W- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea .

Compound 75: 4- (3-carboxyphenoxine) aniline was synthesized according to the

Method A11 The 4-chloro-3- (trifluoromethyl) phenylisocyanate compound was reacted with 4- (3- (5-methoxycarbonyl) paryloxyl) anine according to the

Method C1f to obtain urea, which was coupled with 3-aminpyridine according to Method D1c.

Compound 76: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. The compound 4-chloro-3- (trifluoromethyl) phenylalsocianate was reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to obtain urea, which was coupled with / V- (4-acetylphenyl) ) piperazine according to Method D1c.

Compound 77: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. The compound 4-chloro-3- (trifluoromethyl) phenoxsocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to obtain urea, which was coupled with 4-fluoroaniline according with the Method

D1c.

Compound 78: 4- (3-Carboxyphenoxy) anne was synthesized according to Method Al 1. 4-Chloro-3- (irifiuoromei) phenylocyanate was reacted with 4 (3-carboxyphenoxy) aniline according to Method C1f to obtain urea, which was coupled with 4- (dimethylamin) aniline according to Method D1c.

Compound 79: 4- (3-carboxyphenoxy) anne was synthesized according to Method A11. 4-Cophore-3- (trfluoromethi) phenoxysocatoate was reacted with 4 (3-carboxyphenoxy) aniline according to Method C1f to obtain urea, which was coupled with N-phenylethylenediamine according to Method D1c.

Compound 80: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. The compound 4-chloro-3- (trifluoromethyl) phenoxsocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to obtain urea, which was coupled with 2-methoxyethylamine according with Method D1c.

Compound 81: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. Compound 4-chloro-3- (trifluoromethyl) phenylsoccinate was reacted with 4- (3-carboxyphenoxy) anifine according to Method C1f to obtain urea, which was coupled with 5-amin-2-methox Pyridine according to Method D1c.

Compound 82: 4- (3-carboxyphenoxy) anlline was synthesized according to Method A11. The compound 4-chloro-3- (trifluoromethyl) phenylsoccinate was reacted with 4- (3-carboxyphenoxy) anne according to the Clf Method to obtain the urea, which was coupled with 4-morpholyniline according to the Method

D1c.

Compound 83: 4- (3-Carboxyphenoxy) anne was synthesized according to Method A11. Compound 4-chloro-3- (trifluoromethyl) phenylsoccinate was reacted with 4- (3-carboxyphenoxy) anine according to Method C1f to obtain urea, which was coupled with / 7- (2 -p¡r¡d¡l) piperazlna according to Method D1c.

Compound 84: 4-Chloroplrld¡n-2-carbonyl chloride, HCI salt was reacted with 2-hydroxyethylamine according to Method A2, Step 3b to form 4-chloro- / V- (2-tr¡¡soprop¡ ls¡l¡loxi) ethylp¡r¡dlna-2-carboxam¡da. The compound 4-chloro-A / - (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide was reacted with trüsopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4- (4- (2- (2- (7V- (2-tr¡sopropiIsil¡Iox¡) ethylcarbamoíl) p¡rtdüoxian¡l¡na. According to Method C1a, the compound 4-chloro-3 (trifiuoromethyl) phenoxysocatoate was reacted with 4- (4- (2 - (/ 7- (291 tri-propylsilyloxy) eti) lcarbamoyl) pyridyloxyaniline to obtain A / - (4-chloro-3 ((trfluoromethyl) phenol) - / 7 '- (4- (4- (2 - (/ 7- (2-tri¡soprop ¡Ls¡l¡lox¡) et¡lcarbamoíl) p¡r¡d¡loxi fen¡l) urea Urea was checked according to Method D5 to obtain

N- (4-chloro-3 - ((trfluoromethyl) phenol) - / 7 '- (4- (4- (2 - (/ V- (2-hydrox)) eticarbamoyl) p Rloxy phenyl) urea.

Compound 85: 4- (2 - (/ 7-methylcarbamoyl) -4-p¡r¡loxy) anne was synthesized according to Method A2. The 4-bromo-3- (trfluoromethyl) anine compound was converted to 4-bromo-3- (trifluoromethyl) phenylisocyanate according to Method B1. According to Method C1a, 4-bromo-3 (trifluoromethyl) phenyl isocyanate was reacted with 4- (2 - (/ 7-methylcarbamoyl) -4-pyridyl) anine to obtain urea

Compound 86: 4- (2 - (/ 7-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. The 4-bromo-3 (trifluoromethyl) aniline compound was converted into an lorHn 4-bromo-3- (trifluoromethyl) phenyl isocyanate

CI or &lt;«&gt; · - * ι ι / Λ or A λ

Ul i ^ UlllpUCOlU (trifluoromethyl) phenylisocyanate was reacted, according to Method C1a, with 4- (2 - (/ 7-methylcarbamoyl) -4-p¡r¡lox¡) -2-chloroaniline for get urea.

Compound 87: 4-Amin-2-chlorophenol was reacted, according to Method A2, Step 4, with 4-chloro- / 7-methyl-2-pyrin-dicarboxamide, which had been synthesized according to Method A2, Step 3b, to obtain 4- (2 - (/ 7-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. The compound 4-bromo-3 (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenylsocnate in accordance with Method B1. The compound 4-bromo-3- (trifluoromethyl) phenylocyanate was reacted, according to Method C1a, with 4- (2 - (/ 7methylcarbamoyl) -4-pyrloxyl) -3-chloroanil. na to get urea.

Compound 88: 4-Chloropyridin-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro- / V-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to obtain 4- (2 - (/ V-etcarbamoyl) -4-pyridyloxyijaniline. Compound 4- Bromo-3- (trifluoromethyl) ani! ina was converted to 4-bromo-3- (trifluoromet.yl) phenylisocyanate according to Method B1. The compound 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted, according to Method C1 a, with 4- (2- (A / -ethylcarbamoyl) -4-pyridylloxy) aniiine to get urea.

Compound 89: The compound 4-chloro- / 7-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3aminophenol according to Method A2, Step 4, to form 3 - (- 2 - (/ 7met¡lcarbamoí!) - 4-p¡rid¡lox¡) an¡! Na. The compound 4-bromo-3 (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenylisocyanate according to Method B1. The compound 4-bromo-3- (trifluoromethyl) phenylocyanate was reacted, according to Method C1a, with 3 - (- 2 (// - methylcarbamoyl) -4-pyridyloxy) aniline to obtain urea.

Compound 90: The 5-am-2-methylphenol compound was reacted, according to Method A2, Step 4, with 4-chloro- / 7-methyl-2-pyrincarboxamide, which had been synthesized according to Method A2, Step 3b, to obtain 3- (2 - (/ 7methylcarbamoyl) -4-p¡r¡loxy) -4-methylaniüna. The compound 4-bromo-3 (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenoxanocyanate according to Method B1. Compound 4-bromo-3- (trifluoromethyl) phenylisocyanate was reacted, according to Method C1a, with 3- (2 - (/ 7methylcarbamoyl) -4-p¡r¡d¡lox¡) -4- metllan¡l¡na to get urea.

Compound 91: The compound 4-chloroplridin-2-carbonium chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro- / V, / 7-d¡met¡l-2-p -ridincarboxamide was reacted with 4-amnophenol according to Method A2, Step 4 to obtain 4- (2 - (/ 7, / 7d¡met Lcarbamoyl) -4-pirld¡lox¡) anil¡na. The compound 4-bromo-3- (trifluorometll) aniline was converted to 4-bromo-3- (trlfluorometl) feni! Socinate according to Method B1. The compound 4-bromo-3- (trfluorometll) phellisocyanate was reacted, according to the Cia Method, with 4- (2 - (/ 7, / 7-dlmetylcarbamoyl) -4plrldloxy) anlline to obtain urea

Compound 92: 4-Chloro-A / -metllp¡r¡dincarboxam¡da was synthesized as described in Method A2, Step 3b. Chloropyridine was reacted with 4-amylphenol according to Method A2, Step 4, to obtain 4- (4- (2 - (/ 7-methylcarbamoyl) phenyl) anine. The compound 4-bromo-3- (trfluorometll) annan was converted to 4-bromo-3- (trifluorometll) fenllsocnate in accordance with Method B1, the compound 4-bromo-3- (tnfluoromethyl) phenylisocyanate was reacted, according to Method C1a, with 4- (4- (2 - (/ 7-methylcarbamoyl) phenylthio) ring to obtain urea.

Compound 93: 4-Chloro- / 7-methylpipyncarboxamide was synthesized as described in Method A2, Step 3b. Chloropyridine was reacted with 3amlnthenophenol according to Method A2, Step 4, to obtain 3- (4- (2 - (/ 7-methylcarbamoyl) phenyl) anil. Compound 4-bromo-3- ( trfluorometll) aniline was converted to 4-bromo-3- (trifluorometll) phenylene isocyanate according to Method B1. The compound 4-bromo-3- (trlfluoromethyl) phenylocyanate was reacted, according to Method C1a, with 3- (4- (2- (A / -methylcarbamoyl) phenyl) an) llna to get urea.

Compound 94: 4- (2- (A / - (2-morphol-4-ethyl) carbamoyl) pyrloxin) was synthesized according to Method A10. 4-Bromo-3 (trifiuoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyisocyanate according to Method B1. The compound 4-bromo-3- (trifluoromethyl) phenylisocyanate was reacted, according to Method C1a, with 4- (2- (A / - (2-morpholin-4ileti!) Carbamoyl) pyridyloxy) aniline to obtain urea

Compound 95: 4- (2 - (/ 7-methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to Method A2. The 4-chloro-2-methox-5 (trfluoromethyl) anine compound was synthesized according to Method A7. 4-Chloro-2-methoxy-5- (trif! Uoromethyl) anine was converted to 4-chloro-2-methoxy-5 (trifluoromethyl) phenylisocyanate according to Method B1. The compound 4-chloro-2-methox-5- (trifluoromethyl) phenoxysocanate was reacted, according to Method C1 a, with 4- (2 - (/ V-methocarbarium) -4- pir¡d¡lox¡) aníi¡na to obtain urea.

Compound 96: 4- (2 - (/ V-methylcarbamoyl) -4-pyridylox!) -2-chloroanillna was synthesized according to Method A6. The compound 4-chloro-2-methoxy-5 (trifluoromethyl) anine was synthesized according to Method A7. 4-Chloro-2-methox-5 (trlfluoromethyl) anine was converted to 4-chloro-2-methox-5 (trifluoromethyl) phenylisocyanate according to Method B1. The compound 4-chloro-2-methoxy-5- (trlfluoromethyl) phenoxsocnate was reacted, according to Method C1a, with 4- (2 - (/ V-methylcarbamoyl) -4-p¡ rld¡lox¡) -2-chloroaniline to obtain urea.

Compound 97: According to Method A2, Step 4, 4-amin-2-chlorophenol was reacted with 4-chloro- / 7-methyl-2-pyridinecarboxamide, which had been synthesized according to the Method A2, Step 3b, to obtain 4- (2 - (/ 7-methylcarbamoyl) -4-pyridylox) -3-chloroaniline. The compound 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) phenylcyanate according to Method B1. The compound 4-chloro-2-methoxy-5 (trifluoromethyl) phenylisocyanate was reacted, according to Method C1a, with 4- (2 - (/ 7-methylcarbamoyl) -4-paryloxy) -3- Chloro'n¡l¡na to get urea.

Compound 98: The compound 4-chloro- / 7-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3aminophenol according to Method A2, Step 4 to form 3 - (- 2 - (/ 7methylcarbamoyl) -4-pyridyloxy) aniline. The compound 4-cJoro-2-methox-5 (tnfluoromethyl) anüine was synthesized according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromet¡I) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenylcyanate according to Method B1. The compound 4-chloro-2-methoxy-5 (trifluoromethyl) phenyl isocyanate was reacted, according to Method C1a, with 3 - (- 2 - (/ 7-methylcarbamoyl) -4-p¡r¡d¡ loxi) anine to obtain urea.

Compound 99: The 4-chloropyridin-2-carbonyl chloride compound was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro- / 7-et-l-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to obtain 4- (2 - (/ 7-ylcarbamoyl) -4-pyridyloxy) anil! na. The compound 4-chloro-2-methoxy-5 (trifluoromethyl) aniline was synthesized according to Method A7. The 4-chloro-296 methoxy-5- (trifluoromethyl) anine was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenylisocyanate according to Method B1. The compound 4-chloro-2-methox-5 (trfluoromethyl) phenoxysocatoate was reacted according to the Method

C1a, with 4- (2 - (/ 7-etcarbamoyl) -4-pyrloxl) anna to obtain urea.

Compound 100: The 4-chloropyridine-2-carbonyl chloride compound was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro- / 7, / 7-d¡met¡l-2-p¡rld¡ncarboxam¡da was reacted with 4aminophenol according to Method A2, Step 4, to obtain 4- (2- (A / , Λ / d¡met¡lcarbamoíl) -4-pir¡d¡lox¡) an¡llna. The compound 4-chloro-2-methoxy-5 (trfluoromethyl) aniline was synthesized according to Method A7. 4-Chloro-2-methox-5- (trif! UorometI) aniline was converted to 4-chloro-2-methoxy-5 (trifluoromethyl) phenoxysocatoate according to Method B1. The compound 4-chloro-2-methoxl-5- (trfluoromethyl) phenylocyanate was reacted, according to Method C1a, with 4- (2 - (/ 7, A / -d¡met¡ Carbamoyl) -4-p¡r¡d¡lox¡) an anllna to obtain urea.

Compound 101: The 4-chloro-A / -methyl-2-pyridinecarboxamide compound, which was synthesized according to Method A2, Step 3a, was reacted with

3-Aminophenol according to Method A2, Step 4 to form 3 - (- 2 - (/ 7-methylcarbamoyl) -4-pyridyloxy) aniline. 2-A-3-methoxynaphthalene was synthesized as described in Method A1. The compound 2-amn-3-methoxynaphthalene was reacted, according to Method C3, with bi (trichloromethyl) carbonate followed by 3 - (- 2 - (/ 7-methylcarbamoyl) -4-plr! d¡lox¡) an¡l¡na to form urea.

Compound 102: 4- (2- (A / -methylcarbamoyl) -4-pyrloxyloxy) aniline was synthesized according to Method A2. 5-tert-Butyl-2- (2,5-dimethyl-pyrrolyl) aniline was synthesized according to Method A4. The compound 5-tert-butyl-297 (2,5-dimethylpyrrolyl) aniiine was reacted with CDI followed by 4- (2 - (/ Vmetylcarbamoyl) -4-pyrrilox) an Line according to Method C2d to obtain urea.

Compound 103: 4-Chloro-N-methyl-2-pyrridcarboxamide was synthesized according to Method A2, Step 3b. The compound 4-chloro-N-methyl-2 -ridridincarboxamide was reacted with 4-amnophenol according to Method A2, Step 4 using DMAC instead of DMF to obtain 4- (2 - (/ Vmetlcarbamoyl) -4-p ¡R¡d¡lox¡) anllina. According to Method C2b, the reaction of 3-amin-2-methoxyquinoline with CDI followed by 4- (2- (N-methylcarbamoyl) -4pridridlox) still allowed to obtain b¡ (4- (2- (A / -methylcarbamoyl) -4-p¡r¡d¡lox¡) phenyl) urea.

The following Tables list the compounds that were synthesized according to the Detailed Experimental Procedures described above:

Boards

The compounds listed below in Tables 1-6 were synthesized according to the general methods described above and the more detailed procedures corresponding to the examples were described in the List of Compounds above and the characterizations are indicated in the Tables.

Table 1.

<img file="CU23213A3_D0065.tif" />

<td>Comp.</td><td>R</td><td>pf ('C)</td><td>HPLC (min.)</td><td>R / TLC</td><td>Sist. Solv. FTA</td><td>Spec. mass [Source]</td><td>Mét. Sint</td>

<td> 1</td><td>0 i-NH^Me</td><td></td><td></td><td> 0,22</td><td>50% EtOAc / hexane 50%</td><td>418 (M + H) + (HPLC ES-MS)</td><td>A13 C3</td>

<td> 2</td><td></td><td></td><td></td><td> 0,58</td><td>50% EtOAc / hexane 50%</td><td>403 (M + H) + (HPLC ES-MS)</td><td>A13 C3</td>

<td> 3</td><td>0 V-NH</td><td> 133- 135</td><td></td><td> 0,68</td><td>100% EtOAc</td><td>448 (M + H) + (FAB)</td><td>A8 C2d</td>

Table 2. 5-tert-butyl-2-methoxyfenides

<img file="CU23213A3_D0066.tif" />

<td>Comp.</td><td>R</td><td>pf (° C)</td><td>HPLC (min.)</td><td>TLC R_r</td><td>Sist. Solv. FTA</td><td>Spec. Dough [Source]</td><td>Mét. Sint</td>

<td> 4</td><td>Vnh^Me</td><td></td><td> 5,93</td><td></td><td></td><td>448 (M + H) + (HPLC ES-MS)</td><td>A13 B1 C1a</td>

<td> 5</td><td>OR V-NH £ and_or 0-_or“:</td><td> 120- 122</td><td></td><td> 0,67</td><td>100% EtOAc</td><td>478 (M + H) + (FAB)</td><td>A8 C2d</td>

<td> 6</td><td>and^NH 0</td><td></td><td></td><td> 0,40-</td><td>50% EtOAc / hexane 50%</td><td>460 (M + H) + (HPLC ES-MS)</td><td>A3 C2d</td>

<td> 7</td><td>\ ^ NH</td><td></td><td></td><td> 0,79</td><td>50% EtOAc / hexane 50%</td><td>446 (M + H) + (HPLC ES-MS)</td><td>A12 C2d</td>

Table 3. 5- (trifluoromethyl) -2-methoxfen.

<img file="CU23213A3_D0067.tif" />

<td>Comp.</td><td>R</td><td>pf (° C)</td><td>HPLC (min.)</td><td>TLC R,</td><td>Sist. Solv. FTA</td><td>Spec. Mass [Source]</td><td>Mét. Yes</td>

<td> 8</td><td>0 Vnh^Me</td><td>250 (dec)</td><td></td><td></td><td></td><td>460 (M + H) + (FAB)</td><td>A13 C2a</td>

<td> 9</td><td></td><td> 206- 208</td><td></td><td> 0,54</td><td>10% MeOH / CH₂CI₂ 90%</td><td>446 (M + H) + (HPLC ES-MS)</td><td>A3 step two, A8 step 4, B1, C1a</td>

<td> 10</td><td>or »cn.</td><td></td><td></td><td> 0,33</td><td>50% EtOAc / pet ether fifty%</td><td>445 (M + H) + (HPLC ES-MS)</td><td>A13 C3</td>

<td> 11</td><td>-frf Vnh r = \ Me ° A7^J</td><td></td><td></td><td> 0,20</td><td>Hey₃N 2% / EtOAc 98%</td><td>461 (M + H) + (HPLC ES-MS)</td><td>A2 C4</td>

<td> 12</td><td>/ rx —__ pb-NH₂OZ N</td><td></td><td></td><td> 0,27</td><td>Et₃N 1% / EtOAc 99%</td><td>447 (M + H) + (HPLC ES-MS)</td><td>A2 04</td>

<td> 13</td><td>0 Vnh^Me</td><td></td><td></td><td> 0,52</td><td>100% EtOAc</td><td>461 (M + H) + (FAB)</td><td>A2 C2a</td>

<td> 14</td><td>0 V-nh₂- /) - θ — C // N</td><td> 114- 117</td><td></td><td> 0,40</td><td>Et₃N 1% / EtOAc 99%</td><td>447 (M + H) + (FAB)</td><td>A2 C4</td>

<td> 15</td><td>0 Vnh ΓΛ / = \ ^Me—C / ^0_4 # ^0Me</td><td> 232- 235</td><td></td><td> 0,54</td><td>100% EtOAc</td><td>490 (M + H) + (FAB)</td><td>A8 C2d</td>

<td> 16</td><td>0 I V-NH^JbW </td><td> 210- 213</td><td></td><td> 0,29</td><td>5% MeOH / EtOAc 45% / pet ether fifty%</td><td>475 (M + H) + (HPLC ES-MS)</td><td>TO 5 B1 C1c</td>

100

<td> 17</td><td>0 Cl U-NH XX · "</td><td> 187- 188</td><td></td><td> 0,17</td><td>50% EtOAc / pet ether fifty%</td><td>495 (M + H) + (HPLC ES-MS)</td><td>A6 B1 C1a</td>

<td> 18</td><td>—Me Ν H ₂0 — N AND //</td><td></td><td></td><td> 0,48</td><td>100% EtOAc</td><td>475 (M + H) + (HPLC ES-MS)</td><td>A2 step 4, B1 C1a</td>

<td> 19</td><td>0 Ϋ-ΝΗ uzyuz?</td><td> 194- 196</td><td></td><td> 0,31</td><td>5% MeOH / EtOAc 45% / pet ether fifty%</td><td>475 (M + H) + (HPLC ES-MS)</td><td>A2 B1 C1a</td>

<td> 20</td><td>0 Cl V — NH XX</td><td> 214- 216</td><td></td><td> 0,25</td><td>5% MeOH / EtOAc 45% / pet ether fifty%</td><td>495 (M + H) + (HPLC ES-MS)</td><td>A2 C1a</td>

<td> 21</td><td></td><td> 208- 210</td><td></td><td> 0,30</td><td>50% EtOAc / hexane 50%</td><td>481 (M + H) + (HPLC ES-MS)</td><td>A19 C2a</td>

<td> 22</td><td>0 V nh₂and x</td><td> 188- 190</td><td></td><td> 0,30</td><td>70% EtOAc / hexane 30%</td><td>447 (M + H) + (HPLC ES-MS)</td><td>A15, step 4, C1a</td>

<td> 23</td><td>-OR-^0_Ow ° and^NH 0</td><td></td><td> •</td><td> 0,50</td><td>70% EtOAc / hexane 30%</td><td>472 (M + H) + (FAB)</td><td>A3 B1 C1a</td>

<td> 24</td><td>0 me</td><td> 203- 205</td><td></td><td> 0,13</td><td>100% EtOAc</td><td>479 (M + H) + (HPLC ES-MS).</td><td>A2 B1 C1a</td>

<td> 25</td><td>\ ^ nh</td><td></td><td></td><td> 0,09</td><td>EtOAc 75% / hexane 25%</td><td>458 (M + H) + (HPLC ES-MS)</td><td>A12C2d</td>

<td> 26</td><td>MeO</td><td> 169- 171</td><td></td><td> 0,67</td><td>50% EtOAc / pet ether fifty%</td><td>474 (M + H) + (HPLC ES-MS)</td><td>A13 step 1, A13 Step 4, A16, B1 Inc</td>

<td> 27</td><td>v-nh U&gt; -d </td><td> 218- 219</td><td></td><td> 0,40</td><td>50% EtOAc / pet ether fifty%</td><td>477 (M + H) + (HPLC ES-MS)</td><td>A2 step 3b, A2 step 4, B1,</td>

101

<td></td><td colspan="4"></td><td></td><td></td><td></td><td></td><td></td><td>C1a</td>

<td> 28</td><td></td><td></td><td> /=\</td><td>, ρ</td><td> 212-</td><td></td><td> 0,30</td><td>EtOAc 40% /</td><td></td><td>A9</td>

<td></td><td>\ = λ</td><td>-or</td><td>F</td><td>Ύ ^ NMe</td><td> 214</td><td></td><td></td><td>hexane 50%</td><td></td><td>B1 C1a</td>

<td></td><td></td><td></td><td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 29</td><td></td><td></td><td> 0</td><td rowspan="2">ΝΗ Me</td><td></td><td></td><td> 0,33</td><td>50% EtOAc /</td><td>474 (M + H) +</td><td>A2 step</td>

<td></td><td>Μ</td><td></td><td></td><td></td><td></td><td></td><td>pet ether</td><td>(HPLC ES-MS)</td><td>3b,</td>

<td></td><td></td><td> 5—&lt;</td><td rowspan="2"> 0</td><td></td><td></td><td></td><td></td><td> 50%</td><td></td><td>A2 step</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 4,</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>B1,</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>C1a</td>

<td> 30</td><td></td><td></td><td> 0</td><td>-ΝΗ</td><td> 210-</td><td></td><td></td><td></td><td></td><td rowspan="2">A2 B1 C1a</td>

<td></td><td></td><td>-or-</td><td rowspan="2">ο</td><td>Pr-¡</td><td> 211</td><td></td><td></td><td></td><td></td>

<td></td><td> \=/</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 31</td><td></td><td></td><td> 0</td><td>-ΝΗ</td><td> 210-</td><td></td><td> 0,43</td><td>10% MeOH /</td><td></td><td>A14 B1</td>

<td></td><td></td><td></td><td></td><td></td><td> 204</td><td></td><td></td><td>CH₂CI₂</td><td></td><td>C1a D4</td>

<td></td><td>-Ο</td><td>or-</td><td>ί ^ζ?</td><td rowspan="2"> &lt;</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>Ν</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 32</td><td></td><td></td><td> 0</td><td>-ΝΗ</td><td> 247-</td><td></td><td> 0,57</td><td>10% MeOH /</td><td></td><td>A14 B1</td>

<td></td><td></td><td></td><td></td><td rowspan="2">Me</td><td> 249</td><td></td><td></td><td>CH₂CI₂</td><td></td><td>C1a D4</td>

<td></td><td>Ο</td><td>-or-</td><td>Ό</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>+ -Ν</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 33</td><td></td><td></td><td> 0,</td><td>ΝΗ</td><td>017 1 I</td><td></td><td>η Π7 V, kJ I</td><td>10% MeOH /</td><td></td><td>Λ Ί AD 4 ry i “t l&gt; t</td>

<td></td><td></td><td></td><td></td><td></td><td> 219</td><td></td><td></td><td rowspan="2">ch₂ci₂</td><td></td><td>C1a D4</td>

<td></td><td>-ο</td><td>or-</td><td>Λ ν</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>+ -Ν</td><td>Me</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 34</td><td></td><td></td><td> 0</td><td>-ΝΗ</td><td></td><td></td><td> 0,11</td><td>70% EtOAc /</td><td></td><td>A11 B1</td>

<td></td><td></td><td></td><td></td><td> \_</td><td></td><td></td><td></td><td>hexane 30%</td><td></td><td>C1fD1c</td>

<td></td><td>-JT \</td><td rowspan="2">-or-</td><td></td><td>ρ</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Ό</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 35</td><td></td><td></td><td></td><td></td><td></td><td></td><td> 0,38</td><td>70% EtOAc /</td><td></td><td>A11 B1</td>

<td></td><td></td><td>c</td><td>Ζ</td><td></td><td></td><td></td><td></td><td>hexane 30%</td><td></td><td>C1f D1c</td>

<td></td><td></td><td></td><td>χ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>Ζ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> /</td><td> —0</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td rowspan="2">-Ό</td><td rowspan="2">-ο</td><td>ζ = \</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>ZJ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

102

<td> 36</td><td>F — V \ —NH nfl</td><td></td><td></td><td> 0,77</td><td>70% EtOAc / hexane 30%</td><td></td><td>A11 B1 C1fD1c</td>

<td> 37</td><td>Me '-' \ = Q AC</td><td></td><td></td><td> 0,58</td><td>70% EtOAc / hexane 30%</td><td></td><td>A11 B1 Clf D1c</td>

<td> 38</td><td>MeO-Ο ANH</td><td></td><td></td><td> 0,58</td><td>70% EtOAc / hexane 30%</td><td></td><td>A11 B1 C1f D1C</td>

<td> 39</td><td>d Ny y — nh \ - / m = /</td><td></td><td></td><td> 0,17</td><td>70% EtOAc / hexane 30%</td><td></td><td>A11 B1 C1f D1c</td>

<td> 40</td><td>&lt;ry_NQ_N_ £ and_N,</td><td></td><td></td><td> 0,21</td><td>70% EtOAc / hexane 30%</td><td></td><td>A11 B1 C1f D1c</td>

Table 4, 3- (trifluoromethyl) -4-chlorophenolureas

<img file="CU23213A3_D0068.tif" />

<td>Comp.</td><td>R</td><td>pf ro</td><td>HPLC (min.)</td><td>TLC R,</td><td>Sist. Solv. FTA</td><td>Spec. Mass [Source]</td><td>Mét. Yes</td>

<td> 41</td><td>OR Anh -oo^Me</td><td> 163- 165</td><td></td><td> 0,08</td><td>50% EtOAc / pet ether fifty%</td><td>464 (M + H) + (HPLC ES-MS)</td><td>A13 C3</td>

<td> 42</td><td>OR Anh 00^Me</td><td> 215</td><td></td><td> 0,06</td><td>50% EtOAc / pet ether fifty%</td><td>465 (M + H) + (HPLC ES-MS)</td><td>A2C1a</td>

<td> 43</td><td>OR V-nh₂yy ₀-and_N</td><td></td><td></td><td> 0,10</td><td>50% EtOAc / pet ether fifty%</td><td>451 (M + H) + (HPLC ES-MS)</td><td>A2 C1a</td>

103

<td> 44</td><td>5 ^ ΝΗ₂° ~ Cⁿ</td><td></td><td></td><td> 0,25</td><td>EtOAc 30% / pet ether 70%</td><td>451 (M + H) + (HPLC ES-MS)</td><td>A2 C1a</td>

<td> 45</td><td>-Γ} Vnh y = (Me ° ~ v</td><td></td><td></td><td> 0,31</td><td>EtOAc 30% / pet ether 70%</td><td>465 (M + H) + (HPLC ES-MS)</td><td>A2C1a</td>

<td> 46</td><td>-O'Ol V 0</td><td> 176- 179</td><td></td><td> 0,23</td><td>EtOAc 40% / hexane 60%</td><td>476 (M + H) + (FAB)</td><td>A3C1a</td>

<td> 47</td><td>0 Me Ϋ-ΝΗ OÜ </td><td></td><td></td><td> 0,29</td><td>5% MeOH / EtOAc 45% / pet ether fifty%</td><td>478 (M + H) + (HPLC ES-MS)</td><td>A5C1c</td>

<td> 43</td><td>O., ° 'S-NH OO *</td><td> 206- 209</td><td></td><td></td><td></td><td></td><td>A15 Cía</td>

<td> 49</td><td>0 ci Vnh OO </td><td> 147- 151</td><td></td><td> 0,22</td><td>50% EtOAc / pet ether fifty%</td><td>499 (M + H) + (HPLC ES-MS)</td><td>A6C1a</td>

<td> 50</td><td>—Fy— Me V- NH '^ O / = ¾ M® ° Oⁿ</td><td></td><td></td><td> 0,54</td><td>100% EtOAc</td><td>479 (M + H) + (HPLC ES-MS)</td><td>A2C1a</td>

<td> 51</td><td>0 V-NH^Et</td><td> 187- 189</td><td></td><td> 0,33</td><td>5% MeOH / EtOAc 45% / pet ether fifty%</td><td>479 (M + H) + (HPLC ES-MS)</td><td>A2 C1a</td>

<td> 52</td><td>0 ci 'onh oo *</td><td> 219</td><td></td><td> 0,18</td><td>5% MeOH / EtOAc 45% / pet ether fifty%</td><td>499 (M + H) + (HPLC ES-MS)</td><td>A2 C1a</td>

<td> 53</td><td> -0-0¾</td><td> 246- 248</td><td></td><td> 0,30</td><td>EtOAc 50% / hexane fifty%</td><td>485 (M + H) + (HPLC ES-MS)</td><td>A19, C1a</td>

<td> 54</td><td>00¾ Me</td><td> 196- 200</td><td></td><td> 0,30</td><td>EtOAc 70% / hexane 30%)</td><td>502 (M + H) + (HPLC ES-MS)</td><td>A15C1a '</td>

104

<td> 55</td><td colspan="2"></td><td>-ο-</td><td>γ</td><td>0 r</td><td>'-or Me</td><td> 228- 230</td><td></td><td> 0,30</td><td>EtOAc 30% / CH₂CI₂ 70%</td><td>466 (M + H) + (HPLC ES-MS)</td><td></td>

<td> 56</td><td rowspan="2"> -&lt;</td><td rowspan="2"> &gt;</td><td></td><td>Λ</td><td>= Ν</td><td> .0</td><td> 238-</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>-Q-</td><td>Λ</td><td> }</td><td>TO NH</td><td> 245</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>Me^Z</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 57</td><td></td><td></td><td></td><td></td><td></td><td rowspan="3">0 Γ</td><td> 221-</td><td></td><td> 0,75</td><td>EtOAc 80% /</td><td>492 (M + H) +</td><td>Cid D1a</td>

<td></td><td></td><td></td><td rowspan="2">I ΖΙ 1</td><td> 0</td><td></td><td> 222</td><td></td><td></td><td>20% hexane</td><td rowspan="2">(FAB)</td><td></td>

<td></td><td></td><td> &gt;</td><td> 1</td><td> &lt;</td><td></td><td></td><td></td><td></td><td></td>

<td> 58</td><td></td><td></td><td></td><td></td><td></td><td rowspan="2">0 TO</td><td> 247</td><td></td><td> 0,35</td><td>100% EtOAc</td><td></td><td>Cid Day</td>

<td></td><td></td><td></td><td rowspan="3">-Κ-</td><td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td>D2</td>

<td></td><td>—Λ</td><td>TO</td><td>II</td><td>Γ</td><td>Λ</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>V:</td><td> =/</td><td></td><td>ν_</td><td>and</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 59</td><td></td><td></td><td></td><td></td><td> 0</td><td rowspan="2">Me --N Me 4</td><td> 198-</td><td></td><td> 0,09</td><td>100% EtOAc</td><td>479 (M + H) +</td><td>A2 C1a</td>

<td></td><td>_TO</td><td>Α</td><td>-ο-</td><td>Α</td><td>J /</td><td> 200</td><td></td><td></td><td></td><td>(HPLC ES-MS)</td><td></td>

<td> 60</td><td></td><td></td><td></td><td></td><td colspan="2">MeO</td><td> 158-</td><td></td><td rowspan="2"> 0,64</td><td>50% EtOAc /</td><td></td><td></td>

<td></td><td></td><td>Α</td><td> -0-</td><td rowspan="2">γ</td><td rowspan="2">J</td><td>N //</td><td> 160</td><td></td><td>pet ether</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>Me</td><td></td><td></td><td></td><td> 50%</td><td></td><td></td>

<td> 61</td><td></td><td></td><td></td><td></td><td> 0</td><td>-NH</td><td> 195-</td><td></td><td> 0,39</td><td>10% MeOH /</td><td></td><td>A13C1a</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td> \_</td><td> 197</td><td></td><td></td><td rowspan="2">CH₂CI₂</td><td></td><td></td>

<td></td><td>—Yes</td><td> \\</td><td rowspan="2"> -0-</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>ν</td><td> )</td><td> &lt;</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 62</td><td></td><td></td><td></td><td></td><td> 0</td><td>-NH</td><td> 170-</td><td></td><td> 0,52</td><td>10% MeOH /</td><td></td><td>A13 C1a</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td> \</td><td> 172</td><td></td><td></td><td rowspan="2">CH₂CI₂</td><td></td><td></td>

<td></td><td>Γ</td><td>ν</td><td rowspan="2">-ο-</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>Α</td><td> )</td><td> &lt;</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 63</td><td></td><td></td><td></td><td></td><td> 0</td><td>-NH</td><td> 163-</td><td></td><td> 0,39</td><td>10% MeOH /</td><td></td><td>A13 C1a</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 171</td><td></td><td></td><td>CH₂CI₂</td><td></td><td></td>

<td></td><td>_ / Γ</td><td>Α</td><td rowspan="2">-ο-</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>χ</td><td>J</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 64</td><td></td><td></td><td></td><td></td><td rowspan="2">0 TO</td><td>AND</td><td> 176-</td><td></td><td rowspan="2"> 0,35</td><td>10% MeOH /</td><td></td><td>A13 C1a</td>

<td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2">-NH</td><td rowspan="2"> 177</td><td rowspan="2"></td><td rowspan="2">CH2CL2</td><td rowspan="2"></td><td rowspan="2"></td>

<td></td><td></td>

<td></td><td></td><td>Α</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>Ό ”</td><td>V</td><td> )</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

105

<td rowspan="2"> 65</td><td rowspan="2">_J</td><td rowspan="2"></td><td rowspan="2">&gt; —S</td><td colspan="2"> 0</td><td rowspan="2">-NH Me</td><td rowspan="2"> 130- 133</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2">487 (M + H) + (HPLC ES-MS)</td><td rowspan="2">A2 B1 C1a</td>

<td>TO</td><td>N / j</td>

<td> 66</td><td rowspan="2"></td><td rowspan="2"></td><td></td><td></td><td> 0</td><td rowspan="2">-NH Pr-i</td><td> 155</td><td></td><td></td><td></td><td></td><td>A2 C1a</td>

<td></td><td> —0</td><td rowspan="2">TO</td><td>N</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td> /&gt;</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 67</td><td></td><td></td><td></td><td></td><td colspan="2"> 0</td><td> 225-</td><td></td><td> 0,23</td><td>100% EtOAc</td><td></td><td>C1eD3</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>% -Nl ·</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td rowspan="3">N-</td><td> 0</td><td></td><td>yi \</td><td> 229</td><td></td><td></td><td></td><td></td><td>D1b</td>

<td></td><td>fr</td><td></td><td>II</td><td>r</td><td>λ</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>V</td><td>J</td><td></td><td>TO</td><td>and</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 68</td><td>fr</td><td>TO</td><td rowspan="2"> —0</td><td></td><td></td><td> 0</td><td> 234-</td><td></td><td rowspan="2"> 0,29</td><td>EtOAc 40% /</td><td></td><td>A9 C1a</td>

<td></td><td></td><td></td><td>TO</td><td>TO</td><td>^ NMe</td><td> 236</td><td></td><td>hexane 60%</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 69</td><td colspan="2">fr ~</td><td></td><td></td><td> 0</td><td>NH</td><td></td><td></td><td> 0,48</td><td>50% EtOAc /</td><td>481 (M + H) +</td><td></td>

<td></td><td></td><td> 7=</td><td></td><td></td><td></td><td>Me</td><td></td><td></td><td></td><td>pet ether</td><td>(HPLC ES-MS)</td><td></td>

<td></td><td></td><td></td><td>s-</td><td>V</td><td>N //</td><td></td><td></td><td></td><td></td><td> 50%</td><td></td><td></td>

<td> 70</td><td></td><td></td><td></td><td></td><td> 0</td><td>-NH</td><td></td><td></td><td> 0,46</td><td>5% MeOH /</td><td>564 (MH) +</td><td>A10 C1a</td>

<td></td><td>fr</td><td>TO.</td><td>-or-</td><td rowspan="2">TO</td><td>N</td><td>TO</td><td></td><td></td><td></td><td>CH₂CI₂ 95%</td><td>(HPLC ES-MS)</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> &lt;</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 71</td><td></td><td></td><td></td><td></td><td> 0 \\</td><td>-NH</td><td> 199-</td><td></td><td> 0,50</td><td>10% MeOH /</td><td></td><td>A14 C1a</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 201</td><td></td><td></td><td>CH2CL2</td><td></td><td>D4</td>

<td></td><td>fr</td><td>TO</td><td>-or-</td><td>TO</td><td>// -N</td><td> &lt;</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 72</td><td></td><td></td><td></td><td></td><td> 0</td><td>-NH</td><td> 235-</td><td></td><td> 0,55</td><td>10% MeOH /</td><td></td><td>A14 C1a</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="2">Me</td><td> 237</td><td></td><td></td><td>CH2CL2</td><td></td><td>D4</td>

<td></td><td>fr</td><td>TO</td><td>-or-</td><td rowspan="2">TO</td><td> //</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>-N</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 73</td><td></td><td></td><td></td><td></td><td> 0</td><td>-NH</td><td> 200-</td><td></td><td> 0,21</td><td>50% MeOH /</td><td></td><td>A14 C1a</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td> \_</td><td> 201 '</td><td></td><td></td><td>CH2CL2</td><td></td><td>D4</td>

<td></td><td>F</td><td>TO</td><td>-or-</td><td>TO</td><td> //</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>-N</td><td>Me</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 74</td><td></td><td></td><td></td><td>c</td><td> \\</td><td></td><td> 145-</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td colspan="2">r — NH</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td rowspan="2">Γ</td><td rowspan="2">TO</td><td></td><td></td><td></td><td></td><td> 148</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>-okay</td><td> \\</td><td> /)</td><td>YOU</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td colspan="2">N</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

106

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 75</td><td>fy_NH % = / \ = Q</td><td></td><td></td><td> 0,12</td><td>70% EtOAc / hexane 30%</td><td>527 (M + H) + (HPLC ES-MS)</td><td>A11 C1f D1c</td>

<td> 76</td><td>0 Me- b 0 y = o 0-0</td><td></td><td></td><td> 0,18</td><td>70% EtOAc / hexane 30%</td><td></td><td>A11 Clf D1c</td>

<td> 77</td><td>F — f / —NH V = / \ = or Nr-X</td><td></td><td></td><td> 0,74</td><td>70% EtOAc / hexane 30%</td><td></td><td>A11 Clf D1c</td>

<td> 78</td><td>^MeN-0 and — NH Me^Z Y = O 0-0</td><td></td><td></td><td> 0,58</td><td>70% EtOAc / hexane 30%</td><td></td><td>A11 Clf D1c</td>

<td> 79</td><td>0 —NH</td><td></td><td></td><td> 0,47</td><td>70% EtOAc / hexane 30%</td><td>569 (M + H) + (HPLC ES-MS)</td><td>A11 C1f D1c</td>

<td> 80</td><td>0 V- NH ^ -Q</td><td></td><td></td><td> 0,18</td><td>70% EtOAc / hexane 30%</td><td>508 (M + H) + (HPLC ES-MS)</td><td>A11 C1f D1c</td>

<td> 81</td><td>MeO— ~ A — NH - ^ 3 == 0 -00</td><td></td><td></td><td> 0,58</td><td>70% EtOAc / hexane 30%</td><td>557 (M + H) - * (HPLC ES-MS)</td><td>A11 C1f D1C</td>

<td> 82</td><td>0 ΛΑ__ΝΗ\ - / V = ​​/ \ = Q ^ -Q</td><td></td><td></td><td> 0,37</td><td>70% EtOAc / hexane 30%</td><td>611 (M + H) + (HPLC ES-MS)</td><td>A11 C1f D1C</td>

107

<td> 83</td><td>c</td><td>π</td><td></td><td></td><td> 0,19</td><td>70% EtOAc / hexane 30%</td><td></td><td>A11 C1f D1c</td>

<td></td><td></td><td>j = °</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>or-</td><td>-Ό</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 84</td><td>-or-</td><td>0 V-NH Q</td><td> 179- 183</td><td></td><td></td><td></td><td></td><td>A2 A17 C1a D5</td>

<td>Table 5</td><td colspan="4">3- (trfluorometl) -4-bromophenol F F_x_</td><td>eas X</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td colspan="2">^R-N^TOTO Η H</td><td>r</td><td></td><td></td><td></td>

<td>Comp.</td><td>R</td><td></td><td>pf</td><td>HPLC</td><td>TLC R,</td><td>Sist. Solv.</td><td>Spec. Dough</td><td>Mét. Yes</td>

<td></td><td></td><td></td><td>(° C)</td><td>(min.)</td><td></td><td>FTA</td><td>[Source]</td><td></td>

<td> 85</td><td></td><td>0 V-NH Me w¹</td><td> 186- 187</td><td></td><td> 0,13</td><td>50% EtOAc / pet ether fifty%</td><td>509 (M + H) + (HPLC ES-MS)</td><td>A2 B1 C1a</td>

<td> 86</td><td>Cl</td><td>0 Ϋ — NH</td><td> 150-</td><td></td><td> 0,31</td><td>50% EtOAc /</td><td>545 (M + H) +</td><td>A6 B1</td>

<td></td><td></td><td>r = \ Me w</td><td> 152</td><td></td><td></td><td>pet ether fifty%</td><td>(HPLC ES-MS)</td><td>C1a</td>

<td> 87</td><td>Cl - (^^ - Q—</td><td>0 V-NH / = \ Me</td><td> 217- 219</td><td></td><td> 0,16</td><td>50% EtOAc / pet ether fifty%</td><td>545 (M + H) + (HPLC ES-MS)</td><td>A2 B1 C1a</td>

<td> 88</td><td>or</td><td>0 Unh r = {Et w</td><td> 183- 184</td><td></td><td> 0,31</td><td>50% EtOAc / pet ether fifty%</td><td>525 (M + H) + (HPLC ES-MS)</td><td>A2 B1 C1a</td>

<td> 89</td><td>YOU</td><td>0 f — NH = \ Me</td><td></td><td></td><td> 0,21</td><td>50% EtOAc / pet ether</td><td>511 (M + H) + (HPLC ES-MS)</td><td>A2 B1 C1a</td>

<td></td><td>or</td><td>N //</td><td></td><td></td><td></td><td> 50%</td><td></td><td></td>

<td> 90</td><td>-Me</td><td>0 V NH = \ Me</td><td></td><td></td><td> 0,28</td><td>50% EtOAc / pet ether</td><td>525 (M + H) + (HPLC ES-MS)</td><td>A2 B1 C1a</td>

<td></td><td>° A</td><td>N</td><td></td><td></td><td></td><td> 50%</td><td></td><td></td>

108

<td> 91</td><td>0 me</td><td> 214- 216</td><td></td><td> 0,28</td><td>50% EtOAc / pet ether fifty%</td><td>522 (M + H) + (HPLC ES-MS)</td><td>A2 B1 C1a</td>

<td> 92</td><td>0 V-NH OO ^Me</td><td></td><td></td><td> 0,47</td><td>50% EtOAc / pet ether fifty%</td><td>527 (M + H) + (HPLC ES-MS)</td><td>A2 step 3b, A2 step 4, B1, C1a</td>

<td> 93</td><td>—V-NH O), = (Me^S TO /^Nh</td><td></td><td></td><td> 0,46</td><td>50% EtOAc / pet ether fifty%</td><td>527 (M + H) + (HPLC ES-MS)</td><td>A2 step 3b, A2 step 4, B1, C1a</td>

<td> 94</td><td>0 Ó-NH o ° o</td><td> 145- 150</td><td></td><td> 0,41</td><td>5% MeOH / CH₂CI₂ 95%</td><td></td><td>A10 B1 C1a</td>

Table 6. 5- (Trifluoromethyl) -4-Chloro-2-Methoxfen Fences

<img file="CU23213A3_D0069.tif" />

<td>Comp.</td><td>R</td><td>pf fC)</td><td>HPLC (min.)</td><td>TLC R,</td><td>Sist. Solv. FTA</td><td>Spec. Mass [Source]</td><td>Mét. Sint</td>

<td> 95</td><td>OR V-NH -oo^Me</td><td> 140- 144</td><td></td><td> 0,29</td><td>5% MeOH / EtOAc 45% / pet ether fifty%</td><td>495 (M + H) + (HPLC ES-MS)</td><td>A2 A7 B1 C1a</td>

<td> 96</td><td>0 Cl V-NH</td><td> 244- 245</td><td></td><td> 0,39</td><td>5% MeOH / EtOAc 45% / pet ether fifty%</td><td>529 (M + H) + (HPLC ES-MS)</td><td>A6 A7 B1 C1a</td>

<td> 97</td><td>0 Cl V-NH</td><td> 220- 221</td><td></td><td> 0,25</td><td>5% MeOH / EtOAc 45% / pet ether fifty%</td><td>529 (M + H) + (HPLC ES-MS)</td><td>A2 A7 Bl- Cla</td>

109

<td> 98</td><td>-A Vnh r = (Me OA N V //</td><td></td><td></td><td>0.27 c'eOH 5% / EiOAe 45% / e * er of pet. : € - “/ o</td><td>495 (M⁺H) + (HPLC ES-MS)</td><td>A2 A7 81 Inc</td>

<td> 99</td><td>0 V-NH^AND*</td><td> 180- 181</td><td></td><td>0.52. 5% VOH / X; 45% OAc /: e; er of pet. Σ%</td><td>509 (M + H) + (HPLC ES-MS)</td><td>A2 A7 B1 C1a</td>

<td> 100</td><td>0 Xnh xx^PÑ</td><td> 162- 165</td><td></td><td> !</td><td></td><td>A2 A7 B1 C1a</td>

Additional areas

Table 7.

fO • rl

OR

M-1

OR

Φ + J

C

Φ

Cr

<td>Comp.</td><td>R</td><td>pf (° C)</td><td>HPLC (min.)</td><td colspan="2">TLC rJ System Solv. FTA</td><td>Spec. Dough [Source]</td><td>Mét. Yes</td>

<td> 101</td><td>ί ^ ΑΧΑΧ * Η H OMe</td><td> 162- 165</td><td></td><td></td><td></td><td></td><td>Α1 A2 C3</td>

<td> 102</td><td>Ϋ or VAX "^and'Η H Me- ^ x^Nx me to</td><td></td><td></td><td> 0,10</td><td>Ξ-ΤΑο 50% / 'c / year 50%</td><td>442 (M + H) + (HPLC ES-MS)</td><td>A2 A4 C2d</td>

<td> 103</td><td>0 tf HN NH O o Or 0 bb⁰⁼Λ Λ = ° NH-Me Me-NH</td><td>125- 1 on 1 UMV</td><td></td><td> 0,24</td><td>ΞΤΤΑο40% / &gt; eno / l \ JW ZO</td><td>512 (M + H) + / r λ D \ V mu /</td><td>A2 C2b</td>

<img file="CU23213A3_D0070.tif" />

The preceding examples can be substituted for the reagents and / or conditions specifically described in this invention c in the preceding examples.

From the above description, it is easy to ascertain of the characteristics that 'departing from the spirit and the scope of the most changes and modifications in the invention with e' and conditions,

- Repeat with similar success operative generically or: r those who used rspecialist in the art can cial of this invention and, without ma, can make various' n to adapt it to different uses

110