JP4472669B2 - Diphenylurea derivatives as RAF kinase inhibitors - Google Patents

Description

Field of the invention

  The present invention relates to the use of arylureas in the treatment of raf-mediated diseases and pharmaceutical compositions for use in such treatment.

Background of the invention

The p21 ^ras oncogene is a major contributor to the development and progression of human solid tumors and changes abruptly in 30% of all human cancers (Bolton et al. Ann. Rep. Med. Chem. 1994, 29, 165). -74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal non-mutated form, the ras protein is a key element of the signal transduction cascade directed by growth factors in almost all tissues (Avruch)
et al. Trends Biochem. Sci. 1994, 19, 279-83). Physiologically, ras is a guanine nucleotide binding protein and cycling between GTP-bound activated and GDP-bound dormant forms is tightly controlled by ras' endogenous GTPase activity and other regulatory proteins. In the ras mutant protein in cancer cells, endogenous GTPase activity is relieved and therefore this protein transmits a constructive growth signal to downstream effectors such as the enzyme raf kinase. This leads to cancerous growth of cells carrying these mutant proteins (Magnuson et al. Semin. Cencer Biol. 1994, 5, 247-53). Inhibition of the effect of active ras by inhibiting the raf kinase signaling pathway by administration of a deactivating antibody to raf kinase or by co-expression of dominant negative raf kinase or a dominant negative MEK that is a substrate for raf kinase is Have been shown to lead to reversion of transformed cells to a normal growth phenotype (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 showed that inhibition of raf expression by antisense RNA blocks cell proliferation in a membrane-associated oncogene. Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) correlated in vitro and in vivo with inhibition of growth of various human tumor types (Monia et al. Nat. Med. 1996, 2, 668- 75).

Summary of the present invention

The present invention provides compounds that are inhibitors of the enzyme raf kinase. Since this enzyme is a downstream effector of p21 ^ras , this inhibitor is intended for human and animal use where inhibition of the raf kinase pathway is indicated, eg, for the treatment of tumor and / or cancer cell growth mediated by raf kinase. Useful in pharmaceutical compositions. In particular, these compounds are useful for the treatment of human or animal solid cancers such as murine cancer. This is because the progression of these cancers depends on the ras protein signal transduction cascade and is therefore sensitive to treatment by disruption of this cascade, ie, inhibition of raf kinase. Thus, the compounds of the present invention include solid cancers such as, for example, carcinomas (eg of lung, pancreas, thyroid, bladder or colon), bone marrow abnormalities (eg myeloid leukemia) or adenomas (eg choriocolonous colon adenoma). It is useful for treatment of cancer.

  The present invention therefore provides compounds generally described as arylureas, including aryl and heteroaryl analogs, that inhibit the raf kinase pathway. The present invention also provides methods for treating raf-mediated pathological conditions in humans and mammals. Thus, the present invention is directed to compounds that inhibit the enzyme raf kinase, compounds, compositions and methods for the treatment of cancer cell proliferation mediated by raf kinase, wherein the compound of formula I: Acceptable salts are administered.

            A-D-B (I)

In Formula I, D is
-NH-C (CO) -NH-;
A is a substituent of formula -LML ¹ ; where L is phenyl optionally substituted with halogen up to perhalo and Wn, n is 0-3, W is C ₁ Independently selected from the group consisting of —C ₅ linear or branched alkyl, C ₁ -C ₅ linear or branched haloalkyl up to perhaloalkyl, and C ₁ -C ₃ alkoxy; L ¹ is —C (O) R _x And pyridyl optionally substituted with 1 to 3 additional substituents independently selected from the group consisting of R ⁷ and halogen;
Where R _x is NR _a R _b and R _a and R _b are
A) Independently
a) hydrogen,
_b) C 1 _{-C 10} alkyl,
c) C ₆ aryl,
d) pyridyl,
e) substituted _C 1 _{-C 10} alkyl,
f) substituted C ₆ aryl,
g) substituted pyridyl,
h) -phenylpiperazine (pyridinyl),
i) -phenylmorpholinyl,
j) -ethylmorpholinyl,
k) -ethylpiperidyl,
l) -methylpyrrolidinyl,
m) - are methyl tetrahydrofuryl or _{n) -C 2 H 4 NH,} ( phenyl);
When R _a and R _b are substituted groups, they are
a) Halogen up to Belhalo,
b) hydroxy,
_{c) -N (CH 3) 2} ,
_d) C 1 _{-C 10} alkyl,
_e) C 1 _{-C 10} alkoxy,
f) halo-substituted _C 1 -C ₆ alkyl or g) -OSi, (Pr-i ) 3
Is replaced by, or
B) R _a and R _b are combined to form piperazine or substituted piperazine, and the substituent of the substituted piperazine is
a) halogen,
b) hydroxy,
_c) C 1 _{-C 10} alkyl,
d) pyridinyl,
_e) C 1 _{-C 10} alkoxy,
f) C ₆ aryl,
g) halo-substituted C ₆ aryl, and h) N- (4-acetylphenyl)
Selected from the group consisting of;
M is selected from oxygen or sulfur; and B is phenyl substituted by 1 to 3 substituents selected from the group consisting of halogen or R ₇ , wherein R ₇ is
a) C ₁ -C ₆ linear or branched alkyl optionally substituted by 1 to 3 halogens, or b) C ₁ -C ₆ linear or alkoxy.

  Suitable alkyl groups throughout and the alkyl portion of groups such as alkoxy include all linear and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc. methyl, ethyl, propyl, butyl, etc. including.

  Suitable aryl groups containing no heteroatoms include, for example, phenyl, 1- and 2-naphthyl.

The term “cycloalkyl” as used herein refers to a cyclic structure with or without an alkyl substituent, so that for example C ₄ cycloalkyl includes methyl-substituted cyclopropyl and cyclobutyl groups. The term “cycloalkyl” as used herein also includes saturated heterocyclic groups.

  Suitable halogen groups include F, Cl, Br and / or I, where 1 to per substitution (ie, all H on the group is replaced by a halogen atom) is possible when the alkyl group is replaced by a halogen. Yes, mixed substitution of halogen atom types on a given group is also possible.

The present invention relates to the compound of formula I itself.
The present invention is directed to pharmaceutically acceptable salts of compounds of formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfone. Acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, And base salts of inorganic and organic acids such as mandelic acid. In addition, pharmaceutically acceptable salts include salts containing alkali cations (eg Li ⁺ , Na ⁺ or K ⁺ ), alkaline earth cations (eg Mg ⁺² , Ca ⁺² or Ba ⁺² ), ammonium cations. And salts of inorganic bases such as aliphatic and aromatic substituted ammonium, and triethylamine, N, N-diethylamine, N, N-dicyclohexylamine, lysine, pyridine, N, N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] nonene-5 (DBN) and 1,8-diazabicyclo [5.4.0] unde- Includes organic base acid salts containing ammonium cations such as those resulting from protonation or peralkylation of 7-cene (DBU) .

  Many of the compounds of formula I have asymmetric carbon atoms and therefore exist in racemic and optically active forms. Methods for separating enantiomeric and diastereomeric mixtures are well known to those skilled in the art. The present invention includes isolated racemic or optically active forms of the compounds described in Formula I having an inhibitory effect.

General Preparation Methods Compounds of Formula I, some can be prepared from commercially available starting materials using known chemical reactions and procedures. Nevertheless, the following general preparation methods are provided to help those skilled in the art to synthesize these compounds. More detailed examples are provided in the subsequent experimental section.

Substituted anilines can be generated using standard methods (March, Advanced Organic Chemistry 3rd Ed, John Willy, New York (1985); Larock, Comprehensive Organic Transformations;
Publishers, New York (1985)). As shown in Scheme 1, arylamines are commonly nitroaryl using a metal catalyst such as Ni, Pd or Pt and H ₂ or using a hydrogen transfer agent such as formate, cyclohexadiene or borohydride. (Rylander, Hydrogenation Methods; Academic)
Press, London, UK (1985)). Nitroaryl also uses a strong hydrogen source such as LiAlH ₄ (Syden-Penne, Reduction by the Alumino-and Borohydrides).
in Organic Synthesis; VCH Publishers; New York (1991), or often using zero valent metals such as Fe, Sn, or Ca in acidic media (March, Advanced Organic Chemistry 3rd Ed, 1985). Larock, Comprehensive Organic Transformations; VCH Publishers; New York (1989)), can also be reduced directly.

Scheme I. Reduction of nitroaryls to arylamines Nitroaryls are commonly produced by electrophilic aromatic nitration using HNO ₃ or an alternative NO ₂ ⁺ source. Nitroaryl may be further modified before reduction. For this reason, nitroaryl is

Potential leaving groups (eg, F, Cl, Br, etc.) can undergo substitution reactions in the treatment with thiolates (illustrated in Scheme II) or nucleophiles such as phenoxides. Nitroaryls can also undergo Ullman-type coupling reactions (Scheme II).

Scheme II. Selected nucleophilic aromatic substitutions using nitroaryl Nitroaryl can also undergo transition metal mediated cross-coupling reactions. For example, nitroaryl nucleophiles such as nitroaryl bromide, iodide or triflate are aryl nucleophiles such as aryl boronic acids (Suzuki reaction, exemplified below), aryl tin (still reaction) or aryl zinc (Negishi reaction). Subject to testing and palladium-mediated cross-reaction to give biaryl (5).

Either nitroaryl or aniline can be converted to the corresponding arenesulfonyl chloride (7) upon treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source such as KF then gives the sulfonyl fluoride (8). Reaction of sulfonyl fluoride (8) with trimethylsilyl trifluoromethane such as tris (dimeramino) sulfonium difluorotrimethylsiliconate (FASF) in the presence of a fluoride source leads to the corresponding trifluoromethyl sulfone (9). Instead, the sulfonyl chloride (7) is reduced to the arenethiol (10), for example with zinc amalgam. Reaction of thiol (10) with CHClF _{2 in} the presence of base gives difluoromethyl mercaptan (11), which contains CrO ₃ acetic anhydride (Sedova et al. Zh. Org. Khim. 1970, 6, 568). It can be oxidized to sulfone (12) with any kind of oxidizing agent.

Scheme III. Selected Methods for Fluorinated Aryl Sulfone Synthesis As shown in Scheme IV, asymmetric urea formation can involve reaction of aryl isocyanate (14) with arylamine (13). Heteroaryl isocyanates are heterogeneous by treatment with phosgene or phosgene equivalents such as trichloromethyl chloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene), or N, N′-carbonyldiimidazole (CDI). It can be synthesized from arylamines. Isocyanates can also be obtained by Curtius type rearrangement from heterocyclic carboxylic acid derivatives such as esters, acid halides or anhydrides. Thus, reaction of the acid derivative (16) with an azide source and subsequent rearrangement gives the isocyanate. The corresponding carboxylic acid (17) can also be subjected to a curtium type rearrangement using diphenylphosphoryl azide (OPPA) or similar reagents.

Scheme IV. Selected Methods for Asymmetric Urea Production Finally, urea can be further processed using methods well known to those skilled in the art.

  The invention also includes a pharmaceutical composition comprising a compound of formula I and a physiologically acceptable carrier.

  The compounds can be administered orally, topically, parenterally, by inhalation or spray, vaginally, rectally or sublingually in dosage unit formulations. Administration by injection includes intravenous, intramuscular, subcutaneous and parenteral injection, and use of infusion techniques. One or more compounds can be present in combination with one or more pharmaceutically acceptable carriers and, if desired, other active ingredients.

  Compositions intended for oral use can be prepared according to suitable methods known to those skilled in the art for the manufacture of pharmaceutical compositions. Such compositions can be included to prepare a formulation that can be taken with one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preservatives. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These adjuvants include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; and eg magnesium stearate, stearic acid or talc. Can be a binder. Tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. These compounds can also be prepared in a solid immediate release form.

  Formulations for oral use are as hardened gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient is water or an oily medium such as peanut oil, fluid It can also be provided as a soft gelatin capsule mixed with paraffin or olive oil.

  Aqueous suspensions containing the active ingredients in admixture with adjuvants suitable for the manufacture of aqueous suspensions may also be used. Such adjuvants are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, acacia gum, and dispersing or wetting agents are naturally occurring phosphatides such as lecithin, or long Condensation products of ethylene oxide with chain aliphatic alcohols, for example, condensation products of ethylene oxide with fatty acids such as heptadecaethylene oxycetanol or polyoxyethylene sorbitol monooleate and partial esters obtained from hexitol, or fatty acids and anhydrous It may be a condensation product of ethylene oxide with a partial ester obtained from hexitol, for example polyoxyethylene sorbitan monooleate. Aqueous suspensions contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate; one or more colorants; one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin. be able to.

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

  The compounds can be formulated in a non-aqueous liquid formulation, for example an oily suspension, which can be formulated by dispersing the active ingredient in a vegetable oil, such as arachis oil, olive oil or peanut oil, or in a mineral oil such as liquid paraffin. It may be a shape. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide an oral dosage form that can be taken. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

  The pharmaceutical composition of the present invention can be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifiers include natural gums such as gum acacia or tragacanth, natural phosphatides such as soy lecithin, and esters or partial esters derived from fatty acids and anhydrous hexitol such as sorbitan monooleate, and condensation products of said esters with ethylene oxide such as polyoxy Contains ethylene sorbitan monooleate. Emulsions can contain sweetening and flavoring agents.

  Syrups and elixirs can be formulated with sweetening agents, for example glycerose, propylene glycol, sorbitol or sucrose. Such formulations can contain emollients, preservatives, flavoring agents and coloring agents.

  The compounds can also be administered in the form of suppositories for rectal administration of the drug. These compositions are prepared by mixing the drug with a suitable nonirritating adjuvant that is solid at room temperature but liquid at rectal or vaginal temperature and melts in the rectum or vagina to release the drug. can do. Such materials include cocoa butter and polyethylene glycol.

  For all therapies of use described herein for compounds of formula I, the daily oral regimen will preferably be from 0.01 to 200 mg / kg of total body weight. The daily dose for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injection, and use of infusion techniques will preferably be from 0.01 to 200 mg / kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg / kg of total body weight. The daily topical regimen will preferably be 0.1 to 200 mg administered 1 to 4 times daily. The daily inhalation regimen will preferably be from 0.01 to 10 mg / kg of total body weight.

  One skilled in the art will recognize that the particular method of administration depends on various factors and is routinely considered when administering all of the therapeutic agents. However, the specific dose level for a given patient depends on the specific activity of the administered compound, patient age, patient weight, patient general health, patient sex, patient diet, administration time, administration It will be appreciated that it depends on various factors, including route, excretion rate, drug combination, and severity of the condition being treated. Further, those skilled in the art will know the optimal course of treatment, i.e. the number of daily administrations of the compound of formula I or a pharmaceutically acceptable salt thereof for a mode of treatment and a limited number of days using conventional treatment test courses. It will be appreciated that can be verified.

  However, the specific dosage level for a specific patient is the activity, age, weight, general health status, sex, diet, time of administration, route of administration, excretion rate, drug formulation, and It will be appreciated that it depends on various factors, including the severity of the condition being treated.

  Provisional application No. 10 filed on Jan. 13, 1999. No. 60 / 115,877 and non-provisional application no. The entire disclosures of all applications, patents and publications cited above and below, including 09 / 257,266, are hereby incorporated by reference.

  Compounds of formula I can be prepared from known compounds (or from starting materials that can be prepared from known compounds), for example through the general preparation methods set forth above. The activity of a given compound that inhibits raf kinase can be routinely assayed, eg, according to the procedures disclosed below. The following examples are for illustrative purposes only and are not intended and should not be construed as limiting the present invention in any way.

  All reactions were carried out in glassware that was flame-dried or oven-dried under a positive pressure of dry argon or dry nitrogen and were magnetically stirred unless otherwise stated. Sensitive liquids and solutions were transferred by syringe or cannula and introduced into the reaction vessel through a rubber stopper. Unless otherwise stated, the term “concentration under reduced pressure” refers to the use of a Buchi rotary evaporator at about 15 mm Hg. Unless otherwise specified, “under high vacuum” means 0.4 to 1.0 mmHg.

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

Commercial grade reagents and solvents were used without further purification. N-cyclohexyl-N ′-(methylpolystyrene) carbodiimide is obtained from Calbiochem-Novabiochem Corp. Purchased from. 3-t-butylaniline, 5-t-butyl-2-methoxyaniline, 4-bromo-3- (trifluoromethyl) aniline, 4-t-butyl-2-nitroaniline, 3-amino-2-naphthol, Ethyl 4-isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-5- (trifluoromethyl) aniline and 4-chloro-3- (trifluoromethyl) phenyl isocyanate are purchased and without further purification used. Synthesis of 3-amino-2-methoxyquinoline (E. Cho et
al. WO 98/00402; Cordi et al. EP 542,609; IBID Bioorg. Med. Chem. 3, 1995, 129), 4- (3-carbamoylphenoxy) -1-nitrobenzene (K. Ikawa, Pharmaceutical Journal 79, 1950, 760; Chem. Abstr. 53, 1959, 12761b), 3-t-butylphenyl isocyanate. (O. Rohr et al., DE 2,436, 108) and 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (K. Inukai et al., JP 42025067, IBID Industrial Journal 70, 1967, 491) have previously been published. Are listed.

  Thin layer chromatography (TLC) was performed using Whatman precoated glass-backed silica gel 60A F-254 250 μm plates. Plate visualization was performed by one or more of the following techniques. (A) UV irradiation, (b) exposure to iodine vapor, (c) immersion and subsequent heating of plate in 10% solution of phosphomolybdic acid in ethanol, (d) immersion and subsequent heating of plate in cerium sulfate solution; e) Immersion of plate in acidic ethanol solution of 2,4-dinitrophenylhydrazine and subsequent heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM science silica gel.

Melting point (mp) is either Thomas-Hoover melting point apparatus or Mettler
Determined using FP66 automatic melting point apparatus and not corrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy series spectrophotometer. Proton ( ¹ H) nuclear magnetic resonance (NMR) spectra were measured on a General Electric GN-Omega 300 (300 MHz) spectrometer with Me ₄ Si (δ 0.00) or protonated solvent (CHCl ₃ δ 7.26; MeOH δ3) as standard. .30; DMSO δ 2.49). Carbon ( ¹³ C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer and solvent (CDCl ₃ δ77.0; MeOD-d ₃ ; δ49.0; DMSO-d ₆ δ39.5) as standards. It was done. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were obtained as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained on a Hewlett-Packard 5989A mass spectrometer equipped with a Vacuum desorption chemical ionization probe for sample introduction. The ion source was maintained at 250 ° C. Electron impact ionization was performed with an electron energy of 70 eV and a trap current of 300 μA. A liquid cesium secondary ion mass spectrum (FAB-MS), the latest version of fast atom bombardment, was obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectrum (CI-MS) uses methane or ammonia as a reagent gas (1 × 10 ⁻⁴ torr to 2.5 × 10 ⁻⁴ torr) and a Hewlett-Packard MS-Engine (5989A). Obtained. A direct insertion desorption chemical ionization (DCI) probe (Vacumetrics, Inc.) was launched from 0-15A in 10 seconds and held at 10A until all traces of the sample disappeared (˜1-2 minutes). The spectrum was scanned from 50-800 amu at 2 seconds / scan. HPLC electrospray mass spectrometry (HPLC ES-MS) uses a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, variable wavelength detector, C-18 column, and Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Obtained. The spectrum was scanned from 120 to 800 amu using variable ion time according to the number of ions in the source. Gas chromatography / ion-selective mass spectrum (GC-MS) is a Hewlett-Packard 5890 gas chromatograph equipped with an HP-1 methylsilicone column (0.33 mM coating; 25 m × 0.2 mm), and Hewlett-Packard 5971 mass. Obtained with a selective detector (ionization energy 70 eV). Elemental analysis was performed by Robertson MicroLab Labs. Performed by Madison NJ.

  All compounds displayed NMR spectra, LRMS and elemental analysis or HRMS consistent with the assigned structure.

List of abbreviations AcOH Acetic acid anh Anhydrous BOC t-Butoxycarbonyl CDI 1,1′-carbonyldiimidazole conc Concentrated d Day dec Decomposed DMAC N, N-dimethylacetamide DMPU 1,3-dimethyl-3,4,5,6 -Tetrahydro-
Z (1H) pyrimidine DMF dimethylformamide DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azide EDCI 1- (3-dimethylaminopropyl) -3-ethyl carbonate
Ruvodiimide EtOAc Ethyl acetate EtOH Ethanol (100%)
Et ₂ O diethyl ether Et ₃ N triethylamine h HOBT 1-hydroxybenzotriazole m-CPBA 3-chloroperoxybenzoic acid MeOH methanol pet. ether petroleum ether (boiling range 30-60 ° C)
temp temperature THF tetrahydrofuran TFA trifluoroAcOH
Tf trifluoromethanesulfonyl

A. General synthesis of substituted anilines.
A1. General method for arylamine formation via ester formation followed by ester saponification, Curtius rearrangement and carbamate deprotection. Synthesis of 2-amino-3-methoxynaphthalene.

Step 1: Methyl 3-methoxy-2-naphthoate A slurry of methyl 3-hydroxynaphthoate (10.1 g, 50.1 mmol) and K ₂ CO ₃ (7.96 g, 57.6 mmol) in DMF for 15 minutes at room temperature. Stir and then treat with iodomethane (3.43 ml, 55.1 mmol). The mixture was stirred overnight at room temperature and then treated with water (200 ml). The resulting mixture is extracted with EtOAc (2 × 200 ml) and the combined organic layers are washed with saturated NaCl solution (100 ml), dried (MgSO ₄ ), concentrated under reduced pressure (approximately 0.4 mm Hg overnight), and amber. Methyl 3-methoxy-2-naphthoate (10.30 g) was obtained as a color oil. ¹ H-NMR (DMSO-d ₆ ) δ 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (appt, J = 8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J = 8.09 Hz, 1H), 7.84 (d, J = 8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H) )

Step 2: 3-Methoxy-2-naphthoic acid A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 ml) in MeOH (100 ml) at room temperature with 1N NaOH solution (33 .4 ml, 33.4 mmol). The mixture was heated at reflux for 3 hours and acidified with 10% citric acid solution. The resulting solution was extracted with EtOAc (2 × 100 ml). The combined organic layers were washed with saturated brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was kneaded with hexane and washed several times with hexane to give 3-methoxy-2-naphthoic acid (5.40 g, 92%) as a white solid. ¹ H-NMR (DMSO-d ₆ ) δ 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d , J = 8.09 Hz, 1H), 7.91 (d, J = 8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (brs, 1H)

Step 3: 2- (N- (carbobenzyloxy) amino-3-methoxynaphthalene 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et ₃ N (2. 59 ml, 18.6 mmol) and Et ₃ N (2.59 ml, 18.6 mmol) are stirred at room temperature for 15 minutes, then pipetted with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 ml). The resulting mixture was heated for 2 hours at 80 ° C. After cooling the mixture to room temperature, benzyl alcohol (2.06 ml, 20 mmol) was added via syringe. The resulting mixture was cooled to room temperature, 10% citric acid solution was added and extracted with EtOAc (2 × 100 ml). Washed with brine, dried (MgSO _4), under reduced pressure and concentrated. The residue was purified by column chromatography (14% EtOAc / 86% ethanol), 2 as a pale yellow oil (N- carbobenzyloxy) amino-3 -Methoxynaphthalene (5.1 g, 100%) was obtained ¹ H-NMR (DMSO-d ₆ ) 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-methoxynaphthalene 2- (N- (carbobenzyloxy) amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and Pd / C (0.5 g) in EtOAc (70 ml) The slurry was maintained under H ₂ atmosphere (balloon) at room temperature overnight The resulting mixture was filtered through celite and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene (2.40 g, 85 as a pink powder). ¹ H-NMR (DMSO-d ₆ ) δ 3.86 (s, 3H), 6.85 (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-carbamylaniline via formation of carbamylpyridine followed by nucleophilic coupling with arylamine. Synthesis of 4 (2-N-methylcarbamyl-4-pyridyloxy) aniline.

Step 1a; Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide via Menisci reaction Note: This is a highly dangerous and potentially explosive reaction. To a stirred solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 ml) at room temperature was added concentrated sulfuric acid (3.55 ml) to generate heat. To this mixture was added H ₂ O ₂ (30% wt in H ₂ O, 17 ml) and then FeSO ₄ .7H ₂ O to generate heat. The resulting mixture was stirred in the dark at room temperature for 1 hour and then slowly warmed to 45 ° C. over 4 hours. When foaming subsided, the reaction was heated at 60 ° C. for 16 hours. The resulting opaque brown solution was diluted with H ₂ O (700 ml) and then 10% NaOH solution. The resulting mixture was extracted with EtOAc (3 × 500 ml). The organic phases were washed separately with saturated brine (3 × 150 ml), combined, dried (MgSO ₄ ) and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc / 50% hexanes to 80% EtOAc / 20% hexanes). The resulting yellow oil crystallized at 0 ° C. over 72 hours to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%). TLC (50% EtOAc / 50% hexane) Rf 0.50; ¹ H-NMR (CDCl ₃ ) δ 3.04 (d, J = 5.1 Hz, 3H), 7.43 (dd, J = 5.4, 2 .4 Hz, 1 H), 7.96 (br s, 1 H), 8.21 (s, 1 H), 8.44 (d, J = 5.1 Hz, 1 H), CI-Ms m / z 173 [(M + H ) ⁺ ]

Step 1b; Synthesis of 4-chloropyridine-2-carbonyl chloride HCl salt via picolinic acid Anhydrous DMF (6.0 ml) was added to SOCl ₂ (180 ml) between 40-50 ° C. The solution was stirred for 10 minutes within this temperature range, then picolinic acid (60.0 g, 487 mmol) was added in portions over 30 minutes. The resulting solution was heated at 72 ° C. (violent SO ₂ evolution) for 16 hours resulting in a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 ml. This toluene addition / concentration process was repeated twice. The resulting almost dry residue was filtered and the solid was washed with toluene (2 × 200 ml) and dried under high vacuum for 4 hours to give 4-chloropyridine-2-carbonyl chloride HCl salt (92.0 g, 89%).

Step 2: Synthesis of 4-chloropyridine-2-carboxylic acid methyl HCl salt Anhydrous DMF (10.0 ml) was added to SOCl ₂ (300 ml) between 40-48 ° C. The solution was stirred for 10 minutes within this temperature range, then picolinic acid (100 g, 812 mmol) was added over 30 minutes. The resulting solution was heated at 72 ° C. (violent SO ₂ evolution) for 16 hours to produce a yellow solid. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 ml. The toluene addition / concentration process was repeated twice. The resulting almost dry residue was filtered and the solid was washed with toluene (50 ml) and dried under high vacuum for 4 hours to give 4-chloropyridine-2-carbonyl chloride HCl salt (27.2 g, 16%) as an off-white solid. Got. This material was set aside.

To the red filtrate, MeOH (200 ml) was added at a rate to keep the internal temperature at 55 ° C. The contents were stirred for 45 minutes at room temperature, cooled to 5 ° C. and treated dropwise with Et ₂ O (200 ml). The resulting solid was filtered, washed with Et ₂ O (200 ml) and dried under reduced pressure at 35 ° C. to give methyl 4-chloropyridine-2-carboxylate HCl salt as a white solid (110 g, 65%). ¹ H-NMR (CDSO-d ₆ ) δ 3.88 (s, 3H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1 H), 8.68 (d, J = 5.5 Hz, 1 H), 10.68 (br s, 1 H),; HPLC ES-MS m / z 178 [(M + H) ⁺ ]

Step 3a; Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from methyl 4-chloro-2-pyridine-2-carboxylate 4-chloro-2-pyridinecarboxyl in MeOH (75 ml) at 0 ° C. A suspension of acid methyl HCl salt (89.0 g, 428 mmol) was treated with a 2.0 M methylamine solution in THF (1 L) at a rate to keep the internal temperature below 5 ° C. The resulting mixture was stored at 3 ° C. for 5 hours and then concentrated in vacuo. The resulting solid was suspended in EtOAc (1 L) and filtered. The filtrate was washed with saturated brine (500 ml), dried (MgSO ₄ ), and concentrated under reduced pressure to give 4-chloro-N-methyl-2-pyridinecarboxamide (71.2 g, 97%) as pale yellow crystals. It was. mp 41-43 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ2.81 (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 (brd, 1H); CI-MS m / z [(M + H) ⁺ ]

Step 3b; Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carbonyl chloride 4-chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) Little by little to a 0 ° C. mixture of 2.0M methylamine solution in THF (100 ml) and MeOH (20 ml). The resulting mixture was left at 3 ° C. for 4 hours and then concentrated in vacuo. The resulting almost dry solid was suspended in EtOAc (100 ml) and filtered. The filtrate was washed with saturated NaCl solution (2 × 100 ml), dried (MgSO ₄ ) and concentrated in vacuo to give 4-chloro-N-methyl-3-pyridinecarboxamide (4.95 g, 88%) as yellow crystals. Obtained. mp37-40 ° C

Step 4: Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anhydrous DMF (150 ml) was added to potassium t-butoxide. (10.29 g, 91.7 mmol) and the reddish brown mixture was stirred for 2 hours at room temperature. The contents were treated with 4-chloro-N-methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and K ₂ CO ₃ (6.50 g, 47.0 mmol) and heated at 80 ° C. for 8 hours. . The mixture was cooled at room temperature and partitioned between EtOAc (500 ml) and saturated brine (500 ml). The aqueous phase was back extracted with EtOAc. The combined organic layers were washed with saturated brine (4 × 1000 ml), dried (MgSO ₄ ) and concentrated in vacuo. The obtained solid was dried at 35 ° C. under reduced pressure for 3 hours to obtain 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline as a light brown solid. ¹ H-NMR (DMSO-d ₆ ) δ 2.77 (d, J = 4.8 Hz, 3H), 5.17 (brs, 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, 1 H), 8.73 (br d, 1 H); HPLC ES-MS m / z [(M + H) ⁺ ]

A3. General method of aniline synthesis by nucleophilic aromatic addition followed by nitroarene reduction. Synthesis of 5- (4-aminophenoxy) isoindoline-1,3-dione.

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

Step 2: Synthesis of 5- (4-nitrophenoxy) isoindoline-1,3-dione To a stirred slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 ml) at room temperature, DMF (40 ml) A solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in was added dropwise. The light yellow-green mixture was allowed to warm to room temperature, stirred for 1 hour, and then 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added in 3-4 portions using a syringe. The resulting mixture was heated at 70 ° C. overnight, then cooled to room temperature, diluted slowly with water (150 ml) and extracted with EtOAc (2 × 100 ml). The combined organic layers were dried (MgSO ₄ ) and concentrated in vacuo to give 5- (4-nitrophenoxy) isoindoline-1,3-dione (3.3 g, 62%) as a yellow solid. TLC (30% EtOAc / 70% hexane) Rf 0.28; ¹ H-NMR (DMSO-d ₆ ) δ 7.32 (d, J = 12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 9 Hz, 2H), 11.43 (br s, 1H); CI-MS m / z [(M + H) ⁺ , 100%]

Step 3; Synthesis of 5- (4-aminophenoxy) isoindoline 1,3-dione 5- (4-Nitrophenoxy) isoindoline-1,3-dione in concentrated AcOH (12 ml) and water (0.1 ml) A solution of (0.6 g, 2.11 mmol) was stirred under a stream of argon while iron powder (0.59 g, 55.9 mmol) was added slowly. The mixture was stirred at room temperature for 72 hours, then diluted with water (25 ml) and extracted with EtOAc (3 × 50 ml). The combined organic layers were dried (MgSO ₄ ) and concentrated in vacuo to give 5- (4-aminophenoxy) isoindoline-1,3-dione (0.4 g, 75%) as a brown solid. TLC (50% EtOAc / 50% hexane) Rf0z27; ¹ H-NMR (DMSO-d ₆ ) δ 5.14 (br s, 2H), 6.62 (d, J = 8.7 Hz, 2H), 6.84 (D, J = 8.7 Hz, 2H), 7.03 (d, J = 2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J = 8.4 Hz, 1H) , 11.02 (s, 1 H); HPLC ES-MS m / z 255 [(M + H) ⁺ , 100%]

A4. General method for the synthesis of pyrrolylaniline. Synthesis of 5-t-butyl-2- (2,5-dimethylpyrrolyl) aniline.

Step 1: Synthesis of 1- (4-t-butyl-2-nitrophenyl) -2,5-dimethylpyrrole 2-nitro-4-t-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 ml) ) AcOH (0.1 ml) and acetonylacetone (0.299 g, 2.63 mmol) were added to the solution with stirring using a syringe. The reaction mixture was heated at 120 ° C. for 72 hours with azeotropic removal of volatiles. The reaction mixture was cooled to room temperature, diluted with CH ₂ Cl ₂ (10 ml), washed sequentially with 1N HCl (15 ml), 1N NaOH solution (15 ml) and saturated brine (15 ml), dried (MgSO ₄ ) and reduced pressure Concentrated. The resulting orange brown solid was purified by column chromatography (60 g SiO ₂ ; gradient from 67 EtOAc / 94% hexane to 25% EtOAc / 75% hexane) to give 1- (4-t-butyl-2 as an orange-yellow solid. -Nitrophenyl) -2,5-dimethylpyrrole (0.34 g, 49%) was obtained. TLC (15% EtOAc / 85% hexane) Rf 0.67; ¹ H-NMR (CDCl ₃ ) δ 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7 19-7.24 (m, 1H), 7.62 (dd, 1H), 7.88 (d, J = 2.4 Hz, 1H); CI-MS m / z
273 [(M + H) ⁺ , 50%]

Step 2: Synthesis of 5-t-butyl-2- (2,5-dimethylpyrrolyl) aniline 1- (4-t-butyl-2-nitrophenyl) -2,5- under H ₂ atmosphere (balloon) A slurry of dimethylpyrrole (0.341 g, 1.25 mmol), 10% Pd / C (0.056 g), and EtOAc (50 ml) was stirred for 72 hours and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give 5-t-butyl-2- (2,5-dimethylpyrrolyl) aniline (0.30 g, 99%) as a yellow solid. TLC (10% EtOAc / 90% hexane) Rf 0.43;
¹ H-NMR (DMSO-d ₆ ) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 ( m, 3H), 7.28 (br s, 1H)

A5. General synthesis of anilines from anilines by nucleophilic aromatic substitution. Synthesis of 4- (2-N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline hydrochloride.

A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 ml) was treated with potassium t-butoxide (10.86 g, 96.77 mmol) and the black mixture was Stir at room temperature until the flask is at room temperature. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 ° C. for 8 hours. The mixture was cooled to room temperature and diluted with water (75 ml). The organic layer was extracted with EtOAc (5 × 100 ml). The combined organic layer was washed with saturated brine (200 ml), dried (MgSO ₄ ), and concentrated under reduced pressure. The residual black oil was treated with Et ₂ O (50 ml) and sonicated. The solution was then treated with HCl (1M in Et ₂ O, 100 ml) and stirred at room temperature for 5 minutes. The resulting dark pink solid (7.04 g, 24.1 mmol) was filtered from the solution and stored under anaerobic conditions at 0 ° C. before use. ¹ H-NMR (DMSO-d ₆ ) δ 2.41 (s, 3H), 2.78 (d, J = 4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J = 8.5, 2.6 Hz, 1H), 7.23 (dd, J = 5.5, 2.6 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.55 (D, J = 2.6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 5.9 Hz, 1H), 8.99 (q, J = 4.8Hz, 1H)

A6. General synthesis of anilines from hydroxyanilines by N-protection, nucleophilic aromatic substitution and deprotection. Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline.

Step 1: Synthesis of 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol Iron (3.24 g, 58.00 mmol) was added to TFA (200 ml) with stirring. To this slurry was added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 ml). This gray slurry was stirred for 6 days at room temperature. Iron was filtered from the solution and the remaining material was concentrated in vacuo. The resulting gray solid was dissolved in water (20 ml). To the resulting yellow solution was added saturated NaHCO ₃ solution (50 ml). The solid that precipitated from the solution was removed. The filtrate was treated with NaHCO ₃ solution until the product separated from the solution so that it was visible (determined using a minivial). The slightly cloudy yellow solution was extracted with EtOAc (3 × 125 ml). The combined organic layers were washed with saturated NaCl solution (125 ml), dried (MgSO ₄ ) and concentrated in vacuo. ¹ H-NMR showed a 1: 1 ratio of nitrophenol starting material to the desired product 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol. The crude material was used in the next step without further purification.

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

Step 3: Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline Crude 4- (2- (N-methylcarbamoyl) -4 in dry 4-dioxane (20 ml) A solution of -pyridyloxy) -2-chlorophenyl- (2,2,2-tolufluoro) acetamide (8.59 g, 23.0 mmol) was treated with 1N NaOH solution (20 ml). The brown solution was stirred for 8 hours and EtOAc (40 ml) was added to the solution. The green organic layer is extracted with EtOAc (3 × 40 ml) and the solvent is concentrated and 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline as a green oil that solidifies upon standing. (2.86 g, 10.30 mmol) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 2.77 (d, J = 4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J = 8.5, 2.6 Hz, 1H), 6.76 (d, J = 2.6, 1H), 7.03 (d, J = 8.5 Hz, 1H), 7.07 (dd, J = 5.5, 2.6 Hz, 1H) ), 7.27 (d, J = 2.6 Hz, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.75 (q, J = 4.8 Hz, 1H)

A7. General method for deprotection of acylated anilines. Synthesis of 4-chloro-2-methoxy-5- (trifluoromethyl) aniline.

3-Chloro-6- (N-acetyl) -4- (trifluoromethyl) anisole (4.00 g, 14.95 mmol) in 6M HCl solution (24 ml) was heated to reflux for 1 hour. The resulting solution was cooled to room temperature and solidified slightly during that time. The resulting mixture was diluted with water (20 ml) and treated with a mixture of solid NaOH and saturated NaHCO ₃ solution until the solution was basic. The organic layer was extracted with CH ₂ Cl ₂ (3 × 50 ml) and the combined organic layers were dried (MgSO ₄ ), concentrated under reduced pressure and 4-chloro-2-methoxy-5- (trifluoromethyl) as a brown oil. Aniline (3.20 g, 14.2 mmol) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H)
A8. General synthesis of ω-alkoxy-ω-carboxyphenylaniline. Synthesis of 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline.

Step 1; 4- (3-Methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene 4- (3-carboxy-4-hydroxyphenoxy) -1-nitrobenzene (Aspect similar to that described in Method A13, Step 1 Prepared from 2,5-dihydroxybenzoic acid; 12 mmol) in acetone (50 ml) was added K ₂ CO ₃ (5 g) and dimethyl sulfate (3.5 ml). The resulting mixture was heated at reflux overnight, cooled to room temperature and filtered through a pad of celite. The resulting solution was concentrated under reduced pressure, absorbed onto SiO ₂ and purified by column chromatography (50% EtOAc / 50% hexane) to give 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1- Nitrobenzene (3 g) was obtained. mp115-118 ° C

Step 2: 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene (1.2 g) and KOH (0 .33 g) and water (5 ml) were stirred at room temperature overnight and then heated at reflux for 4 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50 ml) and the aqueous mixture was acidified with 1N HCl solution. The resulting mixture was extracted with EtOAc (50 ml). The organic layer was dried (MgSO ₄ ) and concentrated in vacuo to give 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (1.04 g).

Step 3; 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (12 ml) in CH ₂ Cl ₂ (12 ml) SOCl ₂ (0.64 ml, 8.77 mmol) was added little by little to the 0.50 g, 1.75 mmol) solution. The resulting solution was heated at reflux for 18 hours, cooled to room temperature and concentrated under reduced pressure. The obtained yellow solid was dissolved in CH ₂ Cl ₂ (3 ml), and the resulting solution was treated little by little with a methylamine solution (2.0 M in THF, 3.5 ml, 7.03 mmol) (caution: gas evolution). Stir at room temperature for 4 hours. The resulting mixture was treated with 1N NaOH solution and extracted with CH ₂ Cl ₂ (23 ml). The organic layer was dried and dried under reduced pressure to give 4- (3-N-methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene (0.50 g, 95%) as a yellow solid.

Step 4: 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene (0 in EtOH (55 ml) .78 g, 2.60 mmol) and 10% Pd / C (0.20 g) slurry was stirred for 2.5 days under 1 atmosphere of H ₂ (balloon) and filtered through a pad of celite. The obtained solution was concentrated under reduced pressure to obtain 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline (0.68 g, 96%) as an off-white solid. TLC (0.1% Et ₃ N / 99.9% EtOAc) Rf 0.36
A9. General synthesis method for omega-alkylphthalimide-containing anilines. Synthesis of 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione.

ステップ１；５−（４−ニトロフェノキシ）−２−メチルイソインドリン−１，３−ジオンの合成
ＤＭＦ（１５ｍｌ）中５−（４−ニトロフェノキシ）イソインドリン−１，３−ジオン（Ａ３ステップ２；１．０ｇ，３．５２ｍｍｏｌ）とＮａＨ（０．１３ｇ，５．２７ｍｍｏｌ）のスラリーを室温で１時間攪拌し、コウ化メチル（０．３ｍｌ，４．５７ｍｍｏｌ）で処理した。得られた混合物を室温で一夜攪拌し、０℃へ冷却し、水（１０ｍｌ）で処理した。得られた固体を集め、減圧乾燥し、明黄色固体として５−（４−ニトロフェノキシ）−２−メチルイソインドリン−１，３−ジオン（０．８７ｇ，８３％）を得た。ＴＬＣ（３５％ＥｔＯＡｃ／６５％ヘキサン）Ｒｆ０．６１

Step 1: Synthesis of 5- (4-nitrophenoxy) -2-methylisoindoline-1,3-dione 5- (4-Nitrophenoxy) isoindoline-1,3-dione (A3 Step 2) in DMF (15 ml) A slurry of 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) was stirred at room temperature for 1 hour and treated with methyl oxalate (0.3 ml, 4.57 mmol). The resulting mixture was stirred at room temperature overnight, cooled to 0 ° C. and treated with water (10 ml). The resulting solid was collected and dried under reduced pressure to give 5- (4-nitrophenoxy) -2-methylisoindoline-1,3-dione (0.87 g, 83%) as a light yellow solid. TLC (35% EtOAc / 65% hexane) Rf 0.61

Step 2: Synthesis of 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione Nitrophenoxy-2-methylisoindoline-1,3-dione (0.87 g, 2.78 mmol) in MeOH ) And 10% Pd / C (0.10 g) was stirred overnight under 1 atmosphere of H ₂ (balloon). The resulting mixture was filtered through a pad of celite and concentrated in vacuo. The resulting yellow solid was dissolved in EtOAc (3 ml) and filtered through a pad of SiO ₂ (60% EtOAc / 40% hexane) as a yellow solid 5- (4-aminophenoxy) -2-methylisoindoline-1,3 -Dione (0.67 g, 86%) was obtained. TLC (40% EtOAc / 60% hexane) Rf 0.27

A10. General synthesis of ω-carbamoylarylanilines via reaction of ω-alkoxycarbonylaryl precursors with amines. Synthesis of 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline.

Step 1: Synthesis of 4-chloro-2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridine 4-chloropyridine-2-carboxylic acid methyl HCl salt in THF (20 ml) (Method A2, Step 2) 4 (2-aminoethyl) morpholine (2.55 ml, 19.4 mmol) was added dropwise to a solution of 1.01 g, 4.86 mmol) and the resulting solution was heated at reflux for 20 hours and cooled to room temperature. , Treated with water (50 ml). The resulting mixture was extracted with EtOAc (50 ml). The organic layer was dried (MgSO ₄ ) and concentrated in vacuo to give 4-chloro-2- (N- (2-morpholin-4-ylethyl) carbamoylpyridine (1.25 g, 95%) as a yellow oil. (10% MeOH / 90% EtOAc) Rf 0.50

Step 2: Synthesis of 4- (2- (N-2-morpholin-4-ylethyl) carbamoyl) pindyloxy) aniline 4-aminophenol (0.49 g, 4.52 mmol) and potassium t-butoxide in DMF (8 ml) A solution of (0.53 g, 4.75 mmol) is stirred at room temperature for 2 hours, then 4-chloro-2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridine (1.22 g, 4.52 mmol) And K ₂ CO ₃ (0.31 g, 2.26 mmol) sequentially. The resulting mixture was heated at 75 ° C. overnight, cooled to room temperature, and partitioned between EtOAc (25 ml) and saturated NaCl solution (25 ml). The aqueous phase was back extracted with EtOAc (25 ml) and the combined organic layers were washed with saturated NaCl solution (3 × 25 ml) and concentrated in vacuo. The resulting brown solid was purified by column chromatography (58 g; gradient from 100% EtOAc to 25% MeOH / 75% EtOAc) and 4- (2- (N-morpholin-4-ylethyl) carbamoyl) pyridyloxy) Aniline (1.0 g, 65%) was obtained. TLC (10% MeOH / 90% EtOAc) Rf 0.32

A11. General method for reduction of nitroarenes to arylamines. Synthesis of 4- (3-carboxyphenoxy) aniline.

ＭｅＯＨ（１２０ｍｌ）中の４−（３−カルボキシフェノキシ）−１−ニトロベンゼン（５．３８ｇ，２０．７ｍｍｏｌ）と１０％Ｐｄ／Ｃ（０．５０ｇ）のスラリーをＨ₂ 雰囲気下（バルーン）２日攪拌した。得られた混合物をセライトのパッドを通して濾過し、減圧濃縮して４−（３−カルボキシフェノキシ）アニリンを褐色固体（２．２６ｇ，４８％）として得た。ＴＬＣ（１０％ＭｅＯＨ／９０％ＣＨ₂ Ｃｌ₂ ）Ｒｆ０．４４（縞状）

A slurry of 4- (3-carboxyphenoxy) -1-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd / C (0.50 g) in MeOH (120 ml) under H ₂ atmosphere (balloon) for 2 days. Stir. The resulting mixture was filtered through a pad of celite and concentrated in vacuo to give 4- (3-carboxyphenoxy) aniline as a brown solid (2.26 g, 48%). TLC (10% MeOH / 90% CH ₂ Cl ₂ ) Rf 0.44 (striped)

A12. General synthesis of isoindolinone-containing anilines. Synthesis of 4- (1-oxoisoindoline-5-yloxy) aniline.

Step 1: Synthesis of 5-hydroxyisoindoline-1-one Zinc dust (47.6 g, 729 mmol) was slowly added in portions to a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 ml), then The mixture was heated at reflux for 40 minutes, filtered hot and concentrated in vacuo. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 kg SiO ₂ ; gradient from 60% EtOAc / 40% hexanes to 25% MeOH / 75% EtOAc) to give 5-hydroxyiso Indoline-1-one (3.77 g) was obtained. TLC (100% EtOAc) Rf 0.17; HPLC ES-MS m / z [(M + H) ⁺ ]

Step 2; 4- (1-isoindoline-5-yloxy) -1-nitrobenzene To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 ° C. 5-hydroxyisoindoline-1-one (2.0 g). , 13.4 mmol) was added little by little. The resulting slurry was warmed to room temperature and stirred for 45 minutes, then 4-fluoro-1-nitrobenzene was added and heated at 70 ° C. for 3 hours. The mixture was cooled to 0 ° C. and water was added dropwise until precipitation occurred. The resulting solid was collected to give 4- (1-isoindoline-5-yloxy) -1-nitrobenzene (3.23 g, 89%) as a dark yellow solid. TLC (100% EtOAc) Rf 0.35

Step 3; 4- (1-oxoisoindoline-5-yloxy) aniline with 4- (1-isoindolinone-5-yloxy) -1-nitrobenzene (2.12 g, 7.8 mmol) in EtOH (50 ml) A slurry of 10% Pd / C (0.20 g) was stirred under H ₂ atmosphere (balloon) for 4 hours and filtered through a pad of celite. The filtration was concentrated under reduced pressure to give 4- (1-oxoisoindoline-5-yloxy) aniline as a dark yellow solid. TLC (100% EtOAc) Rf 0.15

A13. General synthesis of ω-carbamoylaniline via EDCI mediated amide formation followed by nitroarene reduction. Synthesis of 4- (3-N-methylcarbamoylphenoxy) aniline.

Step 1: Synthesis of 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene 4-Fluoro-1-nitrobenzene (16 ml, 150 mmol) in DMF (125 ml) and ethyl 3-hydroxybenzoate (25 g, 150 mmol) , K ₂ CO ₃ (41 g, 300 mmol) was heated at reflux overnight, cooled to room temperature and treated with water (250 ml). The resulting mixture was extracted with EtOAc (3 × 150 ml) and the combined organic layers were washed sequentially with water (3 × 100 ml) and saturated NaCl solution (2 × 100 ml), dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography (10% EtOAc / 90% hexane) to give 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene (38 g) as an oil.

Step 2: Synthesis of 4- (3-carboxyphenoxy) -1-nitrobenzene 3: 1 of 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene (5.14 g, 17.9 mmol) in THF / water solution (75 ml) To the vigorously stirred mixture was added a solution of LiOH.H ₂ O (1.50 g, 35.8 mmol) in water (36 ml). The resulting mixture was heated at 50 ° C. overnight, cooled to room temperature, concentrated under reduced pressure, and adjusted to pH 2 with 1M HCl solution. The resulting light yellow solid was collected by filtration and washed with hexane to give 4- (3-carboxyphenoxy) -1-nitrobenzene (4.40 g, 95%).

Step 3; 4- (3- (N-methylcarbamoyl) phenoxy) -1-nitrobenzene CH ₂ Cl ₂ (45 ml) solution of 4- (3-carboxy-phenoxy) -1-nitrobenzene (3.72 g, 14.4 mmol) And a mixture of EDCI.HCl (3.63 g, 18.6 mmol) and N-methylmorpholine (1.6 ml, 14.5 mmol) was stirred at room temperature for 3 days, and then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 ml) and the mixture was extracted with 1M HCl solution (50 ml). The aqueous layer was back extracted with EtOAc (2 × 50 ml) and the combined organic layers were washed with saturated NaCl solution (50 ml), dried (MgSO ₄ ), concentrated in vacuo and 4- (3- (N-methyl) as an oil. Carbamoyl) phenoxy) -1-nitrobenzene (1.89 g) was obtained.

Step 4: Synthesis of 4- (3- (N-methylcarbamoyl) phenoxy) aniline 4- (3- (N-methylcarbamoyl) phenoxy) -1-nitrobenzene (1.89 g, 6.95 mmol) in EtOAc (20 ml). ) And 10% Pd / C (0.24 g) in a H ₂ atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of celite, concentrated in vacuo, and the residue was purified by column chromatography (5% MeOH / 95% CH ₂ Cl ₂ ). The resulting oil solidified overnight under vacuum to give 4- (3- (N-methylcarbamoyl) phenoxy) aniline (0.95 g, 56%) as a yellow solid.

A14. Synthesis of ω-carbamoylaniline via EDCI mediated amide formation followed by nitroarene reduction. Synthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline.

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

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

A15. Synthesis of aniline by electrophilic nitration followed by reduction. Synthesis of 4- (3-methylsulfamoylphenoxy) aniline.

ステップ１；Ｎ−メチル−３−ブロモベンゼンスルホンアミドの合成
ＴＨＦ（１５ｍｌ）中の３−ブロモベンゼンスルホニルクロライド（２．５ｇ，１１．２ｍｍｏｌ）溶液へ℃においてメチルアミン（ＴＨＦ中２．０Ｍ；２８ｍｌ，５６ｍｍｏｌ）を加えた。得られた溶液を室温へ暖め、室温で一夜攪拌した。得られた混合物をＥｔＯＡｃ（２５ｍｌ）と１Ｍ ＨＣｌ溶液（２５ｍｌ）間で分離し、水相をＥｔＯＡｃ（２×２５ｍｌ）で逆抽出した。合併した有機層を水（２×２５ｍｌ）と飽和ＮａＣｌ溶液（２５ｍｌ）で順次洗い、乾燥（ＭｇＳＯ₄ ）し、減圧濃縮し、白色固体としてＮ−メチル−３−ブロモベンゼンスルホンアミド（２．８ｇ，９９％）を得た。

Step 1: Synthesis of N-methyl-3-bromobenzenesulfonamide Methylamine (2.0 M in THF; 28 ml) at 0 ° C. to a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 ml) 56 mmol) was added. The resulting solution was warmed to room temperature and stirred overnight at room temperature. The resulting mixture was separated between EtOAc (25 ml) and 1M HCl solution (25 ml) and the aqueous phase was back extracted with EtOAc (2 × 25 ml). The combined organic layers were washed successively with water (2 × 25 ml) and saturated NaCl solution (25 ml), dried (MgSO ₄ ), concentrated under reduced pressure, and N-methyl-3-bromobenzenesulfonamide (2.8 g) as a white solid. 99%).

Step 2: Synthesis of 4- (3- (N-methylsulfamoyl) phenyloxy) benzene Phenol (1.9 g, 20 mmol) in DMF (25 ml) with K ₂ CO ₃ (6.0 g, 40 mmol) , N-methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol) was added to a slurry of CuI (4 g, 20 mmol) and the resulting mixture was stirred at reflux overnight, cooled to room temperature and EtOAc (50 ml). ) And 1N HCl solution (50 ml). The aqueous layer was back extracted with EtOAc (2 × 50 ml) and the combined organic phases were washed sequentially with water (2 × 50 ml) and saturated NaCl solution (50 ml), dried (MgSO ₄ ) and concentrated in vacuo. The residual oil was purified by column chromatography (30% EtOAc / 70% hexane) to give 4- (3- (N-methylsulfamoyl) phenoxy) benzene (0.30 g).

Step 3; Synthesis of 4- (3- (N-methylsulfamoyl) phenyloxy) -1-nitrobenzene 4- (3- (N-methylsulfamoyl) phenyloxy) benzene (0 in TFA (6 ml) .30 g, 1.14 mmol) NaNO ₂ (0.097 g, 1.14 mmol) was added in portions over 5 minutes. The resulting solution was stirred at −10 ° C. for 1 hour, warmed to room temperature, and concentrated under reduced pressure. The residue was separated between EtOAc (10 ml) and water (10 ml) and the organic phase was washed successively with water (10 ml) and saturated NaCl solution (10 ml), dried (MgSO ₄ ), concentrated in vacuo and 4- (3 -(N-methylsulfamoyl) phenyloxy) -1-nitrobenzene (0.20 g) was obtained. This material was used in the next step without further purification.

Step 4: Synthesis of 4- (3- (N-methylsulfamoyl) phenyloxy) aniline 4- (3- (N-methylsulfamoyl) phenyloxy) -1-nitrobenzene (0 .30 g) and 10% Pd / C (0.030 g) slurry was stirred overnight under H ₂ atmosphere (balloon). The resulting mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (30% EtOAc 170% hexane) to give 4- (3- (N-methylsulfamoyl) phenyloxy) aniline (0.070 g).

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

To a slurry of 4- (4-acetylphenoxy) aniline HCl salt (Method A13, prepared in a manner analogous to Step 4; 1.0 g, 3.89 mmol) in EtOH (10 ml) and pyridine (1.0 ml). -Methylhydroxylamine HCl salt (0.65 g, 7.78 mmol, 2.0 eq) was added. The resulting mixture was heated at reflux for 30 minutes, cooled to room temperature, and concentrated under reduced pressure. The obtained solid was kneaded with water (10 ml) and washed with water to obtain 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt (0.85 g) as a yellow solid, TLC (50 % EtOAc / 50% petroleum ether) Rf 0.78; ¹ H-NMR (DMSO-d ₆ ) δ 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m / z [(m + H) ⁺ ]

A17. Synthesis of N- (ω-silyloxyalkyl) amide. Synthesis of 4- (4- (2- (N-2-triisopropylsiloxy) ethylcarbamoyl) pyridyloxyaniline.

Step 1; 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide 4-chloro-N- (2-hydroxyethyl) pyridine-2-carboxama in anhydrous DMF (7 ml) To a solution of id (Method A2, prepared in a manner analogous to Step 3b; 1.5 g, 7.5 mmol) triisopropylsilyl chloride (1.59 g, 8.2 mmol), 1.1 eq) and imidazole (1.12 g, 16.4 mmol, 2.2 eq.) Was added. The resulting yellow solution was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was separated between water (10 ml) and EtOAc (10 ml) and the aqueous phase was extracted with EtOAc. The combined organic layers were dried (MgSO ₄ ), concentrated under reduced pressure, and 4-chloro-2- (N- (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide (2.32 g, 88%) as an orange oil. ) This was used in the next step without further purification.

Step 2; 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline) To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anhydrous DMF (8 ml). Potassium pt-butoxide (0.67 g, 6.0 mmol, 1 eq) was added in one portion (exothermic) When the mixture was cooled to room temperature, 4-chloro-2- (4 ml) in DMF (4 ml). N- (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide (2.32 g, 6 mmol, 1 eq) is added, followed by K ₂ CO ₃ (0.42 g, 3.0 mmol, 0.50 eq). The resulting mixture was cooled to 0 ° C. with an ice-water bath, and then water (about 1 ml) was slowly added dropwise The organic layer was extracted with EtOAc (3 × 10 ml) and the combined presence was Wash the layer with saturated NaCl solution (20 ml), dried (MgSO _4), purified under reduced pressure and concentrated. The brown oily residue by column chromatography _{(SiO 2, 30% EtOAc /} 70% petroleum ether), as a brown oil 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline (0.99 g, 38%) was obtained.

A18. Synthesis of 2-pyridinecarboxylate ester via oxidation of 2-ethylpyridine. Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline.

Step 1; 4- (5- (2-methyl) pyridyloxy-1-nitrobenzene 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-nitrobenzene (DMF, 100 ml) A mixture of 9.8 ml, 91.6 mmol, 1 eq), K ₂ CO ₃ (25 g, 183 mmol, 2.0 eq) was heated overnight at reflux temperature The resulting mixture was cooled to room temperature and water (200 ml) And extracted with EtOAc (3 × 100 ml) The combined organic layers were washed sequentially with water (2 × 100 ml) and saturated NaCl solution (100 ml), dried (MgSO ₄ ), concentrated in vacuo and as a brown solid 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene (12.3 g) was obtained.

Step 2: Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene (1.70 g, in pyridine (20 ml)) 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 eq) were heated at reflux for 5 hours and cooled to room temperature. The resulting slurry was filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (100 ml) and the solution was treated with concentrated HCl solution (7 ml), then heated at reflux for 3 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc (50 ml) and 1N NaOH (50 ml). The aqueous layer was extracted with EtOAc (2 × 50 ml) and the combined organic layers were washed sequentially with water (2 × 50 ml) and saturated NaCl solution (50 ml), dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography _{(SiO 2, 50% EtOAc /} 50% hexane) to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.70 g).

Step 3: Synthesis of 4- (5- (3-methoxycarbonyl) pyridyloxy) aniline 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene in a mixture of EtOAc (20 ml) and MeOH (5 ml) (0.50 g) and 10% Pd / C (0.050 g) slurry was placed in H ₂ atmosphere F (balloon) overnight. The resulting mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography _{(SiO 2, 70% EtOAc /} 30% hexane) to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline (0.40 g).
A19. Synthesis of ω-sulfonylaniline. Synthesis of 4- (4-methylsulfonylphenyloxy) aniline.

Step 1; 4- (4-Methylsulfonylphenoxy) -1-nitrobenzene To a solution of 4- (4-methylthiophenoxy) -1-nitrobenzene (2.0 g, 7.7 mmol) in CH ₂ Cl ₂ (75 ml) at 0 ° C. M-CPBA (57-86%, 4.0 g) was added slowly and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was treated with 1N NaOH solution (25 ml). The organic layer was washed sequentially with 1N NaOH solution (25 ml), water (25 ml) and saturated NaCl solution (25 ml), dried (MgSO ₄ ), dried under reduced pressure and 4- (4-methylsulfonyloxy) -1- Nitrobenzene was obtained.

Step 2; 4- (4-Methylsulfonylphenoxy) -1-aniline 4- (4-Methylsulfonylphenoxy) -1-nitrobenzene was reduced to aniline in a manner similar to that described in Method A18, Step 3.

B. Synthesis of urea precursors.
B1. Synthesis of isocyanate from aniline using CDI. Synthesis of 4-bromo-3- (trifluoromethyl) phenyl isocyanate.

Step 1: Synthesis of 4-bromo-3- (trifluoromethyl) aniline HCl salt To a solution of 4-bromo-3- (trifluoromethyl) aniline (64 g, 267 mmol) in Et ₂ O (500 ml) with HCl solution (Et 1M in ₂ O, 300 ml) was added dropwise and the resulting mixture was stirred at room temperature for 16 hours. The resulting pink white precipitate was removed by filtration and washed with Et ₂ O (50 ml) to give 5-bromo-3- (trifluoromethyl) aniline HCl salt (73 g, 98%).

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

C. Urea production method.
C1a. General synthesis of urea by reaction of isocyanate and aniline. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea.

CH ₂ Cl ₂ (35 ml) of 4-chloro-3- (trimethyl) phenyl isocyanate (14.60g, 65.90mmol) solution of CH ₂ Cl ₂ (35 ml) solution of 4- (2-(N-methylcarbonyl ) -4-Pyridyloxy) aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) was added dropwise at 0 ° C. The resulting mixture was stirred at room temperature for 22 hours. The resulting yellow solid was collected by filtration, washed with CH ₂ Cl ₂ (2 × 30 ml), dried under reduced pressure (about 1 mmHg) and N- (4-chloro-3- (trifluoromethyl) phenyl) as an off-white solid. -N '-(4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (28.5 g, 93%) was obtained. mp 207-209 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 2.77 (d, J = 4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J = 2.5 Hz) , 1H), 7.62 (m, 4H), 8.11 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m / z 465 [(M + H) ⁺ ]

C1b. General synthesis of urea by reaction of isocyanate and aniline. Synthesis of N- (4-bromo-3- (trifluoromethyl) phenyl) -N '-(4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea.

CH ₂ Cl ₂ (80 ml) solution of 4-bromo-3- (trifluoromethyl) phenyl isocyanate (Method B1, Step 2; 8.0 g, 30.1 mmol) the solution CH ₂ Cl ₂ (40 ml) solution of 4- To a solution of (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) was added dropwise at 0 ° C. The resulting mixture was stirred at room temperature for 16 hours. The resulting yellow solid was collected by filtration, washed with CH ₂ Cl ₂ (2 × 50 ml), dried under reduced pressure (about 1 mmHg) at 40 ° C., and N- (4-bromo-3- (trimethylfluoro) phenyl)- N ′-(4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea was obtained as a pale yellow solid (13.2 g, 90%). mp 203-205 ° C .; ¹ H-NMR (DMSO-d ₆ ) δ 2.77 (d, J = 4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J = 2.5 Hz) , 1H), 7.58 (m, 3H), 7.77 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 5.5 Hz, 1 H), 8.77 (br d, 1 H), 8.99 (s, 1 H), 9.21 (s, 1 H); HPLC ES-MS m / z 509 [(M + H) ⁺ ]

C1c. General synthesis of urea by reaction of isocyanate and aniline. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(2-methyl-4- (2-N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea.

A solution of ₂ -methyl-4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (Method A5; 0.11 g, 0.45 mmol) in CH ₂ Cl ₂ (1 ml) was added to Et ₃ N (0 .16 ml) and 4-chloro-3- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temperature for 6 days and then treated with water (3 ml). The aqueous layer was back extracted with EtOAc (3 × 5 ml) and the organic layer was dried (MgSO ₄ ) and concentrated in vacuo to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′ as a brown oil. -(2-Methyl-4- (2-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.11 g, 0.22 mmol) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 2.27 (s, 3H), 2.77 (d, J = 4.8 Hz, 3H), 7.03 (dd, J = 8.5, 2.6 Hz, 1H), 7.11 (d, J = 2.9 Hz, 1H), 7.15 (dd, J = 5.5, 2.6 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H) ), 7.62 (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 Hz, 1H), 9.52 (s, 1H); HPLC ES-MS m / z 479 [( M + H) ⁺ ]

C1d. General synthesis of urea by reaction of isocyanate and aniline. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(4-aminophenyl) urea.

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (2.77 g, 10.3 mmol) in CH ₂ Cl ₂ (308 ml) was added p-phenylenediamine (3.32 g, 30.7 mmol) at once. It was. The resulting mixture was stirred at room temperature for 1 hour, treated with CH ₂ Cl ₂ (100 ml) and concentrated in vacuo. The resulting pink solid was dissolved in a mixture of EtOAc (110 ml) and MeOH (15 ml) and the clear solution was washed with 0.05N HCl solution. The organic layer was concentrated under reduced pressure to obtain impure N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(4-aminophenyl) urea (3.3 g). TLC (100% EtOAc) Rf 0.72

C1e. General synthesis of urea by reaction of isocyanate and aniline. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(4-ethoxycarbonylphenyl) urea.

To a solution of ethyl 4-isocyanate benzoate (3.14 g, 16.4 mmol) in CH ₂ Cl ₂ (30 ml) was added 4-chloro-3- (trifluoromethyl) aniline (3.31 g, 16.4 mmol). The solution was stirred overnight at room temperature. The resulting slurry was diluted with CH ₂ Cl ₂ (50 ml), filtered and N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(4-ethoxycarbonylphenyl) urea as a white solid. (5.93 g, 97%) was obtained. TLC (40% EtOAc / 60% hexane) Rf 0.44

C1f. General synthesis of urea by reaction of isocyanate and aniline. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(3-carboxyphenyl) urea.

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (1.21 g, 5.46 mmol) in CH ₂ Cl ₂ (8 ml) 4- (3-carboxyphenoxy) aniline (Method A11; 0.81 g, 5.76 mmol) was added and the resulting mixture was stirred overnight at room temperature, treated with MeOH (8 ml) and stirred for an additional 2 hours. The resulting mixture was concentrated under reduced pressure. The resulting brown solid was kneaded with a 1: 1 EtOAc / hexane solution and N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(3-carboxyphenyl) urea (1.21 g, 1.2 g, 76%).

C2a. General method for urea synthesis by reaction of aniline with N, N′-carbonyldiimidazole followed by addition of a second aniline. Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N ′-(4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea.

To a solution of ₂ -methoxy-5- (trifluoromethyl) aniline (0.15 g) in anhydrous CH ₂ Cl ₂ (15 ml) was added CDI (0.13 g) at 0 ° C. The resulting solution was warmed to room temperature over 1 hour, stirred at room temperature for 16 hours, and then treated with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 72 hours and treated with H ₂ O (125 ml). The resulting aqueous mixture was extracted with EtOAc (2 × 150 ml) and the combined organic layers were washed with saturated NaCl solution (100 ml), dried (MgSO ₄ ) and concentrated in vacuo. The residue was kneaded (90% EtOAc / 10% hexanes) and the resulting white solid was collected by filtration and washed with EtOAc. The filtrate was concentrated in vacuo and the residual oil was purified by column chromatography (gradient from 33% EtOAc / 67% hexane to 50% EtOAc / 50% hexane) to give N- (2-methoxy-5- ( Trifluoromethyl) phenyl) -N ′-(4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenylurea (0.098 g, 30%) was obtained, TLC (100% EtOAc) Rf0. 62; ¹ H-NMR (DMSO-d ₆ ) δ 2.76 (d, J = 4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 (m, 11H), 8 4-8.6 (m, 11H), 8.75 (d, J = 4.8 Hz, 1H), 9.55 (s, 1H); FAB-MS m / z 461 [(M + H) ⁺ ]

C2b. General method for urea synthesis by reaction of aniline with N, N′-carbonyldiimidazole followed by addition of a second aniline. Symmetric urea as a byproduct of the N, N'-carbonyldiimidazole reaction procedure. Bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea.

CDI (0.13 g) was added at 0 ° C. with stirring into a solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH ₂ Cl ₂ (15 ml). The resulting solution was warmed to room temperature over 1 hour and stirred at room temperature for 16 hours. The resulting mixture was treated with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g) and the resulting yellow solution was stirred at room temperature for 72 hours, then water ( 125 ml). The resulting aqueous mixture was extracted with EtOAc (2 × 150 ml) and the combined organic layers were washed with saturated NaCl solution (100 ml) and concentrated in vacuo. The residue is kneaded (90% EtOAc / 10% hexane) and the resulting white solid is filtered off, washed with EtOAc and bis (4- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.081 g). 44%, TLC (100% EtOAc) Rf 0.50; ¹ H-NMR (DMSO-d ₆ ) δ 2.76 (d, J = 5.1 Hz, 6H), 7.1-7.6 ( m, 12H), 8.48 (d, J = 5.4 Hz, 1H), 8.75 (d, J = 4.8 Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m / z 513 [(M + H) ⁺ ]

C2c. General synthesis of urea by reaction of isocyanate and aniline. Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '-(4- (1,3-dioxoindoline-5-yloxy) phenylurea.

To a stirred solution of 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.47 mmol) in CH ₂ Cl (1.5 ml) 5- (4-aminophenoxy) indoline-1,3- Dione (Method A3, Step 3; 0.12 g, 0.47 mmol) was added in one portion. The resulting mixture was stirred for 12 hours and then treated with CH ₂ Cl ₂ (10 ml) and MeOH (5 ml). The resulting mixture was washed sequentially with 1N HCl solution (15 ml) and saturated NaCl solution (15 ml), dried (MgSO ₄ ), concentrated in vacuo and N- (2-methoxy-5- (trifluoromethyl) as a white solid. Phenyl) -N ′-(4- (1,3-dioxoisoindoline-5-yloxy) phenyl) urea (0.2 g, 96%) was obtained. TLC (70% EtOAc / 30% hexane) Rf 0.50; ¹ H-NMR (DMSO-d ₆ ) δ 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.37 ( d, J = 9.3 Hz, 2H), 7.80 (d, J = 8.7 Hz, 1H), 8.53 (brs, 2H), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS m / z 472.0 [(M + H) ⁺ , 100%]

C2d. General method of urea synthesis by reaction of aniline with N, N'-carbonyldiimidazole followed by addition of a second aniline. Of N- (5- (t-butyl) -2- (2,5-dimethylpyrrolyl) phenyl) -N ′-(4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea Synthesis.

To a stirred solution of CDI (0.21 g, 1.30 mmol) in CH ₂ Cl ₂ (2 ml) 5- (t-butyl) -2- (2.5-dimethylpyrrolyl) aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) was added at once. The resulting mixture was stirred at room temperature for 4 hours, then 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.065 g, 0.267 mmol) was added in one portion. The resulting mixture was heated at 36 ° C. overnight, cooled to room temperature and diluted with EtOAc (5 ml). The resulting mixture was washed sequentially with water (15 ml) and 1N HCl solution (15 ml), dried, filtered through a silica gel pad (50 g) and N- (5- (t-butyl) -2- (2 , 5-dimethylpyrrolyl) phenyl) -N ′-(4- (2-methylcarbamoyl) -4-pyridyloxy) urea (0.033 g, 24%) was obtained. TLC (40% EtOAc / 60% hexane) Rf 0.24; ¹ H-NMR (acetone-d ₆ ) δ 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J = 4.8 Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H) , 8.43 (d, J = 5.4 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 [(M + H) ⁺ , 100%]

C3. Combination method of diphenylurea synthesis using triphosgene.
One of the anilines to be linked was dissolved in dichloroethane (0.10M). This solution was added to an 8 ml vial (0.5 ml) containing dichloroethane (1 ml). To this was added bis (trichloromethyl) carbonate solution (0.12M in dichloroethane, 0.2 ml, 0.4 eq) followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 ml, 1.2 eq). . The vial was capped and heated at 80 ° C. for 5 hours and cooled to room temperature in about 10 hours. A second aniline was added (0.10 M in dichloroethane, 0.5 ml, 1.0 equiv) followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 ml, 1.2 equiv). The resulting mixture was heated at 80 ° C. for 4 hours, cooled to room temperature and treated with MeOH (0.5 ml). The resulting mixture was concentrated under reduced pressure and purified by reverse phase HPLC.

C4. General method of urea synthesis by reaction of aniline with phosgene followed by addition of a second aniline. Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '-(4-2 (N-methylcarbamoyl) -4-pyridyloxy) -phenyl) urea.

To a solution of phosgene (1.9 M in toluene, 2.07 ml, 0.21 g, 1.30 mmol) in CH ₂ Cl ₂ (20 ml) at 0 ° C. with stirring anhydrous pyridine (0.32 ml) and then 2-methoxy-5 -(Trifluoromethyl) aniline (0.75 g) was added. The yellow mixture was stirred for 1 hour and then concentrated in vacuo. The resulting solid was added to toluene (20 ml) followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (prepared as in Method A2, 0.30 g) and the resulting suspension was obtained. The suspension was heated at 80 ° C. for 20 hours and cooled to room temperature. The resulting mixture was diluted with water (100 ml) and made basic with saturated NaHCO ₃ solution (2-3 ml). The basic solution was extracted with EtOAc (2 × 250 ml) and the organic layers were washed separately with saturated NaCl solution, combined, dried (MgSO ₄ ) and concentrated in vacuo. The resulting pink brown residue was dissolved in MeOH and absorbed onto SiO ₂ (100 g). Column chromatography (300 g SiO ₂ ; gradient from 1% Et ₃ N / 33% EtOAc / 66% hexane to 1% Et ₃ N / 99% EtOAc to 1% Et ₃ N / 20% MeOH / 79% EtOAc), Concentration at 45 ° C. under reduced pressure then gave a warm EtOAc solution. This was treated with hexane (10 ml) to give N- (2-methoxy-5- (trifluoromethyl) phenyl) -N ′-(4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea. Slowly formed crystals (0.44 g). TLC (1% Et ₃ N / 99% EtOAc) Rf 0.40

D. Interconversion of urea.
Synthesis of N- (4-chloro-3-((trifluoromethyl) phenyl) -N ′-(4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea.
D1a. Conversion of ω-aminophenylurea to ω-aroylaminourea. Synthesis of N- (4-chloro-3-((trifluoromethyl) phenyl) -N ′-(4- (3-methylcarbamoyl) phenyl) carboxyaminophenyl) urea.

N- (4-Chloro-3-((trifluoromethyl) phenyl) -N ′-(4-aminophenyl) urea (Method C1d; 0.050 g, 1.52 mmol), monomethylisophthalate in DMF (8 ml) To a solution of (0.25 g, 1.38 mmol), HOBT.H ₂ O (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 ml, 3.03 mmol), EDCI.HCl (0.29 g, 1 The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (25 ml) and washed sequentially with water (25 ml) and saturated NaHCO ₃ solution (25 ml) .The organic layer was dried (MgSO _4). The resulting solid was kneaded with EtOAc solution (80% EtOAc / 20% hexane) to give N- (4-chloro-3-((tri Fluoromethyl) phenyl) -N ′-(4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea (0.27 g, 43%) was obtained, mp 121-122 ° C.; TLC (80% EtOAc / 20% hexane) Rf0.75

D1b. Conversion of ω-carboxyphenylurea to ω- (arylcarbamoyl) phenylurea. Synthesis of N- (4-chloro-3-((trifluoromethyl) phenyl) -N '-(4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea.

N- (4-Chloro-3-((trifluoromethyl) phenyl) -N ′-(4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol) in DMF (3 ml) ), 3-methylcarbamoylaniline (0.080 g, 0.55 mmol), HOBT.H ₂ O (0.14 g, 1.07 mmol) and N-methylmorpholine (0.5 ml, 1.07 mmol) at 0 ° C. EDCI.HCl (0.10 g, 0.53 mmol) was added at rt 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 layer was concentrated under reduced pressure and the resulting yellow solid was dissolved in EtOAc (3 ml) and filtered through a silica gel pad (17 g, 70% EtOAc / 30% hexane to 10% MeOH / 90% EtOAc gradient), N- (4-chloro-3-((trifluoromethyl) phenyl) -N ′-(4- (3-methylcarbamoyl) as a white solid Phenyl) carbamoylphenyl) urea (0.097 g, 41%) was obtained, mp 225-229 ° C.; TLC (100% EtOAc) Rf 0.23

D1c. A combinatorial approach to the conversion of ω-carboxyphenylurea to ω- (arylcarbamoyl) phenylurea. Synthesis of N- (4-chloro-3-((trifluoromethyl) phenyl) -N '-(4- (N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea.

N- (4-Chloro-3-((trifluoromethyl) phenyl) -N ′-(3-carboxyphenyl) urea (Method C1f; 0.030 g, 0.067 mmol) in 1,2-dichloroethane (1 ml) And a mixture of N-cyclohexyl-N- (methylpolystyrene) carbimide (55 mg) was treated with a solution of 3-aminopyridine in CH ₂ Cl ₂ (1M; 0.074 ml, 0.074 mmol) (insoluble or suspended). In some cases, a small amount of DMSO was added.) The resulting mixture was heated at 36 ° C. overnight, the cloudy reaction mixture was treated with THF (1 ml) and heating was continued for 18 hours. Stir for 72 hours, cool to room temperature, filter, filter the resulting solution through a pad of silica gel (1 g), concentrate under reduced pressure with N- (4-chloro-3-(( Rifluoromethyl) phenyl) -N ′-(4- (N- (3- (N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea (0.024 g, 59%) was obtained. 70% EtOAc / 30% hexane) Rf 0.12

D2. Conversion of ω-carboalkoxy aryl urea to ω-carbamoyl aryl urea. Synthesis of N- (4-chloro-3-((trifluoromethyl) phenyl) -N '-(4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea.

  Methylamine to N- (4-chloro-3-((trifluoromethyl) phenyl) -N ′-(4- (3-carbomethoxyphenyl) carboxyaminophenyl) urea sample (0.17 g, 0.34 mmol) (2M in THF; 1 ml, 1.7 mmol) was added and the resulting mixture was stirred at room temperature overnight and concentrated in vacuo to give N- (4-chloro-3-((trifluoromethyl) phenyl) as a white solid. -N ′-(4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea was obtained, mp 247 ° C.; TLC (100% EtOAc) Rf 0.35

D3. Conversion of ω-carboalkoxyarylurea to ω-carboxyarylurea. Synthesis of N- (4-chloro-3-((trifluoromethyl) phenyl) -N '-(4-carboxyphenyl) urea.

  To a slurry of N- (4-chloro-3-((trifluoromethyl) phenyl) -N ′-(4-ethoxycarbonylphenyl) urea (Method C1e; 5.93 g, 15.3 mmol) in MeOH (75 ml) Aqueous solution (2.5 N, 10 ml, 23 mmol) was added and the resulting mixture was heated at reflux for 12 hours, cooled to room temperature and concentrated in vacuo.The residue was diluted with water (50 ml) and diluted with 1N HCl solution. Treatment to pH 2-3 Collected solid, dried under reduced pressure and N- (4-chloro-3-((trifluoromethyl) phenyl) -N ′-(4-carboxyphenyl) as a white solid. ) Urea (5.05 g, 92%) was obtained.

D4. Conversion of ω-alkoxy esters to ω-alkyl amides. Synthesis of N- (4-chloro-3-((trifluoromethyl) phenyl) -N '-((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea.

Step 1; Synthesis of N- (4-chloro-3-((trifluoromethyl) phenyl) -N ′-((4- (3- (5-carboxypyridyl) oxyphenylurea N- (4-chloro-3 -(Trifluoromethyl) phenyl) -N '-(4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea was prepared in a manner analogous to Method Cla by 4-chloro-3- (trifluoromethyl) phenyl. Synthesized from isocyanate and 4- (3- (5-methoxycarbonylhydridyl) oxyaniline (Method A14, Step 2) N- (4-Chloro-3- (trifluoromethyl) in MeOH (10 ml) Phenyl) -N ′-((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea (0.26 g, 0.56 mmol) suspension in water (1 ml) in K The mixture was treated with OH (0.14 g, 2.5 mmol) solution and stirred for 1 hour at room temperature, the resulting mixture was adjusted to pH 3 with 1N HCl solution, and the resulting precipitate was collected by filtration and washed with water. The solid was dissolved in EtOH (10 ml), and the solution was concentrated under reduced pressure.This EtOH / concentration operation was repeated twice, and N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(4- (3 -(5-Carboxypyridine) oxyphenyl) urea (0.18 g, 71%) was obtained.

Step 2: Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl-N ′-((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea.
N- (4-Chloro-3- (trifluoromethyl) phenyl) -N ′-((4- (3- (5-carboxypyridyl) oxyphenyl) urea (0.050 g, 0.011 mmol), N, N-dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N-methylmorpholine (0.035 g, 0.28 mmol) and EDCI.HCl ( 0.032 g, 0.17 mmol) was stirred overnight at room temperature The resulting solution was separated between EtOAc (50 ml) and water (50 ml) and the organic layer was washed with water (35 ml) and dried ( MgSO ₄₎ and concentrated under reduced pressure. the residue was dissolved in a minimal amount of CH ₂ Cl ₂ (approximately 2 ml), was added dropwise Et ₂ O to the solution as a white precipitate N-(4 -Chloro-3- (trifluoromethyl) phenyl) -N '-((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea (0.48 g, 84%). ¹ H-NMR (DMSO-d ₆ ) δ 2.10 (s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7 .60 (m, 3H), 8.05 (s, 1H), 8.43 (s, 1H), 8.58 (t, 1H), 8.69 (s, 1H) 8.90 (s, 1H) ), 9.14 (s, 1H); HPLC ES-MS m / z 522 [(M + H) ⁺ ]

D5. General method for deprotection of N-ω- (silyloxyalkyl) amide. Synthesis of N- (4-chloro-3-((trifluoromethyl) phenyl) -N '-(4- (4- (2- (N- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea).

N- (4-Chloro-3- (trifluoromethyl) phenyl) -N ′-(4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl)) in anhydrous THF (2 ml) To a solution of pyridyloxyphenylurea (prepared in a manner similar to Method C1a; 0.25 g, 0.37 mmol) was added tetrabutylammonium fluoride solution (1.0 M in THF, 2 ml), and the mixture was at room temperature for 50 minutes. Stirred and treated with water (10 ml) The aqueous mixture was extracted with EtOAc (3 × 10 ml), the organic layer was dried (MgSO ₄ ) and concentrated in vacuo The residue was column chromatographed (SiO ₂ ; 100% hexanes). To 40% EtOAc / 60% hexane) and purified as a white solid with N- (4-chloro-3- (trifluoromethyl) phenyl. ) -N '- to give the (4- (4- (2- (N- (2- hydroxy) ethylcarbamoyl) pyridyloxy phenyl) urea (0.019g, 10%).

The following is a list of the compounds listed in the following table that were synthesized according to the detailed experimental procedure above.
Synthesis of exemplified compounds (see table for compound characterization)

Entry 1:
4- (3-N-methylcarbamoylphenoxy) aniline was synthesized according to Method A13. According to Method C3, 3-t-butylaniline was reacted with bis (trichloromethyl) carbonate followed by 4- (3-N-methylcarbamoylphenoxy) aniline to give urea.

Entry 2:
4-Fluoro-1-nitrozene was reacted with p-hydroxyacetophenone according to Method A13, Step 1, to give 4- (4-acetylphenoxy) -1-nitrobenzene. This compound was reduced according to Method A13, Step 4, to give 4- (4-acetylphenoxy) aniline. According to Method C3, 3-t-butylaniline was reacted with bis (trichloromethyl) carbonate and then 4- (4-acetylphenoxy) aniline to obtain urea.

Entry 3:
According to Method C2d, 3-t-butylaniline was reacted with CDI and then 4- (3-N-methylcarbamoyl) -4-methoxyphenoxy) aniline prepared according to Method A8 to give urea.

Entry 4:
According to Method B1, 5-t-butyl-2-methoxyaniline was converted to 5-t-butyl-2-methoxyphenyl isocyanate. 4- (3-N-methylcarbamoylphenoxy) aniline prepared according to Method A13 was reacted with this isocyanate to give urea.

Entry 5:
According to Method C2d, 5-t-butyl-2-methoxyaniline was reacted with CDI and then 4- (3-N-methylcarbamoyl) -4-methoxyphenoxy) aniline (prepared according to Method A8) to give urea.

Entry 6:
5- (4-Aminophenoxy) isoindoline-1,3-dione was prepared according to Method A3. According to Method C2d, 5-t-butyl-2-methoxyaniline was reacted with CDI and then with 5- (4-aminophenoxy) isoindoline-1,3-dione to give urea.

Entry 7:
4- (1-Oxoisoindoline-5-yloxy) aniline was synthesized according to Method A2. According to Method C2d, 5-t-butyl-2-methoxyaniline and CDI were reacted with 4- (1-oxoisoindoline-5-yloxy) aniline to obtain urea.

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

Entry 9:
According to Method A3, Step 2, 4-hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine to give 4- (4-acetylphenoxy) -5-nitropyridine. 4- (4-Acetylphenoxy) -5-nitropyridine was reduced to 4- (4-acetylphenoxy-5-aminopyridine according to Method A8, Step 4. According to Method B1, 2-methoxy-5- (trifluoro) Methyl) aniline was converted to 2-methoxy-5- (trifluoromethyl) phenyl isocyanate, which was reacted with 4- (4-acetylphenoxy) -5-aminopyridine according to Method C1a to give urea.

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

Entry 11:
4-Chloro-N-methyl-2-pyridinecarboxamide synthesized according to Method A2, Step 3a is reacted with 3-aminophenol according to Method A2, Step 4, using DMAC instead of DMF, and 3- ( 2- (N-methylcarbamoylphenoxy) -4-pyridyloxy) aniline was obtained. According to Method C4, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene and then with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to obtain urea.

Entry 12:
According to Method A2, Step 3b, 4-chloropyridine-2-carbonyl chloride HCl and ammonia were reacted to produce 4-chloro-2-pyridinecarboxamide. This compound was reacted with 3-aminophenol according to Method A2, Step 4, using DMAC instead of DMF to give 3- (2-carbamoyl-4-pyridyloxy) aniline. According to Method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene and then with 3- (2-carbamoyl-4-pyridyloxy) aniline to give urea.

Entry 13:
4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. This compound was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. According to Method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI and then 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Entry 14:
According to Method A2, Step 3b, 4-chloropyridine-2-carbonyl chloride HCl was reacted with ammonia to produce 4-chloro-2-pyridinecarboxamide. This compound was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to give 4- (2-carbamoyl-4-pyridyloxy) aniline. According to Method C4, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene and then 4- (2-carbamoyl-4-pyridyloxy) aniline to give urea.

Entry 15:
According to Method C2d, 5- (trifluoromethyl) -2-methoxyaniline is reacted with CDI and then 4- (3-N-methylcarbamoyl) -4-methoxyphenoxy) aniline prepared according to Method A8 to give urea. It was.

Entry 16:
4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was synthesized according to Method A5. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. This isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline according to Method C1 to obtain urea.

Entry 17:
4- (2- (N-methylcarbamoyl) -4-pyridyloxy-2-chloroaniline was synthesized according to Method A6 and 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) according to Method B1. The isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy-2-chloroaniline according to Method C1a to give urea.

Entry 18:
According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide synthesized according to Method A2, Step 3b to give 3- (2- (N- Methylcarbamoyl) -4-pyridyloxy) -4-methylaniline was obtained. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. This isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline according to Method C1a to give urea.

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

Entry 20:
According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide synthesized according to Method A2, Step 3b to give 4- (2- (N- Methylcarbamoyl) -4- (pyridyloxy) -3-chloroaniline was obtained and 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl-2-methoxyphenyl isocyanate according to Method B1. This isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline according to Method C1a to give urea.

Entry 21:
4- (4-Methylthiophenoxy) -1-nitrobenzene was oxidized according to Method A19, Step 1, to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. This nitrobenzene was reduced according to Method A19, Step 2, to give 4- (4-methylsulfonylphenoxy) -1-aniline. According to Method C1a, 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (4-methylsulfonylphenoxy) -1-aniline to give urea.

Entry 22:
4- (3-carbamoylphenoxy) -1-nitrobenzene was reduced to 4- (3-carbamoylphenoxy) aniline according to Method A15, Step 4. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3-carbamoylphenoxy) aniline according to Method C1a to give urea.

Entry 23:
5- (4-Aminophenoxy) isoindoline-1,3-dione was synthesized according to Method A3. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. This isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione according to Method C1a to give urea.

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

Entry 25:
4- (1-Oxoisoindoline-5-yloxy) aniline was synthesized according to Method A12. 5- (Trifluoromethyl) -2-methoxyaniline was treated with CDI and then 4- (1-oxoisoindoline-5-yloxy) aniline according to Method C2d to give urea.

Entry 26:
4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1, to give 4- (4-acetylphenoxy) nitrobenzene. The nitrobenzene is reduced according to Method A13, Step 4, to 4- (4-acetylphenoxy) aniline, and this compound is converted to 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt according to Method A16. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1, which was converted to 4- (4- (1- ( N-methoxy) iminoethyl) phenoxyaniline HCl salt was reacted to give urea.

Entry 27:
4-Chloro-N-methylpyridylcarboxamide was synthesized as described in Method A2, Step 3b. This chloropyridine was reacted with 4-aminophenol according to Method A2, Step 4, to give 4- (4- (2- (N-methylcarbamoyl) phenylthioaniline. 5- (Trifluoromethyl) -2-methoxy. The aniline is converted to 5- (trifluoromethyl-2-methoxyphenyl isocyanate according to Method B1, which is reacted with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline according to Method C1a to give urea. It was.

Entry 28:
5- (4-Aminophenoxy) -2-methylisoindoline-1,3-dione was synthesized according to Method A9. 5- (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1, which is converted to 5- (4-aminophenoxy) -2-methyl according to Method C1a. Reaction with isoindoline-1,3-dione gave urea.

Entry 29:
4-Chloro-N-methylpyridinecarboxamide was synthesized according to Method A2, Step 3b. This chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4, to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 5- (Trifluoromethyl) -2- Methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1, which is reacted with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline according to Method C1a to form urea. Got.

Entry 30:
4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4, to give 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline. Got. 5- (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1, which is converted to 4- (2- (N-isopropylcarbamoyl) according to Method C1a. Reaction with -4-pyridyloxy) aniline gave urea.

Entry 31:
4- (3- (5-methoxycarbonyl) aniline was synthesized according to Method A14 and 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. After conversion, the isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to give urea N- (5- (trifluoromethyl) -2-methoxyphenyl)- Saponification of N ′-(4- (3- (5-methoxycarbonylpyridine) oxy) phenyl) urea according to Method D, Step 1, and the corresponding acid to 4- (2-aminoethyl) morpholine and Method D4, Step 2 To give the amide.

Entry 32:
4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14. 5- (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1, and the isocyanate is converted to 4- (3- (5-methoxycarbonyl) according to Method C1a. Pyridyloxy) aniline was reacted with urea. Saponification of N- (5- (trifluoromethyl) phenyl) -N ′-(4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea according to Method D4, Step 1 and the corresponding acid to Method D4 , Coupled with methylamine according to step 2 to give the amide

Entry 33:
4- (3- (5-methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14. Convert 5- (trifluoromethyl) -2-methoxyaniline to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1 and convert this isocyanate to 4- (3- (5-methoxycarbonyl) according to Method C1a. Reaction with pyridyloxy) aniline gave urea. Saponification of N- (5- (trifluoromethyl) -2-methoxyphenyl) -N ′-(4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea according to method D4, step 1 and corresponding The acid was coupled with N, N-dimethylethylenediamine according to Method D4, Step 2, to give the amide.

Entry 34:
4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. Convert 5- (trifluoromethyl) -2-methoxyaniline to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1 and react this isocyanate with 4- (3-carboxyphenoxy) aniline according to Method C1f. To N- (5- (trifluoromethyl) -2-methoxyphenyl) -N ′-(3-carboxyphenoxyphenyl) urea, which was linked to 3-aminopyridine according to Method D1c.

Entry 35:
4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. Convert 5- (trifluoromethyl) -2-methoxyaniline to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1 and react this isocyanate with 4- (3-carboxyphenoxy) aniline according to Method C1f. To give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N ′-(3-carboxyphenyl) urea. This compound was coupled with N- (4-fluorophenyl) piperazine according to Method D1c.

Entry 36:
4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. Convert 5- (trifluoromethyl) -2-methoxyaniline to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1 and react this isocyanate with 4- (3-carboxyphenoxy) aniline according to Method C1f. To N- (5- (trifluoromethyl) -2-methoxyphenyl) -N ′-(3-carboxyphenyl) urea, which was linked to 4-fluoroaniline according to Method D1c.

Entry 37:
4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. Convert 5- (trifluoromethyl) -2-methoxyaniline to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1 and react this isocyanate with 4- (3-carboxyphenoxy) aniline according to Method C1f. To N- (5- (trifluoromethyl) -2-methoxyphenyl) -N ′-(3-carboxyphenyl) urea, which was linked to 4- (dimethylamino) aniline according to Method D1c.

Entry 38:
4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. Convert 5- (trifluoromethyl) -2-methoxyaniline to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1 and react this isocyanate with 4- (3-carboxyphenoxy) aniline according to Method C1f. To N- (5- (trifluoromethyl) -2-methoxyphenyl) -N ′-(3-carboxyphenyl) urea, which was coupled with 5-amino-2-methoxypyridine according to Method D1c.

Entry 39:
4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. Convert 5- (trifluoromethyl) -2-methoxyaniline to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1 and react this isocyanate with 4- (3-carboxyphenoxy) aniline according to Method C1f. To N- (5- (trifluoromethyl) -2-methoxyphenyl) -N ′-(3-carboxyphenyl) urea, which was linked to 4-morpholinoaniline according to Method D1c.

Entry 40:
4- (3-Carboxyphenoxy) aniline was synthesized according to Method A11. Convert 5- (trifluoromethyl) -2-methoxyaniline to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1 and react this isocyanate with 4- (3-carboxyphenoxy) aniline according to Method C1f. To N- (5- (trifluoromethyl) -2-methoxyphenyl) -N ′-(3-carboxyphenyl) urea, which was linked to N- (2-pyridyl) piperazine according to Method D1c.

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

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

Entry 43:
According to Method A2, step 3b, 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia to produce 4-chloro-2-pyridinecarboxamide. This was reacted with 4-aminophenol according to Method A2, Step 4, to produce 4- (2-carbamoyl-4-pyridyloxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2-carbamoyl-4-pyridyloxy) aniline to obtain urea.

Entry 44:
According to Method A2, step 3b, 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia to produce 4-chloro-2-pyridinecarboxamide. This was reacted with 3-aminophenol according to Method A2, Step 4, to produce 3- (2-carbamoyl-4-pyridyloxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2-carbamoyl-4-pyridyloxy) aniline to obtain urea.

Entry 45:
According to Method A2, Step 3a, 4-chloro-N-methyl-2-pyridinecarboxamide is reacted with 3-aminophenol according to Method A2, Step 4 to give 3- (2- (N-methylcarbamoyl) -4- Pyridyloxy) aniline was produced. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to obtain urea.

Entry 46:
5- (4-Aminophenoxy) isoindoline-1,3-dione was synthesized according to Method A3. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to obtain urea.

Entry 47:
4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was synthesized according to Method A5. According to Method C1e, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to obtain urea.

Entry 48:
According to method 15, 4- (3-N-methylsulfonyl) phenyloxy) aniline was synthesized. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-N-methylsulfonyl) phenyloxy) aniline to obtain urea.

Entry 49:
4- (2- (N-methylcarbamoyl) -4- (pyridyloxy) -2-chloroaniline was synthesized according to Method A6, and 4-chloro-3- (trifluoromethyl) phenyl isocyanate was synthesized according to Method C1a. Reaction with-(2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline gave urea.

Entry 50:
According to method A2, step 4, 5-amino-2-methylphenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide (synthesized according to method A2, step 3b) to give 3- (2- (N -Methylcarbamoyl) -4-pyridyloxy-4-methylaniline was obtained and 4-chloro-3- (trifluoromethyl) phenyl isocyanate was converted to 3- (2- (N-methylcarbamoyl) -4- according to method C1a. Reaction with pyridyloxy) -4-methylaniline gave urea.

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

Entry 52:
According to Method A2, Step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide (synthesized according to Method A2, Step 3b) to give 4- (2- (N -Methylcarbamoyl) -4-pyridyloxy-3-chloroaniline was obtained and 4-chloro-3- (trifluoromethyl) phenyl isocyanate was converted to 4- (2- (N-methylcarbamoyl) -4- according to method C1a. Reaction with pyridyloxy) -3-chloroaniline gave urea.

Entry 53:
According to Method A19, Step 1, 4- (4-methylthiophenoxy) -1-nitrobenzene was oxidized to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. This nitrobenzene was reduced according to Method A19, Step 2, to give 4- (4-methylsulfonylphenoxy) -1-aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4-methylsulfonylphenoxy) -1-aniline to obtain urea.

Entry 54:
According to Method A15, Step 1, 4-bromobenzenesulfonyl chloride was reacted with methylamine to give N-methyl-4-bromobenzenesulfonamide. According to Method A15, Step 2, N-methyl-4-bromobenzenesulfonamide was coupled with phenol to give 4- (4- (N-methylsulfonyl) phenoxy) benzene. This compound is converted to 4- (4- (N-methylsulfamoyl) phenoxy) -1-nitrobenzene according to Method 15, Step 3, which is converted to 4- (4-N-methylsulfuric acid according to Method A15, Step 4. Reduction to moyl) phenyloxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-N-methylsulfamoyl) phenyloxy) aniline to obtain urea.

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

Entry 56:
According to Method A18, Step 1, 5-hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene to give 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene. This methylpyridine was oxidized to a carboxylic acid and esterified according to Method A18, Step 2, to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene. This nitrobenzene was reduced to 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline according to Method A18, Step 3. This aniline is reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method C1a to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(4- (2-methoxy Carbonyl) -5-pyridyloxy) phenyl) urea was obtained. This methyl ester is reacted with methylamine according to Method D2 and N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(2- (N-methylcarbamoyl) -5-pyridyloxy) phenyl) Urea was obtained.

Entry 57:
N- (4-Chloro-3- (trifluoromethyl) phenyl) -N ′-(4-aminophenyl) urea was prepared according to Method C1d. This compound was coupled with monomethylisophthalate according to Method D1a to obtain urea.

Entry 58:
N- (4-Chloro-3- (trifluoromethyl) phenyl) -N ′-(4-aminophenyl) urea was prepared according to Method C1d. According to Method D1a, N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(4-aminophenyl) urea is coupled with monomethylisophthalate and N- (4-chloro-3- (trimethyl) Fluoromethyl) phenyl) -N ′-(4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea was obtained. The urea was treated with methylamine according to Method D2 to give the corresponding methylamide.

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

Entry 60:
According to Method A13, Step 1, 4-hydroxyacetophenone was reacted with 4-fluoronitrobenzene to give 4- (4-acetylphenoxy) nitrobenzene. The nitrobenzene was reduced to 4- (4-acetylphenoxy) aniline according to Method 13, Step 4, which was converted to 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt according to Method A16. According to Method C1a, 4-chloro-3- (trifluoromethyl) -phenyl isocyanate was reacted with 4- (4-acetylphenoxy) aniline to obtain urea.

Entry 61:
4- (3-Carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, Step 2. This nitrobenzene was coupled with 4- (2-aminoethyl) morpholine according to Method A13, Step 3, to give 4- (3- (N- (2-morpholinylethyl) carbamoyl) phenoxy-1-nitrobenzene. The nitrobenzene was reduced to 4- (3- (N- (2-morpholinylethyl) carbamoyl) phenoxy) aniline according to A13, Step 4. According to Method C1a, the aniline was converted to 4-chloro-3- (trifluoro Reaction with methyl) phenyl isocyanate gave urea.

Entry 62:
4- (3-Carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, Step 2. This nitrobenzene was coupled with 1- (2-aminoethyl) piperidine according to Method A13, Step 3, to give 4- (2-piperidylethyl) carbamoyl) phenoxy-1-nitrobenzene. This was reduced to 4- (3- (N- (2-piperidylylethyl) carbamoyl) phenoxy) aniline according to Method 13, Step 4. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N- (2-piperidylethyl) carbamoyl) phenoxy) aniline to obtain urea.

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

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

Entry 65:
4-Chloro-N-methylpyridine carboxamide was synthesized as in Method 2, Step 3b. This chloropyridine was treated with 4-aminothiophenol according to Method A2, Step 4, to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. According to Method C1a, 4-chloro-3- Trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline to obtain urea.

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

Entry 67:
N- (4-Chloro-3- (trifluoromethyl) phenyl) -N ′-(4-ethoxycarbonylphenyl) urea was synthesized according to Method C1e. This urea was saponified according to Method D3 to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(4-carboxyphenyl) urea. This is coupled with 3-methylcarbamoylaniline according to method D1b to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea. It was.

Entry 68:
5- (4-Aminophenoxy) -2-methylisoindoline-1,3-dione was synthesized according to Method A9. According to Method C1a, 4-chloro-3- (trifluoro) phenyl isocyanate was reacted with 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione to obtain urea.

Entry 69:
4-Chloro-N-methylpyridinecarboxamide was synthesized according to Method A2, Step 3b. This chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. According to Method C1a, 4-chloro-3- (Trifluoromethyl) phenyl isocyanate was reacted with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline to obtain urea.

Entry 70:
4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was synthesized according to Method A10. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to give urea.

Entry 71:
4- (3- (5-methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14. According to method C1a, this is reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(4- (3- ( 5-Methoxycarbonylpyridyl) oxy) phenyl) urea was obtained. This was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4- (2-aminoethyl) morpholine to give the amide.

Entry 72:
4- (3- (5-methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14. According to method C1a, this is reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(4- (3- ( 5-methoxycarbonylpyridyloxy) phenylurea was obtained, which was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine to give the amide.

Entry 73:
4- (3- (5-methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14. According to method C1a, this is reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(4- (3- ( 5-methoxycarbonylpyridyloxy) phenyl) urea was obtained, which was saponified according to method D4, step 1, and the corresponding acid was coupled with N, N-dimethylethylenediamine to give the amide.

Entry 74:
According to Method A2, Step 3b, 4-chloropyridine-2-carbonyl chloride HCl salt is reacted with 2-hydroxyethylamine to give 4-chloro-N- (2-N- (2-triisopropylsiloxy) ethylpyridine-2- Carbosamide was formed and reacted with 4-aminophenol according to Method A17 to give 4- (4- (2- (N- (2-triisopropylsiloxy) ethylcarbamoyl) pyridyloxyaniline. Method C1a This is reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(4- (4- (2- (N- (2-triisopropylsiloxy) ethylcarbamoyl) pyridyloxyphenyl) urea was obtained.

Entry 75:
4-Chloro- (3-carboxyphenoxy) aniline was synthesized according to Method A11. This was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to method C1f to give urea and linked with 3-aminopyridine according to method D1c.

Entry 76:
4-Chloro- (3-carboxyphenoxy) aniline was synthesized according to Method A11. This was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method C1f to give urea and coupled with N- (4-acetylphenyl) piperazine according to Method D1c.

Entry 77:
4-Chloro- (3-carboxyphenoxy) aniline was synthesized according to Method A11. This was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method C1f to give urea and coupled with 4-fluoroaniline according to Method D1c.

Entry 78:
4-Chloro- (3-carboxyphenoxy) aniline was synthesized according to Method A11. This was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method C1f to give urea and linked with 4- (dimethylamino) aniline according to Method D1c.

Entry 79:
4-Chloro- (3-carboxyphenoxy) -aniline was synthesized according to Method A11. This was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to method C1f to give urea and coupled with N-phenylethylenediamine according to method D1c.

Entry 80:
4-Chloro- (3-carboxyphenoxy) -aniline was synthesized according to Method A11. Reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method C1f to give urea and coupled with 2-methoxyethylamine according to Method D1c.

Entry 81:
4-Chloro-3- (carboxyphenoxy) aniline was synthesized according to Method A11. This was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method C1f to give urea and coupled with 5-amino-2-methoxypyridine according to Method D1c.

Entry 82:
4-Chloro-3- (carboxyphenoxy) aniline was synthesized according to Method A11. This was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method C1f to give urea and coupled with 4-morpholinoaniline according to Method D1c.

Entry 83:
4-Chloro-3- (carboxyphenoxy) aniline was synthesized according to Method A11. This was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to method C1f to give urea and coupled with N- (2-pyridyl) piperazine according to method D1c.

Entry 84:
According to Method A2, Step 3b, 4-chloropyridine-2-carbonyl chloride HCl salt is reacted with 2-hydroxyethylaniline to give 4-chloro-N- (2-triisopropylsiloxy) ethylpyridine-2-carboxamide. Obtained. According to Method A17, this was reacted with triisopropylsilyl chloride and then 4-aminophenol to give 4- (4- (2- (N- (2-triisopropylsiloxy) ethylcarbamoyl) pyridyloxyaniline. According to Method C1a, reacting with 4-chloro-3- (trifluoromethyl) phenyl isocyanate and N- (4-chloro-3- (trifluoromethyl) phenyl) -N ′-(4- (4- (2- (N-2-triisopropylsiloxy) ethylcarbamoyl) pyridyloxy) phenylurea was obtained.

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

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

Entry 87:
According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide synthesized according to Method A2, Step 3b to give 4- (2- (N- Methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline was obtained. According to Method B1, 4-bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to give urea.

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

Entry 89:
4-Chloro-N-methyl-2-pyridinecarboxamide synthesized according to Method A2, Step 3a is reacted with 3-aminophenol according to Method A2, Step 4 to give 3- (2- (N-methylcarbamoyl) -4 -Pyridyloxy) aniline was obtained. According to Method B1, 4-bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to obtain urea.

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

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

Entry 92:
4-Chloro-N-methylpyridinecarboxamide was synthesized according to Method A2, Step 3b. This chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4, to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 4-Bromo-3- (trifluoromethyl ) The aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1, and 4-bromo-3- (trifluoromethyl) phenyl isocyanate was converted to 4- (4- (2- (2- ( Reaction with N-methylcarbamoyl) phenylthio) aniline gave urea.

Entry 93:
4-Chloro-N-methylpyridinecarboxamide was synthesized according to Method A2, Step 3b. This chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4, to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 4-Bromo-3- (trifluoromethyl ) The aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1, and 4-bromo-3- (trifluoromethyl) phenyl isocyanate was converted to 3- (4- (2- (2- ( Reaction with N-methylcarbamoyl) phenylthio) aniline gave urea.

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

Entry 95:
4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to Method A2. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7 and converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, this isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to obtain urea.

Entry 96:
4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. 4-Chloro-2-methoxy-5- (trifluoromethyl) arinin was synthesized according to Method A7 and converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, this isocyanate was reacted with 4- (2-N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to give urea.

Entry 97:
According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide synthesized according to Method A2, Step 3b to give 4- (2- (N- Methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline was obtained. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7 and converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, this isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to give urea.

Entry 98:
According to Method A2, Step 3a, the synthesized 4-chloro-N-methyl-2-pyridinecarboxamide is reacted with 3-aminophenol according to Method A2, Step 4, and 3- (2- (N-methylcarbamoyl)- 4-Pyridyloxy) aniline was obtained. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7 and converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, this isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Entry 99:
4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4, to give 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. Got. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7 and converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, this isocyanate was reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) arinin to give urea.

Entry 100:
4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N, N-dimethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4, to give 4- (2- (N, N-dimethylcarbamoyl) -4- Pyridyloxy) aniline was obtained. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method 7 and converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, this isocyanate was reacted with 4- (2- (N, N-dimethylcarbamoyl-4-pyridyloxy) aniline to give urea.

Entry 101:
4-Chloro-N-methyl-2-pyridinecarboxamide synthesized according to Method A2, Step 3a is reacted with 3-aminophenol according to Method A2, Step 4 to give 3- (2- (N-methylcarbamoyl) -4 -Pyridyloxy) aniline was obtained. 2-Amino-3-methoxynaphthalene was synthesized as described in Method A1. According to Method C3, 2-amino-3-methoxynaphthalene was reacted with bis (trichloromethyl) carbonate and then 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to obtain urea.

Entry 102:
4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to Method A2. 5-t-butyl-2- (2,5-dimethylpyrrolyl) aniline was synthesized according to Method A5, which was synthesized according to Method C2d with CDI and then 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. To give urea.

Entry 103:
4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. This was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. According to Method C2b, the reaction of 3-amino-2-methoxyquinoline with CDI and then 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline is bis (4- (2- (N-methylcarbamoyl)). -4-pyridyloxy) phenyl) urea was given.

The following table lists the compounds synthesized according to the above detailed experimental procedure.

  The compounds listed in Tables 1-6 below are synthesized by the general method shown above, and more detailed experimental procedures are in the entry list above, and characterization is shown in the table.

Claims (6)

A compound of formula I or a pharmaceutically acceptable salt thereof:
A-D-B (I)
In Formula I,
D is —NH—C (O) —NH—;
A is a substituent of formula -LML ¹ ; wherein L is phenyl optionally substituted with halogen or C ₁ -C ₅ alkyl;
L ¹ is pyridyl substituted with —C (O) R _x , where R _x is NR _a R _b , R _a and R _b are independently a) hydrogen,
b) C ₁ -C ₁₀ alkyl c) morpholinoethyl d) dimethylaminoethyl e) hydroxyethyl, or f) triisopropylsiloxyethyl;
M is selected from oxygen or sulfur;
B is
a) 5- (trifluoromethyl) -2-methoxyphenyl,
b) 3- (trifluoromethyl) -4-chlorophenyl,
c) selected from 3- (trifluoromethyl) -4-bromophenyl, or d) 5- (trifluoromethyl) -4-chloro-2-methoxyphenyl;
However, except when B is 5- (trifluoromethyl) -2-methoxyphenyl, when L is unsubstituted or chloro-substituted phenyl, -C (O) R _x does not mean carbamoyl or N-methylcarbamoyl .   Pharmaceutically acceptable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (tosylate), 1-naphthalenesulfonic acid, 2 -Selected from the group consisting of naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid The compound of claim 1 which is a base salt of an organic acid and an inorganic acid. N- (2-methoxy-5-trifluoromethyl) phenyl-N′-3- (2-carbamoyl-4-pyridyloxy) phenylurea;
N- (2-methoxy-5-trifluoromethyl) phenyl-N′-3- (2-N-methylcarbamoyl-4-pyridyloxy) phenylurea;
N- (2-methoxy-5-trifluoromethyl) phenyl-N′-4- (2-carbamoyl-4-pyridyloxy) phenylurea;
N- (2-methoxy-5-trifluoromethyl) phenyl-N′-4- (2-N-methylcarbamoyl-4-pyridyloxy) phenylurea;
N- (2-methoxy-5-trifluoromethyl) phenyl-N′-2-methyl-4-[(2- (N-methylcarbamoyl) -4-pyridyloxy] phenylurea;
N- (2-methoxy-5-trifluoromethyl) phenyl-N ′-(2-chloro-4- [2- (N-methylcarbamoyl) -4-pyridyloxy] phenylurea;
N- (2-methoxy-5-trifluoromethyl) phenyl-N′-3-chloro-4- [2- (N-methylcarbamoyl) -4-pyridyloxy] phenylurea;
N- (2-methoxy-5-trifluoromethyl) phenyl-N′-4- [2- (N, N-dimethylcarbamoyl) -4-pyridyloxy] phenylurea;
N- (2-methoxy-5-trifluoromethyl) phenyl-N′-4- [2- (N-methylcarbamoyl) -4-pyridylthio] phenylurea;
N- (2-methoxy-5-trifluoromethyl) phenyl-N′-3- [2- (N-methylcarbamoyl) -4-pyridylthio] phenylurea;
N- (2-methoxy-5-trifluoromethyl) phenyl-N′-4- [3- (N-morpholinoethylcarbamoyl) -5-pyridyloxy] phenylurea;
N- (2-methoxy-5-trifluoromethyl) phenyl-N′-4- [3- (N-methylcarbamoyl) -5-pyridyloxy] phenylurea; and N- (2-methoxy-5-trifluoromethyl) ) Phenyl-N′-4- [3- (N, N-dimethylaminoethylcarbamoyl) -5-pyridyloxy] phenylurea;
The compound of claim 1 selected from the group consisting of: N- (4-chloro-3-trifluoromethyl) phenyl-N′-2-methyl-4-[(2-N-methylcarbamoyl) -4-pyridyloxy] phenylurea;
N- (4-chloro-3-trifluoromethyl) phenyl-N′-4-methyl-3- [2- (N-methylcarbamoyl) -4-pyridyloxy] phenylurea;
N- (4-chloro-3-trifluoromethyl) phenyl-N′-4- [2- (N-ethylcarbamoyl) -4-pyridyloxy] phenylurea;
N- (4-chloro-3-trifluoromethyl) phenyl-N′-4- [2- (N, N-dimethylcarbamoyl) -4-pyridyloxy] phenylurea;
N- (4-chloro-3-trifluoromethyl) phenyl-N′-4- [2- (N-isopropylcarbamoyl) -4-pyridyloxy] phenylurea;
N- (4-chloro-3-trifluoromethyl) phenyl-N′-4- [2- (N-morpholinoethylcarbamoyl) -4-pyridyloxy] phenylurea;
N- (4-chloro-3-trifluoromethyl) phenyl-N′-4- [2- (N-morpholinoethylcarbamoyl) -5-pyridyloxy] phenylurea;
N- (4-chloro-3-trifluoromethyl) phenyl-N′-4- [2- (N- (2-N, N-dimethylaminoethyl) carbamoyl) -4-pyridyloxy] phenylurea;
N- (4-chloro-3-trifluoromethyl) phenyl-N′-4-[(3-N-3- (triisopropyl) siloxyethylcarbamoyl) -5-pyridyloxy] phenylurea; and N- (4 -Chloro-3-trifluoromethyl) phenyl-N'-4-[(2-N-hydroxyethylcarbamoyl) -4-pyridyl] phenylurea;
The compound of claim 1 selected from the group consisting of: N- (4-bromo-3-trifluoromethyl) phenyl-N′-4- [2- (N-ethylcarbamoyl) -4-pyridyloxy] phenylurea;
N- (4-bromo-3-trifluoromethyl) phenyl-N′-4-methyl-3- [2- (N-methylcarbamoyl) -4-pyridyloxy] phenylurea; and N- (4-bromo- 3-trifluoromethyl) phenyl-N′-4- [2- (N-morpholinoethylcarbamoyl) -4-pyridyloxy] phenylurea;
The compound of claim 1 selected from the group consisting of: N- (2-methoxy-4-chloro-5-trifluoromethyl) phenyl-N′-4-[(2-N-ethylcarbamoyl) -4-pyridyloxy] phenylurea; or N- (2-methoxy- 4-chloro-5-trifluoromethyl) phenyl-N′-4- [2- (N-isopropylcarbamoyl) -4-pyridyloxy] phenylurea;
The compound of claim 1 which is