BRPI0017535B1 - COMPOUND OF DIFENYL-UREAS REPLACED WITH? - CARBoxy-ARYLAS - Google Patents

Abstract

diphenyl ureas substituted with <sym> carboxy aryls, as well as their use in the manufacture of medicines. This invention relates to a group of arylureas as well as their use for the manufacture of medicaments for treating raf-mediated diseases.

Description

(54) Title: COMPOSITE OF DIPHENYL-UREAS REPLACED WITH 7-CARBÓXI-ARILAS (51) Int.CI .: C07D 211/78; C07D 211/72; A61K 31/33; A61K 31/54; A61K 31/535; A61K 31/17; A61P 35/00; A61P 43/00; C07C 275/20; C07C 275/22; C07C 275/24; C07C 275/28 (30) Unionist Priority: 1/13/1999 US 60 / 115,877, 10/22/1999 US 09 / 425,228, 2/25/1999 US 09 / 257,266 (73) Holder (s): BAYER HEALTHCARE LLC (72) Inventor (s): BERND RIEDL; JACQUES DUMAS; UDAY KHIRE; TIMOTHY B. LOWINGER; WILLIAM J. SCOTT; ROGER A. SMITH; JILL E. WOOD; MARY-KATHERINE MONAHAN; REINA NATERO; JOEL RENICK; ROBERT N. SIBLEY “COMPOSITE OF DIPHENYL-UREAS REPLACED WITH ω-CARBÓXI-ARILAS”

Split application for PI 0007487-0, filed on 12 January 2000.

FIELD OF THE INVENTION

This invention relates to a group of aryl urea as well as its use for the manufacture of drugs to treat raf-mediated diseases.

BACKGROUND OF THE INVENTION

The p21 ^ras oncogene is an important contributor to the development and progression of compact human cancers and mutates in 30% of all human cancers Bolton et al., Ann. Rep. Med. Chem. 1994, 29: 165-74; Bose. Cancer Res. 1989, 49: 4682-9).

In its normal form without mutation, the ras protein is an important element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avruch et al., Trends Bioche. Sci. 1994, 19: 279-83 ). Biochemically, ras is a guanine nucleotide-binding protein, and recycling between an activated form attached to GTP and an inactivated form attached to GDP, is strictly controlled by the activity of endogenous ras GTPase and other regulatory proteins. In ras mutants in cancer cells, endogenous GTPase activity is reduced, and therefore the protein sends constitutive growth signals to downstream 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, by inhibiting the active ras effect by inhibiting the raf kinase signaling pathway through the administration of raf kinase-deactivating antibodies or by the co-expression of dominant negative raf kinase or dominant negative MEK, the raf kinase substrate leads the reversal of transformed cells to the normal growth phenotype (see: Daum et al., Trends Biochem. Sci. 1994, 19: 474-80; Fridman et al., J.Biol.Chem. 1994, 269: 30105-8 Kolch et al. (Nature 1991, 349: 426-28) further indicated that inhibition of raf expression by "anti-sense" RNA blocks cell proliferation in membrane-associated oncogenes. Similarly, inhibition of raf kinase ( by oligodeoxynucleotides) was correlated, in vitro and in vivo, with inhibition of the growth of a series of types of human tumors (Monia et al., Nat. Med. 1996, 2: 668-75).

SUMMARY OF THE INVENTION

The present invention provides compounds that are inhibitors of the enzyme raf kinase.

As the enzyme is an effector downstream of p21 ^ras , the inhibitors are useful in pharmaceutical compositions for human or veterinary use, where inhibition of the raf kinase pathway is indicated, for example, in the treatment of tumors and / or the growth of cancer cells mediated by raf kinase. Particularly, the compounds are useful in the treatment of compact human or animal cancers, such as murine cancer, as the progression of these cancers is dependent on the ras protein signal transduction variety and, therefore, susceptible to treatment by interrupting the cascade, that is, by inhibiting raf

Petition 870170083282, of 10/30/2017, p. 9/85 kinase. Consequently, the compounds of the invention are useful in the treatment of cancers, such as, for example, carcinomas (such as those of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders (such as myeloid leukemia) or adenomas ( for example, villous adenoma of the colon).

The present invention therefore provides compounds generically described as aryl ureas, including aryl and heteroaryl analogues, which inhibit the raf kinase pathway. The invention also provides a method for treating a raf-mediated sickness in humans or mammals. Therefore, the invention relates to compounds that inhibit the raf kinase enzyme and also compounds, compositions and methods for treating cancer cell growth mediated by raf kinase, where a compound of the following Formula I or a pharmaceutical salt thereof is administered:

A - D - B (I) where:

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

A is a substituted group, having up to 40 carbon atoms, of the formula: -L (ML ¹ ) q, where L is a cyclic structure with 5 or 6 members, directly linked to D, L ¹ comprises a substituted cyclic group, having at least 5 members, M is a group that has at least one atom, q is an integer between 1 and 3; and each cyclic structure of L and L ¹ contains 0 to 4 members of the group consisting of nitrogen, oxygen and sulfur, and

B is an aryl or heteroaryl group at the most tricyclic, substituted or unsubstituted, having up to 30 carbon atoms with at least one 6-membered cyclic structure directly linked to D, containing 0 to 4 members of the group consisting of nitrogen, oxygen and sulfur , where L ¹ is substituted with at least one substituent selected from the group consisting of -SO2Rx, -C (O) Rx and -C (NRy) Rz;

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

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

Rx is Rz or NRaRb, where Ra and Rb are:

a) independently hydrogen, a carbon-based group with up to 30 carbon atoms, containing option 870170083282, of 10/30/2017, p. 10/85 optionally heteroatoms selected from N, S and O, and optionally substituted with halogen, hydroxy and carbon-based substituents with up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O, and optionally substituted with halogen , or

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

b) Ra and Rb together form a 5 to 7 membered heterocyclic structure with 1 to 3 heteroatoms selected from N, S and O, or a 5 to 7 membered heterocyclic structure with 1 to 3 heteroatoms selected from N, S and O, substituted with halogen, hydroxy or carbon-based substituents with up to 24 atoms, which optionally contain heteroatoms selected from N, S and O, and optionally substituted with halo15 genius; or

c) one between Ra or Rb is -C (O) -, a divalent C1-C5 alkylene group or a substituted C1-C5 alkylene group attached to group L, to form a cyclic structure with at least 5 members, where the substituents of the divalent C1-C5 alkylene substituted group are selected from the group consisting of halogen, hydroxy and carbon-based substitutes with up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O, and are optionally replaced with halogen;

where B is substituted, L is substituted or L ¹ is additionally substituted, the substituents being 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, CO2R ⁷ , -C (O) NR ⁷ R ⁷ , -C (O) -R ⁷ , -NO2, -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) OR ⁷ , -NR ⁷ C (O) R ⁷ , -Q-Ar, and carbon-based groups with up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O , and optionally substituted with one or more substituents independently selected from the group consisting of -CN, -CO2R ⁷ , -C (O) NR ⁷ R ⁷ , -C (O) -R ⁷ , -NO2, -OR ⁷ , - SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) R ⁷ , -NR ⁷ C (O) OR ⁷ , and halogen to per-halo; each R ⁷ being independently selected from H or a carbon-based group with up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O, optionally substituted with halogen, where Q is -O-, -S-, -N (R ⁷ ) -, - (CH2) m, -C (O) -, -CH (OH) -, - (CH2) mO-, - (CH2) mS-, (CH2) mN (R ⁷ ) -, -O (CH2) m-CX ^a -, -CX ^a 2-, -S- (CH2) m- and -N (R ⁷ ) (CH2) m-, where m = 1-3, and X ^a is halogen ; and

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Ar is an aromatic structure with 5 or 6 members, containing 0 to 2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted with halogen, up to per-halo, and optionally substituted with Zn1, where n1 is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO2R ⁷ , 5 C (O) NR ⁷ R ⁷ , -C (O) -R ⁷ , -NO2, -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) R ⁷ , -NR ⁷ C (O) OR ⁷ , and a carbon-based group with up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O, optionally substituted with one or more substituents selected from the group consisting of -CN, -CO2R ⁷ , -C (O) NR ⁷ R ⁷ , -C (O) -R ⁷ , -NO2, OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) R ⁷ , -NR ⁷ C (O) OR ⁷ , where R ^{7 is} as defined above.

In Formula I, appropriate heteroaryl groups include, but are not limited to, aromatic rings with 5 to 12 carbon atoms or ring systems containing 1 to 3 rings, at least one of which is aromatic, in which one or more carbon atoms carbon, for example, 1 to 4, in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3 to 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 5imidazolyl, 1- , 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2 -, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazole-1-, -4- or —5-yl, 1,2,4-triazole- 1-, -3 or —5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazole-4- or —5-yl, 1,2,4-oxadiazole-3- or 5-yl, 1 , 3,4-thiadiazole-2- or —5-yl, 1,2,4-oxadiazole-3- or —5-yl, 1,3,420 thiadiazole-2- or —5-yl, 1,3,4- thiadiazole-3- or —5-yl, 1,2,3-thiadiazole-4- or —5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7benzofuryl, 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-benisoxazolyl, 1-, 3-, 4-, 5-, 6 - or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 725 benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7 - or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or the following optionally substituted optionally: phenyl, 2 - or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrrilla, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl,

1-methyl-3-pyrrilla, 1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-1,2,4-thiadiazol-2-yl.

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

Aryl groups that do not contain heteroatoms include, for example, phenyl and 1- and 235 naphthyl.

The term "cycloalkyl", as used herein, refers to cyclic structures with or without alkyl substituents, such as, for example, "C4 cycloalkyl", includes cycloPetition groups 870170083282, of 10/30/2017, p. 12/85 propyl substituted with methyl, as well as cyclo-butyl groups. The term "cycloalkyl", as used herein, also includes saturated heterocyclic groups.

Suitable halogen groups include F, Cl, Br and / or I, from one to per-substitution (ie, all H atoms in a group replaced by a halogen atom), being possible when an alkyl group is replaced with halogen , and mixed substitution of types of halogen atoms is also possible in a given group.

The invention also relates to compounds of Formula I itself.

The invention further relates to the use of the compounds of the present invention as well as their pharmaceutically acceptable salts in the manufacture of medicaments for the treatment of cancer cell growth mediated by raf kinase.

The present invention also relates to pharmaceutical use salts of the compound of

Formula I. Suitable pharmaceutical salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoro-methane- sulfonic, benzene-sulfonic acid, p-toluene-sulfonic acid, 1-naphthalene-sulfonic acid, 2-naphthalene-sulfonic acid, acetic acid, trifluoro-acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, acid succinic, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, salts for pharmaceutical use include acidic inorganic based salts, such as salts containing alkaline cations (such as Li +, Na + or K +), alkaline earth metal cations (such as Mg ²⁺ , Ca ²⁺ or Ba ²⁺ ), the ammonium cation, as well as acid salts of organic bases, including ammonium cation substituted with aliphatics and aromatics, and quaternary ammonium cations, such as those arising from the protonation or peralkylation of triethylamine, N, N-diethylamine, N, N-dicyclohexylamine, lysine, pyridine, N, N-dimethyl25 amino-pyridine (DMAP), 1,4-diazabicyclo [2.2.2] -octane (DABCO), 1,5-diazabicycles [4.3.0] -non5-ene (DBN) and 1,8-diazabicycles [5.4.0] -undec-7eno (DBU).

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

GENERIC METHODS OF PREPARATION

The compounds of Formula I can be prepared by using known chemical reactions and procedures, some from commercially available starting materials35. However, generic methods of preparation are provided below to assist those skilled in these techniques in synthesizing these compounds, and detailed examples are provided in the following experiment section.

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Substituted anilines may be generated using standard methods (March in "Advanced Organic Chemistry", 3rd edition, John Wiley, New York (1985); Larock, "Comprehensive Transformations", VCH Publishers, New York (1989)). As indicated in Scheme I, aryl amines are commonly synthesized by reducing nitro-aryls, using a metallic catalyst, such as Ni, Pd or Pt, and H2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander, “Hydrogenation Methods”, Academic Press, London, United Kingdom (1985)). Nitro-aryls can also be reduced directly, using a strong hydride source, such as LiAlH (Seyden-Penne, “Reductions by Alumino- and Borohydrides in Organic Synthesis”, VCH Publishers, New York (1991)), or using a metal with zero valence, such as Fe, Sn or Ca, often in an acid medium. There are many methods to synthesize nitro-Arilas (March, "Advanced Organic Chemistry", 3rd Edition, John Wiley, New York (1985); Larock, "Comprehensive Transformations", VCH Publishers, New York (1989)).

H2 / catalyst

ArNO ₂ / \ -! Í £ l \ M (0) (eg Ni, Pd, Pt)

ArNH ₂ (eg Fe, Sn, Ca)

Scheme I

Reduction of Nitro-Aryls to Aril-Amines

Nitro-aryls are commonly formed by electrophilic aromatic nitration, using HNO3, or an alternative source of NO2. Nitro-aryls can be made even before reduction. Therefore, nitro-aryls substituted with

HNO ₃

Ar-H -►- ArNO ₂ potential leaving groups (such as F, Cl, Br, etc.) may undergo substitution reactions in treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide. Nitro-aryls can also undergo Ullman-type coupling reactions (Scheme II).

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Select Nucleophilic Aromatic Replacement Using Nitro-aryls

Nitro-aryls can also undergo cross-coupling reactions mediated with transition metals. For example, nitro-aryl electrophiles, such as nitro-aryl bromides, iodides or triflates, undergo palladium-mediated cross-coupling reactions with aryl nucleophiles, such as aryl-boronic acids (Suzuki reactions, exemplified below ), aryl-tin (Stille reactions) or aryl-zinc (Negishi reaction), to produce biaryl (5).

Nitro-aryls or anilines can be converted to the corresponding arene-sulfonyl chloride (7) in treatment with chlorosulfonic acid. The reaction of the sulfonyl chloride with a fluoride source, such as KF, then produces sulfonyl fluoride (8). The reaction of sulfonyl fluoride 8 with trimethyl-silyl-trifluor-methane, in the presence of a fluoride source, such as tris (dimethyl-amino) -sulphonium (TASF) diflouror-trimethyl-silicate (TASF) leads to trifluor-methyl-sulfone (9) corresponding. Alternatively, sulfonyl chloride 7 can be reduced to arenethiol (10) with, for example, zinc amalgam. The reaction of thiol 10 with CHCF2, in the presence of a base, gives diflúor-methyl mercaptan (11), which can be oxidized to sulfone (12) with any of a series of oxidants, including CrO3-acetic anhydride (Sedova et al., Zh. Org. Khim. 1970, 6 (568).

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Select Methods of Synthesis of Fluorinated Arylsulfones

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

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Scheme IV

Select Asymmetric Urea Formation Methods

Finally, urea can be manipulated using methods familiar to those skilled in these techniques.

The invention also includes pharmaceutical compositions that include a compound of the

Formula I and a pharmaceutical vehicle.

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

Compositions intended for oral use can be prepared according to any appropriate method known in those techniques for making pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, saporifying agents, coloring agents and preserving agents, to provide palatable preparations. The tablets contain the active ingredient mixed with non-toxic pharmaceutical excipients that are suitable for the manufacture of tablets. Such excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating or disintegrating agents, for example, corn starch, or alginic acid; and binding agents, such as, for example, magnesium stearate, stearic acid or talc. The tablets may not be coated or they may be coated by known techniques, to delay disintegration and adsorption in the gastrointestinal tract, and thereby provide a prolonged action for a longer period. For example, a retardant material such as glyceryl monostearate can be used

Petition 870170083282, of 10/30/2017, p. 17/85 or glyceryl distearate. These compounds can also be prepared in the rapidly released solid form.

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

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. These excipients are suspending agents, such as, for example, sodium carbonoxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, poly (vinylpyrrolidone), tragacanth gum and acacia gum; dispersing or wetting agents can be a naturally occurring phosphatide, such as lecithin, or condensation products of an alkylene oxide with fatty acids, such as polyoxyethylene stearate, or products of the condensation of ethylene oxide15 with long-chain aliphatic alcohols, such as heptadecaethyleneoxyethanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or products of condensation of ethylene oxide with derived partial esters fatty acids and hexitol anhydrides, such as polyethylene sorbitan monoleate. The aqueous suspensions may also contain one or more preservatives, such as, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more saporifying agents, and one or more sweetening agents, such as sucrose or saccharin.

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

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

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

Syrups and elixirs can be formulated with sweetening agents, such as glycerin, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and saporifying 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 an appropriate non-irritating excipient, which is solid at normal temperatures, but liquid at the rectal temperature, and therefore will melt in the rectum to release the drug.

These materials include cocoa butter and polyethylene glycols.

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

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

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

Any inclusion of all patent applications, patents and publications cited above and below are hereby incorporated by reference, including provisional patent application No. Serial 60 / 115,877, filed January 13, 199 and patent application no series no. ² of series 09 / 257,266, filed on February 25, 1999.

The compounds can be produced from known compounds (or from starting materials which, in turn, can be produced from known compounds), such as, for example, the generic preparation methods indicated below. The activity of a given compound to inhibit raf kinase can be tested routinely, for example, according to the procedures described below. The following examples are provided for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any way.

EXAMPLES

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

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

Industrial grade reagents and solvent were used without further purification. N-cyclohexyl-N '- (methyl-polystyrene) -carbodiimide was purchased from Calbiochem30 Novabiochem Corp. 3-tert-butyl-aniline, 5-tert-butyl-2-methoxy-aniline, 4-bromo-3- (trifluoromethyl) -aniline, 4-chloro-3- (trifluoromethyl) -aniline, 2-methoxy -5- (trifluoro-methyl) -aniline, 4-tert-butyl2nitro-aniline, 3-amino-2-naphthol, ethyl 4-isocyanate-benzoate, N-acetyl-4-chloro-2-methoxy-5 (trifluoro-methyl) -aniline and 4-chloro-3- (trifluoro-methyl) -phenyl-isocyanate were purchased and used without further purification. Syntheses of 3-amino-2-methoxy-quinoline (E. Cho et al docu35 tion No. WO 98/00402;. A. Cordi et al document No. EP 542 609; ibid. 1995 Bioorg Med Chem,... 3: 129), 4- (3-carbamoyl-phenoxy) -1-nitro-benzene (K. Ikawa, Yakugaku Zasshi 1959, 79: 760; Chem.Abstr. 1959, 53: 12761b), 3-tert-butyl- phenyl isocyanate (O. Rohr et al. documenPetição 870 170 083 282 of 10.30.2017, p. 20/85 to No. dE 2,436,108) and 2-methoxy-5- (trifluoro-methyl) -phenyl isocyanate (K. Inukai, document No. JP 42,025,067; IBID Kogyo Kagaku Zasshi 1967, 70: 491) have been described previously.

Thin film chromatography (TLC) was performed using Whatman® 60 F254 250 μm silica gel plates with pre-coated glass bottom. The plates were visualized by one or more of the following techniques: (a) ultraviolet lighting, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phospho-molybdic acid in ethanol, followed by heating, (d) immersing the plate in an acidic ethanol solution of 2,4-dinitro-phenylhydrazine, followed by heating. Column chromatography (flame chromatography) was performed using 0.063-0.037 mm (23010 400 mesh) EM Science® silica gel.

Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or 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 (NMR) spectra ( ¹ H) were measured with a General Electric GN-Omega 300 spectrophotometer (300 MHz) with Me4Si (δ 0.00) or protonated residual solvent (CHCl3 δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. Carbon ( ¹³ C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrophotometer with solvent (CDCh δ 77.0; MeOD-d3; δ 49.0; DMSO-d6 δ 39.5 ) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were obtained as electron impact mass spectra (EI) or as mass spectra with fast atom bombardment (FAB). Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Chemical Ionization Probe with Vacuometric Desorption for sample introduction. The ionic source was maintained at 250 ^o C. The ionization with electron impact was performed with electronic energy of 70 eV and a capture current of 300 μA. Secondary ionic mass spectra in liquid cesium (FAB-MS), an updated version of 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 machine (5989A) with methane or ammonia as reagent gas (1x10 ^-4 torr to 2.5x10 ^-4 torr). The direct insertion desorption chemical ionization probe (DCI) (Vaccumetrics, Inc.) was scaled between 0-11.5 amps in 10 s and maintained in 10 amps until all traces of the sample disappeared (~ 1-2 min). The spectra were scanned between 50-800 amu at 2 s per scan. The mass spectra in electrospray of

HPLC (HPLC ES-MS) were obtained using a Hewlett Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C18 column, and a Finnigan LCQ ion capture mass spectrometer with ionization by

Petition 870170083282, of 10/30/2017, p. 21/85 electrospray. The spectra were scanned between 120-800 amu using an ionic time variable according to the number of ions in the source. Gas chromatography - ion selective mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25 mx 0.2 mm ) and a Hewlett Packard 5971 Selective Mass Detector (70 eV ionization energy). Elemental analyzes were conducted by Robertson Microlit Labs, Madison, NJ, USA

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

List of Abbreviations and Acronyms:

AcOH - anetic acetic acid - anhydrous atm - atmosphere (s)

BOC - tert-butoxy-carbonyl

CDI - 1,1'-carbonyl-diimidazole conc - concentrate d - day (s) dec - decomposition

DMAC - N, N-dimethyl-acetamide

DMPU - 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pi-rimidone

DMF - N, N-dimethyl-formamide DMSO - dimethyl sulfoxide DPPA - diphenyl-phosphoryl-azide

EDCI - 1- (3-dimethyl-amino-propyl) -3-ethyl-carbo-diimide

EtOAc - ethyl acetate

EtOH - ethanol (100%)

Et2O - diethyl ether Et3N - triethylamine H - hour (s)

HOBT - 1-hydroxy-benzotriazole m-CPBA - 3-chloro-peroxybenzoic acid MeOH - methanol ether p. - petroleum ether (boiling point range 30-60 ^o C) temp - temperature

THF - tetrahydro-furan

TFA - trifluorine-AcOH

Tf - trifluoro-methane-sulfonyl

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A. Generic Methods for Synthesis of Substituted Anilines

AI. Generic Aryl-amine Formation Method via Ether Formation, followed by Ester Saponification, Curtius Rearrangement, and Carbamate Deprotection. Synthesis of

2-Amino-3-methoxy-naphthalene.

Step 1.3-Methyl-2-methyl naphthoate

A slurry of methyl 3-hydroxy-2-naphttoate (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, and then treated with iodine-methane (3.43 ml, 55.1 mmol). The mixture was left stirring at room temperature overnight, and then treated with water (200 ml). The resulting mixture was extracted with EtOAc (2 x 200 ml). The combined organic layers were washed with a concentrated NaCl solution (100 ml), dried (MgSO4), concentrated under reduced pressure (approximately 0.4 mm Hg overnight), to give methyl 3-methoxy-2-naphttoate as an amber oil (10.30 g): ¹ H-NMR (DMSO-de) δ 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J = 8, 09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J = 8.09 Hz, 1H), 7.84 (d, J = 8.09 Hz, 1H), 7, 90 (s,

1H), 8.21 (s, 1H).

Step 2. 3-Methoxy-2-naphthoic acid

A solution of methyl 3-methoxy-2-naphttoate (6.28 g, 29.10 mmol) and water (10 ml) in MeOH (100 ml) at room temperature was treated with a solution of 1 N NaOH (33, 4 ml, 33.4 mmol). The mixture was heated to reflux temperature for 3 h, cooled to room temperature, and made acidic with a 10% citric acid solution. The resulting solution was extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO4), and concentrated under reduced pressure. The residue was triturated with hexane and then washed with hexane several times, to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): 'Ή-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 (br s, 1H).

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Step 3.2- (N- (Carbobenzyloxy) -amino-3-methoxy-naphthalene

A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et3N (2.59 ml, 18.6 mmol) in anhydrous toluene (70 ml) was stirred at room temperature for 15 min , and then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 ml), using a pipette. The resulting mixture was heated to 80 C for 2 h. After cooling the mixture to room temperature, benzyl alcohol (2.06 ml, 20 mmol) was added via syringe. The mixture was then heated to 80 ° C all night. The resulting mixture was cooled to room temperature, quenched with a 10% citric acid solution, extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc / 86% hexane), to give 2- (N- (Carbobenzyloxy) -amino-3-methoxy-naphthalene as a light yellow oil (5.1 g, 100%): ¹ H-NMR (DMSO-de) δ 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7 , 75 (m, 2H), 8.20 (s, 1H), 8.76 (s, 1H).

Step 4.2-Amino-3-methoxy-naphthalene

A slurry of giving 2- (N- (Carbobenzyloxy) -amino-3-methoxy-naphthalene (5.0 g, 16.3 mmol) and 10% Pd / C (0.5 g) in EtOAc (70 ml) kept under an atmosphere of H2 (in a balloon) at room temperature overnight The resulting mixture was filtered through Celite® and concentrated under reduced pressure to give 2-amino-3-methoxy-naphthalene as a light pink powder (2.40 g, 85%): ¹ H-NMR (DMSO-d6) δ 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H) , 7.43 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H); EI-MS m / z 173 (M +).

A2. Synthesis of ω-Carbamyl-anilines via Formation of a Carbamyl-pyridine, followed by Core-phyl Coupling with an Aryl-amine. Synthesis of 4- (2-N-Methyl-carbamyl-4pyridyloxy) -aniline.

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Step 1. Synthesis of 4-chloro-N-methyl-2-pyridine-carboxamide via Menisci Reaction

Caution: This is a highly dangerous, potentially explosive reaction. Concentrated H2SO4 (3.55 ml) was added to a solution of 4-chloro-pyridine (10.0 g) and N-methylformamide (250 ml) at room temperature with stirring, to generate an exothermic process. To this mixture was added H2O2 (30% pp in H2O, 17 ml), followed by FeSO4 »7H2O (0.56 g), to generate another exothermic process. The resulting mixture was stirred in the dark at room temperature for 1 h, and then slowly heated for 4 h to 45 ^o C. When the bubbling subsided, the reaction was heated to 60 ^o C for 16 h. The resulting brown-opaque 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 NaCl solution (3 x 150 ml), and then they were combined, dried (MgSO4) and filtered through a bed of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient between 50% EtOAc / 50% hexane and 80% EtOAc / 20% hexane). The resulting yellow oil crystallized at 0 ^o C for 72 h, to give 4-chloro-N-methyl-2-pyridine-carboxamide (0.61 g, 5.3%). TLC (50% EtOAc / 50% hexane) Rf 0.50; ¹ H-NMR (CDCh) δ 3.04 (d, J = 5.1 Hz, 3H), 7.43 (dd, J = 5.4, 2.4 Hz, 1H), 7.96 (br s , 1H), 8.21 (s, 1H), 8.44 (d, J = 5.1 Hz, 1H); CI-MS m / z 171 ((M + H) ⁺ ).

Step 1b.Synthesis of 4-Chloro-pyridine-2-carbonyl hydrochloride via picolinic acid

Anhydrous DMF (6.0 ml) was added slowly to SOCh (180 ml) between 40 ^o C and 50 ^o C. The solution was stirred in this temperature range for 10 min, and then picolinic acid (60.0 g, 487 mmol) in portions for 30 min. The resulting solution was heated to 72 ^o C (intense 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 / concentration addition process was repeated twice. The resulting nearly dry residue was filtered and the solids were washed with toluene (2 x 200 ml) and dried under high vacuum for 4 h to produce 4-chloro-pyridine-2-carbonyl hydrochloride as a yellow-orange solid (92 , 0 g, 89%).

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Step 2. Methyl 4-Chloro-pyridine-2-carboxylate hydrochloride synthesis

Anhydrous DMF (10.0 ml) was added slowly to SOCb (300 ml) between 40 ^o C and 48 ^o C. The solution was stirred in this temperature range for 10 min, and then picolinic acid (100.0 g, 812 mmol) in portions for 30 min. The resulting solution was heated to 72 ^o C (intense 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 200 ml. The toluene / concentration addition 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 h, to produce 4-chloro-pyridine-2-carbonyl hydrochloride as an off-white solid (27.2 g, 16%). This material has been saved.

The red filtrate was added to MeOH (200 ml) at a rate that maintained the internal temperature below 55 ^o C. The contents were stirred at room temperature for 45 min, cooled to 5 ^o C and treated with Et2O (200 ml) in drops. The resulting solids were filtered, washed with Et2O (200 ml) and dried under reduced pressure at 35 ^o C, to provide methyl 4-chloro-pyridine-2-carboxylate hydrochloride as a white solid (110 g, 65%), mp 108-112 ^o C. ¹ H-NMR (DMSO-de) δ 3.88 (s, 3H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 8.08 ( d, J = 2.2 Hz, 1H), 8.68 (d, J = 5.5 Hz, 1H), 10.68 (br s, 1H); HPLC ES-MS m / z 172 ((M + H) ⁺ ).

Step 3a. Synthesis of 4-Chloro-N-methyl-2-pyridine-carboxamide from methyl 4-chloropyridine-2-carboxylate

A suspension of 4-chloropyridine-2-carboxylate Methyl (89.0 g, 428 mmol) in MeOH (75 mL) at 0 C was treated with a solution of methylamine 2.0 M in THF (1 liter) at a speed that kept the internal temperature below 5 ^o C. The resulting mixture was stored at 3 ^o C for 5 h, and then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 liter) and filtered. The filtrate was washed with a saturated NaCl solution (500 ml), dried (Na2SO4) and concentrated under reduced pressure, to yield 4-chloro-N-methyl-2-pyridine-carboxamide as light yellow crystals (71.2 g , 97%), mp 41-43 ^o C. ¹ H-NMR (DMSO-de) δ 2.81 (s, 3H), 7.74 (dd, J = 5.1.2.2 Hz, 1H) , 8.00 (d, J = 2.2, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.85 (br d, 1H); CI-MS m / z 171 ((M + H) +).

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Step 3b.Synthesis of 4-Chloro-N-methyl-2-pyridine-carboxamide from chloride

4-Chloro-pyridine-2-carbonyl

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

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

A solution of 4-amino-phenol (9.60 g, 88.0 mmol) in anhydrous DMF (150 ml) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the brown mixture reddish was stirred at room temperature for 2 h. The contents were treated with 4-chloro-N-methyl-2-pyridine-carboxamide (15.0 g, 87.9 mmol) and K2CO3 (6.50 g, 47.0 mmol) and then heated to

80 ^o C for 8 h. The mixture was cooled to room temperature and partitioned between EtOAc (500 ml) and a saturated NaCl solution (500 ml). The aqueous phase was back-extracted with EtOAc (300 ml). The combined organic layers were washed with a saturated NaCl solution (4 x 1,000 ml), dried (Na2SO4) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 ^o C for 3 h to produce 4- (220 (N-methyl-carbamoyl) -4-pyridyloxy) -aniline as a light brown solid (17.9 g, 84% ). 'Ή-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 (br d, 1H); HPLC ES-MS m / z 244 ((M + H) +).

A3.Generic Method for the Synthesis of Anilines by Nucleophilic Aromatic Addition,

Followed by Nitro-Arene Reduction. Synthesis of 5- (4-Amino-phenoxy) -isoindoline-1,3-dione

Step '. Synthesis of 5-hydroxy-isoindolin-1,3-dione

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4-Hydroxy-phthalic acid (5.0 g, 27.45 mmol) was added slowly to a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in concentrated AcOH (25 ml). The resulting mixture was heated to 120 ^o C for 45 min, and then, the intense light yellow mixture was heated to 160 ^o C for 2 h. The resulting mixture was maintained at 160 ° C and was concentrated to approximately 15 mL and then cooled to room temperature and adjusted to pH 10 with 1 N NaOH. This mixture was cooled to 0 ^o C and slowly acidified to pH 5, using 1 N HCl solution. The resulting precipitate was collected by filtration and dried under reduced pressure, to produce 5-hydroxy-isoindoline-1,3-dione as a light yellow powder (3.24 g, 72%). ¹ H-NMR (DMSO-d6) δ 7.00-7.03 (m, 2H), 7.56 (d, J = 9.3

Step 2. Synthesis of 5- (4-nitro-phenoxy) -isoindoli-no-1,3-dione

A solution of 5-hydroxy-isoindolin-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 ml) was added dropwise to a slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 ml) at 0 ° C under stirring. The intense yellow-green mixture was allowed to return to room temperature, and was stirred for 1 h, and then 1-fluorine-4-nitro-benzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated to 70 ° C all night, 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 give 5- (4-nitro-phenoxy) 20 isoindoline-1,3-dione as a yellow solid (3.3 g, 62%). TLC (30% EtOAc / 70% hexane). Rf 0.28; ¹ H-NMR (DMSO-de) 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%).

Step 3. Synthesis of 5- (4-amino-phenoxy) -isoindoli-no-1,3-dione

A solution of 5- (4-nitro-phenoxy) -isoindoline-1,3-dione (0.6 g, 2.11 mmol) in

Concentrated AcOH (12 ml) and water (0.1 ml) was stirred under a stream of argon while powdered iron (0.59 g, 55.9 mmol) was slowly added. This mixture was stirred at room temperature for 72 h, and then diluted with water (25 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure, to give 5- (4-amino-phenoxy) -isoindoline-1,3-dione as a brownish solid Petition 870170083282, 10/30/2017, pg. 28/85 ° C (0.4 g, 75%). TLC (50% EtOAc / 50% hexane) Rf 0.27; ¹ H-NMR (DMSO-de) δ 5.14 (br s, 2H), 6.62 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H ), 7.03 (d, J = 2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J = 8.4 Hz, 1H), 11.02 (s, 1H ); HPLC ES-MS m / z 255 ((M + H) +, 100%).

A4.Generic Method for the Synthesis of Pyrrolylanilines. Synthesis of 5-tert-Butyl-2-

Step 1. Synthesis of 1- (4-tert-butyl-2-nitro-phenyl) -2,5-dimethyl-pyrrole

AcOH (0.1 ml) and acetonyl acetone (0.299 g, 2.63 mmol) were added via syringe to a solution of 2-nitro-4-tert-butyl aniline (0.5 g, 2 , 57 mmol) in cyclohexane (10 ml) with stirring. The reaction mixture was heated to 120 ° C for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temperature, diluted with CH2O2 (10 ml) and washed sequentially with a 1 N solution of HCl (15 ml), a 1 N solution of NaOH (15 ml) and a saturated solution of NaCl ( 15 ml), dried (MgSO4) and concentrated under reduced pressure. The brown-orange solids were purified by column chromatography (60 g SiO2; gradient between 6% EtO15 Ac / 94% hexane and 25% EtOAc / 75% hexane), to give 1- (4- tert-butyl-2-nitro-phenyl) 2,5-dimethyl-pyrrole as a yellow-orange solid (0.34 g, 49%). TLC (15% EtOAc / 85% hexane) Rf 0.67; ¹ H-NMR (CDCls) δ 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H)

7.62 (dd, 1H), 7.88 (d, J = 2.4 Hz, 1H); CI-MS m / z 273 ((M + H) +, 50%).

Step 2. Synthesis of 5-tert-butyl-2- (2,5-dimethyl-pyrrolyl) -aniline 20 A slurry of 1- (4-tert-butyl-2-nitro-phenyl) -2,5-dimethyl- pyrrole (0.341 g, 1.25 mmol),

10% Pd / C (0.056 g) and EtOAc (50 ml) under an atmosphere of H2 (in a flask) was stirred for 72 h, and then filtered through a Celite® mattress. The filtrate was concentrated under reduced pressure, to give 5-tert-butyl-2- (2,5-dimethyl-pyrrolyl) -aniline as yellowish solids (0.30 g, 99%): TLC (10% EtOAc / 90% hexane) Rf 0.43; ¹ H-NMR (CDCls) 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).

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A5.Generic Method for the Synthesis of Anilines from Anilines by Nucleophilic Aromatic Substitution. Synthesis of 4- (2- (N-Methyl-carbamoyl) -4-pyridyloxy) -2-methylaniline hydrochloride

A solution of 4-amino-3-methyl-phenol (5.45 g, 44.25 mmol) in anhydrous dimethyl-acetamide 5 (75 ml) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol), and the black mixture was stirred at room temperature until the flask reached room temperature. The contents were then treated with 4-chloro-N-methyl-2-pyridine-carboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 ^o C for 8 h. The mixture was cooled to room temperature and diluted with water (75 ml). The organic layer was extracted with EtOAc (5 x 100 ml). The combined organic layers were washed with a saturated NaCl solution (200 ml), dried (MgSO4), and concentrated under reduced pressure. The residual black oil was treated with Et2O (50 ml) and sonified. The solution was then treated with HCl (1 M in Et2O; 100 ml) and stirred at room temperature for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration of the solution and stored under anaerobic conditions at

0 ^o C before use. ¹ H-NMR (DMSO-de) δ 2.41 (s, 3H), 2.78 (d, J = 4.4 Hz, 3H), 4.93 (br s,

2H), 7.19 (dd, J = 8.5, 2.6 Hz, 1H), 7.23 (dd, J = 5.5, 2.6 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 5 , 9 Hz, 1H), 8.99 (q, J = 4.8 Hz, 1H).

A6.Generic Method for Synthesis of Anilines from Hydroxy-anilines by N20 protection, Nucleophilic Aromatic Replacement and Deprotection. Synthesis of 4- (2- (N-Methyl-

Step 1. Synthesis of 3-Chlorine-4- (2,2,2-trifluor-acetyl-amino) -phenol

Iron (3.24 g, 58.00 mmol) was added to TFA (200 ml) with stirring. To this slurry were added 2-chloro-4-nitro-phenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 ml). This gray sludge was stirred at room temperature for 6 d. The filtered iron from the solution and the remaining material was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 ml). Saturated NaHCO3 solution was added to the resulting yellow solution. The solid that precipitated from the solution was removed. The filtrate was slowly quenched with the sodium bicarbonate solution until the product visibly separated from the

Petition 870170083282, of 10/30/2017, p. 30/85 solution (determined using a crafting mini-bottle). 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. ¹ H NMR (DMSO-d6) indicated a 1: 1 ratio of the phenolic nitro5 starting material to the desired product, 3-chloro-4- (2,2,2-trifluor-acetyl-amino) -phenol. The crude material was washed for the next step without further purification.

Step 2. Synthesis of 4- (2- (N-Methyl-carbamoyl) -4-pyridyloxy) -2-chloro-phenyl- (2,2,2-trifluor) acetamide

A solution of crude 3-chloro-4- (2,2,2-trifluor-acetyl-amino) -phenol in anhydrous dimethyl10 acetamide (50 ml) was treated with potassium tert-butoxide (5.16 g, 45.98 mmol) and the brownish black mixture was stirred at room temperature until the flask had cooled to room temperature. The resulting mixture was treated with 4-chloro-N-methyl-2piridino-carboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated to 100 ° C under argon for 4 d. The black reaction mixture was cooled to room temperature and then poured into cold water (100 ml). The mixture was extracted with EtOAc (3 x 75 ml) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by column chromatography (gradient between 20% EtOAc / petroleum ether and 40% EtOAc / petroleum ether), to produce 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) - 2-chlorophenyl (222-trifluoro) -acetamide as a yellow solid (8.59 g, 23.0 mmol).

Step 3. Synthesis of 4- (2- (N-Methyl-carbamoyl) -4-pyridyloxy) -2-chloro-aniline

A solution of crude 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -2-chlorophenyl- (222-trifluor) acetamide (8.59 g, 23.0 mmol) in anhydrous 4-dioxane (20 ml) was treated with a 1 N NaOH solution (20 ml). This brown solution was left stirring for 8 h. EtOAc (40 ml) was added to this solution. The green organic layer was extracted with EtOAc (3 x 40 ml) and the solvent was concentrated, to yield 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -2-chloroaniline as a green oil which solidified on rest (2.86 g, 10.30 mmol). 'Ή-NMR (DMSO-de) δ 2.77 (d, J = 4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J = 8.5, 2.6 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 7.07 (dd, J = 5.5, 2 , 6 Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.75 (q, J = 4.8 , 1H).

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A7. Generic Method for the Deprotection of an Acylated Aniline. Synthesis of 4-Chloro-2-methoxy-5- (trifluoro-methyl) -aniline

A suspension of 3-chloro-6- (N-acetyl) -4- (trifluoromethyl) -anisole (4.00 g, 14.95 mmol) in a 6 M HCl solution (24 ml) was heated to the temperature reflux for 1 h. The resulting solution was allowed to cool to room temperature, during which time it solidified slightly. The resulting mixture was diluted with water (20 ml), and then treated with a combination of solid NaOH and a saturated solution of NaHCO3 until the solution was basic. The organic layer was extracted with CH2O2 (3 x 50 ml). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure, to produce 410 chloro-2-methoxy-5- (trifluoro-methyl) -aniline as a brown oil (3.20 g, 14.2 mmol). ¹ H-NMR (DMSO-de) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

A8.Generic method for the synthesis of o-alkoxy-o-carboxy-phenyl-anilines. Synthesis of

Step 1.4- (3-Methoxy-carbonyl-4-methoxy-phenoxy) -1-nitro-benzene

SOCb K2CO3 (5 g) and dimethyl sulfate (3.5 ml) were added to a solution of 4 (3-carboxy-4-hydroxy-phenoxy) -1-nitro-benzene (prepared from dihydroxy-benzoic acid in a manner analogous to that described in Method A13, Step 1; 12 mmol) in acetone (50 ml). The resulting mixture was heated to reflux temperature overnight, then cooled to room temperature, and was filtered through a Celi20 te® mattress. The resulting solution was concentrated under reduced pressure, absorbed over SO2, and purified by column chromatography (50% EtOAc / 50% hexane), to give 4- (3-methoxycarbonyl-4-methoxy-phenoxy) -1-nitro-benzene as a yellow powder (3 g); mp 115-118 ^o C.

Step 2.4- (3-Carboxy-4-methoxy-phenoxy) -1-nitro-benzene

A mixture of 4- (3-methoxy-carbonyl-4-methoxy-phenoxy) -1-nitro-benzene (1.2 g), KOH 25 (0.33 g) and water (5 ml) in MeOH (45 ml ) was stirred at room temperature all night,

Petition 870170083282, of 10/30/2017, p. 32/85 and then heated to reflux temperature for 4 h. The resulting mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in water (50 ml), and the aqueous mixture was made acidic with a 1 N solution of HCl. The resulting mixture was extracted with EtOAc (50 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure, to give 4- (3-carboxy-4-methoxy-phenoxy) -1-nitro-benzene (1.04 g).

Step 3.4- (3- (N-Methyl-carbamoyl) -4-methoxy-phenoxy) -1-nitro-benzene

SOCb (0.64 ml, 8.77 mmol) was added portionwise to a solution of 4- (3carboxy-4-methoxy-phenoxy) -1-nitro-benzene (0.50 g, 1.75 mmol) in CH2O2 (12 ml). The resulting solution was heated to reflux for 18 h, cooled to room temperature, and concentrated under reduced pressure. The resulting yellow solids were dissolved in CH2O2 (3 ml), and then the resulting solution was treated with a methyl amine solution (2.0 M in THF; 3.5 ml, 7.02 mmol) in portions (CAUTION: evolution of gas), and stirred at room temperature for 4 h. The resulting mixture was treated with a 1 N NaOH solution, and then extracted with CH2O2 (25 ml). The organic layer was dried (Na2SO ₄ ) and concentrated under reduced pressure, to give 4- (3- (N-methyl-carbamoyl) -4-methoxy-phenoxy) -1nitro-benzene as a yellow solid (0.50 g, 95%).

Step 4.4- (3- (N-Methyl-carbamoyl) -4-methoxy-phenoxy) aniline

A slurry of 4- (3- (N-methyl-carbamoyl) -4-methoxy-phenoxy) -1-nitro-benzene (0.78 g, 2.60 mmol) and 10% Pd / C (0.20 g ) in EtOH (55 ml) was stirred under 1 atm of H2 (in a balloon) for

2.5 d, and then filtered through a Celite® mattress. The resulting solution was concentrated under reduced pressure, to yield 4- (3- (N-methyl-carbamoyl) -4-methoxy-phenoxy) -aniline as an off-white solid (0.68 g, 96%). TLC (0.1% Et3N / 99.9% EtOAc) Rf 0.36.

A9.Generic Method for the Preparation of Anilines Containing ω-Alkyl-phthalimides. Synthesis of 5- (4-Amino-phenoxy) -2-methyl-isoindolin-1,3-dione

Step 1. Synthesis of 5- (4-Nitro-phenoxy) -2-methyl-isoindoline-1,3-dione

A 5- (4-nitro-phenoxy) -isoindoline-1,3-dione slurry (A3, Step 2; 1.0 g, 3.52 mmol)

Petition 870170083282, of 10/30/2017, p. 33/85 and NaH (0.13 g, 5.27 mmol) in DMF (15 ml) was stirred at room temperature for 1 h, and then treated with methyl iodide (0.3 ml, 4.57 mmol). The resulting mixture was stirred at room temperature all night, and then cooled to ° C and treated with water (10 mL). The resulting solids were collected and dried under reduced pressure, to give 5- (45 nitro-phenoxy) -2-methyl-isoindoline-1,3-dione as an intense yellow solid (0.87 g, 83%). TLC (35% EtOAc / 65% hexane) Rf 0.61.

Step 2. Synthesis of 5- (4-Amino-phenoxy) -2-methyl-isoindoline-1,3-dione

A sludge of 5- (4-nitro-phenoxy) -2-methyl-isoindo-lino-1,3-dione (0.87 g, 2.78 mmol) and

10% Pd / C (0.10 g) in MeOH was stirred under 1 atm of H2 (in a flask) overnight. The resulting mixture was filtered through a Celite® mattress, and concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 ml) and filtered through a plug of SO2 (60% EtOAc / 40% hexane), to yield 5- (4-amino-phenoxy) -2methyl-isoindo-lino-1, 3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc / 60% hexane) Rf 0.27.

A10. Generic Method for the Synthesis of ω-Carbamoyl-aryl-anilines through the Reaction of ω-Alkoxy-carbonyl-aryl Precursors with Amines. Synthesis of 4- (2- (N- (2-morpholin4-yl-ethyl) -carbamoyl) -pyridyloxy) -aniline

Step 1. Synthesis of 4-Chloro-2- (N- (2-morpholin-4-yl-ethyl) -carbamoyl) -pyridine 4- (2-Amino-ethyl) -morpholine (2.55 ml, 19.4 mmol) in drops to a solution of methyl 4-chloro-pyridine-2-carboxylate hydrochloride (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 ml), and the resulting solution was heated to reflux for 20 h, cooled to room temperature, and treated with water (50 ml). The resulting mixture was extracted with EtOAc (50 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure, to produce 4-chloro-2- (N- (2-morpholin-4-yl-ethyl) -carbamoyl) -pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH / 90% EtOAc) Rf 0.50.

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Step 2. Synthesis of 4- (2- (N- (2-Morfolin-4-yl-ethyl) -carbamoyl) -pyridyloxy) -aniline

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75 mmol) in DMF (8 ml) was stirred at room temperature for 2 h, and then sequentially treated with 4-chloro- (N- (2-morpholin-4-yl-ethyl) -carbamoyl) -pyridine (1.22 g, 4.52 mmol) and K2CO3 (0.31 g, 2.26 mmol ). The resulting mixture was heated to 75 ° C throughout the night, cooled to room temperature, and fractionated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The aqueous layer was back-extracted with EtOAc (25 ml). The combined organic layers were washed with 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 between 100% EtOAc and 25% MeOH / 75% EtOAc), to yield 4- (2- (N- (2-morpholin-4-yl -ethyl) -carbamoyl) -pyridyl (xi) -aniline (1.0 g, 65%): TLC (10% MeOH / 90% EtOAc) Rf 0.32.

A11.Generic method for the reduction of nitro-arenes to aryl-amines. Synthesis of 4- (3-Carboxy-phenoxy) -aniline

A slurry of 4- (3-carboxy-phenoxy) -1-nitro-benzene (5.38 g, 20.7 mmol) and 10% Pd / C (0.50 g) in MeOH (120 ml) was stirred under an atmosphere of H2 (in a balloon) for 2 d. The resulting mixture was filtered through a bed of Celite®, and then concentrated under reduced pressure, to yield 4- (3-carboxy-phenoxy) -aniline as a brown solid (2.26 g, 48%): TLC (10 % MeOH / 90% CH2O2) Rf 0.44 (tracer).

A12.Generic method for the synthesis of anilines containing isoindolinones. Synthesis of 4- (1-Oxoisoindolin-5-yloxy) -aniline

Step 1. Synthesis of 5-Hydroxy-isoindolin-1-one

Zinc powder (47.6 g, 729 mmol) was added slowly in portions to a solution of 5-hydroxy-phthalimide (19.8 g, 121 mmol) in AcOH (500 ml), and then the mixture was heated until at reflux temperature for 40 min, filtered hot, and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 kg SO2; gradient between 60% EtOAc / 40% hexane and 25% MeOH / 75% EtOAc), to give 5-hydroxy -isoindolin-1-one (3.77 g): TLC (100% EtOAc) Rf 0.17; HPLC ES-MS m / z 150 ((M + H) +).

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Step 2. Synthesis of 4- (1-isoindolinon-5-yloxy) -1-nitro-benzene

5-hydroxy-isoindolin-1-one (2.0 g, 13.4 mmol) was added portionwise to a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 ^o C. The slurry The resulting mixture was allowed to warm to room temperature and was stirred for 45 min, and then 4-fluoro-1-nitrobenzene was added, and then the mixture was heated to 70 ^o C for 3 h. The mixture was cooled to 0 ^o C and treated with droplet water until a precipitate formed. The resulting solids were collected, to give 4- (1-isoindolinon-5-yloxy) -1-nitro-benzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf 0.35.

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

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

A13.Generic Method for Synthesis of ω-Carbamoyl-anilines via EDCI-Mediated Amide Formation, followed by Nitro-Arene Reduction. Synthesis of 4- (3-N-Methylcarbamoyl-phenoxy) -aniline

Step 1. Synthesis of 4- (3-ethoxy-carbonyl-phenoxy) -1-nitro-benzene

A mixture of 4-fluoro-1-nitro-benzene (16 ml, 150 mmol), methyl 3-hydroxy-benzoate (25 g, 150 mmol) and K2CO3 (41 g, 300 mmol) in DMF (125 ml) heated to reflux temperature all night, 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 (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc / 90% hexane), to yield 4- (3-ethoxycarbonyl-phenoxy) -1-nitro-benzene as an oil (38 g).

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Step 2. Synthesis of 4- (3-carboxy-phenoxy) -1-nitro-benzene

A solution of LiOH »H2O (1.50 g, 35.8 mmol) in water (36 ml) was added under intense stirring to a mixture of 4- (3-ethoxy-carbonyl-phenoxy) -1-nitro-benzene ( 5.14 g, 17.9 mmol) in a 3: 1 solution of THF: water (75 ml). The resulting mixture was heated to 50 ^o C overnight, cooled to room temperature, concentrated under reduced pressure, and had its pH adjusted to 2 with a 1 M HCl solution. The resulting bright yellow solids were removed by filtration and washed with hexane, to give 4- (3-carboxyphenoxy) -1-nitro-benzene (4.40 g, 95%).

Step 3. Synthesis of 4- (3- (N-methyl-carbamoyl) -phonoxy) -1-nitro-benzene

A mixture of 4- (3-carboxy-phenoxy) -1-nitro-benzene (3.72 g, 14.4 mmol), EDCI »HCl (3.63 g, 18.6 mmol), N-methyl-morpholine (1.6 ml, 14.5 mmol) and methylamine (2.0 M in THF; 8 ml, 16 mmol) in CH2O2 (45 ml) was stirred at room temperature for 3 d, and then concentrated under reduced pressure . The residue was dissolved in EtOAc (50 ml) and the resulting mixture was extracted with a 1 M HCl solution (50 ml). The aqueous layer was back-extracted with EtOAc (2 x 50 ml). The combined organic phases were washed with a saturated NaCl solution (50 ml), dried (Na2SO4), and concentrated under reduced pressure, to give 4- (3- (N-methyl-carbamoyl) -phenoxy) -1-nitro- benzene as an oil (1.89 g).

Step 4. Synthesis of 4- (3- (N-Methyl-carbamoyl) -phonoxy) -aniline 20 A slurry of 4- (3- (N-methyl-carbamoyl) -phenoxy) -1-nitro-benzene ( 1.89 g, 6.95 mmol) and

5% Pd / C (0.24 g) in EtOAc (20 ml) was stirred under an atmosphere of H2 (in a flask) overnight. The resulting mixture was filtered through a Celite® mattress and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH / 95% CH2O2). The resulting oil solidified under vacuum overnight, to give 4- (3- (N-methyl25 carbamoyl) -phenoxy) -aniline as a yellow solid (0.95 g, 56%).

A14.Generic method for the synthesis of ω-Carbamoyl anilines via formation of

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EDCI-Mediated Amide, followed by Nitro-Arene Reduction. Synthesis of 4-3- (5-Methylcarbamoyl) -pyridyloxy) -aniline

Step 1. Synthesis of 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -1-nitro-benzene A solution of methyl 5-hydroxy-nicotinate (2.0 g, 13.1 mmol) was added in

DMF (10 ml) to a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 ml). The resulting mixture was added to a solution of 4-fluoro-nitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 ml) and the resulting mixture was heated to 70 ° C throughout the night, cooled to room temperature, and treated with MeOH (5 ml), followed by water (50 ml). The resulting mixture was extracted with EtOAc (100 ml). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc / 70% hexane), to yield 4- (3 (5-methoxy-carbonyl) -pyridyloxy) -1-nitro-benzene (0.60 g).

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

A slurry of 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -1-nitro-benzene (0.60 g, 2.20 mmol) and 10% Pd / C in MeOH / EtOAc was stirred under an atmosphere H2 (in a balloon) for 72 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient between 10% EtOAc / 90% hexane and 30% EtOAc / 70% hexane to 50% EtOAc / 50% hexane), to yield 4- (3- (5-methoxy-carbonyl)) pyridyloxy) -aniline (0.28 g, 60%): Ή-NMR (CDCh) 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 via electrophilic nitration, followed by reduction. Synthesis of 4- (3-Methyl-sulfamoyl-phenoxy) -aniline

Step 1. Synthesis of N-methyl-3-bromo-benzene-sul-phonamide

Methylamine (2.0 M in THF; 28 ml, 56 mmol) was added to a solution of bromo-benzene sulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 ml) at 0 ^o C. The resulting solution was allowed to warm to room temperature and was stirred at room temperature overnight. The resulting mixture was partitioned between EtOAc (25 ml) and a 1 M solution of

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HCl (25 ml). The aqueous phase was back-extracted with EtOAc (2 x 25 ml). The combined organic phases were washed sequentially with water (2 x 25 ml) and a saturated NaCl solution (25 ml), dried (MgSO4) and concentrated under reduced pressure, to give N-methyl3-bromo-benzene-sulfonamide as a solid white (2.8 g, 99%).

Step 2. Synthesis of 4- (3- (N-methyl-sulfamoyl) -phonyloxy) -benzene

N-methyl-3-bromo-benzene sulfonamide (2.5 g, 10 mmol) was added to a phenol slurry (1.9 g, 20 mmol), K2CO3 (6.0 g, 40 mmol) and Cul (4 g, 20 mmol) in DMF (25 ml), and the resulting mixture was stirred to reflux overnight, cooled to room temperature, and partitioned between EtOAc (50 ml) and a 1 N solution of HCl (50 ml).

The aqueous layer was back-extracted with EtOAc (2 x 50 ml). The combined organic phases were washed sequentially with water (2 x 50 ml) and a saturated NaCl solution (50 ml), dried (MgSO4), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc / 70% hexane), to give 4- (3- (N-methyl-sulfamoyl) phenyloxy) -benzene (0.30 g).

Step 3. Synthesis of 4- (3- (N-methyl-sulfamoyl) -phonyloxy) -1-nitro-benzene

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

Step 4. Synthesis of 4- (3- (N-methyl-sulfamoyl) -phonyloxy) -aniline

A slurry of 4- (3- (N-methyl-sulfamoyl) -phenyloxy) -1-nitro-benzene (0.30 g) and 10% Pd / C (0.030 g) in EtOAc (20 ml) was stirred under a H2 atmosphere (in balloon) throughout the nightPetition 870170083282, of 10/30/2017, p. 39/85 te. The resulting mixture was filtered through a Celite® mattress. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc / 70% hexane), to give 4- (3- (N-methyl-sulfamoyl) -phenyloxy) -aniline (0.070 g).

A16.Modification of ω-ketones. Synthesis of 4- (4- (1- (N-methoxy) -imino5 ethyl) -phenoxy-aniline hydrochloride

O-methylhydroxylamine hydrochloride (0.65 g, 7.78 mmol, 2.0 equiv.) Was added to a 4- (4-acetyl-phenoxy) -aniline hydrochloride slurry (prepared in an analogous manner that of Method A13, Step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 ml) and pyridine (1.0 ml). The resulting solution was heated to reflux for 30 min, cooled to room temperature, and concentrated under reduced pressure. The resulting solids were triturated with water (10 ml) and washed with water, to give 4- (4- (1- (N-methoxy) imino-ethyl) -phenoxy-aniline hydrochloride as a yellow solid (0.85 g ): TLC (50% EtOAc / 50% petroleum ether) Rf 0.78; ¹ H-NMR (DMSO-de) δ 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m / z 257 ((M + H) +).

A17.Synthesis of N-fa-Silyloxy-alkyl) -amides. Synthesis of 4- (4- (2- (N- (2-Triisopropylsilyloxy) -ethyl-carbamoyl) -pyridyloxy-aniline

Step 1.4-Chlorine-N- (2-triisopropyl-silyloxy) -ethyl-pyridine-2-carboxamide

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

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Step 2.4- (4- (2- (N- (2-Triisopropyl-silyloxy) -ethyl-carbamoyl) -pyridyloxy-aniline Potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) in one portion to a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anhydrous DMF (8 ml), causing an exothermic process.When this mixture had cooled to room temperature, it added a solution of 4-chloro-2- (N- (2-triisopropyl-silyloxy) -ethyl) -pyridine-carboxamide (2.32 g, 6 mmol, 1 equiv.) in DMF (4 ml), followed by K2CO3 (0.42 g, 3.0 mmol, 0.50 equiv.). the resulting mixture was heated to 80 ° C all night. An additional portion of potassium tert-butoxide (0.34 g, 3 mmol, 0 , 5 equiv.) Was then added and the mixture was stirred at 80 ^o C for an additional 4 h The mixture was cooled to 0 ^o C with an ice / water bath, and then water (approximately 1 ml) was added slowly The organic layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with a saturated NaCl solution (2 0 ml), dried (MgSO4) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (SiO2; 30% EtOAc / 70% petroleum ether), to yield 4- (4- (2- (N- (2-triisopropyl-silyloxy) -ethyl-carbamoyl) pyridyloxy -aniline as a clear light brown oil (0.99 g, 38%).

A18.Synthesis of 2-Pyridine-carboxylate Esters via Oxidation of 2-Methyl-pyridines. Synthesis of 4- (5- (2-methoxy-carbonyl) -pyridyloxy) -aniline

Step 1.4- (5- (2-Methyl) -pyridyloxy) -1-nitro-benzene

A mixture of 5-hydroxy-2-methyl-pyridine (10.0 g, 91.6 mmol), 1-fluor-4-nitrobenzene (9.8 ml, 91.6 mmol, 1.0 equiv.), K2CO3 (25 g, 183 mmol, 2.0 equiv.) In DMF (100 ml) was heated to reflux temperature overnight. The resulting mixture was cooled to room temperature, treated with water (200 ml), and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed sequentially with water (2 x 100 ml) and a saturated NaCl solution (100 ml), dried (MgSO4) and concentrated under reduced pressure, to give 4- (5- (2-Methyl) -pyridyloxy ) -1-nitro-benzene as a brown solid (12.3 g).

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Step 2. Synthesis of 4- (5- (2-Methoxy-carbonyl) -pi-ridyloxy) -1-nitro-benzene

A mixture of 4- (5- (2-Methyl) -pyridyloxy) -1-nitro-benzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3, 0 equiv.) In pyridine (20 ml) was heated to reflux for 5 h, and then cooled to room temperature. The resulting slurry was filtered, and then concentrated under reduced pressure. The residue was dissolved in MeOH (100 ml). The solution was treated with a concentrated solution of HCl (7 ml), and then heated to reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (50 ml) and a 1 N NaOH solution (50 ml). The aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic layers were washed sequentially with water (2 x 50 ml) and 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 yield 4 (5- (2-methoxy-carbonyl) -pyridyloxy) -1-nitro-benzene (0.70 g).

Step 3. Synthesis of 4- (5- (2-Methoxy-carbonyl) -pi-ridyloxy) -aniline

A slurry of 4- (5- (2-methoxy-carbonyl) -pyridyloxy) -1-nitro-benzene (0.50 g) and 10%

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

A19.Synthesis of ω-Sulfonyl-phenyl-anilines. Synthesis of 4- (4-Methyl-sulfonyl-phenoxy) -aniline

Step 1.4- (4-Methyl-sulfonyl-phenoxy) -1-nitro-benzene

M-CPBA (57-86%, 4.0 g) was added slowly to a solution of 4- (4-methylthiophenoxy) -1-nitro-benzene (2.0 g, 7.7 mmol) in CH2O2 (75 ml) at 0 ^o C, and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a 1 N HCl solution (25 ml). The organic layer was washed sequentially with a 1 N NaOH solution (25 ml), water (25 ml) and a saturated NaCl solution (25 ml), dried (MgSO4), and concentrated under reduced pressure, to give 4- ( 4-methyl-sulfonyl-phenoxy) -1-nitro-benzene as a solid (2.1 g).

Step 2.4- (4-Methyl-sulfonyl-phenoxy) -aniline

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4- (4-Methyl-sulfonyl-phenoxy) -1-nitro-benzene was reduced to aniline in a manner analogous to that described in Method A18, Step 3.

B. Synthesis of Urea Precursors

B1. Generic method for the synthesis of isocyanates from anilines, using CDI. Synthesis of 4-Bromo-3- (trifluoro-methyl) -phenyl-isocyanate

Step 1. 4-Bromo-3- (trifluoro-methyl) -aniline hydrochloride synthesis

A solution of HCl (1 M in Et2O; 300 ml) was added dropwise to a solution of 4-bromo-3- (trifluoromethyl) -aniline (64 g, 267 mmol) in Et2Ü (500 ml) and The resulting mixture was stirred at room temperature for 16 h. The pinkish-white precipitate was removed by filtration and washed with Et2O (50 ml), to yield 4-bromo-3- (trifluoromethyl) aniline hydrochloride (73 g, 98%).

Step 2. Synthesis of 4-Bromo-3- (trifluoro-methyl) -phenyl-isocyanate

A suspension of 4-bromo-3- (trifluoro-methyl) -aniline hydrochloride (36.8 g, 133 mmol) in toluene (278 ml) was treated with drops of trichloro-methyl formate in 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), and then concentrated under reduced pressure. The residue was treated with CH2O2 (500 ml), and then concentrated under reduced pressure. The treatment protocol with CH2Cb / concentration was repeated and the resulting amber oil was stored at -20 ^o C for 16 h to produce 4-Bromo-3 (trifluoromethyl) -phenyl-isocyanate as a tan solid (35.1 g, 86%). GC-MS m / z 265 (M +).

C. Urea Formation Methods

C1a. Generic method for the synthesis of urea by the reaction of an isocyanate with an aniline. Synthesis of N- (4-Chloro-3- (trifluoro-methyl) -phenyl) -N '' (4- (2- (N-methyl-carbamoyl) -4pyridyloxy) -phenyl) -urea

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A solution of 4-chloro-3- (trifluoro-methyl) -phenyl-isocyanate (14.60 g, 65.90 mmol) in CH2 Cl2 (35 ml) was added dropwise to a suspension of 4- (2- (N -methyl-carbamoyl) -4pyridyloxy) -aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH2O2 (35 ml) at 0 ^o C. The resulting mixture was stirred at room temperature for 22 h. The resulting yellow solids were removed by filtration, and then washed with CH2O2 (2 x 30 ml) and dried under reduced pressure (approximately 1 mm Hg), to produce N- (4-chloro-3- (trifluoromethyl) - phenylN '- (4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -phenyl) -urea as an off-white solid (28.5 g, 93%); mp 207-209 ^o C; ¹ H- 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. Generic method for the synthesis of urea by the reaction of an isocyanate with an aniline. Synthesis of N- (4-Bromo-3- (trifluoromethyl) -phenyl) -N '- (4- (2- (N-methyl-carbamoyl) -4pyridyloxy) -phenyl) -urea

A solution of 4-bromo-3- (trifluoro-methyl) -phenyl-isocyanate (Method B1, Step 2; 8.0 g, 30.1 mmol) in CH2O2 (80 ml) was added dropwise to a suspension of 4 - (2- (N-methylcarbamoyl) -4-pyridyloxy) -aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH2Cl2 (40 ml) at 0 ^o C. The resulting mixture was stirred at room temperature for 16 h. The resulting yellow solids were removed by filtration, then washed with CH2O2 (2 x 50 ml) and dried20 under reduced pressure (approximately 1 mm Hg) at 40 ^o C, to produce N- (4bromo-3- (trifluorine- methyl) -phenyl-N '- (4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -phenyl) -urea as a light yellow solid (13.2 g, 90%); mp 203- 205 ^o C. ¹ H-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J = 2.5 Hz, 1h), 7.58 (m, 3H), 7.77 (d, J = 8.8 Hz, 1h), 8.11 (d, J = 2.5 Hz, 1H), 8.49 ( d, J = 5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m / z 509 (( M + H) +).

C1c.Generic method for the synthesis of urea by the reaction of an isocyanate with an aniline. Synthesis of N- (4-Chloro-3- (trifluoro-methyl) -phenyl) -N '' (2-methyl-4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl) -urea

A solution of 2-methyl-4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline (Method A5;

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0.11 g, 0.45 mmol) in CH2 Cl2 (1 ml) was treated with Et3N (0.16 ml) and 4-chloro-3- (trifluoromethyl) -phenyl-isocyanate (0.10 g, 0.45 mmol ). The resulting brown solution was stirred at room temperature for 6 d, and then treated with water (5 ml). The aqueous layer was back-extracted with EtOAc (3 x 5 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure, to produce N- (4-chloro-3- (trifluoromethyl) -phenyl) -N '- (2methyl-4- (2- (N-methyl -carbamoyl) - (4-pyridyloxy)) - phenyl) -urea as a brown oil (0.11 g, 0.22 mmol). Ή-NMR (DMSO-de) δ 2.27 (s, 3H), 2.77 (d, J = 4.8 Hz, 3H), 7.03 (dd, J = 8.5, 2.6 Hz , 1H), 7.11 (d, J = 2.9 Hz, 1H), 7.15 (dd, J = 5.5, 2.6 Hz, 1H), 7.38 (d, J = 2, 6 Hz, 1H), 7.62 (app d, J = 2.6 Hz, 2H), 7.84 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 8, 17 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.78 (q, J = 5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m / z 479 ((M + H) +).

C1d. Generic method for the synthesis of urea by the reaction of an isocyanate with an aniline. Synthesis of N- (4-Chloro-3- (trifluor-methyl) -phenyl) -N '- (4-amino-phenyl) -urea

P-Phenylene diamine (3.32 g, 30.7 mmol) was added in one portion to a solution of 4-chloro-3- (trifluoromethyl) -phenyl-isocyanate (2.27 g, 10.3 mmol) in CH2O2 (100 ml). The resulting mixture was stirred at room temperature for 1 h, treated with CH2O2 (100 ml), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc (110 ml) and MeOH (15 ml), and the clear solution was washed with a 0.05 N HCl solution. The organic layer was concentrated under reduced pressure, to produce N- (4-chloro-3- (trifluoromethyl) -phenyl) -N '- (4-amino-phenyl)-impure urea (3.3 g): TLC (100% EtOAc) Rf 0.72.

C1e. Generic method for the synthesis of urea by the reaction of an isocyanate with an aniline. Synthesis of N- (4-Chloro-3- (trifluoro-methyl) -phenyl) -N '- (4-ethoxy-carbonyl-phenyl) -urea

4-Chloro-3- (trifluoromethyl) -aniline (3.21 g, 16.4 mmol) was added to a solution of ethyl 4-isocyanate-benzoate (3.14 g, 16.4 mmol) in CH2O2 (30 ml) and the solution was stirred at room temperature overnight. The resulting slurry was diluted with CH2O2 (50 ml) and filtered to produce N- (4-chloro-3- (trifluoromethyl) -phenyl) -N '- (4-ethoxy-carbonyl-phenyl) -urea as a white solid (5.93 g, 97%). TLC (40% EtOAc / 60% hexane) Rf 0.44.

C1f. Generic method for the synthesis of urea by the reaction of an isocyanate with an aniline. Synthesis of N- (4-Chloro-3- (trifluoro-methyl) -phenyl) -N '- (3-carboxy-phenyl) -urea

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4- (3- (carboxy-phenoxy) -aniline (Method A11; 0.81 g, 5.76 mmol) was added to a solution of 4-chloro-3- (trifluoromethyl) -phenyl-isocyanate (1 , 21 g, 5.46 mmol) in CH2O2 (8 ml), and the resulting mixture was stirred at room temperature overnight, and then treated with

MeOH (8 ml) and stirred for another 2 h. The resulting mixture was concentrated under reduced pressure. The resulting brown solids were ground with a 1: 1 solution of EtOAc: hexane, to give N- (4-chloro-3- (trifluoromethyl) -phenyl) -N '- (3-carboxy-phenyl) -urea as an off-white solid (1.21 g, 76%).

C2a. Generic method for the synthesis of urea by the reaction of an aniline with

N, N'-Carbonyl-diimidazole, followed by the addition of a second aniline. Synthesis of N- (2Methoxy-5- (trifluoromethyl) -phenyl) -N '- (4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -phenyl) -urea

CDI (0.13 g) was added to a solution of 2-methoxy-5- (trifluoromethyl) -aniline (0.15 g) in anhydrous CH2O2 (15 ml) at 0 ^o C. The resulting solution was left heat to room temperature for 1 h, stirred at room temperature for 16 h, and then treated with 4 (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 72 h, and then treated with water (125 ml). The resulting aqueous mixture was extracted with EtOAc (2 x 150 ml). The combined organic phases were washed with a saturated NaCl solution (100 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was triturated (90% EtOAc / 10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil was purified by column chromatography (gradient between 33% EtOAc / 67% hexane and 50% EtOAc / 50% hexane to 100% EtOAc), to give N- (2-Methoxy- 5 (trifluoro-methyl) -phenyl) -N '- (4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -phenyl) -urea as a light tan solid (0.098 g, 30% ): TLC (100% EtOAc) Rf 0.62. ¹ H-NMR (DMSO-de) δ 2.76 (d, J = 4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, J = 4.8 Hz, 1H), 9.55 (s, 1H); FAB-MS m / z 461 ((M + H) +).

C2b.Generic method for the synthesis of urea by the reaction of an aniline with N, N'-carbonyl-diimidazole, followed by the addition of a second aniline. Symmetric ureas as by-products of a reaction procedure with N, N'-Carbonyl-diimidazole. Synthesis

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CDI (0.13 g) was added to a solution of 3-amino-2-methoxy-quinoline (0.14 g) in anhydrous CH2O2 (15 ml) at 0 ^o C. The resulting solution was allowed to warm to the temperature room for 1 h, and stirred at room temperature for 16 h. The resulting mixture was treated with 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 72 h, and then treated with water (125 ml). The resulting aqueous mixture was extracted with EtOAc (2 x 150 ml). The combined organic phases were washed with a saturated NaCl solution (100 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was triturated (90% EtOAc / 10% hexane). The resulting white solids were collected by filtration and washed with EtOAc, to give bis- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -phenyl) -urea (0.081 g, 44%): TLC (100% EtOAc) Rf 0.50. ¹ H-NMR (DMSO-de) δ 2.76 (d, J = 5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J = 5.4 Hz, 1H), 8.75 (d, J = 4.8 Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m / z 513 ((M + H) +).

C2c.Generic method for the synthesis of urea by the reaction of an isocyanate with an aniline. Synthesis of N- (2-methoxy-5- (trifluoro-methyl) -phenyl) -N '- (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) -urea

5- (4-Amino-phenoxy) -isoindoline-1,3-dione (Method A3, Step 3; 0.12 g,

0.47 mmol) in one portion to a solution of 2-methoxy-5- (trifluoromethyl) -phenyl-isocyanate (0.10 g, 0.47 mmol) in CH2O2 (1.5 ml) with stirring. The resulting mixture was stirred for 12 h, and then treated with CH2O2 (10 ml) and MeOH (5 ml). The resulting mixture was washed sequentially with a 1 N HCl solution (15 ml) and a saturated NaCl solution (15 ml), dried (MgSO ₄ ) and concentrated under reduced pressure, to produce N- (2-methoxy-5- (trifluoro25 methyl) -phenyl) -N '- (4- (1,3-dioxoisoindo-lin-5-yloxy) -phenyl) -urea as a white solid (0.2 g,

96%): TLC (70% EtOAc / 30% hexane) Rf 0.50. ¹ H-NMR (DMSO-de) δ 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J = 9.3 Hz, 2H), 7, 80 (d, J = 8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS 472.0 ((M + H) +, 100%).

C2d.Generic Method for the Synthesis of Urea by Reaction of Aniline with

N, N'-Carbonyl-diimidazole, followed by the addition of a second aniline. Synthesis of N- (5- (tertPetition 870170083282, of 10/30/2017, page 47/85 butyl) -2- (2,5-dimethyl-pyrrolyl) -phenyl) -N '- (4- (2- (N-methyl-car-bamoyl) -4-pyridyloxy) -phenyl-urea

5- (tert-butyl) -2- (2,5-dimethyl-pyrrol-lil) -aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) was added in one portion to a solution of CDI (0.21 g, 1.30 mmol) in CH2O2 (2 ml) with stirring. The resulting mixture was stirred at room temperature for 4 h, and then 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline (0.065 g, 0.267 mmol) was added in one portion. The resulting mixture was heated to 36 ° C all night, then cooled to room temperature and diluted with EtOAc (5 mL). The resulting mixture was washed sequentially with water (5 ml) and a 1 N HCl solution (15 ml), dried (MgSO4), and filtered through a silica gel mat (50 g), to produce N- (5 - (tert-butyl) -2- (2,5-dimethyl-pyrrolyl) -phenyl) N '- (4- (2- (N-methyl-car-bamoyl) -4-pyridyloxy) -phenyl-urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc / 60% hexane) Rf 0.24 ¹ H NMR (acetone-de) δ 1.37 (s, 9H), 1.89 (s. 6H), 2.89 (d, J = 4.8 Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J = 5.4 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M + H) +, 100%).

C3.Combinatory Method for the Synthesis of Diphenyl Urea Using Triphosgene One of the anilines to be coupled was dissolved in dichloroethane (0.10 M). This solution (0.5 ml) was added to an 8 ml flask containing dichloroethane (1 ml). To this was added a solution of bis (trichloro-methyl) carbonate (0.12 M in dichloro-ethane; 0.2 ml,

0.4 equiv.), Followed by diisopropyl-ethyl-amine (0.35 M in dichloro-ethane; 0.2 ml, 1.2 equiv.). The bottle was capped and heated to 80 ^o C for 5 h, and then allowed to cool to room temperature for approximately 10 h. The second aniline was added (0.10 M in dichloroethane; 0.5 ml, 1.0 equiv.), Followed by diisopropyl-ethyl-amine (0.35 M in dichloro-ethane; 0.2 ml, 1.2 equiv.). The resulting mixture was heated to 80 ^o C for 4 h, then allowed to cool to room temperature, and treated with MeOH (0.5 ml). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.

C4.Generic method for the synthesis of urea by the reaction of an aniline with phosgene, followed by the addition of a second aniline. Synthesis of N- (2-Methoxy-5-trifluoromethyl) -phenyl) -N '' (4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -phenyl-urea

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Anhydrous pyridine (0.32 ml) was added, followed by 2-methoxy-5- (trifluoromethyl) -aniline (0.75 g) to a solution of phosgene (1.9 M in toluene; 2.07 ml , 0.21 g, 1.30 mmol) in CH2Cl2 (20 mL) at 0 ° C under stirring. The yellow solution was allowed to warm to room temperature, during which time a precipitate formed. The yellow mixture was stirred for 1 h, and then concentrated under reduced pressure. The resulting solids were treated with anhydrous toluene (20 ml), followed by 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline (prepared as described in Method A2; 0.30 g), and The resulting suspension was heated to 80 ^o C for 20 h, then allowed to cool to room temperature. The resulting mixture was diluted with water (100 ml), and then made basic with a saturated solution of NaHCO3 (2-3 ml). The basic solution was extracted with EtOAc (2 x 250 ml). The organic layers were washed separately with a saturated NaCl solution, combined, dried (MgSO4), and concentrated under reduced pressure. The resulting pinkish-brown residue was dissolved in MeOH and adsorbed on SiO2 (100 g). Column chromatography (300 g SiO2;

gradient between 1% Et3N / 33% EtOAc / 66% hexane and 1% Et3N / 99% EtOAc to 1% Et3N / 20%

MeOH / 79% EtOAc), followed by concentration under reduced pressure at 45 ^o C, gave a concentrated solution in hot EtOAc, which was treated with hexane (10 ml), to slowly form N- (2-methoxy-5-) crystals trifluoro-methyl) -phenyl) -N '- (4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) phenyl-urea (0.44 g): TLC (1% Et3N / 99% EtOAc) Rf 0.40.

D. Urea Interconversion

D1a.Conversion of ω-Amino-phenyl-ureas into <a- (Aroyl-amino) -phenyl-ureas. Synthesis of

N- (4-Chloro-3 - ((trifluoro-methyl) -phenyl) -N '' (4- (3-methoxy-carbonyl-phenyl) -car-boxy-amino-phenyl) -urea

EDCI »HCl (0.29 g, 1.52 mmol) was added to a solution of N- (4-chloro-325 ((trifluoro-methyl) -phenyl) -N '- (4-amino-phenyl) - urea (Method C1d; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 g, 1.38 mmol), HOBT »H2O (0.41 g, 3.03 mmol) and N-methyl- morpholine (0.33 ml, 3.03 mmol) in DMF (8 ml) The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (25 ml) and washed sequentially with water (25 ml) and a saturated NaHCO3 solution (25 ml). The organic layer was dried (Na2SO ₄ ) and concentrated under reduced pressure. The resulting solids were ground with a solution of EtOPetition 870170083282, from 10/30/2017, page 49/85

Ac (80% EtOAc / 20% hexane), to give N- (4-Chloro-3 - ((trifluoro-methyl) -phenyl) -N '- (4- (3-methoxycarbonyl-phenyl) -carboxy-amino- phenyl) -urea (0.27 g, 43%), mp 121-122 ^o C: TLC (80% EtOAc / 20% hexane) Rf 0.75.

D1b.Conversion of ω-Amino-phenyl-ureas into <a- (Aryl-carbamoyl) -phenyl-ureas. Synthesis 5 of N- (4-Chloro-3 - ((trifluoro-methyl) -phenyl) -N '- (4- (3-methyl-carbamoyl-phenyl) -carbamoyl-fe-nyl) -urea

EDCI »HCl (0.10 g, 0.53 mmol) was added to a solution of N- (4-chloro-3 ((trifluoromethyl) -phenyl) -N '- (4-methyl-carbamoyl-phenyl ) -carboxy-amino-phenyl) -urea (0.14 g, 0.48 mmol), 3-methyl-carbamoyl-aniline (0.080 g, 0.53 mmol), HOBT »H2O (0.14 g, 1, 07 mmol), and N10 methyl-morpholine (0.5 ml, 1.07 mmol) in DMF (3 ml) at 0 ^o C. The resulting mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was treated with water (10 ml), and extracted with EtOAc (25 ml). The organic phase was concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 ml), and then filtered through a silica gel mattress (17 g, gradient between 70% EtOAc / 30% hexane and 10% MeOH / 90% EtOAc), to give N - (4-Chloro-3 - ((trifluoro-methyl) -phenyl) -N '- (4- (3-methylcarbamoyl-phenyl) -carbamoyl-phenyl) -urea as a white solid (0.097 g, 41%), mp 225-229 ^o C: TLC (100% EtOAc) Rf 0.23.

D1c.Cominatorial Approach for the Conversion of ω-Carboxy-phenyl-ureas to ω (Aryl-carbamoyl) -phenyl-urea. Synthesis of N- (4-Chloro-3 - ((trifluoromethyl) -phenyl) -N '- (4- (N- (3- (N- (320 pyridyl) -carbamoyl) -phenyl) -carbamoyl) - phenyl) -urea

A mixture of N- (4-chloro-3 - ((trifluoromethyl) -phenyl) -N '- (3-carboxy-phenyl) -urea (Method C1f; 0.030 g, 0.067 mmol) and N-cyclohexyl -N '- (methyl-polystyrene) -carbodiimide (55 mg) in 1,2-dichloroethane (1 ml) was treated with a solution of 3-amino-pyridine in CH2O2 (1 M;

0.074 ml, 0.074 mmol). (In cases of insolubility or turbidity, a small amount of DMSO was also added). The resulting mixture was heated to 36 ° C overnight. The cloudy reactions were then treated with THF (1 ml) and heating continued for 18 h. The resulting mixtures were treated with poly (4- (isocyanato-methyl) styrene) (0.040 g) and the resulting mixture was stirred at 36 ^o C for 72 h, and then cooled to room temperature and filtered. The resulting solution was filtered through a plug of silica gel (1

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g). Concentration under reduced pressure produced N- (4-Chloro-3 - ((trifluoro-methyl) -phenyl) -N '- (4 (N- (3- (N- (3-pyridyl) -carbamoyl) -phenyl) -carbamoyl) -phenyl) -urea (0.024 g, 59%): TLC (70% EtOAc / 30% hexane) Rf 0.12.

D2.Conversion of ω-Carboalkoxy-aryl-ureas into ω-Carbamoil-aryl-urea. Synthesis of N- (4-Chloro-3 - ((trifluor-methyl) -phenyl) -N '- (4- (3-methyl-carbamoyl-phenyl) -carboxy-amino-phenyl) -urea

Methylamine (2 M in THF; 1 ml, 1.7 mmol) was added to a sample of N- (4-chloro-3 - ((trifluoromethyl) -phenyl) -N '- (4- (3- carbomethoxy-phenyl) -carboxy-amino-phenyl) -urea (0.17 g, 0.34 mmol), and the resulting mixture was stirred at room temperature overnight, and then concentrated under reduced pressure, to give N- (4-Chloro-3 - ((trifluoro-methyl) phenyl) -N '- (4- (3-methylcarbamoyl-phenyl) -carboxy-amino-phenyl) -urea as a white solid: mp 247 C; TLC R (100% EtOAc) Rf 0.35.

D3.Conversion of ω-Carboalkoxy-aryl-ureas into ω-Carboxy-aryl-urea. Synthesis of N (4-Chlorine-3 - ((trifluoro-methyl) -phenyl) -N '- (4-carboxy-phenyl) -urea

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

D4.Generic method for the conversion of ω-alkoxy esters into ω-alkyl amides. Synthesis of N- (4-Chloro-3 - ((trifluoromethyl) -phenyl) -N '- (4- (3- (5- (2-dimethyl-amino-ethyl) carbamoyl) pyridyl) -oxyphenyl) - urea

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Step I. Synthesis of N- (4-Chloro-3 - ((trifluor-methyl) -phenyl) -N '- ((4- (3- (5-carboxy-pyridyl) oxyphenyl) -urea

N- (4-Chloro-3 - ((trifluoro-methyl) -phenyl) -N '- ((4- (3- (5-methoxy-carbonyl-pyridyl) -oxyphenyl) -urea was synthesized from isocyanate of 4-chloro-3- (trifluoro-methyl) -phenyl and 4- (3- (5-methoxy5 carbonyl-pyridyl) -oxyaniline (Method A14, Step 2) in a manner analogous to that of Method C1a. (4-Chloro-3 - ((trifluoro-methyl) -phenyl) -N '- ((4- (3- (5-methoxy-carbonylpyridyl) -oxyphenyl) -urea (0.26 g, 0.56 mmol) in MeOH (10 ml) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 ml), and was stirred at room temperature for 1 h. The resulting mixture was adjusted to pH pH 5 with a 1 N HCl solution. The resulting precipitate was removed by filtration and washed with water. The resulting solids were dissolved in EtOH (10 ml) and the resulting solution was concentrated under reduced pressure. The EtOH / concentration procedure was repeated twice, to give N- (4-Chloro-3 - ((trifluoromethyl) -phenyl) -N '- ((4- (3- (5-carboxy-pyridyl) -oxyphenyl) -urea (0.18 g, 71%).

Step 2. Synthesis of N- (4-Chloro-3 - ((trifluoro-methyl) -phenyl) -N '- ((4- (3- (5- (2-dimethyl-aminoethyl) carbamoyl) -pyridyl ) -oxyphenyl) -urea

A mixture of N- (4-chloro-3 - ((trifluoromethyl) -phenyl) -N '- ((4- (3- (5-carboxy-pyridyl) oxyphenyl) -urea (0.050 g, 0.011 mmol) , N, N-dimethyl-ethylene-diamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N-methyl-morpholine (0.035 g, 0.28 mmol), and EDCI »HCl (0.032 g,

0.17 mmol) in DMF (2.5 ml) was stirred at room temperature overnight. The resulting solution was partitioned between EtOAc (50 ml) and water (50 ml). The organic phase was washed with water (35 ml), dried (MgSO4 and concentrated under reduced pressure. The residue was dissolved in a minimum amount of CH2O2 (approximately 2 ml). The resulting solution was treated with Et2O in drops, to give N- (4-Chloro-3 - ((trifluoro-methyl) -phenyl) -N '- ((4- (3- (5- (2-dimethyl25 amino-ethyl) carbamoyl) -pyridyl) -oxyphenyl) - urea as a white precipitate (0.48 g, 84%). ¹ HNMR (DMSO-de) δ 2.10 (s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, 1H), 8.43 (s, 1H), 8.58 (t, 1H) ,. 8.69 ( s, 1H), 8.90 (s, 1H), 9.14 (s, 1H); HPLC ES-MS m / z 522 ((M + H) +).

D5.Generic method for the deprotection of N- (o-Silyloxy-alkyl) -amides. Synthesis of

N- (4-Chloro-3 - ((trifluoro-methyl) -phenyl) -N '- (4- (4- (2- (N- (2-hydroxy) -ethyl-carbamoyl) -pi-ridyloxy-phenyl )urea

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Tetrabutylammonium fluoride (1.0 M in THF; 2 ml) was added to a solution of N- (4-chloro-3 - ((trifluoromethyl) -phenyl) -N '- (4- (4 - (2- (N- (2-triisopropyl-silyloxy) -ethyl-carbamoyl) -pyridyloxyphenyl) -urea (prepared in a manner analogous to that of Method C1a; 0.25 g, 0.37 mmol) in anhydrous THF (2 The mixture was stirred at room temperature for 5 min, and then treated with water (10 ml). The aqueous mixture was extracted with EtOAc (3 x 10 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure The residue was purified by column chromatography (S1O2; gradient between 100% hexane and 40% EtOAc / 60% hexane), to give N- (4-Chloro-3 - ((trifluoromethyl) -phenyl) - N '- (4- (4- (2- (N- (210 hydroxy) -ethyl-carbamoyl) -pi-ridyloxy-phenyl) -urea as a white solid (0.019 g, 10%).

Listed below are the compounds listed in the Tables below that have been synthesized according to the Detailed Experimental Procedures provided above: EXAMPLIFIED COMPOUND SYNTHESES (See Tables for Compound Characterization)

Item 1: 4- (3-N-Methyl-carbamoyl-phenoxy-xi) -aniline was prepared according to Method

A13. According to Method C3, 3-tert-butyl-aniline was reacted with bis (trichloro-methyl) carbonate, followed by 4- (3-N-methyl-carbamoyl-phenoxy) -aniline, to produce urea.

Item 2: 4-Fluorine-1-nitro-benzene was reacted with p-hydroxy-acetophenone according to Method A13, Step 1, to produce 4- (4-acetyl-phenoxy) -1-nitro-benzene. 420 (4-acetyl-phenoxy) -1-nitro-benzene according to Method A13, Step 4, was reduced to produce 4- (4-acetyl-phenoxy) -aniline. According to Method C3, 3-tert-butyl-aniline was reacted with bis- (trichloro-methyl) carbonate, followed by 4- (4-acetyl-phenoxy) -aniline, to produce urea.

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

Item 4: 5-tert-Butyl-2-methoxy-aniline was converted to 5-tert-butyl-2-methoxy-phenylisocyanate according to Method B1. 4- (3-N-Methyl-carbamoyl-phenoxy) -aniline, prepared according to Method A13, was reacted with the isocyanate, according to Method C1a, to produce urea.

Item 5: According to Method C2d, 5-tert-butyl-2-methoxy-aniline was reacted with

CDI, followed by 4- (3-N-methyl-carbamoyl) -4-methoxy-phenoxy) -aniline, which had been prepared according to Method A8, to produce urea.

Item 6: 5- (4-Amino-phenoxy) -isoindoline-1,3-dione was prepared according to Method A3. According to Method 2d, 5-tert-butyl-2-methoxy-aniline was reacted with CDI, sePetição 870170083282, of 10/30/2017, p. 53/85 5- (4-amino-phenoxy) -isoindoline-1,3-dione, to produce urea.

Item 7: 4- (1-Oxoisoindolin-5-yloxy) -aniline was synthesized according to the Method

A12. According to Method 2d, 5-tert-butyl-2-methoxy-aniline was reacted with CDI, followed by 4- (1-oxoisoindolin-5-yloxy) -aniline, to produce urea.

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

Item 9: 4-hydroxy-acetophenone was reacted with 2-chloro-5-nitro-pyridine, to give 4- (4acetyl-phenoxy) -5-nitro-pyridine, according to Method A3, Step 2. with Meto10 of A8, Step 4, 4- (4-acetyl-phenoxy) -5-nitro-pyridine was reduced to 4- (4-acetyl-phenoxy) -5amino-pyridine. 2-Methoxy-5- (trifluoro-methyl) -aniline was converted to 2-methoxy-5- (trifluoro-methyl) -phenyl-isocyanate, according to Method B1. The isocyanate was reacted with 4- (4-acetylphenoxy) -5-amino-pyridine, according to Method C1, to produce urea.

Item 10: 4-Fluorine-1-nitro-benzene was reacted with p-hydroxy-acetophenone, according to Method A13, Step 1, to produce 4- (4-acetyl-phenoxy) -1-nitro-benzene . 4- (4-Acetyl-phenoxy) -1-nitro-benzene was reduced according to Method A13, Step 4, to produce 4- (4-acetyl-phenoxy) -aniline. According to Method C3, 5- (trifluoromethyl) -2methoxy-butyl-aniline was reacted with bis- (trichloro-methyl) carbonate, followed by 4- (4-acetyl-phenoxy) aniline, to produce the urea.

Item 11: 4-Chloro-N-methyl-2-pyridine-carboxamide, which was prepared according to Method A2, Step 3a, was reacted with 3-amino-phenol, according to Method A2, Step 4 , using DMAC in place of DMF, to give 3- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline. According to Method C4, 2-methoxy-5- (trifluoromethyl) -aniline was reacted with phosgene, followed by 3- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline, to produce urea.

Item 12: 4-Chloro-pyridine-2-carbonyl hydrochloride was reacted with ammonia, according to Method A2, Step 3b, to form 4-chloro-2-pyridine-carboxamide. The 4-chloro-2-pyridine-carboxamide was reacted with 3-amino-phenol, according to Method A2, Step 4, using DMAC in place of DMF, to give 3- (2-carbamoyl-4-pyridyloxy) -aniline . According to Method C2a, 2-methoxy-5- (trifluoromethyl) -aniline was reacted with phosgene, followed by 3- (230 carbamoyl-4-pyridyloxy) -aniline, to produce urea.

Item 13: 4-chloro-N-methyl-2-pyridine-carboxamide was synthesized according to

Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridine-carboxamide was reacted with 4-aminophenol according to Method A2, Step 4, using DMAC in place of DMF, to give 4- (2 (N-methyl- carbamoyl) -4-pyridyloxy) -aniline. According to Method C2a, 2-methoxy-535 (trifluoromethyl) -aniline was reacted with CDI, followed by 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline, to produce the urea.

Item 14: 4-Chloro-pyridi-no-2-carbonyl hydrochloride was reacted with ammonia, according to

Petition 870170083282, of 10/30/2017, p. 54/85 with Method A2, Step 3b, to form 4-chloro-2-pyridine-carboxamide. 4-Chloro-2-pyridine-carboxamide was reacted with 4-amino-phenol according to Method A2, Step 4, using DMAC in place of DMF, to give 4- (2-carbamoyl-4-pyridyloxy) -aniline . According to Method C4, 2-methoxy-5- (trifluoro-methyl) -aniline was reacted with phosgene, followed by 4- (25 carbamoyl-4-pyridyloxy) -aniline, to produce urea.

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

Item 16: 4- (2- (N-Methyl-carbamoyl) -4-pyridyloxy) -2-methyl-aniline was synthesized according to Method A5. 5- (trifluoro-methyl) -2-methoxy-aniline was converted to 5- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate according to Method B1. The isocyanate was reacted with 4- (2- (Nmethyl-carbamoyl) -4-pyridyloxy) -2-methyl-aniline, according to Method C1c, to produce urea.

Item 17: 4- (2- (N-Methyl-carbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. 5- (trifluoro-methyl) -2-methoxy-aniline was converted to 5- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate according to Method B1. The 5- (trifluoromethyl) -2-methoxyphenyl-isocyanate was reacted with 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -2-chloroaniline, according to Method C1a, to produce urea.

Item 18: According to Method A2, Step 4, 5-amino-2-methyl-phenol was reacted with

4-chloro-N-methyl-2-pyridine-carboxamide, which had been synthesized according to Method A2, Step 3b, to give 3- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -4- methyl aniline. 5 (trifluoro-methyl) -2-methoxy-aniline was converted to 5- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate according to Method B1. The 5- (trifluoromethyl) -2-methoxy-phenyl-isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methyl-aniline, according to Method C1a, to produce urea.

Item 19: 4-Chloro-pyridine-2-carbonyl chloride was reacted with ethyl amine, according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridine-carboxamide was reacted with 4-amino-phenol, according to Method A2, Step 4, to give 4- (2- (N-ethyl-carbamoyl) - 4 pyridyloxy) -aniline. 5- (trifluoro-methyl) -2-methoxy-aniline was converted to 5- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate according to Method B1. The 5- (trifluoromethyl) -2-methoxy30 phenylisocyanate was reacted with 4- (2- (N-ethyl-carbamoyl) -4-pyridyloxy) -aniline, according to Method C1a, to produce urea.

Item 20: According to Method A2, Step 4, 4-amino-2-chloro-phenol was reacted with 4-chloro-N-methyl-2-pyridine-carboxamide, which had been synthesized according to Method A2 , Step 3b, to give 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -3-chloroaniline. 5- (trifluoro-methyl) -2-methoxy-aniline was converted to 5- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate according to Method B1. 5- (Trifluoro-methyl) -2-methoxy-phenyl-isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloro-aniline according to Method C1a, to give urea.

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Item 21: 4- (4-Methylthiophenoxy) -1-nitro-benzene was oxidized according to Method A19, Step 1, to give 4- (4-methyl-sulfonyl-phenoxy) -1-nitro-benzene. Nitro-benzene was reduced according to Method A19, Step 2, to give 4- (4-methyl-sulfonyl-phenoxy) -1-aniline. According to Method C1a, 5- (trifluoromethyl) -2-methoxy-phenyl-isocyanate was reacted with 4- (45 methyl-sulfonyl-phenoxy) -1-aniline to produce urea.

Item 22: 4- (3-carbamoyl-phenoxy) -1-nitro-benzene was reduced to 4- (3-carbamoyl-phenoxy) -aniline according to Method A15, Step 4. According to Method C1a, reacted 5 - (trifluoro-methyl) -2-methoxy-phenyl-isocyanate with 4- (3-carba-moil-phenoxy) -aniline, to produce urea.

Item 23: 5- (4-Amino-phenoxy) -isoindoline-1,3-dio-na was synthesized according to

Method A3. 5- (trifluoro-methyl) -2-methoxy-aniline was converted to 5- (trifluoro-methyl) -2-methoxyphenyl-isocyanate according to Method B1. 5- (Trifluoro-methyl) -2-methoxy-phenylisocyanate was reacted with 5- (4-amino-phenoxy) -isoindoline-1,3-dione, according to Method C1, to produce urea.

Item 24: 4-Chloro-pyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. 4-Chloro-N, N-dimethyl-2-pyridine-carboxamide was reacted with 4-amino-phenol according to Method A2, Step 4, to give 4- (2- (N, N-dimethylcarbamoyl) -4-pyridi-loxy) -aniline. 5- (trifluoro-methyl) -2-methoxy-aniline was converted to 5 (trifluoro-methyl) -2-methoxy-phenyl-isocyanate according to Method B1. 5- (Trifluoro20 methyl) -2-methoxy-phenyl-isocyanate was reacted with 4- (2- (N, N-dimethyl-carbamoyl) -4-pyridyloxy) -aniline, according to Method C1a, to produce urea.

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

Item 26: 4-hydroxy-acetophenone was reacted with 4-fluoro-nitro-benzene, according to Method A13, Step 1, to give 4- (4-acetyl-phenoxy) -nitro-benzene. Nitro-benzene was reduced according to Method A13, Step 4, to produce 4- (4-acetyl-phenoxy) -aniline, which was converted to 4- (4- (1- (N-methoxy) - hydrochloride) imino-ethyl) phenoxy-aniline according to Method A16. 5- (trifluoromethyl) -2-methoxy-aniline was converted to 5- (trifluoromethyl) -2-methoxy30 phenyl-isocyanate according to Method B1 5- (Trifluoromethyl) -2-methoxy-phenylisocyanate was reacted with 4- (4- (1- (N-methoxy) -imino-ethyl) phenoxy-aniline hydrochloride according to Method C1a, to produce urea.

Item 27: 4-Chloro-N-methyl-pyridine-carboxamide was synthesized as described in Method A2, Step 3b. Chloro-pyridine was reacted with 4-amino-thiophenol, according to Method

A2, Step 4, to give 4- (4- (2- (N-methyl-carbamoyl) -phenylthio) -aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxy-phenyl-isocyanate according to Method B1 5- (Trifluoromethyl) -2-methoxy-phenyl-isocyanate was reacted with 4- (4- (2- (N-methyl-carbamoyl) Petition 870170083282, of 10/30/2017, page 56/85 phenylthio) -aniline, according to Method C1a, to produce urea.

Item 28: 5- (4-Amino-phenoxy) -2-methyl-isoindoline -1,3-dione was synthesized according to Method A9. 5- (trifluoro-methyl) -2-methoxy-aniline was converted to 5- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate according to Method B1. 5- (Trifluoro-methyl) -2-methoxy5-phenyl-isocyanate was reacted with 5- (4-amino-phenoxy) -2-methyl-isoindoline-1,3-dione, according to Method C1a, to produce urea.

Item 29: 4-Chloro-N-methyl-pyridine-carboxamide was synthesized as described in Method A2, Step 3b. Chloro-pyridine was reacted with 3-amino-thiophenol, according to Method A2, Step 4, to give 3- (4- (2- (N-methyl-carbamoyl) -phenylthio) -aniline. (trifluoro-methyl) -2-methoxy10 aniline was converted to 5- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate according to Method B1. The 5- (trifluor-methyl) -2-methoxy was reacted -phenyl-isocyanate with 3- (4- (2- (N-methyl-carbamoyl) phenylthio) -aniline, according to Method C1a, to produce urea.

Item 30: 4-Chloro-pyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. 4-Chloro-N-isopropyl-2-pyridine-carboxamide was reacted with 4-amino-phenol according to Method A2, Step 4, to give 4- (2- (N-isopropylcarbamoyl) -4-pyridi -loxy) -aniline. 5- (trifluoro-methyl) -2-methoxy-aniline was converted to 5 (trifluoro-methyl) -2-methoxy-phenyl-isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxy-phenyl-isocyanate was reacted with 4- (2- (N-isopropyl-carbamoyl) -4-pyridyloxy) -aniline, according to Method C1a, to produce urea.

Item 31: 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -aniline was synthesized according to

Method A14. 5- (trifluoro-methyl) -2-methoxy-aniline was converted to 5- (trifluoro-methyl) -2-methoxyphenyl-isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxy-phenylisocyanate was reacted with 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -aniline, according to Method C1a, to produce urea. N- (5- (trifluoromethyl) -2-methoxy-phenyl) -N '- (4- (3- (5-methoxy-carbonyl-pyridyl) -oxy) 25 phenyl) -urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4- (2-amino-ethyl) -morpholine, to produce the amide, according to Method D4, Step 2.

Item 32: 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -aniline was synthesized according to Method A14. 5- (trifluoro-methyl) -2-methoxy-aniline was converted to 5- (trifluoro-methyl) -2-methoxy30 phenyl-isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxy-phenylisocyanate was reacted with 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -aniline, according to Method C1a, to produce urea. N- (5- (trifluoromethyl) -2-methoxy-phenyl) -N '- (4- (3- (5-methoxy-carbonyl-pyridyl) -oxy) phenyl) -urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methyl amine, according to Method D4, Step 2, to produce the amide.

Item 33: 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -aniline was synthesized according to

Method A14. 5- (trifluoro-methyl) -2-methoxy-aniline was converted to 5- (trifluoro-methyl) -2-methoxyphenyl-isocyanate according to Method B1. The 5- (trifluoro-methyl) -2-methoxy-phenyl was reacted Petition 870170083282, of 10/30/2017, p. 57/85 isocyanate with 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -aniline, according to Method C1a, to produce urea. N- (5- (trifluoromethyl) -2-methoxy-phenyl) -N '- (4- (3- (5-methoxy-carbonyl-pyridyl) -oxy) phenyl) -urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with N, N-dimethyl-ethylene-diamine, according to Method D4, Step 2, to produce the amide.

Item 34: 4- (3- (carboxy-phenoxy) -aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxy-aniline was converted to 5- (trifluoromethyl) ) -2-methoxy-phenyl-isocyanate according to Method B1 5- (Trifluoromethyl) -2-methoxy-phenyl-isocyanate was reacted with 4 (3- (carboxy-phenoxy) -aniline, according to with Method C1f, to produce N- (5- (trifluoromethyl) 10 2-methoxy-phenyl) -N '- (3-carboxy-phenyl) -urea, which was coupled to 3-amino-pyridine according to with Method D1c.

Item 35: 4- (3- (carboxy-phenoxy) -aniline was synthesized according to Method A11. 5- (Trifluoromethyl) -2-methoxy-aniline was converted to 5- (trifluoromethyl) ) -2-methoxy-phenyl-isocyanate according to Method B1 5- (Trifluoromethyl) -2-methoxy-phenyl-isocyanate was reacted with 415 (3- (carboxy-phenoxy) -aniline, according to with Method C1f, to produce N- (5- (trifluoromethyl) 2-methoxy-phenyl) -N '- (3-carboxy-phenyl) -urea, which was coupled to N- (4-fluor-phenyl) ) -piperazine according to Method D1c.

Item 36: 4- (3- (carboxy-phenoxy) -aniline was synthesized according to Method A11. 5- (Trifluor-methyl) -2-methoxy-aniline was converted to 5- (trifluor-methyl) - 2-methoxy-phenyl-isocyanate according to Method B1 5- (Trifluoromethyl) -2-methoxy-phenyl-isocyanate was reacted with 4 (3- (carboxy-phenoxy) -aniline according to Method C1f, to produce N- (5- (trifluoromethyl) 2-methoxy-phenyl) -N '- (3-carboxy-phenyl) -urea, which was coupled to 4-fluorine-aniline according to Method D1c.

Item 37: 4- (3- (carboxy-phenoxy) -aniline was synthesized according to Method A11.

5- (trifluoro-methyl) -2-methoxy-aniline was converted to 5- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate according to Method B1. The 5- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate was reacted with 4 (3- (carboxy-phenoxy) -aniline, according to Method C1f, to produce N- (5- (trifluorine- methyl) 2-methoxy-phenyl) -N '- (3-carboxy-phenyl) -urea, which was coupled to 4- (dimethyl-amino) -aniline according to Method D1c.

Item 38: 4- (3- (carboxy-phenoxy) -aniline was synthesized according to Method A11.

5- (trifluoro-methyl) -2-methoxy-aniline was converted to 5- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate according to Method B1. The 5- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate was reacted with 4 (3- (carboxy-phenoxy) -aniline, according to Method C1f, to produce N- (5- (trifluorine- methyl) 2-methoxy-phenyl) -N '- (3-carboxy-phenyl) -urea, which was coupled to 5-amino-2-methoxy-pyridine according to Method D1c.

Item 39: 4- (3- (carboxy-phenoxy) -aniline was synthesized according to Method A11. 5- (Trifluor-methyl) -2-methoxy-aniline was converted to 5- (trifluor-methyl) - 2-methoxy-phenyl-isocyanate

Petition 870170083282, of 10/30/2017, p. 58/85 according to Method B1. The 5- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate was reacted with 4 (3- (carboxy-phenoxy) -aniline, according to Method C1f, to produce N- (5- (trifluorine- methyl) 2-methoxy-phenyl) -N '- (3-carboxy-phenyl) -urea, which was coupled to 4-morpholino-aniline according to Method D1c.

Item 40: 4- (3- (carboxy-phenoxy) -aniline was synthesized according to Method A11.

5- (trifluoro-methyl) -2-methoxy-aniline was converted to 5- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate according to Method B1. The 5- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate was reacted with 4 (3- (carboxy-phenoxy) -aniline, according to Method C1f, to produce N- (5- (trifluorine- methyl) 2-methoxy-phenyl) -N '- (3-carboxy-phenyl) -urea, which was coupled to N- (2-pyridyl) -piperazine according to Method D1c.

Item 41: 4- (3- (N-methyl-carbamoyl) -phenoxy) -aniline was synthesized according to Method A13. According to Method C3, 4-chloro-3- (trifluoro-methyl) -aniline was converted to the isocyanate, and then reacted with 4- (3- (N-methyl-carbamoyl) -phenoxy) -aniline, to produce urea.

Item 42: 4- (2-N-methyl-carbamyl-4-pyridyloxy) -aniline was synthesized according to

Method A2. 4-Chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (2-N-methyl-carbamyl4-pyridyloxy) -aniline, according to Method C1a, to produce urea.

Item 43: 4-Chloro-pyridine-2-carbonyl hydrochloride was reacted with ammonia according to Method A2, Step 3b, to form 4-chloro-2-pyridine-carboxamide. The 4-chloro-2-pyridine carboxamide was reacted with 4-amino-phenol according to Method A2, Step 4, to form 4- (2-carbamoyl-4-pyridyloxy) -aniline. According to Method C1a, 4-chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (2-carbamoyl-4-pyridyloxy) -aniline to produce urea.

Item 44: 4-Chloro-pyridine-2-carbonyl hydrochloride was reacted with ammonia according to Method A2, Step 3b, to form 4-chloro-2-pididine-carboxamide. The 4-chloro-2-pyridine-carboxamide was reacted with 3-amino-phenol, according to Method A2, Step 4, to form 3- (2-carbamoyl-4-pyridyloxy) -aniline. According to Method C1a, 3- (2carbamoyl-4-pyridyloxy) -aniline was reacted with 4-chloro-3- (trifluoromethyl) -phenyl-isocyanate to produce urea.

Item 45: The 4-chloro-N-methyl-2-pyridine-carboxamity was reacted, which was synthesized according to Method A2, Step 3a, with 3 amino-phenol, according to Method A2, Step 4, to form 3- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline. According to Method C1a, 3- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline was reacted with 4-chloro-3- (tri-fluoro-methyl) phenyl-isocyanate to produce urea.

Item 46: 5- (4-Amino-phenoxy) -isoindoline-1,3-dioine was synthesized according to

Method A3. According to Method C1a, 4-chloro-3- (trifluoro-methyl) -phenylisocyanate was reacted with 5- (4-amino-phenoxy) -isoindoline-1,3-dione, to produce urea.

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Item 47: 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -2-methyl-aniline was synthesized according to Method A5. According to Method C1c, 4-chloro-3- (trifluoromethyl) -phenyl-isocyanate was reacted with 5- (4-amino-phenoxy) -isoindoline-1,3-dione to produce urea.

Item 48: 4- (3- (N-methyl-sufamoyl) -4-phenyloxy) -aniline was synthesized according to Method A15. According to Method C1a, 4-chloro-3- (trifluoromethyl) -phenylisocyanate was reacted with 4- (3- (N-methyl-sufamoyl) -4-phenyloxy) -aniline to produce urea.

Item 49: 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. According to Method C1a, 4-chloro-3- (trifluoromethyl) -phenyl-isocyanate was reacted with 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -2-chloro-aniline , to produce urea.

Item 50: According to Method A2, Step 4, 5-amino-2-methyl-phenol was reacted with 4-chloro-N-methyl-2-pyridine-carboxamide, which had been synthesized according to Method A2 , Step 3b, to give 3- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -4-methyl-aniline. According to Method C1a, 4-chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 3- (2- (N-methyl-carbamoyl) 15 4-pyridyloxy) -4-methyl-aniline, to produce urea.

Item 51: 4-Chloro-pyridine-2-carbonyl chloride was reacted with ethyl amine, according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridine-carboxamide was reacted with 4-amino-phenol, according to Method A2, Step 4, to give 4- (2- (N-ethyl-carbamoyl) - 4 pyridyloxy) -aniline. According to Method C1a, 4-chloro-3- (trifluoro-methyl) -phenyl20 isocyanate was reacted with 4- (2- (N-ethyl-carba-moil) -4-pyridyloxy) -aniline to produce the urea.

Item 52: According to Method A2, Step 4, 4-amino-2-chloro-phenol was reacted with 4-chloro-N-methyl-2-pyridine-carboxamide, which had been synthesized according to Method A2 , Step 3b, to give 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -3-chloroaniline. 4- (2- (N-ethyl-carbamoyl) -4-pyridyloxy) -aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) 25 phenylisocyanate was reacted with 4- (2- (N-ethyl-carbamoyl) -4-pyridyloxy) -aniline to produce urea .

Item 53: 4- (4-Methylthiophenoxy) -1-nitro-benzene was oxidized, according to Method A19, Step 1, to give 4- (4-methyl-sulfonyl-phenoxy) -1-nitro-benzene. Nitro-benzene was reduced according to method A19, Step 2, to give 4- (4-methyl-sulfonyl-phenoxy) -1-aniline. According to Method C1a, 4-chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (2- (N30 methyl-sulfonyl-phenoxy) -1-aniline, to produce urea.

Item 54: 4-Bromo-benzene-sulfonyl was reacted with methyl-amine, according to Method A15, Step 1, to produce N-methyl-4-bromo-benzene-sulfonamide. N-methyl-4bromo-benzene-sulfonamide was coupled to phenol, according to Method A15, Step 2, to produce 4- (4- (N-methyl-sulfamoyl) -phenoxy) -benzene. The 4- (4- (N-methyl-sulfamoyl) -phenoxy) 35 benzene was converted to 4- (4- (N-methyl-sulfamoyl) -phenoxy) -1-nitro-benzene, according to Method A15, Step 3. 4- (4- (N-methyl-sulfamoyl) -phenoxy) -1-nitro-benzene was reduced to 4- (4 (N-methyl-sulfamoyl) -phenyloxy) -aniline, according to the Method A15, Step 4. According to the

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Method C1a, 4-chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (4- (N-methyl-sulfamoyl) phenyloxy) -aniline, to produce urea.

Item 55: The 5-hydroxy-2-methyl-pyridine was coupled to 1-fluoro-4-nitro-benzene, according to Method A18, Step 1, to give 4- (5- (2-methyl) -pyridyloxy) -1-nitro-benzene. Methyl5 pyridine was oxidized to carboxylic acid, and then it was esterified according to Method A18, Step 2, to give 4- (5- (2-methoxy-carbonyl) -pyridyloxy) -1-nitro-benzene. Nitrobenzene was reduced according to Method A18, Step 3, to give 4- (5- (2-methoxycarbonyl) -pyridyloxy) -aniline. Aniline was reacted with 4-chloro-3- (trifluoro-methyl) -phenyl-isocyanate, according to Method C1a, to produce urea.

Item 56: The 5-hydroxy-2-methyl-pyridine was coupled to 1-fluoro-4-nitro-benzene, according to Method A18, Step 1, to give 4- (5- (2-methyl) -pyridyloxy) -1-nitro-benzene. Methylpyridine was oxidized to carboxylic acid, and then it was esterified according to Method A18, Step 2, to give 4- (5- (2-methoxy-carbonyl) -pyridyloxy) -1-nitro-benzene. Nitrobenzene was reduced according to Method A18, Step 3, to give 4- (5- (2-methoxy15 carbonyl) -pyridyloxy) -aniline. Aniline was reacted with 4-chloro-3- (trifluoro-methyl) -phenyl-isocyanate, according to Method C1a, to give N- (4-chloro-3- (trifluor-methyl) -phenyl) -N '- (4- (2- (methoxycarbonyl) -5-pyridyloxy) -phenyl) -urea. The methyl ester was reacted with methyl amine, according to Method D2, to produce N- (4-chloro-3- (trifluoromethyl) -phenyl) -N '- (4- (2- (N- methyl-carbamoyl) -5pyridyloxy) -phenyl) -urea.

Item 57: N- (4-chloro-3- (trifluoro-methyl) -phenyl-N '- (4-amino-phenyl) -urea was prepared according to Method C1d. N- (4-chloro- 3- (trifluoro-methyl) -phenyl-N '- (4-amino-phenyl) -urea was coupled to mono-methyl isophthalate according to Method D1, to produce urea.

Item 58: N- (4-chloro-3- (trifluoro-methyl) -phenyl-N '- (4-amino-phenyl) -urea was prepared according to Method C1d. N- (4-chloro- 3- (trifluoro-methyl) -phenyl-N '- (4-amino-fe-nil) -urea was coupled to mono-methyl isophthalate according to Method D1, to produce N- (4-chloro3- (trifluorine -methyl) -phenyl-N '- (4- (3-methoxy-carbonyl-phenyl) -car-boxy-amino-phenyl) -urea. According to Method D2, N- (4-chlorine) was reacted -3- (trifluoro-methyl) -phenyl-N '- (4- (3-methoxy-carbonyl-phenyl) carboxy-amino-phenyl) -urea with methyl-amine, to produce the corresponding methyl-amide.

Item 59: 4-Chloro-pyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N, N-dimethyl-2-pyridine-carboxamide was reacted with 4-amino-phenol according to Method A2, Step 4, to give 4- (2- (N, Ndimethyl-carbamoyl) ) -4-pyridyloxy) -aniline. According to Method C1a, 4-chloro-3 (trifluoromethyl) -phenyl-isocyanate was reacted with 4- (2- (N, N-dimethyl-carbamoyl) -4-pyridyloxy) -aniline to produce the urea.

Item 60: 4-hydroxy-acetophenone was reacted with 4-fluoro-nitro-benzene, according to Method A13, Step 1, to give 4- (4-acetyl-phenoxy) -nitro-benzene. Nitro-benzene was reduced according to Method A13, Step 4, to produce 4- (4-acetyl-phenoxy) -aniline, which was

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Item 61: The 4- (3-carboxy-phenoxy) -1-nitro-benzene was synthesized according to Mé5 all A13, Step 2. The 4- (3-carboxy-phenoxy) -1-nitro-benzene was coupled to 4- (2-amino-ethyl) morpholine, according to Method A13, Step 3, to give 4- (3- (N- (2-morpholinyl-ethyl) carbamoyl) -phenoxy) -1-nitro-benzene . According to Method A13, Step 4, 4- (3- (N- (2morpholinyl-ethyl) -carbamoyl) -phenoxy) -1-nitro-benzene was reduced to 4- (3- (N- ( 2-morpholinyl-ethyl) carbamoyl) -phenoxy) -aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) 10 phenyl-isocyanate was reacted with 4- (3- (N- (2-morph-linyl-ethyl) -carbamoyl) -phenoxy) -aniline, to produce urea.

Item 62: 4- (3-carboxy-phenoxy) -1-nitro-benzene was synthesized according to Method A13, Step 2. 4- (3-carboxy-phenoxy) -1-nitro-benzene was coupled to 1- (2-amino-ethyl) piperidine, according to Method A13, Step 3, to give 4- (3- (N- (2-piperidyl-ethyl) 15 carbamoyl) -phenoxy) -1-nitro-benzene . According to Method A13, Step 4, the 4- (3- (N- (2piperidyl-ethyl) -carbamoyl) -phenoxy) -1-nitro-benzene was reduced to 4- (3- (N- ( 2-piperidyl-ethyl) carbamoyl) -phenoxy) -aniline. According to Method C1a, 4-chloro-3- (trifluoro-methyl) phenyl-isocyanate was reacted with 4- (3- (N- (2-piperi-dil-ethyl) -carbamoyl) -phenoxy) - aniline, to produce urea.

Item 63: 4- (3-carboxy-phenoxy) -1-nitro-benzene was synthesized according to Method A13, Step 2. 4- (3-carboxy-phenoxy) -1-nitro-benzene was coupled to tetrahydrofur-furylamine, according to Method A13, Step 3, to give 4- (3- (N- (tetrahydrofurfuryl-methyl) carbamoyl) -phenoxy) -1-nitro-benzene. According to Method A13, Step 4, 4- (3- (N (tetrahydrofurfuryl-methyl) -carbamoyl) -phenoxy) -1-nitro-benzene was reduced to 4- (3- (N25 (tetrahydrofurfuryl-methyl) -carbamoyl) -phenoxy) -aniline. According to Method C1a, 4-chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (3- (N- (tetrahydrofurfuryl-methyl) -carbamoyl) phenoxy) -aniline, to produce urea .

Item 64: 4- (3-carboxy-phenoxy) -1-nitro-benzene was synthesized according to Method A13, Step 2. 4- (3-carboxy-phenoxy) -1-nitro-benzene was coupled to 2-amino-ethyl-1-ethyl30 pyrrolidine, according to Method A13, Step 3, to give 4- (3- (N - ((1-methyl-pyrrolidinyl) methyl) -carbamoyl) -phenoxy) -1- nitro-benzene. According to Method A13, Step 4, 4- (3- (N (((1-methyl-pyrrolidinyl) -methyl) -carbamoyl) -phenoxy) -1-nitro-benzene was reduced to 4- (3- ( N - ((1-methylpyrrolidinyl-methyl) -carbamoyl) -phenoxy) -aniline According to Method C1a, 4-chloro3- (trifluoromethyl) -phenyl-isocyanate was reacted with 4- (3- ( N - ((1-methyl-pyrrolidinyl-methyl) -carbamoyl) -phenoxy) 35 aniline, to produce urea.

Item 65: 4-Chloro-N-methyl-pyridine-carboxamide was synthesized according to Method A2, Step 3b. Chloro-pyridine was reacted with 4-amino-thiophenol, according to Method

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A2, Step 4, to give 4- (4- (2- (N-methyl-carbamoyl) -phenylthio) -aniline. According to Method C1a, 4-chloro-3- (trifluor-methyl) - was reacted - phenylisocyanate with 4- (4- (2- (N-methyl-carbamoyl) phenylthio) -aniline, to produce urea.

Item 66: 4-Chloro-pyridine-2-carbonyl chloride was reacted with isopropyl amine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridine-carboxamide was reacted with 4-amino-phenol, according to Method A2, Step 4, to give 4- (2- (Nisopropyl-carbamoyl) -4- pyridyloxy) -aniline. According to Method C1a, 4-chloro-3 (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (2- (N-isopropyl-carbamoyl) -4-pyridyloxy) -aniline to produce urea.

Item 67: N- (4-chloro-3- (trifluoro-methyl) -phenyl-N '- (4-ethoxy-carbonyl-phenyl) -urea was synthesized according to Method C1e. N- (4- chloro-3- (trifluoro-methyl) -phenyl-N '- (4-ethoxy-carbonylphenyl) -urea was saponified according to Method D3, to give N- (4-chloro-3- (trifluoromethyl) -phenyl- N '- (4-carboxy-phenyl) -urea N- (4-chloro-3- (trifluoro-methyl) -phenyl-N' - (4-carboxy-phenyl) urea was coupled to 3-methyl-carbamoyl -aniline, according to Method D1b, to give N- (415 chloro-3- (trifluoro-methyl) -phenyl-N '- (4- (3-methyl-carbamoyl-phenyl) -urea.

Item 68: 5- (4-Amino-phenoxy) -2-methyl-isoindoline -1,3-dione was synthesized according to Method A9. According to Method C1a, 4-chloro-3- (trifluoromethyl) -phenylisocyanate was reacted with 5- (4-amino-phenoxy) -2-methyl-isoindolin-1,3-dione to produce urea .

Item 69: 4-Chloro-N-methyl-pyridine-carboxamide was synthesized as described in Mé20 all A2, Step 3b. Chloro-pyridine was reacted with 3-amino-thiophenol, according to Method A2, Step 4, to give 3- (4- (2- (N-methyl-carbamoyl) -phenylthio) -aniline. Method C1a, 4-chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 3- (4- (2- (N-methyl-carbamoyl) phenylthio) -aniline to produce urea.

Item 70: 4- (2- (N- (2-morpholin-4-yl-ethyl) -carba-moil) -pyridyloxy) -aniline was synthesized according to Method A10. According to Method C1a, 4-chloro-3- (trifluoro-methyl) phenyl-isocyanate was reacted with 4- (2- (N- (2-morpholin-4-yl-ethyl) -carbamoyl) -pyridyloxy) -aniline, to produce urea.

Item 71: 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -aniline was synthesized according to Method A14. 4-Chloro-3- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate was reacted with 4- (3- (5-methoxy30 carbonyl) -pyridyloxy) -aniline, according to Method C1a, to produce the urea. N- (4-chloro3- (trifluoro-methyl) -phenyl-N '- (4- (3- (5-methoxy-carbonyl-pyridyl) -oxy) -phenyl-urea was saponified, according to Method D4 , Step 1, and the corresponding acid was coupled to 4- (2-amino-ethyl) morpholine, to produce the amide.

Item 72: 4- (3- (5-methoxy-carbonyl) -pyridyloxy) -aniline was synthesized according to

Method A14. 4-Chloro-3- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate was reacted with 4- (3- (5-methoxycarbonyl) -pyridyloxy) -aniline, according to Method C1a, to produce urea . The N- (5trifluoro-methyl) -2-methoxy-phenyl-N '- (4- (3- (5-methoxy-carbonyl-pyridyl) -oxy) -fe-nil-urea was saponifiedPetition 870170083282, of 30/10 / 2017, page 63/85 da, according to Method D4, Step 1, and the corresponding acid was coupled to methylamine, according to Method D4, Step 2, to produce the amide.

Item 73: 4- (3- (5-Methoxy-carbonyl) -pyridyloxy) -aniline was synthesized according to Method A14. 4-Chloro-3- (trifluoro-methyl) -2-methoxy-phenyl-isocyanate was reacted with 4- (3- (5-methoxy5 carbonyl) -pyridyloxy) -aniline, according to Method C1a, to produce the urea. N- (5trifluoro-methyl) -2-methoxy-phenyl-N '- (4- (3- (5-methoxy-carbonyl-pyridyl) -oxy) -fe-nil-urea was saponified, according to the Method D4, Step 1, and the corresponding acid was coupled to N, Ndimethyl-ethylene-diamine, according to Method D4, Step 2, to produce the amide.

Item 74: 4-Chloro-pyridine-2-carbonyl hydrochloride was reacted with 2-hydroxy-ethyl10-amine, according to Method A2, Step 3b, to form 4-chloro-N- (2-triisopropyl-silyloxy ) ethyl-pyridine-2-carboxamide. 4-Chloro-N- (2-triisopropyl-silyloxy) -ethyl-pyridine-2-carboxamide was reacted with triisopropyl-silyl chloride, followed by 4-amino-phenol, according to Method A17, to form 4- ( 4- (2- (N- (2-triisopropyl-silyloxy) -ethyl-carbamoyl) -pyridyloxy-aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) -phenyl-isocyanate was reacted with 4- (4- (2- (N15 (2-triiso-propyl-silyloxy) -ethyl-carbamoyl) -pyridyloxy-aniline, to produce N- (4-chloro-3 - ((trifluoromethyl) -phenyl) -N '- (4- (4- (2- (N-triisopropyl-silyloxy) -ethyl-carbamoyl) -pyridyloxy-phenyl) -urea.

Item 75: 4- (3-carboxy-phenoxy) -aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (3- (5-methoxy-carbo-nyl) -pyridyloxy) aniline, according to Method C1f, to produce urea, which was coupled to 3-amino20 pyridine, according to Method D1c.

Item 76: 4- (3-Carboxy-phenoxy) -aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (3-carboxy-phenoxy) -aniline, according to Method C1f, to produce urea, which was coupled to N- ( 4-acetyl-phenyl) -piperazine, according to Method D1c.

Item 77: 4- (3-Carboxy-phenoxy) -aniline was synthesized according to Method A11.

4-Chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (3-carboxy-phenoxy) -aniline, according to Method C1f, to produce urea, which was coupled to 4-fluorine -aniline, according to Method D1c.

Item 78: 4- (3-Carboxy-phenoxy) -aniline was synthesized according to Method A11.

4-Chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (3-carboxy-phenoxy) -aniline, according to Method C1f, to produce urea, which was coupled to 4- ( dimethyl-amino) -aniline, according to Method D1c.

Item 79: 4- (3-carboxy-phenoxy) -aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (3-carboxy-phenoxy) -aniline, according to Method C1f, to produce urea, which was coupled to N- phenyl-ethylene-diamine, according to Method D1c.

Item 80: 4- (3-carboxy-phenoxy) -aniline was synthesized according to Method A11.

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4-Chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (3-carboxy-phenoxy) -aniline, according to Method C1f, to produce urea, which was coupled to 2-methoxy -ethylamine, according to Method D1c.

Item 81: 4- (3-Carboxy-phenoxy) -aniline was synthesized according to Method A11. 5 4-Chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (3-carboxy-phenoxy) -aniline, according to Method C1f, to produce urea, which was coupled to 5- amino-2-methoxy-pyridine, according to Method D1c.

Item 82: 4- (3-carboxy-phenoxy) -aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (3-carboxy-phenoxy) -aniline, according to Method C1f, to produce urea, which was coupled to 4- morpholino-aniline, according to Method D1c.

Item 83: 4- (3-carboxy-phenoxy) -aniline was synthesized according to Method A11. 4-Chloro-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (3-carboxy-phenoxy) -aniline, according to Method C1f, to produce urea, which was coupled to N- ( 2-pyridyl) -piperazine, according to Method D1c.

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

Method A17, to form 4- (4- (2- (N-2-triisopropyl-silyloxy) -ethyl-carbamoyl) -pyridyloxy-aniline. According to Method C1a, 4-chloro-3- (trifluorine was reacted -methyl) -phenyl-isocyanate with 4- (4- (2- (N (2-triisopropyl-silyloxy) -ethyl-carbamoyl) -pyridyloxy-aniline, to produce N- (4-chloro-3 - ((trifluoromethyl) -phenyl) -N '- (4- (4- (2- (N- (2-tri-sopropyl-silyloxy) -ethyl-carbamoyl) -pyridyloxy-phenyl) -urea. Urea was unprotected, according to Method 5, to produce N- (4-chloro-3 - ((trifluoro-methyl) -phenyl) 25 N '- (4- (4- (4- (2- (N- (2-hydroxy) -ethyl- carbamoyl) -pyridyloxy-phenyl) -urea.

Item 85: 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline was synthesized according to

Method A2. 4-bromo-3- (trifluoro-methyl) -aniline was converted to 4-bromo-3- (trifluoro-methyl) phenylisocyanate, according to Method B1. According to method C1a, 4bromo-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline to produce urea .

Item 86: 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. 4-bromo-3- (trifluoro-methyl) -aniline was converted to 4-bromo-3 (trifluoro-methyl) -phenyl-isocyanate, according to Method B1. According to method C1a, 4-bromo-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (2- (N-methyl-carbamoyl) -435 pyridyloxy) -2-chloro-aniline , to produce urea.

Item 87: According to Method A2, Step 4, 4-amino-2-chloro-phenol was reacted with

4-chloro-N-methyl-2-pyridine-carboxamide, which had been synthesized according to the Method

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A2, Step 3b, to give 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -3-chloroaniline. 4-bromo-3 (trifluoro-methyl) -aniline was converted to 4-bromo-3- (trifluoro-methyl) -phenyl-isocyanate, according to Method B1. According to method C1a, 4-bromo-3- (trifluoromethyl) -phenylisocyanate was reacted with 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -3-chloroaniline, to produce urea.

Item 88: 4-Chloro-pyridine-2-carbonyl chloride was reacted with ethyl amine, according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridine-carboxamide was reacted with 4-amino-phenol, according to Method A2, Step 4, to give 4- (2- (N-ethyl-carbamoyl) - 4 pyridyloxy) -aniline. 4-bromo-3- (trifluoro-methyl) -aniline was converted to 4-bromo-3- (trifluoro-methyl) -phenyl-isocyanate, according to Method B1. According to method C1a, 4-bromo-3- (trifluoromethyl) -phenyl-isocyanate was reacted with 4- (2- (N-ethyl-carbamoyl) -4-pyridyloxy) -aniline to produce urea.

Item 89: 4-Chloro-N-methyl-2-pyridine-carboxamide, which had been synthesized according to Method A2, Step 3a, was reacted with 3-amino-phenol, according to Method A2, Step 4, to give 3- (2- (N-ethyl-carbamoyl) -4-pyridyloxy) -aniline. 4-bromo-3- (trifluoro-methyl) 15 aniline was converted to 4-bromo-3- (trifluoro-methyl) -phenyl-isocia-nate, according to Method B1. According to method C1a, 4-bromo-3- (trifluoro-methyl) -phenyl-isocyanate was reacted with 3- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline to produce urea.

Item 90: According to Method A2, Step 4, 5-amino-2-methyl-phenol was reacted with

4-chloro-N-methyl-2-pyridine-carboxamide, which had been synthesized according to the Method

A2, Step 3b, to give 3- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -4-methyl-aniline. 4-bromo-3- (trifluoro-methyl) -aniline was converted to 4-bromo-3- (trifluoro-methyl) -phenyl-isocyanate, according to Method B1. According to method C1a, 4-bromo-3- (trifluoromethyl) -phenylisocyanate was reacted with 3- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -4-methyl-aniline, to produce urea.

Item 91: 4-Chloro-pyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N, N-dimethyl-2-pyridine-carboxamide was reacted with 4-amino-phenol according to Method A2, Step 4, to give 4- (2- (N, Ndimethyl-carbamoyl) ) -4-pyridyloxy) -aniline. 4-bromo-3- (trifluoro-methyl) -aniline was converted to 4bromo-3- (trifluoro-methyl) -phenyl-isocia-nate, according to Method B1. According to method C1a, 4-bromo-3- (trifluoromethyl) -phenyl-isocyanate was reacted with 4- (2- (N, N-dimethyl30 carbamoyl) -4-pyridyloxy) -aniline to produce urea.

Item 92: 4-Chloro-N-methyl-pyridine-carboxamide was synthesized according to Method A2, Step 3b. Chloro-pyridine was reacted with 4-amino-thiophenol, according to Method A2, Step 4, to give 4- (4- (2- (N-methyl-carbamoyl) -phenylthio) -aniline. bromo-3- (trifluoro-methyl) aniline was converted to 4-bromo-3- (trifluoro-methyl) -phenyl-isocyanate, according to the Method

B1. According to method C1a, 4-bromo-3- (trifluoromethyl) -phenyl-isocyanate was reacted with 4- (4- (2- (N-methyl-carbamoyl) -phenylthio) -aniline to produce urea.

Item 93: 4-chloro-N-methyl-pyridine-carboxamide was synthesized according to MéPetição 870170083282, of 10/30/2017, p. 66/85 all A2, Step 3b. Chloro-pyridine was reacted with 3-amino-thiophenol, according to Method A2, Step 4, to give 3- (4- (2- (N-methyl-carbamoyl) -phenylthio) -aniline. bromo-3- (trifluoro-methyl) aniline was converted to 4-bromo-3- (trifluoro-methyl) -phenyl-isocyanate according to Method B1 According to method C1a, 4-bromine was reacted -3- (trifluoro-methyl) -phenyl-isocyanate with 3- (4- (2- (N-methyl-carbamoyl) -phenylthio) -aniline, to produce urea.

Item 94: 4- (2- (N- (2-morpholin-4-yl-ethyl) -carba-moil) -pyridyloxy) -aniline was synthesized according to Method A10. 4-bromo-3- (trifluoro-methyl) -aniline was converted to 4-bromo-3 (trifluoro-methyl) -phenyl-isocyanate, according to Method B1. According to method C1a, 4-bromo-3- (trifluoromethyl) -phenyl-isocyanate was reacted with 4- (2- (N- (2-morpholin-4-yl-ethyl) 10 carbamoyl) -pyridyloxy) -aniline, to produce urea.

Item 95: 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline was synthesized according to Method A2. 4-chloro-2-methoxy-5- (trifluoro-methyl) -aniline was synthesized according to Method A7. 4-chloro-2-methoxy-5- (trifluoro-methyl) -aniline was converted to 4-chloro-2-methoxy-5 (trifluoro-methyl) -phenyl-isocyanate according to Method B1. According to Method C1a, 4-chloro-2-methoxy-5- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline, to produce urea.

Item 96: 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. 4-chloro-2-methoxy-5- (trifluoro-methyl) -aniline was synthesized according to Method A7. 4-chloro-2-methoxy-5- (trifluoro-methyl) -aniline was converted to 4-chloro-220 methoxy-5- (trifluoro-methyl) -phenyl-isocyanate according to Method B1. According to Method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) -phenyl-isocyanate was reacted with 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -2- chloroaniline, to produce urea.

Item 97: According to Method A2, Step 4, 4-amino-2-chloro-phenol was reacted with

4-chloro-N-methyl-2-pyridine-carboxamide, which had been synthesized according to the Method

A2, Step 3b, to give 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -3-chloroaniline. 4-Chloro-2-methoxy -5- (trifluoromethyl) -aniline was synthesized according to Method A7. 4-chloro-2-methoxy-5- (trifluoro-methyl) -aniline was converted to 4-chloro-2-methoxy-5- (trifluoro-methyl) -phenylisocyanate according to Method B1. According to Method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) -phenyl-isocyanate was reacted with 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -3-chlorine30 aniline , to produce urea.

Item 98: 4-Chloro-N-methyl-pyridine-carboxamide was synthesized according to Method A2, Step 3a. Chloro-pyridine was reacted with 3-amino-phenol, according to Method A2, Step 4, to form 3- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline. 4-chloro-2-methoxy-5 (trifluoro-methyl) -aniline was synthesized according to Method A7. 4-chloro-2-methoxy-5- (trifluoro35 methyl) -aniline was converted to 4-chloro-2-methoxy-5- (trifluoro-methyl) -phenyl-isocyanate, according to Method B1. According to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) -phenyl-isocyanate was reacted with 3- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline, to produce the

Petition 870170083282, of 10/30/2017, p. 67/85 urea.

Item 99: 4-Chloro-pyridine-2-carbonyl chloride was reacted with ethyl amine, according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridine-carboxamide was reacted with 4-amino-phenol, according to Method A2, Step 4, to give 4- (2- (N-ethyl5 carbamoyl) -4 -pyridyloxy) -aniline. 4-chloro-2-methoxy-5- (trifluoro-methyl) -aniline was synthesized according to Method A7. 4-chloro-2-methoxy-5- (trifluoro-methyl) -aniline was converted to 4-chloro2-methoxy-5- (trifluoro-methyl) -phenyl-isocyanate, according to Method B1. According to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) -phenyl-isocyanate was reacted with 4- (2- (N-ethylcarbyl moil) -4-pyridyloxy) - aniline, to produce urea.

Item 100: 4-Chloro-pyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N, N-dimethyl-2-pyridine-carboxamide was reacted with 4-amino-phenol according to Method A2, Step 4, to give 4- (2- (N, Ndimethyl-carbamoyl) ) -4-pyridyloxy) -aniline. 4-chloro-2-methoxy-5- (trifluoro-methyl) -aniline was synthesized according to Method A7. 4-chloro-2-methoxy-5- (trifluoro-methyl) -aniline was converted to

4-chloro-2-methoxy-5- (trifluoro-methyl) -phenyl-isocyanate, according to Method B1. According to method C1a, 4-chloro-2-methoxy-5- (trifluoro-methyl) -phenyl-isocyanate was reacted with 4- (2 (N-ethyl-carbamoyl) -4-pyridyloxy) -aniline , to produce urea.

Item 101: 4-Chloro-N-methyl-2-pyridine-carboxamide was synthesized according to Method A2, Step 3a. Chloro-pyridine was reacted with 3-amino-phenol, according to Method 20 of A2, Step 4, to form 3- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline. 2-Amino-3-methoxy-naphthalene was synthesized according to Method A1. According to Method C3, 2-amino-3-methoxy-naphthalene was reacted with bis- (trichloro-methyl) carbonate, followed by 3 (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline , to form urea.

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

Item 103: 4-Chloro-N-methyl-2-pyridine-carboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridine-carboxamide was reacted with 4-amino30 phenol, according to Method A2, Step 4, using DMAC in place of DMF, to give 4- (2 (N-methyl -carbamoyl) -4-pyridyloxy) -aniline. According to Method C2b, the reaction of 3-amino2-methoxy-quinoline with CDI, followed by 4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) -aniline, produced bis- (4- ( 2- (N-methyl-carbamoyl) -4-pyridyloxy) -phenyl) -urea.

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

TABLES

The compounds listed in Tables 1-6 below have been synthesized according to the

Petition 870170083282, of 10/30/2017, p. 68/85 generic methods provided above, and the more detailed example procedures are in the listings in the items above, and the characterizations are in the tables.

TABLE 1

3-tert-butyl-phenyl-ureas

Item R Federal Police (Ç) HPLC (min) TLC RF System of Solvents of TLC Spectr. Pasta [Source] Method of Synthesis 1 o _x V NH 0.22 50% EtOAc / 50% hexane 418 (M + H) + (HPLC ES-MS) A13 C3 2 0.58 50% EtOAc / 50% hexane 403 (M + H) ⁺ (HPLC ES-MS) A13 C3 3 Vnh / = <Me —V — O — 7 laugh— OMe 133- 135 0.68 100% EtOAc 448 (M + H) ⁺ (FAB) A8 C2d

TABLE 2

5-tert-butyl-2-methoxy-phenyl-ureas

Item R mp ( ^o C) HPLC (min) TLC RF System of Solvents of TLC Spectr. Pasta [Source] Method of Synthesis

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4 O Vnh 5.93 448 (M + H) + (HPLC ES-MS) A13 B1 C1a 5 o _x Vnh 120- 122 0.67 100% EtOAc 478 (M + H) ⁺ (FAB) A8 C2d 6 Y ^NH 0 0.40 50% EtOAc / 50% hexane 460 (M + H) ⁺ (HPLC ES-MS) A3 C2d 7 0.79 50% EtOAc / 50% hexane 446 (M + H) ⁺ (HPLC ES-MS) A12 C2d

TABLE 3

5- (trifluoro-methyl) -2-methoxy-phenyl-ureas

Item R mp ( ^o C) HPLC (min) TLC RF System of Solvents of TLC Spectr. Pasta [Source] Method of Synthesis 8 the _K V-NH “ 250 (dec) 460 (M + H) ⁺ (FAB) A13 C2a 9 —N Me 206- 208 0.54 10% MeOH / 90% CH2Cl2 446 (M + H) ⁺ (HPLC ES-MS) A3 step 2, A8 step 4, B1, C1a

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10 0.33 50% EtOAc / 50% ether pet 445 (M + H) + (HPLC ES-MS) A13 C3 11 - / 5> -NH χ == (Me ° A_? ^N 0.20 2% Et3N / 98% EtOAc 461 (M + H) ⁺ (HPLC ES-MS) A2 C4 12 -Q Vnh ₂ 0.27 1% Et3N / 99% EtOAc 447 (M + H) ⁺ (HPLC ES-MS) A2 C4 13 Vnh ^Me 0.62 100% EtOAc 461 (M + H) ⁺ (FAB) A2 C2a 14 0 Y- nh ₂ 0-0 114- 117 0.40 1% Et3N / 99% EtOAc 447 (M + H) ⁺ (FAB) A2 C4 15 Vnh yv / = \ ^Me —7 V — 0 — Λ — OMe 232- 235 0.54 100% EtOAc 490 (M + H) ⁺ (FAB) A8 C2d 16 0 Me V— NH 210- 213 0.29 5% MeOH / 45% EtOAc / 50% ether pet. 475 (M + H) ⁺ (HPLC ES-MS) A5 B1 C1c 17 0 Cl y — NH 187- 188 0.17 50% EtOAc / 50% ether pet. 495 (M + H) ⁺ (HPLC ES-MS) A6 B1 C1a 18 -O ^NH 2 ° -O 0.48 100% EtOAc 475 (M + H) ⁺ (HPLC ES-MS) A2 step 4, B1 C1a 19 0> - NH oo ^a 194- 196 0.31 5% MeOH / 45% EtOAc / 50% ether pet. 475 (M + H) ⁺ (HPLC ES-MS) A2 B1 C1a

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20 O Cl? -NH 214- 216 0.25 5% MeOH / 45% EtOAc / 50% ether pet 495 (M + H) + (HPLC ES-MS) A2 C1a 21 - ⁰ '= /' —J Me 208- 210 0.30 50% EtOAc / 50% hexane 481 (M + H) ⁺ (HPLC ES-MS) A19 C2a 22 0 _Vnh ₂ 188- 190 0.30 70% EtOAc / 50% hexane 447 (M + H) ⁺ (HPLC ES-MS) A15, Step 4, C1a 23 Y ^NH o 0.50 70% EtOAc / 30% hexane 472 (M + H) ⁺ (FAB) A3 B1 C1a 24 0 Me 203- 205 0.13 100% EtOAc 479 (M + H) ⁺ (HPLC ES-MS) A2 B1 C1a 25 \ ^ nh 0.09 75% EtOAc / 25% hexane 458 (M + H) ⁺ (HPLC ES-MS) A12 C2d 26 MeO - ^z Me 169- 171 0.67 50% EtOAc / 50% ether pet. 474 (M + H) ⁺ (HPLC ES-MS) A13 Step 1, A13 step 4, A16, B1, C1a 27 <3 V-NH 218- 219 0.40 50% EtOAc / 50% ether pet. 477 (M + H) ⁺ (HPLC ES-MS) A2 step 3b, A2 step 4, B1, C1a 28 —C> ° ^ o ^ ° 'y.NMe O 212- 214 0.30 40% EtOAc / 60% hexane A9 B1 C1a

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29 ^s ~ O 0.33 50% EtOAc / 50% ether pet 474 (M + H) + (HPLC ES-MS) A2 step 3b, A2 step 4, B1, C1a 30 0 V-NH ^Pr 210- 211 A2 B1 C1a 31 JVnh O ° -Q Á ⁿ a '—o 210- 204 0.43 10% MeOH / CH2Cb A14 B1 C1a D4 32 0. Vnh ^Me \ = / \ _ _N 247- 249 0.57 10% MeOH / CH2Cb A14 B1 C1a D4 33 C> - / p — 0—4 / N-Me '—N Me 217- 219 0.07 10% MeOH / CH2Cb A14 B1 C1a D4 34 O Hnh 0.11 70% EtOAc / 30% hexane A11 B1 C1f D1c 35 O ^ -N > 0 0.38 70% EtOAc / 30% hexane A11 B1 C1f D1c 36 F— / HnH -cy ° -o 0.77 70% EtOAc / 30% hexane A11 B1 C1f D1c 37 ^μ \ _λλ_ _νη Me '-' / = 0 HD 0.58 70% EtOAc / 30% hexane A11 B1 C1f D1c

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38 MeO — 7 / —NH 0.58 70% EtOAc / 30% hexane A11 B1 C1f D1c 39 FAN 0 N— <o — NH - ^z % = / V = o 0.17 70% EtOAc / 30% hexane A11 B1 C1f D1c 40 N ^? \ l - <^ \ - NH \ = / \ - / \ = J 0.21 70% EtOAc / 30% hexane A11 B1 C1f D1c

TABLE 4

3- (trifluoro-methyl) -4-chloro-phenyl-ureas

Η H

Item R Federal Police (° C) HPLC (min) TLC RF System of Solvents of TLC Spectr. Pasta [Source] Method of Synthesis 41 Vnh 163- 165 0.08 50% EtOAc / 50% ether pet 464 (M + H) + (HPLC ES-MS) A13 C3 42 c> V-NH 215 0.06 50% EtOAc / 50% ether pet 465 (M + H) ⁺ (HPLC ES-MS) A2 C1a 43 o 2 ^ NH ₂ 0.10 50% EtOAc / 50% ether pet 451 (M + H) ⁺ (HPLC ES-MS) A2 C1a

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44 -The JV-NH, 0.25 30% EtOAc / 70% ether pet 451 (M + H) + (HPLC ES-MS) A2 C1a 45 ° -W 0.31 30% EtOAc / 70% ether pet 465 (M + H) ⁺ (HPLC ES-MS) A2 C1a 46 Y ^NH o 176- 179 0.23 40% EtOAc / 60% hexane 476 (M + H) ⁺ (FAB) A3 C1a 47 0 Me V — NH 4> ^ ^Me 0.29 5% MeOH / 45% EtOAc / 50% ether pet. 478 (M + H) ⁺ (HPLC ES-MS) A5 C1c 48 Ck P 'S-NH ^Me 206- 209 A15 C1a 49 0 Cl y-NH ^> ^ ^Me 147- 151 0.22 50% EtOAc / 50% ether pet. 499 (M + H) ⁺ (HPLC ES-MS) A6 C1a 50 - / —Me —NH p = \ Me ^o_ w 0.54 100% EtOAc 479 (M + H) ⁺ (HPLC ES-MS) A2 C1a 51 V ^nh O 187- 189 0.33 5% MeOH / 45% EtOAc / 50% ether pet. 479 (M + H) ⁺ (HPLC ES-MS) A2 C1a 52 O Cl y- NH 219 0.18 5% MeOH / 45% EtOAc / 50% ether pet. 499 (M + H) ⁺ (HPLC ES-MS) A2 C1a 53 Λ \ Z = \ ⁰ - ° —C / ^- s, '° ^ == /' - 'Me 246- 248 0.30 50% EtOAc / 50% hexane 485 (M + H) ⁺ (HPLC A19, C1a

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ES-MS) 54 , -s r = \ O -00 ° NH Me 196- 200 0.30 70% EtOAc / 30% hexane 502 (M + H) + (HPLC ES-MS) A15 C1a 55 228- 230 0.30 30% EtOAc / 70% CH2Cb 466 (M + H) ⁺ (HPLC ES-MS) 56 / = ^N v // ° ^{x = /} NH Me ' 238- 245 57 221- 222 0.75 80% EtOAc / 20% hexane 492 (M + H) ⁺ (FAB) C1d D1a 58 Vnh 247 0.35 100% EtOAc C1d D1a D2 59 198- 200 0.09 100% EtOAc 479 (M + H) ⁺ (HPLC ES-MS) A2 C1a 60 MeO 158- 160 0.64 50% EtOAc / 50% ether pet 61 JVnH -F2r ^aJ 2j -O 195- 197 0.39 10% MeOH / CH2Q2 A13 C1a 62 0 NH θ 170- 172 0.52 10% MeOH / CH2Cl2 A13 C1a 63 0 y — NH 0 ^ 168- 171 0.39 10% MeOH / CH2Cl2 A13 C1a 64 0 ^Et > 7- NH N ^, -od 176- 177 0.35 10% MeOH / CH2Cl2 A13 C1a

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65 V-NH 130- 133 487 (M + H) + (HPLC ES-MS) A2 B1 C1a 66 c> Vnh ^PrJ 155 A2 C1a 67 O Vnh 225- 229 0.23 100% EtOAc C1e D3 D1b 68 \ _- NMe O 234- 236 0.29 40% EtOAc / 60% hexane A9 C1a 69 0.48 50% EtOAc / 50% ether pet 481 (M + H) ⁺ (HPLC ES-MS) 70 o _v - <λ ^ο -ν θ 0.46 5% MeOH / 95% CH2Q2 564 (M + H) ⁺ (HPLC ES-MS) A10 C1a 71 Ύ-ΝΗ ~ cy ^o_ Q -θ 199- 201 0.50 10% MeOH / CH2Cl2 A14 C1a D4 72 0> -NH ' ^Me 235- 237 0.55 10% MeOH / CH2Cl2 A14 C1a D4 73 0 —O ~ ° ^ O / ^N ' ^Me ' - '' —N Me 200- 201 0.21 50% MeOH / CH2Cl2 A14 C1a D4 74 C> ^NH OSi (Pr-i) ₃ 145- 148 75 N ~ ^ ? Vnh 0.12 70% EtOAc / 30% hexane 527 (M + H) ⁺ (HPLC ES-MS) A11 C1f D1c

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76 0 Me- Q 0 0.18 70% EtOAc / 30% hexane A11 C1f D1c 77 F— / y — NH )> = o -ο-θ-ο 0.74 70% EtOAc / 30% hexane A11 C1f D1c 78 ^Me / T N - < ^z 7 — NH Me Ϋ = Ο 0.58 70% EtOAc / 30% hexane A11 C1f D1c 79 0 Vnh -0 ° -0 / * ^h o 0.47 70% EtOAc / 30% hexane 569 (M + H) + (HPLC ES-MS) A11 C1f D1c 80 0 V-NH —C '/ - θ — c oMe 0.18 70% EtOAc / 30% hexane 508 (M + H) ⁺ (HPLC ES-MS) A11 C1f D1e 81 N— \ MeO—? V-NH ^ -θ <Γ 0.58 70% EtOAc / 30% hexane 557 (M + H) ⁺ (HPLC ES-MS) A11 C1f D1c 82 The N— / V- NH γ> ° <Γ 0.37 70% EtOAc / 30% hexane 611 (M + H) ⁺ (HPLC ES-MS) A11 C1f D1c 83 <Q O N ^ - ° <Γ 0.19 70% EtOAc / 30% hexane A11 C1f D1c 84 -λ ₌ χ ° - \? ^ν ° ^h 179- 183 A2 A17

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C1a D5

TABLE 5

3- (trifluoro-methyl) -4-bromo-phenyl-ureas

Η H

Item R Federal Police (° C) HPLC (min) TLC RF System of Solvents of TLC Spectr. Pasta [Source] Method of Synthesis 85 0 V-NH 186- 187 0.13 50% EtOAc / 50% ether pet 509 (M + H) + (HPLC ES-MS) A2 B1 C1a 86 0 Cl 7-NH 150- 152 0.31 50% EtOAc / 50% ether pet 545 (M + H) ⁺ (HPLC ES-MS) A6 B1 C1a 87 0 Cl y — NH 217- 219 0.16 50% EtOAc / 50% ether pet 545 (M + H) ⁺ (HPLC ES-MS) A2 B1 C1a 88 Vnh ^_ CÁ ^oh O ^{n E} ' 183- 184 0.31 50% EtOAc / 50% ether pet 525 (M + H) ⁺ (HPLC ES-MS) A2 B1 C1a 89 ° ”V / ^N 0.21 50% EtOAc / 50% ether pet 511 (M + H) ⁺ (HPLC ES-MS) A2 B1 C1a 90 -—— M and - Ν H r = {Me 0.28 50% EtOAc / 50% ether pet 525 (M + H) ⁺ (HPLC ES-MS) A2 B1 C1a

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91 214- 216 0.28 50% EtOAc / 50% ether pet 522 (M + H) + (HPLC ES-MS) A2 B1 C1a 92 0 V — NH 0.47 50% EtOAc / 50% ether pet. 527 (M + H) ⁺ (HPLC ES-MS) A2 step 3b, A2 step 4, B1, C1a 93 ^s_ vy 0.46 50% EtOAc / 50% ether pet. 527 (M + H) ⁺ (HPLC ES-MS) A2 step 3b, A2 step 4, B1, C1a 94 c> ^NH 7—0 145- 150 0.41 5% MeOH / 95% CH2Cb A10 B1 C1a

TABLE 6

5- (trifluoro-methyl) -4-chloro-2-methoxy-phenyl-ureas

Item R mp ( ^o C) HPLC (min) TLC RF System of Solvents of TLC Spectr. Pasta [Source] Method of Synthesis 95 O '/ -NH 140- 145 0.29 5% MeOH / 45% EtOAc / 50% ether pet. 495 (M + H) ⁺ (HPLC ES-MS) A2 A7 B1 C1a 96 O Ct V- NH 244- 245 0.39 5% MeOH / 45% EtOAc / 50% ether pet. 529 (M + H) ⁺ (HPLC ES-MS) A6 A7 B1 C1a

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97 O Cl V-NH 220- 221 0.25 5% MeOH / 45% EtOAc / 50% ether pet. 529 (M + H) + (HPLC ES-MS) A2 A7 B1 C1a 98 Vnh '- \ / = \ Me ° -w 0.27 5% MeOH / 45% EtOAc / 50% ether pet. 495 (M + H) ⁺ (HPLC ES-MS) A2 A7 B1 C1a 99 O V — NH zy ° -o ^El 180- 181 0.52 5% MeOH / 45% EtOAc / 50% ether pet. 509 (M + H) ⁺ (HPLC ES-MS) A2 A7 B1 C1a 100 the Ã-NH ^pri 162- 165 A2 A7 B1 C1a

TABLE 7 Additional Ureas

Item R mp ( ^o C) HPLC (min) TLC RF System of Solvents of TLC Spectr. Pasta [Source] Method of Synthesis 101 η χ V „x„ -v v - or. 162- 165 TO 1 A2 C3 102 Ϋ X ’H H vZ 0.10 50% EtOAc / 50% hexane 442 (M + H) ⁺ (HPLC ES-MS) A2 A4 C2d 103 O Hrr nh 0 0 0 o .fi Ã. NH-Me Me — NH 125- 130 0.24 40% EtOAc / 60% hexane 512 (M + H) ⁺ (FAB) A2 C2b

The preceding examples can be repeated with similar success, replacing

Petition 870170083282, of 10/30/2017, p. 81/85 the reagents and / or operational conditions used in the preceding examples by those of this invention, described here generically or specifically.

From the preceding description, those versed in these techniques can easily assess the essential characteristics of this invention and, without departing from the spirit and scope of it, can make several changes and modifications to the invention, to adapt it to various uses and conditions.

Petition 870170083282, of 10/30/2017, p. 82/85

Claims (1)

1. Compound, characterized by having the formula I: A-D-B (I) or a pharmaceutically acceptable salt thereof, where D is -NH-C (O) -NH-, A is a substituted grouping of the formula: -LML ¹ , where L is phenyl, optionally substituted by halogen, until per-halo, and Wn, where n is 0-3; where each W is independently selected from the group consisting of straight or branched C1-C5 alkyl, haloalkyl to straight or branched C1-C5 perhaloalkyl and C1-C3 alkoxy, L ¹ is selected from -C (O) Rx substituted pyridinyl , and optionally substituted with 1 to 3 additional substituents independently selected from the group consisting of R ⁷ and halogen; where Rx is NRaRb, and Ra and Rb are A) independently a) hydrogen, b) C1-C10 alkyl, c) C6 aryl, d) substituted C1-C10 alkyl, or e) substituted C6 aryl, where when Ra and Rb are a substituted group, they are replaced by: a) halogen to per halo, b) hydroxy, c) C1-C10 alkyl, d) C1-C10 alkoxy, or e) halosubstituted C1-C6 alkyl, M is selected from the group consisting of oxygen and sulfur; and B is phenyl, substituted with 1 to 3 substituents independently selected from the group consisting of halogen and R ⁷ , and R ⁷ is (a) straight or branched C1-C6 alkyl, optionally substituted with 1 to 3 halogen substituents; or (b) straight or branched C1-C6 alkoxy, where the compound is different from the following compounds: N- (4-chloro-3- (trifluormethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluormethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) Petition 870170083282, of 10/30/2017, p. 83/85 urea, N- (4-chloro-3- (trifluormethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluormethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea and N- (4-chloro-3- (trifluormethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4pyridyloxy)) phenyl) urea 4-bromo-3- (trifluormethyl) phenyl ureas: N- (4-bromo-3- (trifluormethyl) phenyl) -N '' (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluormethyl) phenyl) -N '' (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluormethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (4-bromo-3- (trifluormethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4pyridyloxy)) phenyl) urea and N- (4-bromo-3- (trifluormethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4pyridyloxy)) phenyl) urea, the 2-methoxy-4-chloro- 5- (trifluormethyl) phenyl ureas: N- (2-methoxy-4-chloro-5- (trifluormethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluormethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4pyridyloxy)) phenyl) urea or a pharmaceutically acceptable salt of same. Petition 870170083282, of 10/30/2017, p. 84/85