HK1087689B - ω-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS - Google Patents

Description

Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors

This application is a divisional application of the 2000-1-12-day chinese patent application 00802685.8, "carbanilide substituted with ω -carboxyaryl as raf kinase inhibitor".

Technical Field

The present invention relates to the use of a group of aryl ureas in the treatment of raf mediated diseases, and pharmaceutical compositions for use in such treatment.

Background

p21^rasOncogenes are one of the major causes of human parenchymal carcinogenesis and development,the gene is mutated in 30% of cancer patients (Bolton et al, Ann. Rep. Med. chem.1994, 29, 165-74; Bos. cancer. Res.1989, 49, 4682-9). The non-mutated normal form of ras protein is a key element in the signaling cascade directed by growth factor receptors in almost all tissues (Avruch et al, Trends biochem. sci.1994, 19, 279-83). Biochemically, ras is a guanine nucleotide-binding protein and the cycle between GTP-bound active state and GDP-bound resting state is tightly controlled by ras endogenous gtpase activity and other regulatory proteins. Mutant ras in cancer cells has increased endogenous gtpase activity, and as a result, downstream effectors of this protein, such as raf kinase, signal constitutive growth. Thus, cancerous growth of cells harboring these mutants is caused (Magnuson et al, Semin. cancer biol.1994, 5,247-53). It is known that the effects of active ras are suppressed by inhibiting the raf kinase signaling pathway, for example by administering a deactivating antibody to raf kinase or co-expressing a dominant negative raf kinase or a dominant negative MEK as a substrate for raf kinase, to restore transformed cells to a normal growth phenotype (see: Daum et al, Trends biochem. Sci.1994, 19, 474-80; Fridman et al, J.biol. chem.1994, 269, 30105-8). Kolch et al, (Nature, 1991, 349, 426-28) further indicated that inhibition of raf expression with antisense RNA in membrane-associated oncogenes inhibits cell proliferation. Similarly, raf kinase inhibition (with antisense oligodeoxynucleotides) has been found to be associated with inhibition of growth of a variety of human tumors, both in vitro and in vivo (Monia et al, nat. Med.1996, 2, 668-75).

Summary of The Invention

The present invention provides compounds that are inhibitors of raf kinase. Since the enzyme is p21^rasThe inhibitors of the invention may be used in pharmaceutical compositions for inhibition of the raf kinase pathway in humans or animals as indicated, for example, in the treatment of tumors or cancerous growth of cells mediated by raf kinase. In particular, these compounds are useful for treating human or animal cancers, e.g., murine, parenchymal cancers, since the development of these cancers is dependent on the ras protein signaling levelIn combination, it is therefore easy to obtain treatment by interrupting the cascade (e.g. by inhibiting raf kinase). Thus, the compounds of the invention are useful in the treatment of solid cancers such as malignant cancers (e.g., lung, pancreas, thyroid, bladder or colon cancer), myelopathies (e.g., myeloid leukemia) or adenomas (e.g., villous colon adenoma).

Accordingly, the present invention provides compounds, collectively referred to as aryl ureas, including aryl and heteroaryl analogs, which inhibit the raf pathway. The invention also provides methods of treating raf mediated diseases in humans or animals. Accordingly, the present invention relates to compounds that inhibit raf kinase, compounds, compositions and methods for treating raf kinase mediated cancer cell recruitment, comprising administering a compound of formula I:

A-D-B (I)

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

a is a compound of the formula-L- (M-L)¹)_qWherein L is a 5-6 membered ring directly attached to D, L is¹Is an at least 5-membered, substituted ring, M is a bridging group of at least one atom, q is an integer from 1 to 3; rings L and L¹Each containing 0 to 4 nitrogen, oxygen or sulfur,

b is a substituted or unsubstituted, up to tricyclic, below 30-carbon aryl or heteroaryl radical in which at least one 6-membered ring is directly connected to D and contains 0 to 4 nitrogen, oxygen or sulfur,

wherein L is¹Is at least one selected from-SO₂R_x，-C(O)R_xand-C (NR)_y)R_zThe substituent (b) of (a) is substituted,

R_yis hydrogen, or a carbon skeleton group of 24 carbons or less, may contain heteroatoms selected from N, S and O, may be halogenated or up to perhalogenated,

R_zis hydrogen, or a carbon skeleton group of 30 or less carbons, may contain heteroatoms selected from N, S and O, may be substituted by halogen, hydroxy or another 24 or less carbonsCarbon skeleton group, which may contain a heteroatom selected from N, S and O, and may be halogenated;

R_xis R_zOr NR_aR_bWherein R is_aAnd R_bIs that

a) Each of which is hydrogen, is a hydrogen atom,

carbon skeleton groups of 30 carbons or less, which may contain heteroatoms selected from N, S and O, which may be substituted by halogen, hydroxy and further carbon skeleton groups of 24 carbons or less, which may contain heteroatoms selected from N, S and O and which may be halogenated; or

-OSi(R_f)₃，R_fIs hydrogen or a carbon skeleton group of 24 carbons or less, may contain heteroatoms selected from N, S and O, may be substituted by halogen, hydroxy and a further carbon skeleton group of 24 carbons or less, may contain heteroatoms selected from N, S and O and may be halogenated; or

b)R_aAnd R_bTaken together to form a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S and O, or a 5-7 membered substituted heterocyclic ring containing 1-3 heteroatoms selected from N, S and O, and substituted with halogen, hydroxy or another 24 carbon or less carbon backbone group, which may contain heteroatoms selected from N, S and O and which may be halogenated; or

c)R_aAnd R_bOne of them being-C (O) -, C_1-5Divalent alkylene radicals or C_1-5Divalent substituted alkylene which is bonded to L to form a ring having at least 5 members, C_1-5The substituent of the divalent substituted alkylene group is selected from halogen, hydroxyl and carbon skeleton group of 24 carbon or less, the substituent may contain hetero atom selected from N, S and O and may be halogenated;

wherein B is substituted, L is substituted, or L¹Is further substituted, the substituents being selected from halogen, perhalogenated and Wn, n is 0 to 3;

w is each selected from-CN, -CO₂R⁷，-C(O)NR⁷R⁷，-C(O)-R⁷，-NO₂，-OR⁷-，-SR⁷，-NR⁷R⁷，-NR⁷C(O)OR⁷，-NR⁷C(O)R⁷Q-Ar and a carbon skeleton group of less than 24 carbons which may contain heteroatoms of N, S and O and which may be mono-or polysubstituted, the substituents being selected from the group consisting of-CN, -CO₂R⁷，-C(O)-R⁷，-C(O)NR⁷R⁷，-OR⁷-，-SR⁷，-NR⁷R⁷，-NO₂，-NR⁷C(O)R⁷，-NR⁷C(O)OR⁷And halo or perhalo; each R⁷Carbon skeleton groups selected from H or less than 24 carbon, which may contain heteroatoms of N, S and O and which may be halogenated,

q is-O-, -S-, -N (R)⁷)-，-(CH₂)_m-，-C(O)-，-CH(OH)-，-(CH₂)_m-O-，-(CH₂)_m-S-，-(CH₂)_mN(R⁷)-，-O(CH₂)_m-，-CHX^a-，-CX^a ₂-，-S-(CH₂)_m-, and-N (R)⁷)(CH₂)_m-, m ═ 1 to 3, X^aIs halogen;

ar is a 5-or 6-membered aromatic structure containing 0 to 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may be halogenated or up to perhalogenated, or by Z_n1Substituted, n1 is 0 to 3, each Z is independently selected from-CN, -CO₂R⁷，-C(O)R⁷，-C(O)NR⁷R⁷，-NO₂，-OR⁷，-SR⁷，-NR⁷R⁷，-NR⁷C(O)OR⁷，-NR⁷C(O)R⁷And a carbon skeleton group of 24 carbons or less, which may contain hetero atoms of N, S and O and may be mono-or polysubstituted by halogen, the substituents being selected from the group consisting of-CN, -CO₂R⁷，-COR⁷，-C(O)NR⁷R⁷，-OR⁷，-SR⁷，-NO₂，-NR⁷R⁷，-NR⁷C(O)R⁷and-NR⁷C(O)OR⁷，R⁷As previously described.

Suitable heteroaryl groups B in formula I include, but are not limited to, aromatic rings of 5 to 12 carbon atoms or one to three ring systems, at least one of which is aromatic, wherein one or more, for example 1 to 4, carbon atoms in one or more of the rings may be substituted by oxygen, nitrogen or sulfur atoms. Each ring typically contains 3 to 7 atoms. For example, B may be 2-or 3-furyl, 2-or 3-thienyl, 2-or 4-triazinyl, 1-, 2-or 3-pyrrolyl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, 1, 2, 3-triazol-1-, -4-or-5-yl, 1, 2, 4-triazol-1-, -3-or-5-yl, 1-or 5-tetrazolyl, 1, 2, 3-oxadiazol-4-or-5-yl, 1, 2, 4-oxadiazol-3-or-5-yl, 1, 3, 4-thiadiazol-2-or-5-yl, 1, 3, 4-thiadiazol-3-or-5-yl, 1, 2, 3-thiadiazol-4-or-5-yl, 2-, 3-, 4-, 5-or 6-2H-thiopyranyl, 2-, 3-or 4-4H-thiopyranyl, 3-or 4-pyridazinyl, thiadiazolyl, Pyrazinyl, 2-, 3-, 4-, 5-, 6-or 7-benzofuranyl, 2-, 3-, 4-, 5-, 6-or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 2-, 4-, 5-, 6-or 7-benzo-1, 3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolinyl, 1-, 2-, 3-, 4-or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridinyl, or 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, or, phenyl which may be further substituted, 2-or 3-thienyl, 1, 3, 4-thiadiazolyl, 3-pyrrolyl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, and the like. For example, B may be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, 1-methyl-3-pyrrolyl, 1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-1, 2, 4-thiadiazol-2-yl.

Suitable alkyl or alkoxy groups and the like include the alkyl portion of the groups herein methyl, ethyl, propyl, butyl and the like, including all straight and branched chain isomers, such as isopropyl, isobutyl, sec-butyl, tert-butyl and the like.

Suitable heteroatom-free aryl radicals are, for example, phenyl and 1-and 2-naphthyl.

"cycloalkyl" as used herein refers to a ring structure with or without alkyl substituents, e.g. "C₄Cycloalkyl "includes methyl-substituted cyclopropyl and cyclobutyl. "cycloalkyl" also includes saturated heterocyclic groups.

Suitable halogens include F, Cl, Br and/or I, and if the alkyl group is substituted with a halogen, it may be mono-to fully substituted (i.e., all H atoms are substituted with halogen atoms), and may be a mixture of different halogen atoms.

The invention also relates to compounds of formula I.

The invention also relates to pharmaceutically acceptable salts of formula I. Suitable pharmaceutically acceptable salts are familiar to those skilled in the art and include basic salts of inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, trifluoromethanesulfonic, benzenesulfonic, p-toluenesulfonic, 1-naphthalenesulfonic, 2-naphthalenesulfonic, acetic, trifluoroacetic, malic, tartaric, citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic and mandelic acids. In addition, pharmaceutically acceptable salts also include acid salts of inorganic bases, e.g., containing an alkali metal cation (e.g., Li)⁺，Na⁺Or K⁺) Alkaline earth metal cations (e.g. Mg)⁺²，Ca⁺²Or Ba⁺²) And salts of ammonium cations, and acid salts of organic bases including ammonium and quaternary ammonium cations substituted with aliphatic or aromatic groups from triethylamine, N-diethylamine, N-dicyclohexylamine, lysine, pyridine, N-Dimethylaminopyridine (DMAP), 1, 4-diazabicyclo [2.2.2 ]]Octane (DABCO), 1, 5-diazabicyclo [4.3.0]Non-5-ene (DBN) and 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU).

Many compounds of formula I have asymmetric carbon atoms and can exist in racemic or optically active forms. Methods for enantiomeric and diastereomeric mixtures are familiar to those skilled in the art. The present invention includes any isolated racemic or optically active form of a compound of formula I having raf kinase inhibitory activity.

General preparation method

The compounds of formula I may be prepared from commercially available starting materials using known chemical reactions or processes. However, the following general preparation methods are provided and detailed examples are given in the examples section describing the working examples to assist the person skilled in the art in the synthesis of the inhibitors.

Substituted anilines were generated by standard methods (March, Advanced Organic Chemistry, 3)^rdEdition; john Wiley: new York (1985) Larock, Comprehensive Organic Transformations; vchpublishers: new York (1989)). As shown in scheme I, the catalyst is prepared by using metal catalyst such as Ni, Pd or Pt and the like and H₂Or formate, cyclohexadiene or borohydride, to synthesize arylanilines by reducing nitroarenes (rylander. hydrogenation Methods; Academic Press: London, UK (1985)). For example, LiAlH may be used₄By means of strong hydride sources (Seyden-Penne. reduction bytho-and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or by direct reduction of nitroarenes with zero-valent metals, such as Fe, Sn or Ca, usually in acidic media. There are many methods for the synthesis of nitroarenes (March. advanced Organic Chemistry, 3)^rdEdition; john Wiley: new York (1985) Larock, Comprehensive Organic Transformations; VCH publishers: new York (1989)).

Scheme I: reduction of nitroarenes to arylanilines

By conventional methods, with HNO₃Or other NO²⁺The aromatic of the source is electrophilically nitrated to form nitroarenes.

The nitroarenes may be further modified prior to reduction. Thus, nitroarenes substituted with a latent leaving group (e.g., F, Cl, Br, etc.) can undergo a substitution reaction with nucleophiles such as thiolates (e.g., scheme II) or phenoxides. Nitroarenes can also be subjected to Ullman-type coupling reactions (scheme II).

Scheme II: nucleophilic aromatic substitution with nitroarenes

Nitroarenes can also undergo cross-linking coupling reactions mediated by transition metals. For example, a nitroarene electrophile such as a nitroarene bromide, iodide, or trifluoromethanesulfonate and an aryl nucleophile such as aryl boronic acid (Suzuki reaction, for example, hereinafter), aryl tin (Stille reaction), or aryl zinc (Negishi reaction) undergo a palladium-mediated cross-linking coupling reaction to obtain biaryl (5).

Either the nitroarene or aniline can be converted to the corresponding arylsulfonyl chloride (7) by chlorosulfonic acid treatment. The sulfonyl chloride is then reacted with a fluorine source, such as KF, to form sulfonyl fluoride (8). The reaction of sulfonyl fluoride (8) with trimethylsilyltrifluoromethane in the presence of a fluorine source, such as tris (dimethylamino) sulfonium difluorotrimethylsilicate (TASF), produces the corresponding trifluoromethyl sulfone (9). Alternatively, sulfonyl chloride 7 can be reduced to aryl thiol (1) with, for example, zinc amalgam0). Thiol 10 with CHCl₂F is reacted in the presence of a base to form trifluoromethylthiol (11), which may comprise CrO₃Oxidation of various oxidants including acetic anhydride to sulfone (12) (Sedova et al, zh. org. khim.1970, 6, (568)).

Scheme III: selected methods of synthesizing fluorinated aryl sulfones

As shown in FIG. IV, aryl isocyanate (14) reacts with arylamine (13) to form an asymmetric urea. Heteroarylisocyanates can be synthesized by reacting a heteroarylamine with phosgene or its counterpart such as trichloromethyl chloroformate (diphosphasol), bis (trichloromethyl carbonate (triphosgene) or N, N' -Carbonyldiimidazole (CDI). The isocyanates can also be produced from heterocyclic carboxylic acid derivatives such as esters, acid halides or anhydrides by Curtius rearrangement.accordingly, acid derivative 16 is reacted with a source of azide and then rearranged to produce the isocyanate.the corresponding carboxylic acid (17) can also be subjected to Curtius rearrangement with Diphenylphosphorylazide (DPPA) or a similar reagent.

Scheme IV: selected method of forming asymmetric ureas

Finally, the urea obtained can be further processed by methods familiar to the person skilled in the art.

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

The compounds of the invention may be administered by injection, inhalation or spray, or rectally, orally, dermally, parenterally, or in unit dosage forms. "administration by injection" includes intravenous, intramuscular, subcutaneous and parenteral injection, as well as the use of infusion techniques. Dermal administration includes topical or transdermal administration. The one or more compounds may be present with one or more pharmaceutically acceptable non-toxic carriers and, optionally, other active ingredients.

The oral compositions may be prepared according to any suitable method known in the art for the manufacture of pharmaceutical compositions. In order to improve the mouthfeel of the formulation, the composition may contain one or more of the following agents: diluents, sweeteners, flavors, colorants and preservatives. Tablets contain the active ingredient in admixture with pharmaceutically acceptable, non-toxic excipients which are suitable for the manufacture of tablets. Such excipients as inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. The compounds may also be prepared in solid, fast-release form.

Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be employed. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a natural phospholipid, for example lecithin, or a condensation product of ethylene oxide with a fatty acid, for example polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example heptadecaoxyethylene cetyl alcohol, or a condensation product of ethylene oxide with a partial ester of a fatty acid with a hexitol such as polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders or granules suitable for constitution with water in an aqueous suspension, the active ingredient being mixed with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents may be mentioned as examples above. Other excipients, for example sweetening, flavouring and colouring agents, may also be present.

The compounds may also be in the form of non-aqueous liquid preparations, for example oily suspensions, which may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. To improve the mouthfeel, the above-mentioned sweeteners and flavors may be added. The composition can be preserved by adding an antioxidant such as ascorbic acid.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid beeswax, or a mixture thereof. Suitable emulsifying agents may be natural gums such as tragacanth and acacia, or natural phosphatides, for example soya bean lecithin or lecithin; partial esters of fatty acids with anhydrohexitols, such as but not limited to sorbitan oleate; condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavors.

Syrups and elixirs may also be formulated with sweetening agents, for example glycerol, polypropylene glycol, sorbitol or sucrose. Such formulations may also contain emollients, preservatives and fragrances and coloring agents.

The compounds may also be administered in the form of suppositories for rectal or vaginal administration. Such compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperatures and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.

In all treatment regimens herein using compounds of formula I, the daily oral dose is preferably from 0.01 to 200mg/kg body weight. The daily dosage of injection, including intravenous, intramuscular, subcutaneous and parenteral injection and application of infusion techniques, is preferably 0.01-200mg/kg body weight. The daily dosage for rectal administration is preferably from 0.01 to 200mg/kg body weight. The daily dosage for external use is 1 to 4 times daily, preferably 0.1 to 200mg each time. The daily dose for inhalation is preferably 0.01-10mg/kg body weight.

One skilled in the art will recognize that the particular mode of administration depends on a variety of factors, all of which are often considered in conventional administration. However, it will also be appreciated that the specific dose for a particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age of the patient, the weight of the patient, the general health of the patient, the sex of the patient, the diet of the patient, the time of administration, the route of administration, the rate of excretion, the drug combination and the severity of the condition being treated. The skilled person will also find that the optimal treatment regime, i.e. the treatment pattern over a certain number of days and the number of daily administrations of the compound of formula I or a pharmaceutically acceptable salt thereof, can be determined by the skilled person using routine treatment trials.

It will be apparent that the specific recorded level for a particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age of the patient, the weight of the patient, the general health of the patient, the sex of the patient, the diet of the patient, the time of administration, the route of administration, the rate of excretion, the drug combination and the severity of the condition being treated.

All patent applications, patents, and publications cited herein are hereby incorporated by reference in their entirety, including provisional application 60/115,877 filed on 13.1.1999 and non-provisional application 09/257, 266 filed on 25.2.1999.

The compounds of the present invention can be prepared from known compounds (or starting materials which can be prepared from known compounds), by, for example, the general methods described later. The activity of the known raf kinase of each compound can be determined by the usual method described later. The following examples are given by way of illustration only and not by way of limitation.

Examples

All reactions were carried out in either flame-dried or oven-dried glassware under positive pressure of dry argon or dry nitrogen with magnetic stirring, unless otherwise noted. The sensitive liquid or solution is transferred by a syringe or a catheter and introduced into the reaction vessel through a rubber septum. Unless otherwise specified, "concentration under reduced pressure" means concentration with a Buchi rotary evaporator at about 15 mmHg. Unless otherwise specified, "under high vacuum" means a vacuum of 0.4 to 1.0 mmHg.

All temperatures reported here are uncorrected ℃. All parts and percentages are by weight unless otherwise indicated.

Commercial grade reagents were used directly without further purification. N-cyclohexyl-N' - (Methylpolystyrene) carbodiimide was purchased from Calbiochem-Novabiochem Corp. 3-tert-butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-3- (trifluoromethyl) aniline, 4-chloro-3- (trifluoromethyl) aniline, 2-methoxy-5- (trifluoromethyl) aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-5- (trifluoromethyl) aniline and 4-chloro-3- (trifluoromethyl) phenyl isocyanate are commercially available without further purification. Synthesis of 3-amino-2-methoxyquinoline (E, Cho et al, WO 98/00402; A. Cordi et al, EP542,609; IBID biochemistry and chemistry 3, 1995, 129), 4- (3-carbamoylphenoxy) -1-nitrobenzene (K, Ikawa, J. Pharma. 79, 1959, 760; chemical abstracts 53, 1959, 12761b), 3-tert-butylphenyl isocyanate (O. Rohr et al, DE2436108), isocyanic acid and 2-methoxy-5- (trifluoromethyl) phenyl ester (K, Inukai et al, JP42,025,067; IBID Kogyo J. chem. 70, 1967, 491) are known. By usingPrecoated glass-lined silica gel 60A F-254 μm plates for Thin Layer Chromatography (TLC). The sheets were observed using one or more of the following techniques: (a) ultraviolet light emission, (b) exposure to iodine vapor, (c) immersing the sheet in a 10% ethanol solution of phosphomolybdic acid and then heating, (d) immersing the sheet in a cerium sulfate solution and then heating, and/or (e) immersing the sheet in an acidic ethanol solution of 2, 4-dinitrophenylhydrazine and then heating. 230-400-mesh EM ScienceSilica gel column chromatography (flash chromatography).

Melting points were determined with a Thomas-Hoover melting point apparatus or a Mettler FP66 automatic melting point apparatus without calibration. The infrared spectra were transformed using a Mattson 4020Galaxy Series spectrophotometer or its Fourier transform. Using a General Electric GN-Omega 300(300MHz) spectrometer, as Me₄Si (d0.00) or residual protonated solvent (CHCl)₃δ 7.26; MeOH, δ 3.30; DMSO, delta 2.49) as standard, determination of protons (H)¹) Nuclear Magnetic Resonance (NMR) spectroscopy. Using a General Electric GN-Omega 300(75MHz) spectrometer, with solvent (CDCl)₃，δ77.0；MeOD-d₃；δ49.0；MeOD-d₃(ii) a δ 39.5) as standard, determination of carbon: (¹³C) NMR spectrum. Low resolution Mass Spectrometry (MS) and High Resolution Mass Spectrometry (HRMS) were determined using Electron Impact (EI) mass spectrometry or fast atom bombardment mass spectrometry (FAB). Electron impact mass spectrometry (EI-MS) was obtained using a Hewlett Packard 5989A mass spectrometer equipped with a Vaccumetics desorption chemical ionization probe for introduction into the sample. The ion source was maintained at 250 ℃. Electron impact ionization was performed with a trapping current of 300. mu.A at an electron energy of 70 eV. An upgraded version of the fast atom bombardment, liquid-cerium secondary ion mass spectrum (FAB-MS), was obtained with a Kratos Concept1-H spectrometer. Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reaction gas (1X 10)^-4To 2.5X 10^-4torr), chemical ionization mass spectrum (CI-MS) was obtained. Direct insertion desorption ionization (DCI) probes (Vaccumetics, Inc.) were raised from 0 amps to 1.5 amps in 10 seconds, and held at 10 amps until all micro samples disappeared (approximately 1-2 minutes). 2 seconds/spokeMass spectrometry scans were performed from 120-. HPLC-electrospray mass spectrometry (HPLC ES-MS) was obtained using a Hewlett packard 1100HPLC equipped with a quaternary pump, variable wavelength detector, C-18 column and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. The mass spectrum was scanned from 120-. Gas chromatography-ion selective mass spectrometry (GC-MS) was obtained using a Hewlett Packard 5890 chromatograph equipped with an HP-1 methyl silica gel column (0.33mM coating; 25 m.times.0.2 mM) and a Hewlett Packard 5971 mass selective detector (70eV ionization energy). Elemental analysis was performed by roberston icrolit Labs, Madison NJ.

NMR, LRMS and elemental analysis or HRMS of all compounds appeared to be consistent with the required structure.

List of abbreviations and acronyms

AcOH acetic acid

anh anhydrous

atm atmospheric pressure

BOC tert-butoxycarbonyl

CDI 1, 1' -carbonyldiimidazole

conc concentrated, concentrated

d days

dec decomposition

DMAC N, N-Dimethylacetamide

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

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

DPPA Diphenylphosphoryl Azide

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

EtOAc ethyl acetate

EtOH ethanol (100%)

Et₂O Ether

Et₃N-Triethylamine

h hours

HOBT 1-hydroxybenzotriazole

m-CPBA 3-chloroperoxybenzoic acid

MeOH methanol

Ether petroleum ether (boiling point between 30-60 ℃ C.)

temp. temperature

THF tetrahydrofuran

TFA trifluoroacetic acid

Tf trifluoromethanesulfonyl radical

A. General procedure for the Synthesis of substituted anilines

A1. General procedure for the synthesis of arylamines: the ether is formed first, then the ester is saponified, Curtius rearranges, and the carbamate is deprotected. Synthesis of 2-amino-3-methoxynaphthalene

Step 1: 3-methoxy-2-naphthoic acid methyl ester

Methyl 3-hydroxy-2-naphthoate (10.1g, 50.1mmol) and K₂CO₃A slurry of (7.96g, 57.6mmol) in DMF (200ml) was stirred at room temperature for 15 minutes and then reacted with methyl iodide (3.43ml, 55.1 mmol). The mixture was stirred at room temperature overnight, then water (200ml) was added. The resulting mixture was extracted with EtOAc (2X 200 mL). The combined organic layers were washed with saturated NaCl solution (100ml) and dried (MgSO)₄) Concentrated under reduced pressure (about 0.4mmHg, overnight) to give methyl 3-methoxy-2-naphthoate (10.30g) as an amber oil:¹HNMR(DMSO-d₆)δ 2.70(s，3H)，2.85(s，3H)，7.38(app t，J＝8.09Hz，1H)，7.44(s，1H)，7.53(app t，J＝8.09Hz，1H)，7.84(d，J＝8.09Hz，1H)，7.90(s，1H)，8.21(s，1H)。

step 2: 3-methoxy-2-naphthoic acid

Methyl 3-methoxy-2-naphthoate (6.28g, 29.10mmol) and water (10ml) in MeOH (100ml) were stirred at room temperature and reacted with 1N NaOH solution (33.4ml, 33.4 mmol). The mixture was heated to reflux for 3 hours, cooled to room temperature, and acidified with 10% citric acid solution. The resulting mixture was extracted with EtOAc (2X 100 mL). The combined organic layers were washed with saturated NaCl solution and dried (MgSO)₄) And concentrating under reduced pressure. Trituration of the residue with hexane followed by several washes with hexane afforded 3-methoxy-2-naphthoic acid as a white solid (5.40g, 92%):¹H NMR(DMSO-d₆)δ3.88(s，3H)，7.34-7.41(m，2H)，7.49-7.54(m，1H)，7.38(d，J＝8.09Hz，1H)，7.91(d，J＝8.09Hz，1H)，8.19(s，1H)，12.83(br s，1H)。

and step 3: 2- (N- (carbobenzoxy) amino-3-methoxynaphthalene

3-methoxy-2-naphthoic acid (3.36g, 16.6mmol) and Et₃A solution of N (2.59ml, 18.6mmol) in dry toluene (70ml) was stirred at room temperature for 15 minutes, and then a solution of DPPA (5.12g, 18.6mmol) in toluene (10ml) was added dropwise. The resulting mixture was heated at 80 ℃ for 2 hours. After cooling to room temperature, benzyl alcohol (2.06ml, 20mmol) was injected via syringe. The mixture was then incubated at 80 ℃ overnight. The resulting mixture was cooled to room temperature, quenched with 10% citric acid solution and extracted with EtOAc (2X 100 ml). The combined organic layers were washed with saturated NaCl solution and dried (MgSO)₄) And concentrating under reduced pressure. The residue was purified by column chromatography (14% EtOAc/86% hexanes) to give 2- (N- (carbobenzoxy) amine-3-methoxynaphthalene (5.1g, 100%):¹H NMR(DMSO-d₆)δ 3.89(s，3H)，5.17(s，2H)，7.27-7.44(m，8H)，7.72-7.75(m，2H)，8.20(s，1H)，8.76(s，1H)。

and 4, step 4: 2-amino-3-methoxynaphthalene

A slurry of 2- (N- (carbobenzyloxy) amino-3-methoxynaphthalene (5.0g, 16.3mmol) and 10% Pd/C (0.5g) in EtOAc (70ml) was in H at room temperature₂Atmosphere (balloon) overnight. By using CeliteThe resulting mixture was filtered and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder (2.40g, 85%):¹HNMR(DMSO-d₆)δ 3.86(s，3H)，6.86(s，2H)，7.04-7.16(m，2H)，7.43(d，J＝8.0Hz，1H)，7.56(d，J＝8.0Hz，1H)；EI-MS m/z 173(M⁺)。

A2. synthesis of omega-carbamoylanilines: carbamoylpyridines are formed first and then coupled nucleophilically with arylamines. Synthesis of 4- (2-N-methylcarbamoyl-4-pyridyloxy) aniline

Step 1 a: synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide by Menisci reaction

Note that: this is a high risk, potentially explosive reaction. A solution of 4-chloropyridine (10.0g) in N-methylformamide (250ml) was added concentrated H with stirring at room temperature₂SO₄(3.55ml), an exotherm occurred. Adding H to the mixture₂O₂(30 wt% aqueous solution, 17ml) and FeSO was then added₄·7H₂O (0.56g), exothermic again. The resulting mixture was stirred at room temperature for 1 hour in the dark and then slowly raised to 45 ℃ over 4 hours. When bubbling stopped, the reaction was carried out at 60 ℃ for 16 hours. The resulting cloudy brown solution was diluted with water (700ml) and then 10% NaOH solution (250ml) was added. The resulting mixture was extracted with EtOAc (3X 500 mL). The organic layers were washed separately with saturated NaCl solution (3X 150ml), the washings combined and dried (MgSO)₄) Filtered through silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient of 50% EtOAc/50% hexanes to 80% EtOAc/20% hexanes) of the residue. The residue obtained is recrystallized at 0 ℃ for 72 hours to give 4-chloro-N-methyl-2-pyridinecarboxamide:¹H NMR(CDCl₃)δ 3.04(d，J＝5.1Hz，3H)，7.43(dd，J＝5.4，2.4Hz，1H)，7.96(br s，1H)，8.21(s，1H)，8.44(d，J＝5.1Hz，1H)；CI-MS m/z 171((M+H)⁺)。

step 1 b: hydrochloride salt formation from picolinic acid to 4-chloropyridine-2-carbonyl chloride

DMF (6.0ml) was added slowly to SOCl between 40 ℃ and 50 ℃₂(180 ml). The solution was stirred at this temperature range for 10 minutes, then picolinic acid (60.0g, 487mmol) was added in portions over 30 minutes. The resulting solution was heated at 72 ℃ for 16 hours (vigorous release of SO)₂) A yellow solid precipitate was produced. The resulting mixture was cooled to room temperature and diluted with toluene (500ml)Released and concentrated to 200 ml. The above toluene/concentration process was repeated 2 times. The resulting near-dry residue was filtered, and the solid was washed with toluene (2X 200ml) and dried under high vacuum for 4 hours to give the hydrochloride salt of 4-chloropyridine-2-carbonyl chloride as a yellow-orange solid (92.0g, 89%).

Step 2: synthesis of 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride

DMF (10.0ml) was added slowly to SOCl between 40 ℃ and 48 ℃₂(300 ml). The solution was stirred at this temperature range for 10 minutes, then picolinic acid (100g, 812mmol) was added over 30 minutes. The resulting solution was heated at 72 ℃ for 16 hours (vigorous release of SO)₂) A yellow solid precipitate was produced. The resulting mixture was cooled to room temperature, diluted with toluene (500ml) and concentrated to 200 ml. The above toluene/concentration process was repeated 2 times. The resulting near dry residue was filtered and the solid washed with toluene (50ml) and dried under high vacuum for 4 hours to give 4-chloropyridine-2-carboxylic acid chloride hydrochloride as a beige solid (27.2g, 16%). Temporarily storing the substance.

The red filtrate was added to MeOH (200ml) controlling the speed, keeping the internal temperature below 55 ℃. Stirring at room temperature for 45 min, cooling to 5 deg.C, and dropping Et₂O (200 ml). The resulting solid was filtered and washed with Et₂O (200ml) and dried at 35 ℃ under reduced pressure to give 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride as a white solid (110g, 65%): mp.108-112 ℃;¹H NMR(DMSO-d₆)δ 3.88(s，3H)，7.82(dd，J＝5.5，2.2Hz，1H)；8.08(d，J＝2.2Hz，1H)；8.68(d，J＝5.5Hz，1H)；10.68(br s，1H)；HPLC ES-MS m/z172((M+H)⁺)。

step 3 a: synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from methyl 4-chloropyridine-2-carboxylate

To a suspension of 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride (89.0g, 428mmol) in 0 ℃ MeOH (75ml) was added 2.0M methylamine THF solution (1L) with rate control to maintain the internal temperature below 5 ℃. The resulting mixture was left at 3 ℃ for 5 hours and then concentrated under reduced pressure. The resulting solid was suspended in EtOAc (1L) and filtered. The filtrate was washed with saturated NaCl solution (500ml) and dried (Na)₂SO₄) And concentrated under reduced pressure to obtain yellow crystals of 4-chloro-N-methyl-2-pyridinecarboxamide (71.2g, 97%): mp.41-43 deg.C;¹H NMR(DMSO-d₆)δ 2.81(s，3H)，7.74(dd，J＝5.1，2.2Hz，1H)；8.00(d，J＝2.2Hz，1H)；8.61(d，J＝5.5Hz，1H)；8.85(br s，1H)；CS-MS m/z 171((M+H)⁺)。

and step 3 b: synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4-chloropyridine-2-carbonyl chloride

4-chloropyridine-2-carbonyl chloride hydrochloride (7.0g, 32.95mmol) was added portionwise to a 2.0M mixture of methylamine in THF (100ml) and MeOH (20ml) at 0 ℃. The resulting mixture was left at 3 ℃ for 4 hours and then concentrated under reduced pressure. The resulting near-dry solid was suspended in EtOAc (100mL) and filtered. The filtrate was washed with saturated NaCl solution (2X 100ml) and dried (Na)₂SO₄) Concentrated under reduced pressure, 4-chloro-N-methyl-2-pyridinecarboxamide yellow crystals (4.95g, 88%): mp.37-40 deg.C;

and 4, step 4: synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline

To a solution of 4-aminophenol (9.60g, 88.0mmol) in anhydrous DMF (150ml) was added potassium tert-butoxide(10.29g, 91.7mmol) and the resulting reddish brown mixture was stirred at room temperature for 2 hours. To this was added 4-chloro-N-methyl-2-pyridinecarboxamide (15.0g, 87.9mmol) and K₂CO₃(6.50g, 47.0mmol) and then heated at 80 ℃ for 8 hours. The mixture was cooled to room temperature and partitioned between EtOAc (500ml) and saturated NaCl (500 ml). The aqueous phase was back extracted with EtOAc (300 mL). The combined organic layers were washed with saturated NaCl solution (4X 1000ml) and dried (Na)₂SO₄) And concentrating under reduced pressure. The resulting solid was dried at 35 ℃ under reduced pressure for 3 hours to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline as a light brown solid (17.9g, 84%):¹H NMR(DMSO-d₆) δ 2.77(d, J ═ 4.8Hz, 3H), 5.17(br s, 2H), 6.64, 6.86(AA 'BB', four peaks, J ═ 8.4Hz, 4H); 7.06(dd, J ═ 5.5, 2.5Hz, 1H); 7.33(d, J ═ 2.5Hz, 1H); 8.44(d, J ═ 5.5Hz, 1H); 8.73(br d, 1H); HPLCES-MS M/z 244((M + H)⁺)。

A3: general procedure for the synthesis of aniline: nucleophilic aromatic addition reaction, and then nitryl aromatic hydrocarbon reduction. Synthesis of 5- (4-aminophenoxy) isoindole-1, 3-dione

Step 1: synthesis of 5-hydroxyisoindole-1, 3-dione

To a mixture of ammonium carbonate (5.28g, 54.9mmol) and concentrated AcOH (25ml) was slowly added 4-hydroxyphthalic acid (5.0g, 27.45 mmol). The resulting mixture was heated at 120 ℃ for 45 minutes, and the resulting clear, bright yellow mixture was then heated at 160 ℃ for 2 hours. The resulting mixture was incubated at 160 ℃ and concentrated to about 15ml, then cooled to room temperature and the pH adjusted to 10 with 1N NaOH solution. The mixture was cooled to 0 ℃ and slowly acidified to pH5 with 1N HCI. The precipitate formed was collected by filtration and dried under reduced pressure to give 5-hydroxyisoindole-1, 3-dione as a pale yellow powder (3.24g, 72%):¹H NMR(DMSO-d₆)δ 7.00-7.03(m，2H)，7.55(d，J＝9.3Hz，1H)。

step 2: synthesis of 5- (4-nitrophenoxy) isoindole-1, 3-dione

To a slurry of NaH (1.1g, 44.9mmol) in DMF (40ml) at 0 ℃ was added dropwise a solution of 5-hydroxyisoindole-1, 3-dione (3.2g, 19.6mmol) in DMF (40ml) with stirring. The bright yellow-green mixture was allowed to return to room temperature, stirred for 1 hour, and then 1-fluoro-4-nitrobenzene (2.67g, 18.7mmol) was added in 3-4 portions by syringe. The resulting mixture was heated at 70 ℃ overnight, then cooled to room temperature, slowly diluted with water (150ml) and extracted with EtOAc (2X 100 ml). The combined organic layers were dried (MgSO)₄) And concentrated under reduced pressure to give 5- (4-nitrophenoxy) isoindole-1, 3-dione as a yellow solid (3.3g, 62%): TLC (30% EtOA/70% hexane) R_f0.28；¹HNMR(DMSO-d₆)δ 7.32(d，J＝12Hz，2H)，7.52-7.57(m，2H)，7.89(d，J＝7.8Hz，1H)，8.29(d，J＝9Hz，2H)，11.43(br s，1H)；CI-MS m/z 285((M+H)⁺，100％)。

And step 3: synthesis of 5- (4-aminophenoxy) isoindole-1, 3-dione

A solution of 5- (4-nitrophenoxy) isoindole-1, 3-dione (0.6g, 2.11mmol) in concentrated AcOH (12ml) and water (0.1ml) was stirred under argon flow while iron powder (0.59g, 55.9mmol) was slowly added. The mixture was stirred at room temperature for 72 h, then diluted with water (25ml) and extracted with EtOAc (3X 50 ml). The combined organic layers were dried (MgSO)₄) And concentrated under reduced pressure to give 5- (4-aminophenoxy) isoindole-1, 3-dione as a brown solid (0.4g, 75%): TLC (50% EtOA/50% hexane) R_f 0.27；¹H NMR(DMSO-d₆)δ 5.14(br，s，2H)，6.62(d，J＝8.7Hz，2H)，6.84(d，J＝8.7Hz，2H)，7.03(d，J＝2.1Hz，1H)，7.23(dd，1H)，7.75(d，J＝8.4Hz，1H)，11.02(s，1H)；HPLC EI-MS m/z 255((M+H)⁺，100％)。

A4: general procedure for the synthesis of pyrrolylanilines. Synthesis of 5-tert-butyl-2- (2, 5-dimethylpyrrolyl) aniline

Step 1: synthesis of 1- (4-tert-butyl-2-nitrophenyl) -2, 5-dimethylpyrrole

A solution of 2-nitro-4-tert-butylaniline (0.5g, 2.57mmol) in cyclohexane (10ml) was stirred while AcOH (0.1ml) and acetonylacetone (0.299g, 2.63mmol) were added thereto by syringe. The reaction mixture was heated at 120 ℃ for 72 hours to azeotropically remove the volatile components. The reaction mixture was cooled to room temperature and quenched with CH₂Cl₂Diluted (10ml), washed successively with 1N HCl (15ml), 1N NaOH (15ml) and saturated NaCl (15ml), dried ((MgSO)₄) And concentrating under reduced pressure. The orange-brown solid obtained is subjected to column chromatography (60g SiO)₂(ii) a Gradient of 6% EtOAc/94% hexanes to 25% EtOAc/75% hexanes) to give 1- (4-tert-butyl-2-nitrophenyl) -2, 5-dimethylpyrrole orange-brown solid (0.34g, 49%): TLC (15% EtOA/85% hexane) R_f0.67；¹H NMR(CDCl₃)d 1.34(s，9H)，1.89(s，6H)，5.84(s，2H)，7.19-7.24(m，1H)，7.62(dd，1H)，7.88(d，J＝2.4Hz，1H)；CI-MS m/z 273((M+H)⁺，50％)。

Step 2: synthesis of 5-tert-butyl-2- (2, 5-dimethylpyrrolyl) aniline

1- (4-tert-butyl-2-nitrophenyl) -2, 5-dimethylpyrrole (0.341g, 1.25mmol) 10% Pd/C (0.056g) and EtOAc (50ml) asThe resulting slurry is in H₂Stirred under the atmosphere for 72 hours and then added with CeliteAnd (5) filtering. The filtrate was concentrated under reduced pressure to give 5-tert-butyl-2- (2, 5-dimethylpyrrolyl) aniline as a yellow solid (0.30g, 99%): TLC (10% EtOA/90% hexane) R_f0.43；¹H NMR(CDCl₃)δ 1.28(s，9H)，1.87-1.91(m，8H)，5.85(brs，2H)，6.73-6.96(m，3H)，7.28(br s，1H)。

A5: general procedure for the synthesis of anilines from anilines by nucleophilic aromatic substitution. Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline HCl salt.

To a solution of 4-amino-3-methylphenol (5.45g, 44.25mmol) in anhydrous dimethylacetamide (75ml) was added potassium tert-butoxide (10.86g, 96.77mmol) and the black mixture was stirred at room temperature until the beaker reached room temperature. 4-chloro-N-methyl-2-pyridinecarboxamide (step 3b of method A2; 7.52g, 44.2mmol) was added thereto, and heated at 110 ℃ for 8 hours. The mixture was cooled to room temperature and diluted with water (75 ml). The organic layer was extracted with EtOAc (5X 100 mL). The organic layers were combined, washed with saturated NaCl solution (200ml), and dried ((MgSO)₄) And concentrating under reduced pressure. Et was added to the remaining black oil₂O (50ml), and ultrasonic treatment was performed. The solution was then reacted with HCl (1M Et)₂O solution; 100ml) was added, and stirred at room temperature for 5 minutes. The dark pink solid formed (7.04g, 24.1mmol) was filtered off and stored at 0 ℃ in an oxygen-free environment before use:¹H NMR(DMSO-d₆)δ 2.41(s，3H)，2.78(d，J＝4.4Hz，3H)，4.93(br s，2H)，7.19(dd，J＝8.5，2.6Hz，1H)，7.23(dd，J＝5.5，2.6Hz，1H)，7.26(d，J＝2.6Hz，1H)，7.55(d，J＝2.6Hz，1H)，7.64(d，J＝8.8Hz，1H)，8.55(d，J＝5.9Hz，1H)，8.99(q，J＝4.8Hz，1H)。

a6: general procedure for the preparation 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 (3.24g, 58.00mmol) was added to TFA (200ml) with stirring. To the slurry were added 2-chloro-4-nitrophenol (10.0g, 58.0mmol) and trifluoroacetic anhydride (20 ml). The grey slurry was stirred at room temperature for 6 days. Filtering to remove iron powder, and concentrating the solution under reduced pressure. The resulting grey solid was dissolved in water (20 ml). To the resulting yellow solution was added saturated NaHCO₃Solution (50 ml). The precipitate in the solution was removed. The reaction was stopped by slowly adding sodium bicarbonate solution to the filtrate until product separation from the solution was visible (as determined with a small prep tube). The slightly cloudy yellow solution was extracted with EtOAc (3X 125 ml). The organic layers were combined, washed with saturated NaCl solution (125ml), and dried ((MgSO)₄) And concentrating under reduced pressure.¹H NMR showed a 1:1 ratio of nitrophenol starting material to desired product 3-chloro-4- (2, 2, 2-trifluoroacetylamino) phenol. The crude product was used directly in the subsequent reaction without purification.

Step 2: 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl (2, 2, 2-trifluoro) acetamide

To a solution of crude 3-chloro-4- (2, 2, 2-trifluoroacetylamino) phenol (5.62g, 23.46mmol) in anhydrous dimethylacetamide (50ml) was added potassium tert-butoxide (5.16g, 45.98mmol) and the brown mixture was stirred at room temperature until the flask cooled to room temperature. 4-chloro-N-methyl-2-pyridinecarboxamide (step 3b of method A2; 1.99g, 11.7mmol) was added thereto, and the mixture was heated at 110 ℃ for 4 days under an argon atmosphere. The black mixture was cooled to room temperature and poured into cold water (100 ml). The mixture was extracted with EtOAc (3X 75 mL). The organic layers were combined and concentrated under reduced pressure. The remaining brown oil was purified by column chromatography (gradient of 20% EtOAc/% petroleum ether to 40% EtOAc/% petroleum ether) to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl (2, 2, 2-trifluoro) acetamide as a yellow solid (8.59g, 23.0 mmol).

And step 3: synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline

To a solution of crude 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl (2, 2, 2-trifluoro) acetamide (8.59g, 23.0mmol) in anhydrous 4-dioxane (20ml) was added a 1N NaOH solution (20 ml). The brown solution was stirred for 8 hours. To the solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3X 40mL), concentrated to remove solvent and allowed to stand to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline as a green oil (2.86g, 10.30 mmol):¹H NMR(DMSO-d₆)δ 2.77(d，J＝4.8Hz，3H)，5.51(s，2H)，6.60(dd，J＝8.5，2.6Hz，1H)，6.76(d，J＝2.6Hz，1H)，7.03(d，J＝8.5Hz，1H)，7.07(dd，J＝5.5，2.6Hz，1H)，7.27(d，J＝2.6Hz，1H)，8.64(d，J＝5.5Hz，1H)，8.75(q，J＝4.8Hz，1H)。

a7: general procedure for deprotection of acylated anilines. Synthesis of 4-chloro-2-methoxy-5- (trifluoromethyl) aniline

A suspension of 3-chloro-6- (N-acetyl) -4- (trifluoromethyl) anisole (4.00g, 14.95mmol) in 6M HCl (24ml) was refluxed for 1 hourThen (c) is performed. The resulting solution was allowed to cool to room temperature during which it precipitated slightly. The resulting mixture was diluted with water (20ml) and then NaOH solid and saturated sodium bicarbonate solution were added until the solution was basic. By CH₂Cl₂The organic layer was extracted (3X 50 ml). The combined organic layers were dried (MgSO)₄) After concentration under reduced pressure, 4-chloro-2-methoxy-5- (trifluoromethyl) aniline brown oil (3.20g, 14.2mmol) was obtained:¹H NMR(DMSO-d₆)δ 3.84(s，3H)，5.30(s，2H)，7.01(s，2H)。

a8: general procedure for the synthesis of omega-alkoxy-omega-carboxyphenylanilines. Synthesis of 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline.

Step 1: 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene:

to a solution of 4- (3-carboxy-4-hydroxyphenoxy) -1-nitrobenzene (12mmol, prepared from 2, 5-dihydroxybenzoic acid according to method A13, step 1) in acetone was added K₂CO₃(5g) And dimethyl sulfate (3.5 ml). The resulting mixture was refluxed overnight, then cooled to room temperature and filtered through CeliteAnd (5) filtering. Concentrating the resulting solution under reduced pressure using SiO₂Absorption and purification by column chromatography (50% EtOAc/50% hexanes) gave 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene as a yellow powder (3 g): mp.115-118 deg.C.

Step 2: 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene:

4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene (1.2g)KOH (0.33g) and water (5ml) were combined in MeOH (45ml), stirred overnight at room temperature, then refluxed for 4 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50ml) and made acidic with 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). Drying (MgSO)₄) Concentrating the organic layer under reduced pressure to obtain 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (1.04g)

And step 3: 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene:

to 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (0.50g, 1.75mmol) in CH₂Cl₂Adding SOCl into the solution in batches₂(0.64ml, 8.77 mmol). The resulting solution was refluxed for 18 hours, then cooled to room temperature and concentrated under reduced pressure. The yellow solid formed is dissolved in CH₂Cl₂(3ml) to the resulting solution was added methylamine solution (2.0M in THF, 3.5ml, 7.02mmol) in portions (note: gas evolution) and stirred at room temperature for 4 hours. To the resulting mixture was added 1N NaOH solution followed by CH₂Cl₂(25ml) extraction. The organic layer was dried (Na)₂SO₄) After concentration under reduced pressure, 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene was obtained (0.50g, 95%).

And 4, step 4: 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline

A slurry of 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene (0.78g, 2.60mmol) and 10% Pd/C (0.20g) in EtOH (55 ml) was stirred under an atmosphere of hydrogen (balloon) at 1atm for 2.5 days, thenAnd (5) filtering. The resulting solution was concentrated under reduced pressure to give 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline as an off-white solid (0.68g, 96%): TLC (0.1% Et)₃N/99.9％EtOAc)R_f0.36。

A9: general procedure for the preparation of omega-alkylphthalimide-containing anilines. Synthesis of 5- (4-aminophenoxy) -2-methylisoindole-1, 3-dione.

Step 1: synthesis of 5- (4-nitrophenoxy) -2-methylisoindole-1, 3-dione

A slurry of 5- (4-nitrophenoxy) isoindole-1, 3-dione (A3 step 2; 1.0g, 3.52mmol) and NaH (0.13g, 5.27mmol) in DMF (15ml) was stirred at room temperature for 1 hour, then methyl iodide (0.3ml, 4.57mmol) was added. The resulting mixture was stirred at room temperature overnight, then cooled to 0 ℃ and water (10ml) was added. The resulting solid was collected and dried under reduced pressure to give 5- (4-nitrophenoxy) -2-methylisoindole-1, 3-dione as a bright yellow solid (0.87g, 83%): TLC (35% EtAc/65% hexane) R_f0.61。

Step 2: synthesis of 5- (4-aminophenoxy) -2-methylisoindole-1, 3-dione

A slurry of 5- (4-nitrophenoxy) -2-methylisoindole-1, 3-dione (0.87g, 2.78mmol) and 10% Pd/C (0.10g) in MeOH (55 ml) was stirred under an atmosphere of hydrogen (balloon) at 1atm overnight then Celite was usedThe resulting solution was filtered and concentrated under reduced pressure. The resulting yellow solid was dissolved in EtOAc (3mL) and washed with SiO₂Filtration (60% EtOAc/40% hexane) afforded 5- (4-aminophenoxy) -2-methylisoindole-1, 3-dione as a yellow solid (0.67g, 86%): TLC (40% EtOAc/60% hexane) R_f0.27。

A10: general procedure for the synthesis of omega-carbamoylanilines by reaction of omega-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

To a solution of 4-chloropyridine-2-carboxylic acid methyl ester HCl salt (method A2 step 2; 1.01g, 4.86mmol) in THF (20ml) was added 4- (2-aminoethyl) morpholine (2.55ml, 19.4mmol) dropwise, the resulting solution was refluxed for 20 hours, cooled to room temperature, and water (50ml) was added. The resulting mixture was extracted with EtOAc (50 mL). Drying (MgSO)₄) The organic layer was concentrated under reduced pressure to give 4-chloro- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridine as a yellow oil (1.25g, 95%): TLC (10% MeOH/90% EtOAc) R_f0.50。

Step 2: synthesis of 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline

4-aminophenol (0.49g, 4.52mmol) and potassium tert-butoxide (0.53g, 4.75mmol) in DMF (8ml) were stirred at room temperature for 2 hours and 4-chloro- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridine (1.22g, 4.52mmol) and K were added sequentially₂CO₃(0.31g, 2.26 mmol). The resulting mixture was cooled to room temperature at 75 ℃ overnight, and partitioned between EtOAc (25ml) and saturated NaCl solution (25 ml). The aqueous phase was back extracted with EtOAc (25 mL). The organic layers were combined and washed with saturated NaCl solution (3X 25ml)Washing and concentrating under reduced pressure. The brown solid formed was purified by column chromatography (58g, gradient 100% EtOAc to 25% MeOH/75% EtOAc) to give 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline (1.0g, 65%): TLC (10% MeOH/90% EtOAc) R_f0.32。

A11: general procedure for the reduction of nitroarenes to arylamines. Synthesis of 4- (3-carboxyphenoxy) aniline

A slurry of 4- (3-carboxyphenoxy) -1-nitrobenzene (5.38g, 20.7mmol) and 10% Pd/C (0.50g) in MeOH (120ml) was stirred under an atmosphere of hydrogen (balloon) for 2 days. By using CeliteThe resulting mixture was filtered and concentrated under reduced pressure to give 4- (3-carboxyphenoxy) aniline as a brown solid (2.26g, 48%): TLC (10% MeOH/90% CH)₂Cl₂)R_f0.44。

A12: general procedure for the synthesis of isoindolone-containing anilines. Synthesis of 4- (1-oxoisoindol-5-yloxy) aniline

Step 1: synthesis of 5-hydroxyisoindol-1-one

To a solution of 5-hydroxyphthalimide (19.8g, 121mmol) in AcOH (500ml) was added zinc dust (47.6g, 729mmol) slowly in portions, then refluxed for 40 minutes, filtered hot and concentrated under reduced pressure. The reaction was repeated on the same scale and the oily residue was combined and purified by column chromatography (1.1kg, SiO)₂(ii) a Gradient: 60% AcOH/40% hexane) to give 5-hydroxyisoindol-1-one (3.77 g): TLC (100% EtOAc) R_f0.17；HPLCES-MS m/z 150(M+H)⁺)。

Step 2: synthesis of 4- (1-isoindolone-5-yloxy) -1-nitrobenzene

To a slurry of NaH (0.39g, 16.1mmol) in DMF at 0 ℃ was added 5-hydroxyisoindol-1-one (2.0g, 13.4mmol) in portions. The resulting slurry was allowed to warm to room temperature, stirred for 45 minutes, then 4-fluoro-1-nitrobenzene was added and the mixture was heated at 72 ℃ for 3 hours. The mixture was cooled to 0 ℃ and water was added dropwise until a precipitate formed. The solid formed was collected to give 4- (1-isoindolon-5-yloxy) -1-nitrobenzene as a dark yellow solid (3.23g, 89%): TLC 100% EtOAc) R_f0.35。

And step 3: synthesis of 4- (1-oxoisoindol-5-yloxy) aniline

4- (1-isoindolon-5-yloxy) -1-nitrobenzene (2.12g, 7.8mmol) and 10% Pd/C (0.20g) in EtOH (50ml) slurry were stirred under a hydrogen atmosphere (balloon) for 4 hours. By using CeliteAnd (5) filtering. Concentrating the filtrate under reduced pressure to obtain 4- (1-oxoisoindol-5-yloxy) aniline dark yellow solid: TLC (100% EtOAc) R_f0.15。

A13: general procedure for the synthesis of omega-carbamoylanilines: the nitroarenes are then reduced by EDCI-mediated amide formation. Synthesis of 4- (3-N-methylcarbamoylphenoxy) aniline

Step 1: synthesis of 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene

4-fluoro-1-nitrobenzene (16ml, 150mmol), ethyl 3-hydroxybenzoate (25g, 150mmol) and K₂CO₃A mixture of (41g, 300mmol) in DMF (125ml) was refluxed overnight, cooled to room temperature and water (250ml) was added. The resulting mixture was extracted with EtOAc (3X 150 mL). The combined organic phases were finely divided with water (3X 100ml) and saturated NaCl solution (2X 100ml) in succession and dried (Na)₂SO₄) And concentrating under reduced pressure. Purification by column chromatography (10% EtOAc/90% hexane) afforded 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene as an oil (38 g).

Step 2: synthesis of 4- (3-carboxyphenoxy) -1-nitrobenzene

A solution of 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene (5.14g, 17.9mmol) in 3:1 THF/water (75ml) was stirred vigorously while adding LiOH. H₂O (1.50g, 35.8mmol) in water (36 ml). The resulting mixture was heated at 50 ℃ overnight, then cooled to room temperature, concentrated under reduced pressure, and adjusted to pH2 with 1M HCl solution. The resulting bright yellow solid was filtered and washed with hexane to give 4- (3-carboxyphenoxy) -1-nitrobenzene (4.40g, 95%).

And step 3: synthesis of 4- (3- (N-methylcarbamoyl) phenoxy) -1-nitrobenzene

4- (3-carboxyphenoxy) -1-nitrobenzene (3.72g, 14.4mmol), EDCI. HCl (3.63g, 18.6mmol), N-methylmorpholine (1.6ml, 14.5mmol) and methylamine (2.0M in TMF, 8ml, 16mmol) in CH₂Cl₂(45ml) was added to the reaction solution, and the mixture was stirred at room temperature for 3 days, followed by concentration under reduced pressure. The residue was dissolved in EtOAc (50ml) and extracted with 1M HCl solution (50 ml). The combined aqueous phases were back extracted with EtOAc (2X 50 mL). Is combined withThe organic phase was washed with saturated NaCl solution (50ml) and dried (Na)₂SO₄) Then, the mixture was concentrated under reduced pressure to give 4- (3- (N-methylcarbamoyl) phenoxy) -1-nitrobenzene as an oily substance (1.89 g).

And 4, step 4: synthesis of 4- (3- (N-methylcarbamoyl) phenoxy) aniline

4- (3- (N-methylcarbamoyl) phenoxy) -1-nitrobenzene (1.89g, 6.95mmol) and 5% Pd/C (0.24g) were slurried in EtOAc (20mL) and stirred overnight under an atmosphere of hydrogen (balloon). By using CeliteThe resulting mixture was filtered and then concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH/95% CH)₂Cl₂). The resulting oil solidified in vacuo overnight to give 4- (3- (N-methylcarbamoyl) phenoxy) aniline as a yellow solid (0.95g, 56%).

A14: general procedure for the synthesis of omega-carbamoylanilines: the nitroarenes are then reduced by EDCI-mediated amide formation. Synthesis of 4-3- (5-methylcarbamoylphenoxy) aniline

Step 1: synthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene

To a slurry of NaH (0.63g, 26.1mmol) in DMF (20ml) was added a solution of methyl 5-hydroxynicotinate (2.0g, 13.1mmol) in DMF (10 ml). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4ml, 13.1mmol) in DMF (10ml), the resulting mixture was heated at 70 ℃ overnight and then cooled to room temperature, MeOH (5ml) was added, followed by water (50 ml). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to 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 (0.60g, 2.20mmol) and 10% Pd/C in MeOH/EtOAc form a mixture which is stirred under an atmosphere of hydrogen (balloon) for 72 h. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient: 10% EtOAc/90% hexane to 30% EtOAc/70% hexane) to give 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline (0.28g, 60%):¹HNMR(CDCl₃)δ 3.92(s，3H)，6.71(d，2H)，6.89(d，2H)，7.73(，1H)，8.51(d，1H)，8.87(d，1H)。

a15: aniline is synthesized by electrophilic nitration followed by reduction. Synthesis of 4- (3-methylsulfamoylphenoxy) aniline.

Step 1: synthesis of N-methyl-3-bromobenzenesulfonamide

To a solution of 3-bromobenzenesulfonyl chloride (2.5g, 11.2mmol) in THF (15mL) at 0 deg.C was added methylamine (2.0M in THF, 28mL, 56 mmol). The resulting solution was allowed to warm to room temperature and stirred at room temperature overnight. The resulting mixture was partitioned between EtOAc (25ml) and 1M HCl solution (25 ml). The aqueous phase was back extracted with EtOAc (2X 25 mL). The combined organic phases were washed with water (2X 25ml) and saturated NaCl solution (25ml) and dried (MgSO 4)₄) And concentrated under reduced pressure to obtain N-methyl-3-bromobenzenesulfonamide as white solid (2.8g, 99%).

Step 2: synthesis of 4- (3- (N-methylsulfamoyl) phenyloxy) benzene

Phenol (1.9g, 20mmol), K₂CO₃(6.0g, 40mmol) and CuI (4g, 20mmol) were slurried in DMF (25ml) to which was added N-methyl-3-bromobenzenesulfonamide (2.5g, 10mmol) and the resulting mixture was stirred at reflux overnight, cooled to room temperature and partitioned between EtOAc (50ml) and 1N HCl solution (50 ml). The aqueous phase was back extracted with EtOAc (2X 50 mL). The combined organic phases were washed with water (2X 50ml) and saturated NaCl solution (50ml) and dried (MgSO 4)₄) Then, the mixture was concentrated under reduced pressure to give 4- (3- (N-methylsulfamoyl) phenoxy) benzene (0.30 g).

And step 3: synthesis of 4- (3- (N-methylsulfamoyl) phenoxy) -1-nitrobenzene

To a solution of 4- (3- (N-methylsulfamoyl) phenyloxy) benzene (0.30g, 1.14mmol) in TFA (6ml) at-10 deg.C was added NaNO portionwise over 5 minutes₂(0.097g, 1.14 mmol). The resulting mixture was stirred at-10 ℃ for 1 hour, then warmed to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (10ml) and water (10 ml). The organic phase was washed with water (10ml) and saturated NaCl solution (10ml) and dried (MgSO)₄) Concentrated under reduced pressure, 4- (3- (N-methylsulfamoyl) phenoxy) -1-nitrobenzene (0.20 g). This material was used directly in the next step without purification.

And 4, step 4: synthesis of 4- (3- (N-methylsulfamoyl) phenoxy) aniline

4- (3- (N-methylsulfamoyl) phenyloxy) -1-nitrobenzene (0.30g) and 10% PA mixture of d/C (0.030g) in EtOAc (20ml) was stirred overnight under an atmosphere of hydrogen (balloon). By using CeliteThe resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to give 4- (3- (N-methylsulfamoyl) phenoxy) aniline (0.070 g).

A16: modification of omega-ketones. 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt

To a slurry of 4- (4-acetylphenoxy) aniline HCl salt (prepared according to A13 step 4, 1.0g, 3.89mmol) in a mixture of EtOH (10ml) and pyridine (1.0ml) was added O-methylhydroxylamine HCl salt (0.65g, 7.78mmol, 2.0 equiv.). The resulting solution was refluxed for 30 minutes, cooled to room temperature and concentrated under reduced pressure. The resulting solid, triturated with water (10ml), was washed with water to give 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt as a yellow solid (0.85g) TCL (50% EtOAc/50% petroleum ether) R_f0.78；¹HNMR(DMSO-d₆)δ3.90(s，3H)，5.70(s，3H)；HPLC-MS m/z 257(M+H)⁺)。

A17: synthesis of N- (. omega. -silyloxy alkyl) amides. Synthesis of 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline.

Step 1: 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide

To a solution of 4-chloro-N- (2-hydroxyethyl) pyridine-2-carboxamide (prepared according to A2 step 3b, 1.5g, 7.4mmol) in anhydrous DMF (7ml) was added triisopropylsilylchloride(1.59g, 8.2mmol, 1.1 equiv.) and imidazole (1.12g, 16.4mmol, 2.2 equiv.). The resulting yellow solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was partitioned between water (10ml) and EtOAc (10 ml). The aqueous phase was extracted with EtOAc (3X 10 mL). The combined organic phases were dried (MgSO)₄) And concentrated under reduced pressure to give 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide as an orange oil (2.32g, 88%). This material was used directly in the next step without purification.

Step 2: 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline

To a solution of 4-hydroxyaniline (0.70g, 6.0mmol) in anhydrous DMF (8ml) was added potassium tert-butoxide (0.67g, 6.0mmol, 1.0 equiv) in one portion, causing an exotherm. After the mixture was cooled to room temperature, a solution of 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide as an orange oil (2.32g, 6mmol, 1 eq) in DMF (4ml) was added followed by K₂CO₃(0.42g, 3.0mmol, 0.50 equiv.). The resulting mixture was heated at 80 ℃ overnight. Potassium tert-butoxide (0.34g, 3mmol, 0.5 eq.) was added again and the mixture heated at 80 ℃ for an additional 4 hours. The mixture was cooled to 0 ℃ with an ice bath and then water (ca. 1ml) was slowly added dropwise. The organic layer was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with saturated NaCl solution (20ml) and dried (MgSO)₄) And concentrating under reduced pressure. By column chromatography (SiO)₂30% EtOAc/70% petroleum ether) to give 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline as a clear, light brown oil (0.99g, 38%).

A18: 2-pyridine carboxylate is synthesized by oxidation of 2-methylpyridine. Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline

Step 1: 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene

5-hydroxy-2-methylpyridine (10.0g, 91.6mmol), 1-fluoro-4-nitrobenzene (9.8ml, 91.6mmol, 1.0 eq), K₂CO₃(25g, 183mmol, 2.0 equiv.) A mixture in DMF (100ml) was refluxed overnight. The resulting mixture was cooled to room temperature, water (200ml) was added and extracted with EtOAc (3X 100 ml). The combined organic phases were washed with water (2X 100ml) and saturated NaCl solution (100ml) and dried (MgSO 4)₄) Then, concentrated under reduced pressure to give 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene as a brown solid (12.3 g).

Step 2: synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene

A mixture of 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene (1.70g, 7.39mmol) and selenium dioxide (2.50g, 22.2mmol, 3.0 eq) in pyridine (20ml) was refluxed for 5 hours and then cooled to room temperature. The resulting slurry was filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (100 ml). Concentrated hydrochloric acid (7ml) was added to the solution, refluxed for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (50ml) and 1NNaOH (50 ml). The aqueous layer was extracted with EtOAc (2X 50 mL). The combined organic phases were washed with water (2X 50ml) and saturated NaCl solution (50ml) and dried (MgSO 4)₄) And concentrating under reduced pressure. Column chromatography (SiO)₂50% EtOAc/50% hexane) to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.70 g).

And step 3: synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline

A mixture of 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.50g) and 10% Pd/C (0.050g) in EtOAc (20ml) was placed under a hydrogen atmosphere (balloon) overnight. By using CeliteThe resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. By column chromatography ((SiO)₂70% EtOAc/30% hexane) to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline (0.40 g).

A19: synthesis of omega-sulfonyl phenyl aniline. Synthesis of 4- (4-methylsulfonylphenoxy) aniline

Step 1: 4- (4-methylsulfonylphenoxy) -1-nitrobenzene:

to a solution of 4- (4-methylthiophenoxy) -1-nitrobenzene (2.0g, 7.7mmol) in CH₂Cl₂To a 0 ℃ solution (75ml) was slowly added m-CPBA (57-86%, 4.0g), and the reaction was stirred at room temperature for 5 hours. To the reaction mixture was added 1N NaOH solution (25 ml). The organic phase was washed successively with 1N NaOH solution (25ml), water (25ml) and saturated NaCl solution (25ml), dried (MgSO)₄) Then, the mixture was concentrated under reduced pressure to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene as a solid (2.1 g).

Step 2: 4- (4-methylsulfonylphenoxy) -1-aniline:

4- (4-Methylsulfonylphenoxy) -1-nitrobenzene was reduced to aniline according to the method of step 3A 18.

B. Synthesis of urea precursors

B1: general procedure for the synthesis of isocyanates from anilines with CDI. Synthesis of 4-bromo-3- (trifluoromethyl) phenyl isocyanate

Step 1: synthesis of 4-bromo-3- (trifluoromethyl) aniline HCI salt

To 4-bromo-3- (trifluoromethyl) aniline (64g, 267mmol) in Et₂O (500ml) solution HCl solution (1M Et) was added dropwise₂O solution, 300ml), the resulting mixture was stirred at room temperature for 16 hours. The pink-white precipitate formed is filtered off and Et₂O (50ml) gave 4-bromo-3- (trifluoromethyl) aniline HCl salt (73g, 98%).

Step 2: synthesis of 4-bromo-3- (trifluoromethyl) phenyl isocyanate

To a suspension of 4-bromo-3- (trifluoromethyl) aniline HCl salt (36.8g, 133mmol) in toluene (278ml) was added dropwise trichloromethyl chloroformate and the resulting mixture was refluxed for 18 hours. The resulting mixture was concentrated under reduced pressure. Toluene (500ml) was added to the residue, and the mixture was concentrated under reduced pressure. Adding CH to the residue₂Cl₂(500ml), concentrated under reduced pressure. Repeat CH₂Cl₂Work-up/concentration step to give an amber oil which was left at-20 ℃ for 16 h to give 4-bromo-3- (trifluoromethyl) phenyl isocyanate as a brown solid (35.1g, 86%): GC-MS M/z 265 (M)⁺)。

C. Method for forming urea

C1 a: general procedure for the synthesis of ureas from the reaction of isocyanates with anilines. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (14.60g, 65.90mmol) in C at 0 deg.CH₂Cl₂(35ml) 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (method A2, step 4, 16.0g, 65.77mmol) in CH solution was added dropwise₂Cl₂(35ml) suspension. The resulting mixture was stirred at room temperature for 72 hours. The yellow solid formed is filtered off and washed with CH₂Cl₂Washed (2X 30ml) and dried under reduced pressure (ca.1 mmHg) to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as a beige solid (28.5g, 93%): mp.207-209 ℃;¹H-NMR(DMSO-d₆)δ 2.77(d，J＝4.8Hz，3H)，7.16(m，3H)，7.37(d，J＝2.5Hz，1H)，7.62(m，4H)，8.11(d，J＝2.5Hz，1H)，8.49(d，J＝5.5Hz，1H)，8.77(br d，1H)，8.99(s，1H)，9.21(s，1H)；HPLC ES-MS m/z 465(M+H)⁺)。

c1 b: general procedure for the synthesis of ureas from the reaction of isocyanates with anilines. Synthesis of N- (4-bromo-3- (trifluoromethyl) phenyl) -N' - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

To 4-bromo-3- (trifluoromethyl) phenyl isocyanate (step 2, 8.0g, 30.1mmol of method B1) at 0 deg.C was added CH₂Cl₂(80ml) 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (method A2, step 4, 7.0g, 28.8mmol) in CH solution was added dropwise₂Cl₂(40ml) suspension. The resulting mixture was stirred at room temperature for 16 hours. The yellow solid formed is filtered off and washed with CH₂Cl₂(2X 50ml) and dried at 40 ℃ under reduced pressure (about 1mmHg) to give N- (4-bromo-3- (trifluoromethyl) phenyl) -N' - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as a pale yellow solid (13.2g, 90%): mp.203-205 ℃;¹H-NMR(DMSO-d₆)δ 2.77(d，J＝4.8Hz，3H)，7.16(m，3H)，7.37(d，J＝2.5Hz，1H)，7.58(m，4H)，7.77(d，J＝8.8Hz，1H)，8.11(d，J＝2.5Hz，1H)，8.49(d，J＝5.5Hz，1H)，8.77(br d，1H)，8.99(s，1H)，9.21(s，1H)；HPLCES-MS m/z 509(M+H)⁺)。

C1C: general procedure for the synthesis of ureas from the reaction of isocyanates with anilines. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (2-methyl-4- (2- (N-methylcarbamoyl) (4-pyridyloxy) phenyl) urea

To 2-methyl-4- (2- (N-methylcarbamoyl) (4-pyridyloxy) aniline (method A5; 0.11g, 0.45mmol) in CH₂Cl₂(1ml) to the solution Et was added₃N (0.16ml) and 4-chloro-3- (trifluoromethyl) phenyl isocyanate (0.10g, 0.45 mmol). The resulting brown solution was stirred at room temperature for 6 hours, then water (5ml) was added. The aqueous phase was back extracted with EtOAc (3X 5 mL). The combined organic phases were dried (MgSO)₄) Then, the mixture was concentrated under reduced pressure to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (2-methyl-4- (2- (N-methylcarbamoyl) (4-pyridyloxy) phenyl) urea as a brown oil (0.11g, 0.22 mmol):¹H-NMR(DMSO-d₆)δ 2.27(s，3H)，2.77(d，J＝4.8Hz，3H)，7.03(d，J＝2.6Hz，1H)，7.11(d，J＝2.9Hz，1H)，7.15(dd，J＝5.5，2.6Hz，1H)，7.38(d，J＝2.6Hz，1H)，7.62(app d，J＝2.6Hz，2H)，7.84(d，J＝8.8Hz，1H)，8.12(s，1H)，7.37(d，J＝2.5Hz，1H)，7.58(m，4H)，7.77(d，J＝8.8Hz，1H)，8.11(d，J＝2.5Hz，1H)，8.50(d，J＝5.5Hz，1H)，8.78(q，J＝5.2Hz，1H)，9.52(s，1H)；HPLC ES-MS m/z 479(M+H)⁺)。

c1 d: general procedure for the synthesis of ureas from the reaction of isocyanates with anilines. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4-aminophenyl) urea

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (2.27g, 10.3mmol)CH (A) of₂Cl₂To the solution (308ml) was added p-phenylenediamine (3.32g, 30.7mmol) in one portion. The resulting mixture was stirred at room temperature for 1 hour, CH was added₂Cl₂(100ml), concentrated under reduced pressure. The pink solid formed was dissolved in a mixture of EtOAc (110ml) and MeOH (15ml) and the clear solution was washed with 0.05N HCl. The organic layer was concentrated under reduced pressure to give impure N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4-aminophenyl) urea (3.3 g): TLC (100% EtOAc) R_f0.72。

C1 e: general procedure for the synthesis of ureas from the reaction of isocyanates with anilines. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4-ethoxycarbonylphenyl) urea

To ethyl 4-isocyanatobenzoate (3.14g, 16.4mmol) in CH₂Cl₂To the solution (30ml) was added 4-chloro-3- (trifluoromethyl) aniline (3.21g, 16.4mmol), and the solution was stirred at room temperature overnight. The formed slurry is mixed with CH₂Cl₂Diluted (50ml) and filtered to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4-ethoxycarbonylphenyl) urea as a white solid (5.93g, 97%): TLC (40% EtOAc/60% hexane) R_f0.44。

C1 f: general procedure for the synthesis of ureas from the reaction of isocyanates with anilines. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (3-carboxyphenyl) urea

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (1.21g, 5.46mmol) in 8ml) was added 4- (3-carboxyphenoxy) aniline (method A11, 0.81g, 5.76mmol), and the resulting mixture was stirred at room temperature overnight, followed by addition of MeOH (8ml) and stirring for an additional 2 hours. The resulting mixture was concentrated under reduced pressure. The resulting brown solid was triturated with 1:1 EtOAc/hexanes to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (3-carboxyphenyl) urea as an off-white solid (1.21g, 76%).

C2 a: general procedure for the synthesis of urea 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 (0.15g) in CH₂Cl₂To a solution (15ml) at 0 ℃ was added CDI (0.13 g). The resulting solution was allowed to warm to room temperature over 1 hour, stirred at room temperature for 16 hours, and then 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.18g) was added. The resulting yellow solution was stirred at room temperature for 72 hours, then water (125ml) was added. The aqueous mixture was extracted with EtOAc (2X 150 mL). The combined organic phases were washed with saturated NaCl solution (100ml) and dried (MgSO)₄) And concentrating under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The white solid formed was collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the remaining oil was purified by column chromatography (gradient: 33% EtOAc/67% hexane to 50% EtOAc/50% hexane) to afford N- (2-methoxy-5- (trifluoromethyl) phenyl) -N' - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as a tan solid (0.098g, 30%): TLC (100% EtOAc) R_f0.62；¹H-NMR(DMSO-d₆) δ 2.76(d, J ═ 4.8Hz, 3H), 3.96(s, 3H), 7.1-7.6 and 8.4-8.6(m, 11H), 8.75(d, J ═ 4.8Hz, 1H), 9.55(s, 1H); FAB-MS M/z 461((M + H)⁺)。

C2 b: general procedure for the synthesis of urea by reaction of aniline with N, N' -carbonyldiimidazole, followed by addition of a second aniline. A symmetrical urea as a by-product of the N, N' -carbonyldiimidazole reaction. Synthesis of bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

Anhydrous CH of 3-amino-2-methoxyquinoline (0.14g) was stirred at 0 deg.C₂Cl₂(15ml) solution to which was added CDI (0.13 g). The resulting solution was allowed to warm to room temperature over 1 hour and stirred at room temperature for 16 hours. The resulting mixture was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting solution was stirred at room temperature for 72 hours, then water (125ml) was added. The aqueous mixture was extracted with EtOAc (2X 150 mL). The combined organic phases were washed with saturated NaCl solution (100ml) and dried (MgSO)₄) And concentrating under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The white solid formed was collected by filtration and washed with EtOAc to give bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.081g, 44%): TLC (100% EtOAc) R_f 0.50；¹H-NMR(DMSO-d₆)δ 2.76(d，J＝5.1Hz，6H)，7.1-7.6(m，12H)，8.48(d，J＝5.4Hz，1H)，8.75(d，J＝4.8Hz，2H)，8.86(s，2H)；HPLC ES-MS m/z 513((M+H)⁺)。

C2C: general procedure for the synthesis of urea by reaction of aniline with isocyanate. Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N' - (4- (1, 3-dioxoisoindol-5-yloxy) phenyl) urea

To a solution of 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (0.10g, 0.47mmol) in CH₂Cl₂To the solution (1.5ml) was added 5- (4-aminophenoxy) isoindol-1, 3-dione in one portion (method A3, step 3; 0.12g, 0.47 mmol). The resulting mixture was stirred for 12 hours, then CH was added₂Cl₂(10ml) and MeOH (5 ml). The resulting mixture was washed successively with 1N HCl solution (15ml) and saturated NaCl solution (15ml), dried (MgSO)₄) Concentrating under reduced pressure to obtain N- (2-methoxy-5- (trifluoromethyl) phenyl) -N' - (4- (1, 3-dioxo-iso)Indol-5-yloxy) phenyl) urea as a white solid (0.2g, 96%): TLC (70% EtOAc/30% hexane) rf0.50;¹H-NMR(DMSO-d₆)δ 3.95(s，3H)，7.31-7.10(m，6H)，7.57(d，J＝9.3Hz，1H)，7.80(d，J＝8.7Hz，1H)，8.53(br s，2H)，9.57(s，1H)，11.27(br s，1H)；HPLC 472.0((M+H)⁺，100％)。

c2 d: general procedure for the synthesis of urea by reaction of aniline with N, N' -carbonyldiimidazole, followed by addition of a second aniline. Synthesis of N- (5-tert-butyl) -2- (2, 5-dimethylpyrrolyl) phenyl) -N' - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

CDI (0.21g, 1.30mmol) in CH was stirred₂Cl₂(2ml) solution while adding 5- (tert-butyl) -2- (2, 5-dimethylpyrrolyl) aniline in one portion (method A4, step 2; 0.30g, 1.24 mmol). The resulting solution was stirred at room temperature for 4 hours, then 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.065g, 0.267mmol) was added in one portion. The resulting mixture was heated at 36 ℃ overnight, then cooled to room temperature and diluted with EtOAc (5 mL). The resulting mixture was washed successively with water (15ml) and 1N HCl solution (15ml) and filtered through silica gel (50g) to give N- (5-tert-butyl) -2- (2, 5-dimethylpyrrolyl) phenyl) -N' - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as a yellow solid (0.033g, 24%): TLC (40% EtOAc/60% hexane) R_f 0.24；¹H-NMR (acetone-d)₆)δ 1.37(s，9H)，1.89(s，6H)，2.89(d，J＝4.8Hz，3H)，5.83(s，2H)，6.87-7.20(m，6H)，7.17(dd，1H)，7.51-7.58(m，3H)，8.43(d，J＝5.4Hz，1H)，8.57(d，J＝2.1Hz，1H)，8.80(br s，2H；HPLC ES-MS 512((M+H)⁺，100％)。

C3: combined method for synthesizing diphenyl urea by using triphosgene

One of the anilines to be coupled was dissolved in dichloromethane (0.10M). This solution (0.5ml) was added to dichloromethane (1ml) in an 8ml test tube. To this was added bis (trichloromethyl) carbonate (0.12M in dichloromethane, 0.2ml, 0.4 eq) followed by diisopropylethylamine (0.35M in dichloromethane, 0.2ml, 1.2 eq). The tube was covered and heated at 80 ℃ for 5 hours, and after about 10 hours, it was cooled to room temperature. A second aniline (0.10M, 0.5ml, 1.0 equiv.) was added followed by diisopropylethylamine (0.35M in dichloromethane, 0.2ml, 1.2 equiv.). The resulting mixture was heated at 80 ℃ for 4h, cooled to room temperature and MeOH (0.5ml) was added. The resulting mixture was concentrated under reduced pressure and the product was purified by reverse phase HPLC.

C4: the general process for the synthesis of urea is carried out by reacting one aniline with phosgene and then adding a second aniline. N- (2-methoxy-5- (trifluoromethyl) phenyl) -N' - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

Stirring phosgene CH at 0 deg.C₂Cl₂(20ml) solution (1.9M in toluene, 2.07ml, 0.21g, 1.30mmol) was added along with pyridine (0.32ml) followed by 2-methoxy-5- (trifluoromethyl) aniline (0.75 g). The yellow solution was allowed to warm to room temperature during which time a precipitate formed. The yellow mixture was stirred for 1 hour and then concentrated under reduced pressure. The resulting solid was treated with toluene (20ml), 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (prepared according to method A2, 0.30g) was then added, and the resulting suspension was heated at 80 ℃ for 20 hours and then cooled to room temperature. The resulting mixture was diluted with water (100ml) and made basic with sodium bicarbonate (2-3 ml). The basic solution was extracted with EtOAc (2X 250 ml). The organic layers were washed with saturated NaCl solution, respectively, then combined and dried (MgSO)₄) And concentrating under reduced pressure. The pink-brown residue formed is dissolved in MeOH and adsorbed to SiO₂(100g) The above. Column chromatography (300g, SiO)₂(ii) a Gradient: 1% Et₃N/33% EtOAc/66% hexane to 1% Et₃N/99% EtOAc to 1% Et₃N/20% MeOH/79% EtOAc), then concentrated at 45 ℃ under reduced pressure to give a warm concentrated EtOAc solution which, upon treatment with hexane (10ml), slowly formed crystals, i.e., N- (2-methoxy-5- (trifluoromethyl) phenyl) -N' - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) urea (0.44 g): TLC (1% Et)₃N/99％EtOAc)R_f0.40。

D. Interconversion of ureas

D1 a: conversion of omega-aminophenyl urea to omega- (aroylamino) phenyl urea. Synthesis of N- (4-chloro-3- ((trifluoromethyl) phenyl) -N' - (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea

To 4-chloro-3- ((trifluoromethyl) phenyl) -N' - (4-aminophenyl) urea (method C1 d; 0.050g, 1.52mmol), monomethyl isophthalate (0.25g, 1.38mmol), HOBT. H₂A solution of O (0.41g, 3.03mmol) and N-methylmorpholine (0.33ml, 3.03mmol) in DMF (8ml) was added EDCI. HCl (0.29g, 1.52 mmol). The resulting mixture was stirred overnight at room temperature, diluted with EtOAc (25mL), and then with water (25mL) followed by saturated NaHCO₃The solution (25ml) was washed. The organic layer was dried (Na)₂SO₄) And concentrating under reduced pressure. The resulting solid was triturated with EtOAc solution (80% EtOAc/20% hexane) to give N- (4-chloro-3- ((trifluoromethyl) phenyl) -N' - (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea (0.27g, 43%): mp 121-122; TLC (80% EtOAc/20% hexane) R%_f0.75。

D1 b: conversion of omega-carboxyphenylurea to omega- (arylcarbamoyl) phenylurea. Synthesis of N- (4-chloro-3- ((trifluoromethyl) phenyl) -N' - (4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea

To N- (4-chloro-3- ((trifluoromethyl) phenyl) -N' - (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea (0.14g, 0.48mmol), 3-methylcarbamoylaniline (0.080g, 0.53mmol), HOBT. H.sub.₂A solution of O (0.14g, 1.07mmol) and N-methylmorpholine (0.5ml, 1.07mmol) in DMF (3ml) was added EDCI. HCl (0.10g, 0.53 mmol). The resulting mixture was allowed to warm to room temperature and stirred overnight. To the resulting mixture was added water (10ml), followed by extraction. The organic layer was concentrated under reduced pressure. The resulting yellow solid was dissolved in EtOAc (3mL) and then washed with silica gel (17g, gradient: 70% EtOAc/30% hexanes to 10% MeOH/90% EtOAc) to afford N- (4-chloro-3- ((trifluoromethyl) phenyl) -N' - (4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea (0.097g, 41%): mp 225-229; TLC (100% EtOAc) R_f0.23。

D1 c: a combined process for the conversion of omega-carboxyphenylurea to omega- (arylcarbamoyl) phenylurea. Synthesis of N- (4-chloro-3- ((trifluoromethyl) phenyl) -N' - (4- (N- (3- (N- (3-pyridinyl) carbamoyl) phenyl) carbamoylphenyl) urea

N- (4-chloro-3- ((trifluoromethyl) phenyl) -N '- (3-carboxyphenyl) urea (method C1 f; 0.030g, 0.067mmol) and N-cyclohexyl-N' - (methyl polystyrene) carbodiimide (55mg) were combined in 1, 2-dichloromethane (1ml) and 3-aminopyridine CH was added₂Cl₂Solution (1M; 0.074ml, 0.074 mmol). (if no dissolution or turbidity occurs, a small amount of DMSO may be added). The resulting mixture was heated at 36 ℃ overnight. THF (1ml) was then added to the cloudy reaction solution and heating was continued for 18 hours. To the resulting mixture was added poly (4- (isocyanatomethyl) styrene) (0.040g), and the resulting mixture was stirred at 36 ℃ for 72 hours, then cooled to room temperature and filtered. The resulting solution was filtered through silica gel (1 g). Concentrating under reduced pressure to obtain N- (4-chloro-3- ((trifluoromethyl) phenyl) -N' - (4- (N- (3- (N- (3-pyridyl) carbamoylphenyl) carbamoyl) phenyl) urea (0.024g, 59%): TLC (70% EtOAc/30% hexane))R_f0.12。

D2: conversion of omega-alkoxycarbonylaryl ureas to omega-carbamoylaryl ureas. Synthesis of N- (4-chloro-3- ((trifluoromethyl) phenyl) -N' - (4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea.

To a sample of N- (4-chloro-3- ((trifluoromethyl) phenyl) -N '- (4- (3-methoxycarbonylphenyl) carboxyamidophenyl) urea (0.17g, 0.34mmol) was added methylamine (2M in THF; 1ml, 1.7mmol) and the resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure to give N- (4-chloro-3- ((trifluoromethyl) phenyl) -N' - (4- (3-methylcarbamoylphenyl) carboxyamidophenyl) urea as a white solid, mp.247, TLC (100% EtOAc) R_f0.35。

D3: conversion of omega-alkoxycarbonylaryl ureas to omega-carboxycarbonylaryl ureas. 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 C1 e; 5.93g, 15.3mmol) in MeOH (75ml) was added aqueous KOH (2.5N, 10ml, 23 mmol.) the resulting mixture was heated at reflux for 12 h, cooled to room temperature, concentrated under reduced pressure, the residue was diluted with water (50ml) and then adjusted to pH2-3 with 1N HCl solution the solid formed was collected and dried under reduced pressure to give N- (4-chloro-3- ((trifluoromethyl) phenyl) -N' - (4-carboxyphenyl) urea as a white solid (5.05g, 92%).

D4: conversion of omega-alkoxy esters to omega-alkyl amides. Synthesis of N- (4-chloro-3- ((trifluoromethyl) phenyl) -N' - ((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridinyl) oxyphenyl) urea.

Step 1: synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - ((4- (3- (5-carboxypyridinyl) oxyphenyl) urea

Preparation of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5-methoxycarbonylpyridinyl) oxyphenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - ((4- (3- (5-methoxycarbonylpyridinyl) oxyphenyl) urea) (0.26g, 0.56mmol) in MeOH (10ml) suspension from 4-chloro-3- (trifluoromethyl) phenyl isocyanate and 4- (3- (5-methoxycarbonylpyridinyl) oxyaniline (method A14, step 2) according to method C1a was treated with a solution of KOH (0.14g, 2.5mmol) in water (1ml), stirred at room temperature for 1 h. the resulting mixture was adjusted to pH5 with 1N HCl solution and the precipitate formed was filtered off, washed with water. The resulting solid solution was EtOH (10ml), and the resulting solution was concentrated under reduced pressure. The EtOH/concentration procedure was repeated twice to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - ((4- (3- (5-carboxypyridyl) oxyphenyl) urea (0.18g, 71%).

Step 2: synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - ((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea

A mixture of N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - ((4- (3- (5-carboxypyridyl) oxyphenyl) urea (0.050g, 0.011mmol), N, N-dimethylethylenediamine (0.22mg, 0.17mmol), HOBT (0.028g, 0.17mmol), N-methylmorpholine (0.035g, 0.28mmol) and EDCI.HCl (0.032g, 0.17mmol) in DMF (2.5ml) was stirred overnight at room temperature the resulting solution was partitioned between EtOAc (50ml) and water (50ml) the organic phase was washed with water (35ml) and dried (MgSO)₄) And concentrating under reduced pressure. The residue was dissolved in a small amount of dichloromethane (about 2 ml). Et was added dropwise to the resulting solution₂O, to obtain N- (4-chloro-3- (trifluoro)Methyl) phenyl) -N' - ((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridinyl) oxyphenyl) urea white precipitate (0.48g, 84%:¹H NMR(DMSO-d₆)δ 2.10(s，6H)，3.26(s，H)，7.03(d，2H)，7.52(d，2H)，7.60(m，3H)，8.05(s，1H)，8.43(s，1H)，8.58(t，1H)，8.69(s，1H)，8.90(s，1H)，9.14(s，1H)；PHLC ES-MS m/z 522((M+H)⁺)。

d5: general procedure for deprotection of N- (. omega. -siloxyalkyl) amides. Synthesis of N- (4-chloro-3- ((trifluoromethyl) phenyl) -N' - (4- (4- (2- (N- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea

To a solution of N- (4-chloro-3- ((trifluoromethyl) phenyl) -N' - (4- (4- (2- (N- (2-triisopropylsiloxy) ethylcarbamoyl) pyridyloxyphenyl) urea (prepared according to procedure C1 a; 0.25g, 0.37mmol) in anhydrous THF (2ml) was added tetrabutylammonium fluoride (1.0M in THF; 2 ml.) the mixture was stirred at room temperature for 5 minutes, then treated with water (10 ml.) the aqueous mixture was extracted with EtOAc (3X 10 ml.) the organic layers were combined and dried (MgSO 10)₄) And concentrating under reduced pressure. Column chromatography purification of the residue (SiO)₂: gradient: 100% hexanes to 40% EtOAc/60% hexanes) to give N- (4-chloro-3- ((trifluoromethyl) phenyl) -N' - (4- (4- (2- (N- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea as a white solid (0.019g, 10%).

Synthesis of exemplary Compounds

(see tables for Compound Properties)

Compound 1: 4- (3-N-methylcarbamoylphenoxy) aniline, prepared according to method A13. The urea is formed by the reaction of C3, 3-tert-butylaniline with bis (trichloromethyl) carbonate and then with 4- (3-N-methylcarbamoylphenoxy) aniline.

Compound 2: the 4-fluoro-1-nitrobenzene reacts with p-hydroxyacetophenone according to step 1 of method A13 to obtain 4- (4-acetylphenoxy) -1-nitrobenzene. The 4- (4-acetylphenoxy) -1-nitrobenzene is reduced according to step 4 of method A13 to give 4- (4-acetylphenoxy) aniline. According to method C3, 3-tert-butylaniline was reacted with bis (trichloromethyl) carbonate and then with 4- (4-acetylphenoxy) aniline to form urea.

Compound 3: reaction of 3-tert-butylaniline with CDI according to procedure C2d followed by reaction with 4- (3-N-methylcarbamoyl-4-methoxyphenoxy) aniline (prepared according to procedure A8) formed urea.

Compound 4: 5-tert-butyl-2-methoxyaniline was converted into 5-tert-butyl-2-methoxyphenyl isocyanate according to method B1. 4- (3-N-methylcarbamoyl) aniline prepared according to method A13 is reacted with the isocyanate according to method C1a to form urea.

Compound 5: reaction of 5-tert-butyl-2-methoxyaniline with CDI according to procedure C2d, followed by reaction with 4- (3-N-methylcarbamoyl-4-methoxyphenoxy) aniline prepared according to procedure A8, leads to the formation of urea.

Compound 6: 5- (4-Aminophenoxy) isoindol-1, 3-dione is prepared according to method A3. The procedure is as described for 2d, 5-tert-butyl-2-methoxyaniline with CDI and then with 5- (4-aminophenoxy) isoindole-1, 3-dione to form urea.

Compound 7: synthesis of 4- (1-oxoisoindol-5-yloxy) aniline according to method A12. The procedure is followed as 2d, 5-tert-butyl-2-methoxyaniline with CDI and then with 4- (1-oxoisoindol-5-yloxy) aniline to form urea.

Compound 8: synthesis of 4- (3-N-methylcarbamoylphenoxy) aniline according to method A13. Following procedure C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI and then with 4- (3-N-methylcarbamoylphenoxy) aniline to form urea.

Compound 9: 2, 4-Hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine to form 4- (4-acetylphenoxy) -5-nitropyridine according to procedure A3. 4- (4-Acetylphenoxy) -5-nitropyridine was reduced to 4- (4-acetylphenoxy) -5-aminopyridine according to method A8, step 4. 2-methoxy-5- (trifluoromethyl) aniline was converted to 2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. The isocyanate was reacted with 4- (4-acetylphenoxy) -5-aminopyridine to form urea according to method C1.

Compound 10: 1, 4-fluoro-1-nitrobenzene was reacted with p-hydroxyacetophenone to form 4- (4-acetylphenoxy) -1-nitrobenzene according to procedure A13. 4- (4-Acetylphenoxy) -1-nitrobenzene was reduced to 4- (4-Acetylphenoxy) aniline according to method A13, step 4. The urea is formed by reaction of 5- (trifluoromethyl) -2-methoxybutylaniline with bis (trichloromethyl) carbonate and then with 4- (4-acetylphenoxy) aniline according to procedure C3.

Compound 11: synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide according to procedure A2, step 3a, and reaction with 3-aminophenol according to procedure A2, step 4, using DMAC instead of DMF, gave 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. According to method C4, 2-methoxy-5- (trifluoromethyl) aniline is reacted with phosgene and then with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to form urea.

Compound 12: the 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia to form 4-chloro-2-pyridinecarboxamide according to procedure A2, step 3 b. Following method A2, step 4, 4-chloro-2-pyridinecarboxamide is reacted with 3-aminophenol using DMAC instead of DMF to form 3- (2-carbamoyl-4-pyridyloxy) aniline. According to method C2a, 2-methoxy-5- (trifluoromethyl) aniline is reacted with phosgene and then with 3- (2-carbamoyl-4-pyridyloxy) aniline to form urea.

Compound 13: synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide according to procedure A2, step 3 b. Following method A2, step 4, 4-chloro-N-methyl-2-pyridinecarboxamide is reacted with 4-aminophenol using DMAC instead of DMF to form 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. Following procedure C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI and then with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to form a urea.

Compound 14: the 4-chloropyridine-2-carbonyl chloroHCl salt was reacted with ammonia gas to form 4-chloro-2-pyridinecarboxamide according to procedure A2, step 3 b. Following method A2, step 4, 4-chloro-2-pyridinecarboxamide is reacted with 4-aminophenol using DMAC instead of DMF to form 4- (2-carbamoyl-4-pyridyloxy) aniline. According to method C4, 2-methoxy-5- (trifluoromethyl) aniline is reacted with phosgene and then with 4- (2-carbamoyl-4-pyridyloxy) aniline to form urea.

Compound 15: reaction of 5- (trifluoromethyl) -2-methoxyaniline with CDI according to procedure C2d, followed by reaction with 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline prepared according to procedure A8 led to the formation of urea.

Compound 16: synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline according to method A5. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline to form a urea according to method C1C.

Compound 17: synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline according to method A6. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to form a urea according to method C1 a.

Compound 18: step 4, 5-amino-2-methylphenol according to method A2 was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide synthesized according to method A2, step 3b to form 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to form a urea according to method C1 a.

Compound 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine as in procedure A2 step 3 b. The 4-chloropyridine-N-ethyl-2-pyridinecarboxamide formed was reacted with 4-aminophenol according to method A2 step 4 to form 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline to form a urea according to method C1 a.

Compound 20: step 4, 4-amino-2-chlorophenol according to procedure A2 was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, synthesized according to procedure A2, step 3b, to form 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to form a urea according to method C1 a.

Compound 21: 4- (4-Methylthiophenoxy) -1-nitrobenzene was oxidized to 4- (4-methylsulfonylphenoxy) -1-nitrobenzene according to method A19, step 1. The nitrobenzene was reduced to 4- (4-methylsulfonylphenoxy) aniline according to method A19, step 2. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (4-methylsulfonylphenoxy) aniline according to method C1a to form a urea.

Compound 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 form urea.

Compound 23: synthesis of 5- (4-aminophenoxy) isoindol-1, 3-dione as procedure A3. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 5- (4-aminophenoxy) isoindole-1, 3-dione to form a urea according to method C1 a.

Compound 24: 4-chloropyridine-2-carbonyl chloride was reacted with dimethylamine in procedure A2, step 3 b. The 4-chloro-N, N-dimethyl-2-pyridinecarboxamide formed was reacted with 4-aminophenol according to method A2 step 4 to form 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline to form a urea according to method C1 a.

Compound 25: synthesis of 4- (1-oxoisoindol-5-yloxy) aniline according to method A12. Following procedure C2d, 5- (trifluoromethyl) -2-methoxyaniline was reacted with CDI and then with 4- (1-oxoisoindol-5-yloxy) aniline to form a urea.

Compound 26: the reaction of 1, 4-hydroxyacetophenone with 4-fluoronitrobenzene to form 4- (4-acetylphenoxy) nitrobenzene is carried out according to method A13. The nitrobenzene is reduced to 4- (4-acetylphenoxy) aniline according to method A13 step 4, then converted to 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt according to method A16 5- (trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1 the isocyanate is reacted with 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt to form urea according to method C1 a.

Compound 27: synthesis of 4-chloro-N-methylpyridine-carboxamide according to procedure A2, step 3 b. The chloropyridine is reacted with 4-aminophenol to form 4- (4- (2- (N, -methylcarbamoyl) thiophenyl) aniline according to method A2 step 4. 5- (trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. the isocyanate is reacted with 4- (4- (2- (N-methylcarbamoyl) thiophenyl) aniline to form urea according to method C1 a.

Compound 28: synthesis of 5- (4-aminophenoxy) -2-methylisoindole-1, 3-dione according to method A9. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 5- (4-aminophenoxy) -2-methylisoindole-1, 3-dione to form a urea according to procedure C1 a.

Compound 29: synthesis of 4-chloro-N-methylpyridine-carboxamide according to procedure A2, step 3 b. The chloropyridine is reacted with 3-aminophenol to form 3- (4- (2- (N-methylcarbamoyl) thiophenyl) aniline according to method A2 step 4. 5- (trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. the isocyanate is reacted with 3- (4- (2- (N, -methylcarbamoyl) thiophenyl) aniline to form urea according to method C1 a.

Compound 30: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to method A2, step 3 b. 4-chloro-N-isopropyl-2-pyridinecarboxamide was formed according to method A2, step 4. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1, which was reacted with 4-aminophenol to give 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline. The isocyanate was reacted with 4- (2- (N-isopropyl-carbamoyl-4-pyridylamino) aniline according to method C1a to form urea.

Compound 31: synthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method A14. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline to form urea according to method C1 a. N- (5- (trifluoromethyl) -2-methoxyphenyl) -N' - (4- (3- (5-methoxycarbonylpyridinyl) oxy) phenyl) urea was saponified according to method 4D, step 1, and the resulting acid was coupled with 4- (2-aminoethyl) morpholine to form the amide according to method D4, step 2.

Compound 32: synthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method A14. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline to form urea according to method C1 a. N- (5- (trifluoromethyl) -2-methoxyphenyl) -N' - (4- (3- (5-methoxycarbonylpyridinyl) oxy) phenyl) urea was saponified according to method 4D, step 1, and the resulting acid was coupled with methylamine to form the amide according to method D4, step 2.

Compound 33: synthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method A14. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline to form urea according to method C1 a. N- (5- (trifluoromethyl) -2-methoxyphenyl) -N' - (4- (3- (5-methoxycarbonylpyridinyl) oxy) phenyl) urea was saponified according to method 4D, step 1, and the resulting acid was coupled with N, N-dimethylethylenediamine to form an amide according to method D4, step 2.

Compound 34: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to method C1f to form N- (5- (trifluoromethyl) -2-methoxyphenyl) -N' - (3-carboxyphenyl) urea, which was coupled with 3-aminopyridine according to method D1C.

Compound 35: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to method C1f to form N- (5- (trifluoromethyl) -2-methoxyphenyl) -N' - (3-carboxyphenyl) urea, which was coupled with N- (4-fluorophenyl) piperazine according to method D1C.

Compound 36: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to method C1f to form N- (5- (trifluoromethyl) -2-methoxyphenyl) -N' - (3-carboxyphenyl) urea, which was coupled with 4-fluoroaniline according to method D1C.

Compound 37: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to method C1f to form N- (5- (trifluoromethyl) -2-methoxyphenyl) -N' - (3-carboxyphenyl) urea, which was coupled with 4- (dimethylamino) aniline according to method D1C.

Compound 38: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to method C1f to form N- (5- (trifluoromethyl) -2-methoxyphenyl) -N' - (3-carboxyphenyl) urea, which was coupled with 5-amino-2-methoxypyridine according to method D1C.

Compound 39: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to method C1f to form N- (5- (trifluoromethyl) -2-methoxyphenyl) -N' - (3-carboxyphenyl) urea, which was coupled with 4-morpholinoaniline according to method D1C.

Compound 40: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to method C1f to form N- (5- (trifluoromethyl) -2-methoxyphenyl) -N' - (3-carboxyphenyl) urea, which was coupled with N- (2-pyridyl) piperazine according to method D1C.

Compound 41: synthesis of 4- (3- (N-methylcarbamoyl) phenoxy) aniline according to method A13. 4-chloro-3- (trifluoromethyl) aniline was converted to isocyanate and then reacted with 4- (3- (N-methylcarbamoyl) phenoxy) aniline to form urea according to procedure C3.

Compound 42: synthesis of 4- (2-N-methylcarbamoyl-4-pyridyloxy) aniline according to method A2. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2-N-methylcarbamoyl-4-pyridyloxy) aniline to form urea.

Compound 43: the 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia to form 4-chloro-2-pyridinecarboxamide according to procedure A2, step 3 b. 4, 4-chloro-2-pyridinecarboxamide reacts with 4-aminophenol according to procedure A2 step to form 4- (2-carbamoyl-4-pyridyloxy) aniline. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2-carbamoyl-4-pyridyloxy) aniline according to method C1a to form a urea.

Compound 44: the 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia to form 4-chloro-2-pyridinecarboxamide according to procedure A2, step 3 b. 4, 4-chloro-2-pyridinecarboxamide reacts with 3-aminophenol according to procedure A2 step to form 3- (2-carbamoyl-4-pyridyloxy) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2-carbamoyl-4-pyridyloxy) aniline to form urea.

Compound 45: synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide according to method A2, step 3a, followed by reaction of amine method A2, step 4, with 3-aminophenol to form 3- (2- (N-methylcarbamoyl-4-pyridyloxy) aniline 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (N-methylcarbamoyl-4-pyridyloxy) aniline to form urea according to method C1 a.

Compound 46: synthesis of 5- (4-aminophenoxy) isoindol-1, 3-dione as procedure A3. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindol-1, 3-dione to form a urea according to method C1 a.

Compound 47: synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline according to method A5. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindol-1, 3-dione to form a urea according to method C1C.

Compound 48: synthesis of 4- (3- (N-methylaminosulfonyl) phenyloxy) aniline according to method A15. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N-methylaminosulfonyl) phenoxy) aniline to form urea according to method C1C.

Compound 49: synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline according to method A6. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to form urea according to procedure C1C.

Compound 50: step 4, 5-amino-2-methylphenol according to method A2 was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide prepared according to method A2, step 3b to form 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline according to procedure C1C to form a urea.

Compound 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine as in procedure A2 step 3 b. The 4-chloro-N-ethyl-2-pyridinecarboxamide formed was reacted with 4-aminophenol according to procedure A2, step 4, to form 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline according to method C1a to form a urea.

Compound 52: step 4, 4-amino-2-chlorophenol according to procedure A2 was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide prepared according to procedure A2, step 3b, to form 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline according to procedure C1a to form a urea.

Compound 53: 4- (4-Methylthiophenoxy) -1-nitrobenzene was oxidized to 4- (4-methylsulfonylphenoxy) -1-nitrobenzene according to method A19, step 1. The nitrobenzene was reduced to 4- (4-methylsulfonylphenoxy) aniline according to method A19, step 2. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4-methylsulfonylphenoxy) aniline according to method C1a to form a urea.

Compound 54: reaction of 1, 4-bromobenzenesulfonyl chloride with methylamine as in procedure A15 gave N-methyl-4-bromobenzenesulfonamide. N-methyl-4-bromobenzenesulfonamide was coupled with phenol to 4- (4- (N-methylsulfamoyl) phenoxy) benzene as per procedure A15, step 2. 4- (4- (N-Methylsulfamoyl) phenoxy) benzene was converted to 4- (4- (N-methylsulfamoyl) phenoxy) -1-nitrobenzene according to method A15, step 3. 4- (4- (N-Methylsulfamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (4- (N-methylsulfamoyl) phenoxy) aniline according to method A15, step 4. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (N-methylsulfamoyl) phenoxy) aniline to form urea according to method C1 a.

Compound 55: coupling of 1, 5-hydroxy-2-methylpyridine with 1-fluoro-4-nitrobenzene to form 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene according to procedure A18 step. The picoline was oxidized with a different carboxylic acid and then esterified to 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene as in method A18, step 2. The nitrobenzene was reduced to 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline according to method A18, step 3. The nitrobenzene was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate to form urea according to method C1 a.

Compound 56: coupling of 1, 5-hydroxy-2-methylpyridine with 1-fluoro-4-nitrobenzene to form 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene according to procedure A18 step. The picoline was oxidized with a different carboxylic acid and then esterified to 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene as in method A18, step 2. The nitrobenzene was reduced to 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline according to method A18, step 3. The aniline was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate to form N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (2-methoxycarbonyl) -5-pyridyloxy) phenyl) urea according to method C1 a. The methyl ester was reacted with methylamine as in method D2 to form N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (2-methoxycarbamoyl) -5-pyridyloxy) phenyl) urea.

Compound 57: n- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4-aminophenyl) urea was prepared according to step C1 d. N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4-aminophenyl) urea was coupled with monomethyl isophthalate to form urea according to method D1 a.

Compound 58: n- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4-aminophenyl) urea was prepared according to step C1 d. N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4-aminophenyl) urea was coupled with monomethyl isophthalate according to method D1a to form N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea. N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea was reacted with methylamine to form the corresponding methylamide according to method D2.

Compound 59: 4-chloropyridine-2-carbonyl chloride was reacted with dimethylamine in procedure A2, step 3. The resulting 4-chloro-N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to procedure a2, step 4, to form 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline according to method C1a to form a urea.

Compound 60: 1, 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene to form 4- (4-acetylphenoxy) nitrobenzene according to procedure A13. The nitrobenzene is reduced to 4- (4-acetylphenoxy) aniline according to method 13, step 4, and then converted to 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt according to method A16 4-chloro-3- (trifluoromethyl) phenyl isocyanate reacts with 4- (4-acetylphenoxy) aniline according to method C1a to form urea.

Compound 61: synthesis of 4- (3-carboxyphenoxy) -1-nitrobenzene according to procedure A13, step 2. Coupling of 4- (3-carboxyphenoxy) -1-nitrobenzene with 4- (2-aminoethyl) morpholine as in procedure A13 step 3 gave 4- (3- (N- (2-morpholinoethyl) carbamoyl) phenoxy) -1-nitrobenzene. 4- (3- (N- (2-morpholinoethyl) carbamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (3- (N- (2-morpholinoethyl) carbamoyl) phenoxy) aniline according to method A13, step 4. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N- (2-morpholinoethyl) carbamoyl) phenoxy) aniline according to method C1a to form urea.

Compound 62: synthesis of 4- (3-carboxyphenoxy) -1-nitrobenzene according to procedure A13, step 2. Coupling of 4- (3-carboxyphenoxy) -1-nitrobenzene with 1- (2-aminoethyl) pyridine formed 4- (3- (N- (2-pyridylethyl) carbamoyl) phenoxy) -1-nitrobenzene according to procedure A13 step 3. 4- (3- (N- (2-pyridylethyl) carbamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (3- (N- (2-pyridylethyl) carbamoyl) phenoxy) aniline according to method A13, step 4. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N- (2-pyridylethyl) carbamoyl) phenoxy) aniline to form urea according to method C1 a.

Compound 63: synthesis of 4- (3-carboxyphenoxy) -1-nitrobenzene according to procedure A13, step 2. Coupling of 4- (3-carboxyphenoxy) -1-nitrobenzene with tetrahydrofurfuryl amine according to procedure A13 step 3 formed 4- (3- (N- (2-tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene. 4- (3- (N- (2-tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (N- (2-tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline according to method A13, step 4. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N- (2-tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline according to method C1a to form urea.

Compound 64: synthesis of 4- (3-carboxyphenoxy) -1-nitrobenzene according to procedure A13, step 2. Coupling of 4- (3-carboxyphenoxy) -1-nitrobenzene with 2-aminomethyl-1-ethylpyrrolidine as in procedure A13 step formed 4- (3- (N- ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene. 4- (3- (N- ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (3- (N- ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) aniline according to method A13, step 4. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N- ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) aniline to form urea according to procedure C1 a.

Compound 65: synthesis of 4-chloro-N-methylpyridine carboxamide according to procedure A2, step 3 b. The chloropyridine was reacted with 4-aminothiophenol according to method A2 step 4 to form 4- (4- (2- (N-methylcarbamoyl) thiophenyl) aniline 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- (N-methylcarbamoyl) thiophenyl) aniline according to method C1a to form urea.

Compound 66: 4-chloro-2-carbonyl chloride was reacted with isopropylamine according to method A2, step 3 b. The 4-chloro-N-isopropyl-2-pyridinecarboxamide formed was reacted with 4-aminophenol according to method A2, step 4, to form 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline according to method C1a to form urea.

Compound 67: synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl-N' - (4-ethoxycarbonylphenyl) urea by method C1e, by method D3, saponification of N- (4-chloro-3- (trifluoromethyl) phenyl-N ' - (4-ethoxycarbonylphenyl) urea to form N- (4-chloro-3- (trifluoromethyl) phenyl-N ' - (4-carboxyphenyl) urea in accordance with method D1b, coupling of N- (4-chloro-3- (trifluoromethyl) phenyl-N ' - (4-carboxyphenyl) urea with 3-methylcarbamoylaniline, n- (4-chloro-3- (trifluoromethyl) phenyl-N' - (4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea is formed.

Compound 68: synthesis of 5- (4-aminophenoxy) -2-methylisoindole-1, 3-dione according to method A9. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) -2-methylisoindole-1, 3-dione to form a urea according to procedure C1 a.

Compound 69: synthesis of 4-chloro-N-methylpyridine carboxamide according to procedure A2, step 3. The chloropyridine was reacted with 3-aminothiophenol according to method A2 step 4 to form 3- (4- (2- (N-methylcarbamoyl) thiophenyl) aniline 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (4- (2- (N-methylcarbamoyl) thiophenyl) aniline according to method C1a to form urea.

Compound 70: synthesis of 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) aniline according to method A10 4-chloro-3- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) aniline according to method C1a to form urea.

Compound 71: synthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method A14. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method C1a to form a urea. N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to procedure D4, step 1, and the corresponding acid was coupled with 4- (2-aminoethyl) morpholine to form the amide.

Compound 72: synthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method A14. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method C1a to form a urea. N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to method D4, step 1 and the corresponding acid was coupled with methylamine to form the amide according to method D4, step 2.

Compound 73: synthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method A14. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method C1a to form a urea. N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to procedure D4, step 1 and the corresponding acid was coupled with N, N-dimethylethylenediamine to form an amide according to procedure D4, step 2.

Compound 74: the 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-hydroxyethylamine according to procedure A2 step 3b to form 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide. By the method A17, 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide is reacted with triisopropylsilylchloride, and then reacted with 4-aminophenol to form 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoylpyridyloxyaniline by method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoylpyridyloxybenzene to form N- (4-chloro-3- ((trifluoromethyl) phenyl-N' -4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoylpyridyloxyphenyl) urea.

Compound 75: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline to form urea according to method C1f, which was then coupled with 3-aminopyridine according to method D1C.

Compound 76: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline to form urea according to procedure C1f, which was coupled with N- (4-acetylphenyl) piperazine according to procedure D1C.

Compound 77: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline to form urea according to procedure C1f, which was then coupled with 4-fluoroaniline according to procedure D1C.

Compound 78: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline to form urea according to procedure C1f, which was then coupled with 4- (dimethylamino) aniline according to procedure D1C.

Compound 79: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline to form urea according to method C1f, which was then coupled with N-phenylethylenediamine according to method D1C.

Compound 80: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline to form urea according to procedure C1f and coupled with 2-methoxyethylamine according to procedure D1C.

Compound 81: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline to form urea according to procedure C1f, which was then coupled with 5-amino-2-methoxypyridine according to procedure D1C.

Compound 82: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline to form urea according to procedure C1f, which was then coupled with 4-morpholinoaniline according to procedure D1C.

Compound 83: synthesis of 4- (3-carboxyphenoxy) aniline according to method A11. 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline to form a urea according to procedure C1f, which was then coupled with N- (2-pyridyl) piperazine according to procedure D1C.

Compound 84: the 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-hydroxyethylamine according to procedure A2 step 3b to form 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide. 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide reacts with triisopropylsilylchloride and then with 4-aminophenol to form 4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl pyridyloxyaniline according to method A17 4-chloro-3- ((trifluoromethyl) phenyl-N' -4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea is formed by reacting 4-chloro-3- (trifluoromethyl) phenyl isocyanate with 4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxybenzene according to method C1 a. The urea was deprotected according to method D5 to give N- (4-chloro-3- ((trifluoromethyl) phenyl-N' -4- (4- (2- (N- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea.

Compound 85: synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline according to method A2. 4-bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline according to procedure C1a to form a urea.

Compound 86: synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline according to method A6. 4-bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to form urea according to procedure C1 a.

Compound 87: step 4, 4-amino-2-chlorophenol according to procedure A2 was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, prepared according to procedure A2, step 3, to form 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 4-bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline according to procedure C1a to form a urea.

Compound 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine as in procedure A2 step 3 b. The 4-chloro-N-ethyl-2-pyridinecarboxamide formed was reacted with 4-aminophenol according to method A2 step 4 to form 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 4-bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to form urea according to procedure C1 a.

Compound 89: synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide according to method A2, step 3a, followed by reaction with 3-aminophenol according to method A2, step 4, to form 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. 4-bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline according to procedure C1a to form a urea.

Compound 90: the 4, 5-amino-2-methylphenol, step A2, was then reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, prepared according to step 3b, method A2, to form 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. 4-bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline according to procedure C1a to form a urea.

Compound 91: 4-chloropyridine-2-carbonyl chloride was reacted with dimethylamine in procedure A2, step 3 b. The 4-chloro-N, N-dimethyl-2-pyridinecarboxamide formed was reacted with 4-aminophenol according to method A2 step 4 to form 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline. 4-bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline according to procedure C1a to form a urea.

Compound 92: synthesis of 4-chloro-N-methylpyridine carboxamide according to procedure A2, step 3 b. The chloropyridine is reacted with 4-aminothiophenol according to method A2 step 4 to form 4- (4- (2- (N-methylcarbamoyl) thiophenyl) aniline 4-bromo-3- (trifluoromethyl) phenyl isocyanate is converted according to method B1 and 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (N-methylcarbamoyl) thiophenyl) aniline according to method C1a to form urea.

Compound 93: synthesis of 4-chloro-N-methylpyridine carboxamide according to procedure A2, step 3 b. The chloropyridine is reacted with 3-aminothiophenol according to method A2 step 4 to form 3- (4- (2- (N-methylcarbamoyl) thiophenyl) aniline 4-bromo-3- (trifluoromethyl) phenyl isocyanate is converted according to method B1 and 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (4- (2- (N-methylcarbamoyl) thiophenyl) aniline according to method C1a to form urea.

Compound 94: synthesis of 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline 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) pyridyloxy) aniline to form a urea.

Compound 95: synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline according to method A2. Synthesis of 4-chloro-2-methoxy-5- (trifluoromethyl) aniline according to method A7. Following procedure B1, 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate. According to method C1a, 4-chloro-2-methoxy 5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to form urea.

Compound 96: synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline according to method A6. Synthesis of 4-chloro-2-methoxy-5- (trifluoromethyl) aniline according to method A7. Following procedure B1, 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate. According to method C1a, 4-chloro-2-methoxy 5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to form urea.

Compound 97: step 4, 4-amino-2-chlorophenol according to procedure A2 was reacted with 4-chloro-2-pyridinecarboxamide prepared according to procedure A2, step 3b to form 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. Synthesis of 4-chloro-2-methoxy-5- (trifluoromethyl) aniline according to method A7. Following procedure B1, 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate. According to method C1a, 4-chloro-2-methoxy 5- (trifluoromethyl) phenyl isocyanate and 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline were reacted to form urea.

Compound 98: the 4-chloro-N-methyl-2-pyridinecarboxamide prepared according to method A2, step 3a was reacted with 3-aminophenol according to method A2, step 4, to form 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. Synthesis of 4-chloro-2-methoxy-5- (trifluoromethyl) aniline according to method A7. Following procedure B1, 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate. According to method C1a, 4-chloro-2-methoxy 5- (trifluoromethyl) phenyl isocyanate and 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline are reacted to form urea.

Compound 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine as in procedure A2 step 3 b. The 4-chloro-N-ethyl-2-pyridinecarboxamide formed was reacted with 4-aminophenol according to method A2 step 4 to form 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. Synthesis of 4-chloro-2-methoxy-5- (trifluoromethyl) aniline according to method A7. Following procedure B1, 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate. According to method C1a, 4-chloro-2-methoxy 5- (trifluoromethyl) phenyl isocyanate and 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline are reacted to form urea.

Compound 100: 4-chloropyridine-2-carbonyl chloride was reacted with dimethylamine in procedure A2, step 3 b. The 4-chloro-N, N-dimethyl-2-pyridinecarboxamide formed was reacted with 4-aminophenol according to method A2 step 4 to form 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline. Synthesis of 4-chloro-2-methoxy-5- (trifluoromethyl) aniline according to method A7. Following procedure B1, 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate. According to method C1a, 4-chloro-2-methoxy 5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline to form urea.

Compound 101: 4-chloro-N-methyl-2-pyridinecarboxamide synthesized according to method A2, step 3a, was reacted with 3-aminophenol according to method A2, step 4, to form 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. Synthesis of 2-amino-3-methoxynaphthalene according to method A1. According to method C3, 2-amino-3-methoxynaphthalene is reacted with bis (trichloromethyl) carbonate and then with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to form urea.

Compound 102: synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline according to method A2. Synthesis of 5-tert-butyl-2- (2, 5-dimethylpyrrolyl) aniline according to method A4. Following procedure C2d, 5-tert-butyl-2- (2, 5-dimethylpyrrolyl) aniline was reacted first with CDI and then with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to form urea.

Compound 103: synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide according to procedure A2, step 3 b. Following method A2, step 4, 4-chloro-N-methyl-2-pyridinecarboxamide with DMAC instead of DMF was reacted with 4-aminophenol to form 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. Following procedure C2d, 3-amino-2-methoxyquinoline was reacted first with CDI and then with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to form bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea.

Listed in the following table are compounds synthesized according to the examples detailed above.

The compounds in tables 1-6 were prepared according to the general procedure above, with specific procedures as described above and characteristics as described in the tables.

TABLE 13 tert-butylphenyl ureas

Table 2: 5-tert-butyl-2-methoxyphenyl urea

Table 3: 5- (trifluoromethyl) -2-methoxyphenyl urea

Table 4: 3- (trifluoromethyl) -4-chlorophenyl urea

Table 5: 3- (trifluoromethyl) -4-bromophenylurea

Table 6: 5- (trifluoromethyl) -4-chloro-2-methoxyphenyl urea

Table 7: other ureas

Similar results were achieved with equal success if the reagents and/or reaction conditions outlined or specified were substituted for those used in the above examples.

In view of the foregoing, it will be seen that those skilled in the art are not aware of the fact that the invention is susceptible to particular embodiments and that various modifications may be made without departing from the spirit and scope of the invention to adapt it to various usages and conditions.

Claims (29)

1. A compound of the formula:

A-D-B (I)

wherein the content of the first and second substances,

d is-NH-C (O) -NH-;

a is-L- (M-L)¹) Wherein, in the step (A),

l is unsubstituted or substituted phenyl or pyridyl, when L contains a substituent selected from the group consisting of halogen and Wn, n is 0 to 3;

m is-O-or-S-;

L¹is represented by-C (O) R_xSubstitutionWhen L is phenyl or pyridyl¹And further containing a substituent selected from the group consisting of halogen and Wn, n is 0 to 3; (ii) a

R_xIs C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy or NR_aR_b，R_aAnd R_bEach is

a) C containing 0-3 hetero atoms selected from N, S and O_3-10A cycloalkyl group,

b)C₆an aryl group, a heteroaryl group,

c) c containing 1-3 hetero atoms selected from O, N and S_3-12(ii) a heteroaryl group, wherein,

d) substituted C containing 0-3 hetero atoms selected from N, S and O_3-10A cycloalkyl group,

e) substituted C₆Aryl radicals

f) Substituted C containing 1-3 hetero atoms selected from N, S and O_3-12(ii) a heteroaryl group, wherein,

g) -phenylpiperazine (pyridyl), or

h)-C₂H₄NH (phenyl);

R_aand R_bOne of them may also be hydrogen, C₁-C₁₀Alkyl and hydroxy substituted or C containing 1-3 hetero atoms selected from O, N and S_3-12Cycloalkyl-substituted C_1-10An alkyl group, a carboxyl group,

when R is_aOr R_bWhen containing a substituent, the substituent is selected from:

a) halogen, to perhalogenated,

b) a hydroxyl group(s),

c)-N(CH₃)₂，

d)C₁-C₁₀an alkyl group, a carboxyl group,

e)C₁-C₁₀an alkoxy group,

f) c containing 1-3 hetero atoms selected from O, N and S_3-12A cycloalkyl group,

g) halogen substituted C_1-6Alkyl, or

h)-OSi(Pr-i)₃；

B is substituted or unsubstituted phenyl, when B contains substituent selected from halogen and Wn, n is 0-3;

each W is-C₁-C₁₀Alkyl or C₁-C₁₀Alkoxy, which may be substituted with one or more substituents selected from halogen or perhalogenation.

2. The compound of claim 1, L¹Is phenyl.

3. The compound of claim 1, L¹Is a pyridyl group.

4. The compound of claim 1, L is phenyl.

5. The compound of claim 1, L is unsubstituted or substituted phenyl, and the substituents are selected from the group consisting of halogen and C₁-C₁₀An alkyl group; l is¹Is C (O) R_xSubstituted pyridyl or phenyl.

6. The compound of claim 1, wherein,

l is unsubstituted or substituted phenyl, the substituents being selected from the group consisting of halogen and C₁-C₁₀An alkyl group;

L¹is-C (O) R_xA substituted pyridyl group;

R_xis NR_aR_b，R_aAnd R_bEach is

a) C containing 0-3 hetero atoms selected from N, S and O_3-10A cycloalkyl group,

b)C₆an aryl group, a heteroaryl group,

c) c containing 1-3 hetero atoms selected from O, N and S_3-12(ii) a heteroaryl group, wherein,

d) substituted C containing 0-3 hetero atoms selected from N, S and O_3-10A cycloalkyl group,

e) substituted C₆Aryl radicals

f) Substituted C containing 1-3 hetero atoms selected from N, S and O_3-12(ii) a heteroaryl group, wherein,

g) -phenylpiperazine (pyridyl), or

h)-C₂H₄NH (phenyl))；

R_aAnd R_bOne of them may also be hydrogen, C₁-C₁₀Alkyl and hydroxy or C containing 1-3 hetero atoms selected from O, N and S_3-12Cycloalkyl-substituted C₁-C₁₀An alkyl group, a carboxyl group,

when R is_aOr R_bWhen containing substituents, the substituents are:

a) a halogen or a perhalogenated compound,

b) a hydroxyl group(s),

c)-N(CH₃)₂，

d)C₁-C₁₀an alkyl group, a carboxyl group,

e)C₁-C₁₀an alkoxy group,

f) c containing 1-3 hetero atoms selected from O, N and S_3-12A cycloalkyl group,

g) halogen substituted C_1-6Alkyl, or

h)-OSi(Pr-i)₃。

7. The compound of claim 1, wherein B is substituted phenyl and the substituents are selected from the group consisting of halogen, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy or halo C₁-C₁₀An alkyl group.

8. The compound of claim 5, wherein B is phenyl having 1-3 substituents selected from the group consisting of Cl, Br, F, trifluoromethyl, methoxy and tert-butyl.

9. The compound of claim 1, L is unsubstituted or halophenyl.

10. The compound of claim 1, L is unsubstituted or substituted phenyl and the substituents are selected from Cl and methyl.

11. The compound of claim 1, M is-O-.

12. The compound of claim 5, wherein M is-O-.

13. The compound of claim 6, wherein M is-O-.

14. A compound of claim 1, R_aAnd R_bAre each selected from hydrogen and C₁-C₁₀Alkyl, M is-O-.

15. A compound of claim 5, R_aAnd R_bAre each selected from hydrogen and C₁-C₁₀Alkyl, M is-O-.

16. A compound of claim 1, R_aOr R_bOne is phenyl, pyridyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.

17. A compound of claim 5, R_aOr R_bOne is phenyl, pyridyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.

18. A compound of claim 6, R_aOr R_bOne is phenyl, pyridyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.

19. A compound of claim 1, R_aAnd R_bEach selected from H and methyl.

20. A compound of claim 5, R_aAnd R_bEach selected from H and methyl.

21. The compound of claim 1 which is a pharmaceutically acceptable salt of the compound of formula I selected from:

a) basic salts of organic and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (tosylate), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid; and

b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkali metal cations, alkaline earth metal cations, ammonium ions, aliphatically substituted ammonium ions and aromatically substituted ammonium ions.

22. The compound of claim 6 which is a pharmaceutically acceptable salt of the compound of formula I selected from:

a) basic salts of organic and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (tosylate), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid; and

b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkali metal cations, alkaline earth metal cations, ammonium ions, aliphatically substituted ammonium ions and aromatically substituted ammonium ions.

23. A pharmaceutical composition for the treatment of cancer comprising a compound of claim 1 or a pharmaceutically acceptable salt of a compound of formula I, and a physiologically suitable carrier.

24. The pharmaceutical composition of claim 23, wherein the compound of formula I is as described in claim 5.

25. The pharmaceutical composition of claim 23, wherein the compound of formula I is as described in claim 6.

26. Use of a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting raf kinase mediated cancerous cell growth.

27. Use of a compound of formula I as described in claim 5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting raf kinase mediated cancerous cell growth.

28. Use of a compound of formula I as described in claim 6, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting raf kinase mediated cancerous cell growth.

29. The compound of claim 1, wherein the substituents of B are independently selected from the group consisting of methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl, tert-butyl, sec-butyl, isobutyl, methoxy, ethoxy, propoxy, Cl, and F.