BG109688A - Carboxyaryl substituted diphenil ureas as raf kinase inhibitors - Google Patents

Abstract

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

Description

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

BACKGROUND OF THE INVENTION

The p21 ^ras oncogene is one that mainly contributes to the development and progression of human solid cancers and mutates in 30% of all human cancers (Bolton et al. Ann. Rep. Med. Chem. 1994, 29, 165-74; Bos Cancer Res. 1989, 49, 4682-9). In its normal, non-mutated form, the ras protein is a key element of the signal transductal cascade through growth factor receptors in almost all tissues (Avruch et al. Trends Biochem. Sci. 1994, Ϊ9, * 2794ίβί4? τ. bibhi • ♦ · * · · From a physical point of view, ras is a guanine nucleotide binding protein ** and the closure of the cycle between the GTP bond in activated form and the resting GTP bond is strictly controlled by endogenous STRasease activity of ras, and other regulatory proteins.In cancer mutants in cancer cells, endogenous STRasease activity is attenuated and, therefore, the protein sends constitutive growth signals, such as the raf kinase enzyme to the downstream effectors, leading to malignant growth of the cells carrying these mutants (Magnuson et al. Semin. Cancer Biol. 1994, 5, 247- 53) It has been shown that by inhibiting the effect of active ras by inhibiting the signaling pathway of raf kinase by administration of inactivating antibodies to raf kinase, or by co-expression of a dominant negative raf kinase, or a dominant negative MEK, the substrate of the raf kinase leads to a backward development of transformation Iran cells to the normal growth phenotype (see: Daum et al. Trends Biochem. Sci. 1994, 19, 474-80); Frigman et al. J. Biol. Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 42628) then showed that inhibition of raf expression by antireceptor RNA (RNA) blocks the proliferation of cells in membrane-bound oncogenes. Similarly, inhibition of ras kinase (by antireceptor oligodeoxynucleotides) has been compared in vitro and in vivo with inhibition of the growth of various types of human tumors (Monia et al., Nat. Med. 1996, 2, 668-75).

SUMMARY OF THE INVENTION

The present invention provides compounds that are inhibitors of the raf kinase enzyme. Because the enzyme is an effector of p21 ^ras downstream, inhibitors are used ^; Pharmaceutical compositions used in man and for veterinary use <when inhibition of the raf kinase pathway is indicated, for example, in the treatment of tumors and / or malignant cell growth mediated by raf kinase. In particular, the compounds are used in the treatment of solid cancers in humans and animals, for example, murine carcinoma, since the progression of these cancers is dependent on the signal transduction cascade of the ras protein, and is therefore sensitive to treatment by interrupting the cascade that is, by inhibiting the Raf kinase. Accordingly, the compounds of the invention are used in the treatment of cancers, including solid cancers, such as, for example, cancers (e.g., lungs, pancreas, thyroid gland, bladder, or colon), myeloid diseases (e.g., myeloma leukemia), or adenomas (e.g., fibrous colon adenoma).

Therefore, the present invention provides compounds commonly described as aryl ureas, including both analogues, and aryl and heteroaryl, which inhibit the Raf kinase pathway. The invention also provides a method of treating raf kinase mediated disease conditions in humans or mammals. Thus, the invention is directed to compounds that inhibit the raf kinase enzyme, and also compounds, compositions and methods for treating cancer cell growth mediated by raf kinase, where a compound of formula I, or a pharmaceutically acceptable salt thereof, is administered.

A-D-B (I)

In Formula I, D is-NH-C (O) -NH-,; ..

'·. ·. ** · *; '. * ··

A is a substituted moiety of up to 40 carbon atoms with fOrIy.-. · * Lats: -L- (ML ¹ ) _q , where L is a 5 to 6 membered cyclic structure bonded directly to D, L ¹ contains a substituted cyclic moiety having at least 5 members, M is a group that bridges, having at least one atom, q is an integer in the order of 1 - 3; and each of the cyclic structures of L and L ¹ consists of 0 - 4 members of the group consisting of nitrogen, oxygen and sulfur, and _ is substituted, or unsubstituted, to tricyclic aryl, or ©

heteroaryl moiety of up to 30 carbon atoms, with at least one 6-membered cyclic structure bonded directly to D containing 0-4 members from the group consisting of nitrogen, oxygen and sulfur, where L ¹ is substituted by at least one substituent selected from the group consisting of -SO ₂ R _X , -C (O) R _X, and -C (NR _y ) R _z ,

R _y is hydrogen or a carbon-based residue of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally halogen substituted, C to per halogen,

_Rz is hydrogen or a carbon-based residue of up to 30 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and 0 and optionally substituted with halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen;

R _x is R _z , or NR _a R _b , where R _a and R _b are ca

a) independently, hydrogen, is a carbonaceous residue of up to 30 adiero ^^ ytemigro. .. ·. ** · '. · ·. * ·· choice containing heteroatoms selected from the group consisting of N, S and 0 and optionally substituted by halogen, hydroxy and carbon-based substituents up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen, or

-OSi (R _f ) ₃ , wherein R _f is hydrogen or a carbon-based residue of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from the group consisting of N, S and 0 and optionally substituted by halogen; or

b) R _a and R _b together form a 5-7 membered heterocyclic structure with 1-3 heteroatoms selected from the group consisting of N, S and 0, or a substituted 5-7 membered heterocyclic structure with

1-3 heteroatoms selected from the group consisting of N, S and 0, substituted by halogen, hydroxy, or carbon-based substituents of up to 24 carbon atoms, optionally containing © heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen; or

c) one of R _a and R _b is -C (O) -, Οϊ -C ₅ divalent alkylene group, or a substituted C 1 -C ₅ divalent alkylene group attached to the residue L, forming a cyclic structure with at least 5 members , where the substituents of the substituted C _5- divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon-based substituents of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of is from N, S and FI [1b * iso. &amp; c _? ·· shades with halogen; Where B is substituted, L is substituted, or L ¹ is further substituted, the substituents are selected from the group consisting of halogen, to per-halogen, and Wn, where η is 0 - 3;

wherein each W is independently selected from the group consisting of -CN, -CO ₂ R ⁷ , -C (O) NR ⁷ R ⁷ , -C (O) -R ⁷ , -Mag, -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) OR ⁷ , -NR ⁷ C (O) R ⁷ , -Q-γγ, and carbon-based residues of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and 0 and optionally substituted with one or more substituents independently selected from the group consisting of -CN, -CO2R ^7, -C (O) -R ^7, -C (O) NR ⁷ R ⁷ , -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NO 2 and -NR ⁷ C (O) R ⁷ , -NR ⁷ C (O) OR ⁷ , and halogen to per-halogen; each R ⁷ being independently selected from H or carbon residue up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen;

wherein Q is -0-, -S-, -N (R ⁷⁾ -, - (CH2) m- , -C (0) -, -CH (OH) -, - (CH2) mO- , - (CH2 ) mS-, - (CH2) mN (R _{⁷⁾ -, -O (CH2) m} - SNH ^a -, -CX ⁸ 2-, -S- (CH2) m-, and -N (R ⁷⁾ (CH2 ) _m - where m = 1 - 3 and X ^a is halogen; and

Ar is a 5- or 6-membered aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen to per-halogen, and optionally substituted by Ζ _η ι, where n1 is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO ₂ R ⁷ , -C (O) R ⁷ , -C (O) NR ⁷ R ⁷ , -mag , -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) OR ⁷ , -NR ⁷ C (O) R ⁷ , and a carbon-based residue of up to 24 carbon atoms optionally containing heteroatoms, selected from the group consisting of N. S and O and optionally substituted by one or more substituents selected from the group consisting of -CN '' -C G ^ R.7 ^; -OOp /: ·. -C (O) NR ⁷ R ⁷ , -OR ⁷ , -SR ⁷ , -NO ₂ , -NR ⁷ R ⁷ , -NR ⁷ C (O) R ⁷ , and

-NR ⁷ C (O) OR ⁷ , wherein R ⁷ is as defined above.

In Formula I, including suitable heteroaryl groups, without being limited to from 5 to 12 carbon atoms, aromatic rings, or ring systems containing 1 to 3 rings, at least one of which is aromatic, in which one or more, for example, 1-4 carbon atoms in one or more of the rings may be substituted by an oxygen, nitrogen, or sulfur atom. Each ring typically has 3-7 atoms. For example, B may be 2- or 3-furyl, 2-, or 3-thienyl, 2-, or 4-tri-azinyl,

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- tri-azol-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-, 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-, 6-, or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- , or 7-benzothienyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 1-, 2-, 4-, or 5-benzimidazolyl, 1-, 3-, 4-, 5 -, 6-, or 7-benzopyrazolyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 3-, 4-,

5-, 6-, or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6-, or 7-benzothiazolyl, 2-, 4-, 5-, 6-, or 7-benzisothiazolyl, 2- , 4-, 5-, 6-, or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-,

3-, 4_, 5-, θ-, 7- ₁ 8-isoquinolinyl, 2-, 3-, 4-, or 9-carbazolyl, 1-, 3, 4-, 5-, 6-, 7-, 8 , or 9-acridinyl, or 2-, 4-, 5-, 6-, 7-, 8-quin- · · · ·; ·· .. azolinyl, or optionally substituted * phenyl; · ^, hyphae

3-thienyl, 1-, 3-, 4-thidiazolyl, 3-pyryl, 3-pyrazolyl, 2-thiazolyl, "or 5-thiazolyl, etc. For example, B may be 4-methylphenyl, 5-methyl -2-thienyl, 4-methyl-2-thienyl, 1-methyl-3-pyryl,

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

Suitable alkyl groups and portions of alkyl groups, for example, alkoxy, etc., fully include methyl, ethyl, propyl, butyl, etc., including all straight and branched chain isomers such as isopropyl, isobutyl , secbutyl, tert-butyl, etc.

Suitable aryl groups that do not contain heteroatoms include, for example, phenyl 1- and 2-naphthyl.

The term "cycloalkyl", as used herein, refers to cyclic structures with or without alkyl substituents such as, for example, "C ₄ cycloalkyl" includes methyl substituted cyclopropyl groups as well as cyclobutyl groups.

The term "cycloalkyl" as used herein also includes saturated heterocyclic groups.

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

The invention also relates to compounds per se (in pure form) of formula I.

The present invention is also directed to pharmaceutically acceptable salts of formula I. Suitable headlamps. : "Pharmaceutically acceptable salts are well known in the art, and include basic salts of mineral acids and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and sulfuric acid. acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,

1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, benzoic acid, acid, and almond acid. In addition, pharmaceutically acceptable salts include mineral bases, such as salts containing alkali cations (e.g., Li ⁺ , Na ⁺ , or K *), alkaline earth cations (e.g., Md ⁺² , Ca ⁺² , or Br ⁺² ). ammonium cation, as well as acidic salts of organic bases including aliphatic and aromatic substituted ammonium radicals, and quaternary ammonium cations, such as those resulting from the protonation or peralkylation of triethylamine, Ν, Ν-diethylamine, Ν, Ν- dicyclohexylamine, lysine, pyridine, N, N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,5-d azabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0.] undec-7-ene (DBU).

Many of the compounds of formula I have asymmetric carbon atoms, and therefore can exist in racemic and optically active forms. Methods for separating enantiomeric and diastereomeric mixtures are well known to those skilled in the art. The present invention encompasses any isolated racemic or optically active form of compounds described in which have inhibitory activity. "·· ** · * .. ·:" ·

Basic methods of production

The compounds of formula I can be prepared using known chemical reactions and techniques, some of the starting materials, which are commercially available. However, the basic preparation methods are shown below to assist those skilled in the art in synthesizing these compounds, with more detailed examples being shown in the experimental section that follows.

Substituted anilines can be generated using standard methods (March. Advanced Organic Chemistry, 3rd ^{ed .} ; John Wiley: New York (1985). Comprehnsive Organic Transformation; VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines are typically synthesized by reducing nitroaryls using metal catalysts such as Ni, Pd, or Pt, and H ₂ , or a hydride transfer agent such as formate, cyclohexadiene, or borohydride ( Rylander Hydrogenation Methods; Academic Press: London, UK (1985). Nitroaryls can also be reduced directly by using a strong hydride source such as LiAIH ₄ (Seyden-Penne. Reduction by the Aluminum and Borohydrides in Organic Synthesis; VCH Publisher: New York (1991)) or by using a zero valence metal , such as Fe, Sn, or Ca, often in acidic media. There are many methods for synthesizing nitroaryl (March. Advanced Organic Chemistry, 3rd ^{ed .} ; John Wiley: New York (1985). Larock. Comprehnsive Organic Transformation; VCH Publishers: New York (1989)).

2 / catalyst

ΑγΝΟ ₂ [Hi

(eg.Fe, Sn, Ca)

Scheme I Reduction of nitroaryl to aryl amines

Nitroaryls are generally obtained by electrophilic aromatic nitration using HNO ₃ or an alternative source of NO ₂ '. Nitroaryl may also be made prior to reduction. Thus, nitroaryl substituted with

Ag-H

HNO ₃ ► ΑγΝΟ ₂ potential leaving groups (eg, F, Cl, Br, etc.) may undergo substitution reactions by acting on nucleophiles such as thiolate (shown in Scheme II for example) or phenoxide. Nitroaryl can also undergo addition reactions (Scheme II).

ArSH

CuO / base

Scheme II Selected Nucleophilic Aromatic * io * ^ Substitution, · * '*' Using Nitroaryl "

Nitroaryls may also undergo transient metal-mediated cross-linking reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides, or triflates, undergo palladium-mediated cross-linking reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reactions shown in the example below), aryl tin, or (Stille reactions). aryl zinc (Negishi reaction) to give biaryl (5).

'· ♦ · ·

Both nitroaryl and aniline can be converted to the corresponding arerenesulfonyl chloride (7) by reaction with chlorosulfonic acid. Reaction of sulfonyl chloride with a fluoride source such as KF then results in sulfonyl fluoride (8). The reaction of sulfonylfluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source such as tris (dimethylamino) sulfonium difluoromethylsiliconate (TASF) results in the corresponding trifluoromethylsulfone (9). Alternatively, the sulfonyl chloride 7 may be reduced to the isthiol (10), for example, with zinc amalgam. The reaction of thiol 10 with CHCIF ₂ in the presence of a base gives difluoromethyl mercaptam (11), which can be oxidized to sulfone (12) with any of the various oxidizers,

wires, including CrO ₃ -acetic

Khim. 1970, 6, (568).

. · * · **. : ** ·· ”, anhydride (SetibvaXt aH * rh .: 0'R $; * ·· * · ··

4— R XtX

SO ^ CI

CISQjH <Xx R 7

(Me ^ N ^ S Μβ ^ ίζ MejSiCf ^

Sp £ F “T ^{- R}

X / 9

CHClfy basis ▼

schf ₂ i ^ X

4 — R [0]

T

SO ^ HF ^

•. ·· · ·. ··

Scheme III Selected Methods for Synthesis of Na'Fpu0rf2Gn '* arylsulfone'

As shown in Scheme IV, non-symmetric urea formation may involve the reaction of aryl isocyanate (14) with aryl amine (13). The heteroaryl isocyanate can be synthesized from heteroaryl amine by acting with a phosgene or phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene), or Ν, Ν'-carbonyldi (CD). The isocyanate may also be separated from a heterocyclic carboxylic acid derivative, such as an ester, acid halide, or anhydride, by a Curcius rearrangement reaction. Thus, reaction of an acidic derivative 16 with an acid source followed by rearrangement results in the production of isocyanate. The corresponding carboxylic acid (17) may also be subjected to Curtius rearrangement reactions using diphenylphosphoryl azide (DPPA) or a similar reagent.

Ar ^{1 -} NH ₂ 13

COCI ₂ n-M-D ²

• ф ·

Scheme IV Selected non-symmetry methods «4hp <} fr '| 5 dying naure ·· ·. ·

Finally, ureas can also be machined using methods similar to those of ordinary skill in the art.

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

The compounds may be administered orally, topically, parenterally, by inhalation, or by spray or rectal, as single dose unit dosage forms. The term "injection by injection" includes intravenous, intramuscular, subcutaneous and parenteral injections as well as the use of infusion techniques. One or more compounds may be present in combination with one or more non-toxic pharmaceutically acceptable carriers, and optionally other active ingredients.

Compositions for oral use may be prepared according to any suitable method known in the art of manufacturing pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide delicious compositions. The tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; and binding agents, for example, magnesium stearate, stearic acid, or talc. The tablets may be uncoated, or they may be coated by known techniques to delay degradation and adsorption in the gastrointestinal tract, thereby providing a delayed action over a longer period of time. For example, delayed-action products such as glycerol monostearate or glyceryl distearate may be used. These compounds can also be obtained as solid, rapidly releasing forms.

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

Aqueous suspensions contain the active products mixed with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxy methyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth resin and acacia resin; dispersing or wetting agents may be naturally occurring phosphatides, for example, lecithin, or condensation products, or fatty acid alkali oxide, for example, polyoxyethylene stearate, or long-chain ethylene oxide condensation products, e.g. or condensation products of ethylene oxide with partial esters, derivatives of fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters, pro aqueous fatty acid and a hexitol anhydride, for example polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or η-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavor enhancers, and one or more sweetening agents, such as sucrose or saccharin.

Dispersion powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by, for example, those indicated immediately above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.

The compounds may also be in the form of non-aqueous liquid dosage forms, for example, oily suspensions, which may be prepared by suspending the active ingredients in vegetable oil, for example, peanut oil, olive oil, sesame oil, or peanut oil, or in mineral oils such as liquid paraffin. Oily suspensions may contain thickening agents, for example beeswax, solid paraffin, or cetyl alcohol. Sweetening agents such as those mentioned above may be added, and flavoring agents may be provided to provide delicious oral compositions. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the form of oil-water emulsions. The oily phase may be a vegetable oil, for example, oil, or peanut oil, or a mineral oil, for example, liquid paraffin, or mixtures thereof. Suitable emulsifying agents may be natural resins, for example, acacia resin or tragacanth resin, natural phosphatides, for example, soy, lecithin, and esters or partial esters, fatty acid derivatives and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of said ethylene oxide partial esters, for example, polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be prepared with sweetening agents, for example, glycerol, propylene glycol, sorbitol, or sucrose. Some dosage forms may also contain irritants, preservatives and taste enhancers.

The compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperature but liquid at rectal temperature and therefore melts in the rectum, thereby releasing the drug. Such products include coconut mAbtr and polyethylene glycols.

For all the uses described herein for the compounds of formula I, the daily oral dosage regimen is preferably from 0.01 to 200 mg / Kg total body weight. The daily dose for injection, including intravenous, intramuscular, subcutaneous and parenteral injection, and the use of infusion techniques, is preferably 0.01 to 200 mg / Kg total body weight. The daily dose for rectal administration is preferably from 0.01 to 200 mg / Kg total body weight. The daily dose for topical administration is preferably from 0.1 to 200 mg once daily up to four times daily. The daily inhalation dose is preferably from 0.01 to 10 mg / Kg total body weight.

It should be noted by those skilled in the art that the specific method of administration depends on various factors, all of which are taken into account by the routine of the attending physician. It should also be noted by those skilled in the art that the specific dosage level for a patient depends on various factors including the specific activity of the compound administered, age, body weight, health, sex, diet, time and route of administration. , the rate of excretion, etc. It should also be noted by those skilled in the art that the optimal course of treatment, i.e., the method of treatment and the number of doses of the compound of formula I, or a pharmaceutical composition thereof o Acceptable salt given for a specified number of days can be ascertained by those skilled in the art using conventional therapeutic tests.

However, it should be noted that the specific dosage level for each individual patient depends on various factors including the activity of the specific compound being used, age, body weight, general health, gender, diet, timing, route of administration , and the rate of excretion, the combination of drugs, and how severe the condition is being treated. _x

V,

The full inclusion of all applications, patents and publications cited above and below made for

Reference, including provisional application Serial No. Serial No. 60 / 115,877, filed Jan. 13, 1999, and non-provisional application 09 / 257q266, filed February 25, 1999.

The compounds may be obtained from known compounds (or from starting materials which, in turn, may be obtained from known compounds), for example, by the general preparation methods shown below. The activity of a compound to inhibit raf kinase can be routinely investigated, for example, according to the procedures described below. The following examples are for illustrative purposes only and are not intended or to be construed as limiting the invention in any way.

EXAMPLES FOR THE IMPLEMENTATION OF THE INVENTION

All reactions take place in flame-dried or oven-dried glassware under positive pressure of dry argon or dry nitrogen and mixed with magnetic stirrers, unless otherwise stated. The exact liquids and solutions are transferred by syringe or cannula, and transferred

• Imported into the reaction vessels through a rubber barrier. Unless otherwise stated, the term "concentration under reduced pressure" means the use of a Buchi rotary evaporator at approximately 15 mmHg. Unless otherwise stated, the term "high vacuum" means a vacuum of the order of 0u4 -1,0 mmHg.

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

Commercial grade reagents and solvents are used without further purification. N-Cyclohexyl-N '- (methylpolystyrene) carbodiimide is 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-4chloro-2-methoxy-5- (trifluoromethyl) aniline , and 4-chloro-3- (trifluoromethyl) phenyl isocyanate are purchased and used without further purification. Syntheses of 3-amino-2-methoxyquinoline (E.Cho. Et al. WO 98/00402; A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem. 3, 1995, 129), 4- (3 -carboylphenoxy) -1nitrobenzene (K. Ikawa Yakugaku Zasshi 79, 1959, 560; Chem. Abstr. 53, 1959, 12761b), 3-tert-butylphenyl isocyanate (Ο. Rohr et al. DE 2,436,108) g 2-; e) (i-5- (trifluoromethyl) phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491) have been described previously.

Thin layer chromatography (TLC) was performed using Whatman® factory-made 60A F-254 250 pm silica gel glass plates. Observation of the plaques

by one or more of the following techniques: (a) ultraviolet light; (b) exposure to iodine vapor; (c) immersion of the dish in 10% solution of phosphomolybdic acid in ethanol, followed by heating; (d) immersion of the dish; in a solution of cerium sulphate, followed by heating, and / or (e) immersing the plate in acidic ethanol solution of 2,4dinitrophenylhydrazine, followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science ® silica gel.

Melting points (mp) are determined using Thomas-Hoover melting point equipment or Mettler FP66 automatic melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton nuclear magnetic resonance (NMR) spectra ( ¹ H) were measured with a General Electric GN-Omega 300 spectrometer (300 MH) or with Me ₄ Si (δ 0.00) or with a residual protonated solution (CHCl 3 δ 7, 26; MeOH δ 3.30; DMSO b 2.49) as standard. Low resolution (MS) and high resolution (HRMS) spectra are obtained either as electron impact (EI) mass spectra or fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) will be obtained with a Hewlett Packard 5989A mass spectrometer equipped with the Vacumetrics Desorption Chemical Ionisation Probe for import. The ion source was maintained at 25 ° C. The electron impact is carried out with an electron energy of 70 eV and a capture current of 300 μΑ. Secondary liquid cesium mass spectrometry (FAB - MS), a modern version of fast atom bombardment, was obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (Cl - MS) were obtained using Hewlett Packard MS - Engine (5989A) with methane or ammonia as a gas reagent (1 x 10 ' ⁴ torr to 2.5 x 10 ⁴ torr). The direct placement of a Chemical Ionization Desorption Probe (DCI) (Vaccumetrics, Inc.) is achieved from 0 -1.5 amps in 10 seconds and

lasts at 10 amps until all traces of the sample disappear (~ 1 - 2 minutes). The spectra were scanned from 50-800 amu for 2 sec. On the scan. HPLC (HPLC) Electrospray Mass Spectra (HPLC ES - MS) were obtained using a Hewlett Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, C-18 column, and a trapped ionization mass spectrometer on Finningan LCQ ions. The spectra were scanned from 120-800 amu using variable ion time according to the number of ions in the source. Gas Chromatography - Ion Selective Mass Spectra (GC - MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP -1 methyl silicone column (0.33 mM coating; 25 m η 0.2 mm) and with a Hewlett Packard 5971 Mac selective detector (ionization energy 70 eV). Elemental analysis was performed by Robertson Microlit Labs, Madison NJ.

All reported NMR spectra of compounds, LRMS and either elemental analysis or HRMS are compatible with certain structures.

List of abbreviations and acronyms:

AsON

Acetic acid

Anhydrous • · * ·· · ·

Atm

BOC

CDI

Cone

D

Dec

DMAC

DMPU

DMF

DMSO

DPPA

EDCI

EtOAc

EtOH

Et ₂ O

Et ₃ N h

HOBT m-CPBA

MeOH

Fri. Ether

Temp.

THF

TFA

Tf

Atmosphere (s)

T ret-butoxycarbonyl

1,1 '-carbonyl diimidazole

Concentrated Day (days)

Degradation

N, N-dimethylacetamide

1,3-dimethyl-3DD6-tetrahydro2 (1H) -pyrimidinone

N, N-d imethylformamide

Dimethylsulfoxide Diphenylphosphoryl azide

- (3-dimethylaminopropyl) -Zetylcarbodium m id

Ethyl acetate

Ethanol (100%)

Diethyl ether

Triethylamine

Hours)

-hydroxybenzotriazole

3-Chloroperoxybenzoic acid

Methanol

Petroleum ether (boiling range 30 - 60 ° C) Tetrahydrofuran temperature TrifluoroAcONE

T rifluoromethanesulfonyl

A. Basic Methods for Synthesis of Substituted | G &

• * · · · · · · · · · · · · · · ·

A1. Basic Methods for Forming an aryl amine "by forming an ether, followed by saponification of an ester, rearrangement of Curtius, and deprotection of carbamate.

Synthesis of 2-amino-3-methoxynaphthalene

Step 1. Methyl 3-methoxy-2-naphthoate

A suspension of methyl 3-hydroxy-2-naphthoate (10.1 g,

50.1 mmol) and K ₂ CO ₃ (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temperature for 15 minutes, then treated with iodomethane (3.43 mL). , 55.1 mmol). The mixture was stirred at room temperature overnight then treated with water (200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with saturated NaCl solution (100 mL), dried (MgSO ₄ ), concentrated under reduced pressure (approximately 0.4 mmHg overnight) to give methyl 3-methoxy-2 -naphthoate as amber-yellow oil (10.3 g): ¹ H-NMR (DMSO-d ₆ ) δ 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J = 8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J = 8.09 Hz, 1H), 7.84 (d, J = 8.09 Hz) , 1H), 7.90 (s, 1H), 8.21 (s, 1H).

• ··

ΟΟ, Η

OMe

Step 2. 3-Methoxy-2-naphthoic acid

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

/ 4 · * ·. ··· · »··

Stage 3. 2- (M- (carbobenzyloxy) amino-3-methoxy-naphthyl &lt; / RTI & gt ^;

• · ··

3-Methoxy-2-naphthoic acid solution (3.36 g,

16.6 mmol) and E ^ N (2.59 mL, 18.6 mmol) in anhydrous toluene (70 mL) was stirred at room temperature for 15 min, then treated with DPPA solution (5 , 12 d,

18.6 mmol) in toluene (10 mL) by pipette. The resulting mixture was heated at 80 ° C for 2 hours. After cooling the mixture to room temperature, benzyl alcohol (2.06 mL, 20 mmol) was added with a syringe. Then the mixture was stirred

heated at 80 ° C overnight. The resulting mixture was cooled to room temperature, quenched with a% citric acid solution, and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated NaCl solution, dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc / 86% hexane) to give 2- (N- (carbobenzyloxy) amino-3-methoxynaphthalene, as a pale yellow oil (5.1 g, 100%): ¹ H-NMR

8H),

OMe

Step 4. 2-Amino-3-methoxynaphthalene

A suspension of 2- (N- (carbobenzyloxy) amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10 5 Pd / C (0.5 g) in EtOAc (7 mL) was kept under an H atmosphere. ₂ (balloon) at room temperature & ρρο- · \ ...

· ** ·· * ·,. · ··; ·; ; ··. for one night. The resulting mixture was filtered ** over * 8 * Celite®, and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder (2.40 g, 85%). ¹ H - NMR (DMSO - d ₆ ) δ 3.86 (s, 3H), 6.86 (s, 2H), 7.04 - 7.16 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H); El - MS m / z 173 (M ⁺ ).

A2. Synthesis of ω-carbamyl anilines by formation of carbamylpyridine followed by nucleophilic coupling with aryl amine.

Synthesis of 4- (2-N-methylcarbamyl-4-pyridyloxy) aniline

Step 1a. Synthesis of 4-χπορο-Ν-methyl-2-pyridinecarboxyl amide by Menisci reaction

Warning: This is an extremely dangerous, potentially explosive reaction!

To a stirred solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temperature, concentrated H ₂ SO ₄ (3.55 mL) was added to generate the exotherm. To this mixture was added H ₂ O ₂ (30% by weight in H ₂ O, 17 mL) and then FeSO ₄ 7 H ₂ O (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temperature for 1 hour, then slowly heated over 29

decrease, the reaction was heated at 60 ° C for 16 hours. The resulting opaque brown solution was diluted with H ₂ O (700 mL) then 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with saturated NaCl solution (3 x 150 mL), then combined, dried (MgSO ₄ ), and filtered through a silica gel pad using EtOAc. The brown oil obtained was purified by column chromatography (gradient from 50% EtOAc / 50% hexane to 80% EtOAc / 20% hexane).

The resulting yellow oil was crystallized at 0 ° C for 72 hours to give 4-χπορο-Ν-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC 50% EtOAc / 50% hexane) R _f 0.50; ¹ H - NMR (CDCI ₃ ) δ 3.04 (d, J = 5.1 Hz, 3H), 7.43 (dd, J = 5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J = 5.1 Hz, 1H); CI-MS m / z 171 ((M + H) ⁺ ).

Step 1b. Synthesis of 4-chloropyridine-2-carbonyl chloride HCl salt by picolinic acid

Anhydrous DMF (6.0 mL) was slowly added to SOCl ₂ (180 mL) between 40 ° C and 50 ° C. The solution was stirred at these temperature limits for 10 minutes, then picolinic acid (60.0 g, 487 mmol) was added in portions for 30 minutes. The resulting solution was heated at 72 ° C (vigorous SO ₂ removal) for 16 hours to generate a yellow solid precipitate. Dfluchen & t ^ p1es * _;; Cooling to room temperature, diluting with toluene (500 mL) and concentrating to 200 mL. The process of adding / concentrating toluene is repeated twice. The resulting almost dry residue was filtered off and the solid was washed with toluene (2 x 200 mL) and dried under high vacuum for 4 hours to give 4-chloropyridine-2-carbonyl chloride HCl salt as a yellow-orange solid (92.0 g, 89%).

πυι

Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HCl salt

Anhydrous DMF (10.0 mL) was slowly added to SOCl ₂ (300 mL) at 40-48 ° C. The solution was stirred at these temperature limits for 10 minutes, then picolinic acid (100 g, 812 mmol) was added over 30 minutes. The resulting solution was heated at 72 ° C (rapid SO ₂ separation) for 16 hours to generate a yellow solid. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. The process of toluene addition / concentration is repeated twice. The resulting almost dry residue was filtered off and the solid was washed with toluene (50 mL) and dried under high vacuum for 4 hours to give 4-chloropyridine31

2-carbonyl chloride HCl salt, in the form of methyl-pyrrolidate; Product (27.2d, 16%). This product is saved. '··' * ·· '

The red filtrate was added to MeOH (200 mL) at a rate that kept the internal temperature below 55 ° C. The contents were stirred at room temperature for 45 minutes, cooled to 5 ° C and treated with Et ₂ O (200 mL) dropwise. The resulting solids were filtered, washed with Et ₂ O (200 mL) and dried under reduced pressure at 35 ° C to give the methyl 4-chloropyridine-2carboxylate HCl salt as a white solid (110 g, 65%): mp 108 - 112 ° C; ¹ H - NMR (DMSO - d ₆ ) δ 3.88 (s, 3H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 8.08 (d, J = 2. 2 Hz, 1H), 8.68 (d, J = 5.5 Hz, 1H), 10.68 (br s, 1H); HPLC ES - MS m / z 172 ((M + H) ⁺ ).

Stage 3. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxyl [With methyl 4-chloropyridine-2-carboxylate amide

A suspension of 4-chloropyridine-2-carboxylate HCl salt (89 g, 428 mmol) in MeOH (75 mL) at 0 ° C was treated with a 2.0 M solution of methylamine in THF (1L) at a rate that maintained the internal temperature below 5 ° C. The resulting mixture was stored at 3 ° C for 5 hours, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1L) and filtered. The filtrate was washed with saturated NaCl solution (500 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 4-chloro-N-methyl 32 · · · · ···. ,.

2-Pyridinecarboxyl Methyl 4-chloropyridic acid; 2.carboxylic acid; ·· ·, in the form of pale yellow crystals (71.2 g, 97%): m.p. *

-43 ° C; NM NMR (DMSO - d ₆ ) δ 2.81 (s, 3H), 7.74 (dd, J = 5.1, ···

2.2 Hz, 1H), 8.00 (d, J = 2.2 Hz, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.85 (br d, 1H); Cl - MS m / z 171 ((M + H) +).

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

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

NHMe • · · ·.

Step 4. Synthesis of 4- (2- (N-methylcarbamyl) ^r 4 ^, yrrrhjl · · · · · oxy) aniline · ♦ ·· ··· ·

To a solution of 4-aminophenol (9.60 g, 88.0 mmol) in anhydrous

DMF (150 mL) was treated with potassium tert-butoxide (10.29 g,

91.7 mmol) and the reddish-brown mixture was stirred at room temperature for 2 hours. The content is

was treated with 4-chloro-N-methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and K ₂ CO ₃ (6.50 g, 47.0 mmol) and then heated at 80 ° C. for 8 hours. The mixture was cooled to room temperature and partitioned between EtOAc (500 mL) and saturated NaCl solution (500 mL). The aqueous phase was re-extracted with EtOAc (3 00 mL). The combined organic layers were washed with saturated NaCl solution (4 x 1000 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 ° C for 3 hours, yielding 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline as a light brown solid (17.9 g, 84%): ¹ H-NMR (DMSO-d ₆ ) δ 2.77 (d, J = 4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA "BB" quartet, J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H) , 8.44 (d, J = 5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES - MS m / z 244 ((M + H) ⁺ ).

AZ. A basic method for synthesizing anilines by nucleophilic aromatic coupling followed by nitroarene reduction.

Synthesis of 5- (4-aminophenoxy) isoindoline-1,3-dione

Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione

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

Stage 2. Synthesis of 5- (4-nitrophenoxy) isoindoline-1,3 dione

To a suspension of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at

O ° C was added dropwise to a solution of 5-hydroxyisoindoline-1,335 dione (3.2 g, 19.6 mmol) in DMF (40 mL). Light yellow / | T®-Zflen'ga. ·. .. ....... · _ββ : ···.:;: ..

the mixture was allowed to reach room temperature. "and" was stirred for 1 hour, then added with a syringe, in 3 - 4 portions of 1-fluoro-4-nitrobenzene ( 2,67 d,

18.7 mmol). The resulting mixture was heated at 70 ° C overnight, then cooled to room temperature and diluted slowly with water (150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (MgSO ₄ ), and concentrated under reduced pressure to give 5- (4-nitrophenoxy) isoindoline-1,3-dione as a yellow solid (3.3 g, 62 5 ): TLC (30% EtOAc / 70% hexane) R _f 0.28; ¹ H NMR (DMSO-d ₆ ) δ 7.32 (d, J = 12 Hz, 2H), 7.52 - 7.57 (m, 2H), 7.89 (d, J = 7.8 Hz) , 1H), 8.29 (d, J = 9 Hz, 2H), 11.43 (br s, 1H);

Cl-MS m / z 285 ((M + H) ⁺ ), 100%.

Stage 3.

Synthesis of 5- (4-aminophenoxy) isoindoline-1,3dione

A solution of 5- (4-nitrophenoxy) isoindoline-1,3-dione (0.6 g,

2.11 mmol) in concentrated AcOH (12 mL) and water (0.1 mL) was stirred in argon stream, while slowly adding iron powder (0.59 g, 55.9 mmol). This mixture was stirred at room temperature for 72 hours, then diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL).

The combined organic layers were dried (MgSO ₄ ) and concentrated

• triturated under reduced pressure to give * 5- (4- <

Aminophenoxy) isoindoline-1,3-dione, as a brownish solid (04 g, 75%): TLC (50% EtOAc / 50% hexane) R _f 0.27; ¹ H - NMR (DMSO - de) δ 5.14 (br s, 2H), 6.62, (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J = 8.4 Hz, 1H), 11.02 (s. 1H); HPLC ES - MS m / z 255 ((M + Hf, 100%).

A 4. Basic method for the synthesis of pyrrolylanilines. Synthesis of 5-tert-butyl-2- (2,5-dimethylpyrrolyl) -aniline

Stage 1. Synthesis of 1- (4-tert-butyl-2-nitrophenyl) -2,5 dimethylpyrrole

To a stirred solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added AcOH (0.1 mL) and acetonylacetone (0.299 g, 2.63 mmol). by means of a syringe. The reaction mixture was heated at 120 ° C for 72 hours with azeotropic removal of the volatile products. The resulting mixture was cooled to room temperature, diluted with H2Cl2 (10 mL) and then immediately washed with 1 N HCl solution (15 mL), 1 N NaOH solution (15 mL), and sat. NaCl (15 mL), dried (MgSO ₄ ), and concentrated under reduced pressure. The resulting orange-brown solid was purified by column chromatography (60 g SiO ₂ ; gradient from 6% EtOAc $ 4% cache & H to · *. ·· ·· * .. ·% EtOAc / 75% hexane), whereby 1- (4-tert-butyl- ·· *%) is obtained.

2-nitrophenyl) -2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc / 85% hexane) R _f 0.67; ¹ H-NMR (CDCl ₃ ) d 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H),

7.19 - 7.24 (m, 1 Η), 7.62 (dd, 1 Η), 7.88 (d, J = 2.4 Hz, 1H); Cl-MS m / z 273 ((M + H) + 50%).

Step 2. Synthesis of 5-tert-butyl-2- (2,5-dimethylpyrrolyl) aniline

A suspension of 1- (4-tert-butyl-2-nitrophenyl) -2,5-dimethylpyrrole (0,341 g, 1.25 mmol), 10% Pd / C (0.056 g) in EtOAc (50 mL) under an atmosphere of H ₂ (balloon) was stirred for 72 hours, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to yield

5-tert-butyl-2- (2,5-dimethylpyrrolyl) -aniline as a yellowish solid (0.30 g, 99%). TLC (10% EtOAc / 90% hexane) R _f 0.43; ¹ H NMR (CDCI ₃ ) δ 1.28 (s, 9H), 1.87 - 1.91 (t, 8H), 5.85 (br s, 2H), 6.73 - 6.96 (t , 3H), 7.28 (br s, 2H).

A 5. A basic method for synthesizing Zdilium bm / ankylkH by nucleophilic aromatic substitution. ”·· ** ··· '

Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2methylaniline HCl salt

© To a solution of 4-amino-3-methylphenol (5.45 g,

44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the black mixture was stirred at room temperature until the flask reached room temperature. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, step 3b; 7.52 g, 44.2 mmol) and heated at 110 ° C for 8 hours. The mixture was cooled to room temperature and diluted with water (75 mL). The organic layer u was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with saturated NaCl solution (200 mL), dried (MgSO ₄ ), and concentrated under reduced pressure.

The residual black oil was treated with Et ₂ O (50 mL) and sonicated. The solution was then treated with HCl (1 M in Et ₂ O; 100 mL) and stirred at room temperature for 5 minutes. The residual dark pink solid (7.04 g, 24.1 mmol) was separated by filtration from the solution and stored under anaerobic conditions at 0 ° C before use: ¹ H-NMR (DMSO-d ₆ ) δ

J = 8.5, 2.6 Hz, 1H), 7.23 (dd, J = 5.5, 2.6 Hz, 1H), 7.26 (elf * J = 2.6 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 5.9 Hz, 1H), 8. 99 (q, J = 4.8 Hz, 1H).

A6. A basic method for synthesizing anilines from hydroxyanilines by N-protection, nucleophilic aromatic substitution and deprotection.

Synthesis of 4- (2- (1M-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline

CI

Step 1: Synthesis of 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol

Iron (3.24 g, 58.00 mmol) was added to stirred TFA (200 mL). To this suspension was added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol), and trifluoroacetic anhydride (20 mL). This gray suspension was stirred at room temperature for 6 days. The iron was filtered off from the solution and the remaining product was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To the resulting yellow solution was added a saturated solution of NaHCO ₃ (50 mL). The solid product which precipitates in the solution is removed. The filtrate was slowly quenched with sodium bicarbonate until the product was visibly separated from the solution (a small laboratory vessel was used). The slightly cloudy yellow solution was extracted with

EtOAc (3 x 125 mL). The combined organic salts were taken up with saturated NaCl solution (125 mL), dried (MgSO ₄ ), and concentrated under reduced pressure. ¹ H-NMR (DMSO-d ₆ ) shows a ratio of 1: 1 of the starting product nitrophenol and the expected product 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol. The crude product is taken to the next step without further purification.

Step 2: Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl (222-trifluoro) acetamide

A solution of crude 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 mL) was treated with potassium tert-butoxide (5.16 g , 45.98 mmol), and the brownish black mixture was stirred at room temperature until the flask was cooled to room temperature. The resulting mixture was treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, step 3b; 1.99 g, 11.7 mmol) and heated at 100 ° C under argon for 4 hours. o'clock. The black reaction mixture was cooled to room temperature and then poured into cold water (100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by column chromatography (gradient from 20% EtOAc / petroleum ether to 40% EtOAc / petroleum ether) at. ·; ··: ····.

to give 4- (2- (N-metilkarbam®yl) '- 441ir14 _{(£ uil.bks-in} -2 ** * * ·. · * chlorophenyl (222-trifluoro) acetamide as a'> Kblt solid product (8.59 g, 23.0 mmol).

Step 3: Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline

A solution of crude 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a 1 N solution of NaOH (20 mL). This brown solution was stirred for 8 hours. EtOAc (40 mL) was added to this solution. The green organic layer was extracted with EtOAc (3 x 40 mL) and the solvent concentrated to give 4- (2- (methylmethylcarbamoyl) -4-pyridyloxy) -2-chloroaniline as a green oil which solidified at mp ((2.86 g, 10.30 mmol): ¹ H-NMR (DMSO-d ₆ ) δ 2.77 (d, J = 4.8 Hz, 3H), 5.51 (s, 2H ), 6.60 (dd, J = 8.5, 2.6 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 7.03 (d, J = 8.5 Hz) , 1H), 7.07 (dd, J = 5.5, 2.6 Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 8.46 (d, J = 5, 5 Hz, 1H), 8.75 (q, J = 4.8 Hz, 1H).

• · · · ·

A7. The main method for removing '' wet ac / t ^ ran ·· · ·; · ·· .. · aniline.

Synthesis of 4-chloro-2-methoxy-5- (trifluoromethyl) aniline

CF ₃

NH ₂

OMe

A suspension of 3-chloro-6- (N-acetyl) -4- (trifluoromethyl) anisole (4.00 g, 14.95 mmol) in 6M HCl solution (24 mL) was heated at reflux in for 1 hour. The resulting solution was allowed to cool to room temperature, during which time it slightly solidified. The resulting mixture was diluted with water (20 mL), then treated with a combination of solid NaOH and saturated NaHCO ₃ solution until the solution became basic. The organic layer was extracted with CH ₂ Cl ₂ (3 x 50 mL). The combined organic products were dried (MgSO ₄ ), and concentrated under reduced pressure to give 4-chloro-2-methoxy-5- (trifluoromethyl) aniline as a brown oil (3.20 g, 14, 95 mmol): Ή-NMR (DMSO-d _e ) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

A8. A basic method for synthesizing ω-alkoxyω-carboxyphenyl anilines.

Synthesis of 4- (3- (N-methylcarbamoyl) -4-methoxy, phenyloxy) ethanol

Step 1. 4- (3-Methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene:

To a solution of 4- (3-carboxy-4-hydroxyphenoxy) -1-nitrobenzene (obtained from 2,5-dihydroxybenzoic acid in a manner analogous to that described in method A13, step 1, 12 mmol) in acetone (50 mL ) was added K ₂ CO ₃ (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated at reflux overnight, then cooled to room temperature, and filtered through a pad of Celite®. The resulting solution was concentrated under reduced pressure, absorbed in SiO ₂ , and purified by column chromatography (50% EtOAc / 50% hexane) to give 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene. as yellow powder (3 g): mp 115-118 ° C.

Step 2. 4- (3-Carboxy-4-methoxyphenoxy) -1-nitrobenzene:

A mixture of 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene (1.2 g), KOH (0.33 g), and water (5 mL) in MeOH (45 mL) was stirred at room temperature in overnight, and then heated at reflux for 4 hours. Semi-raccoon? the emitter goes to room temperature and concentrates under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous mixture was acidified with 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO ₄ ), and concentrated under reduced pressure to give 4- (3carboxy-4-methoxyphenoxy) -1-nitrobenzene (1.04 g).

Step 3. 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene:

To a solution of 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (0.50 g, 1.75 mmol) in CH ₂ Cl ₂ (12 mL) was added SOCl ₂ (0.64 mL, 8, 77 mmol) in portions. The resulting solution was heated at reflux for 18 hours, cooled to room temperature, and concentrated under reduced pressure. The yellow solids obtained were dissolved in CH ₂ Cl ₂ (3 mL), then the resulting solution was treated with a solution of methylamine (2.0 M in THF, 3.5 mL, 7.02 mmol) in portions (CAUTION: gas), and stirred overnight at room temperature for 4 hours. The resulting mixture was treated with a 1N NaOH solution, then extracted with CH ₂ Cl ₂ (25 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give 4- (3- (Ν-Μβτππ45 ···. ·:

yellow solid (0.50 g 95%).

carbamoyl) -4-methoxyphenoxy) -1-nitrobenzene, in the form of '*:: · * ·.

•; ·: ·

·. · · · ·:

·· · ·

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

Suspension of 4- (3- (1-methylcarbamoyl) -4-methoxyphenoxy) -

1-Nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd / C (0.20 g) in EtOH (55 mL) were stirred in 1 atm. H ₂ (balloon) for 2.5 days was then filtered through a pad of Celite®. The resulting solution was concentrated under reduced pressure to give 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline as an off-white solid (0.68 g, 96%): TLC (0 , 1% Et ₃ N / 99.9% EtOAc) R _f 0.36.

A9. A basic method for the preparation of ω-alkylphthalimide-containing anilines.

Synthesis of 5- (4-aminophenoxy) -2-methylisoindoline-

1, 3d ion

Stage 1. Synthesis of 5- (4-nitrophenoxy) -2-methylisoindoline-1,3-dione:

A suspension of 5- (4-nitrophenoxy) isoindoline-1,3-dione (AZ step 2; (1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL ). · ··.

· '. * ··: ·. ·· ••• V :; . · · · · · ·, * Was stirred at room temperature for ’H ′ Wc, then treated with methyl iodide (0.3 mL, 4.57 mmol).

The resulting mixture was stirred at room temperature overnight, then cooled to ° C and treated with water (15 mL). The resulting solids were collected and dried under reduced pressure to give 5- (4-nitrophenoxy) -2-methylisoindoline-1,3-dione as a bright yellow solid (0.87 g, 83% ): TLC (35% EtOAc / 65% hexane) R _f 0.61.

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

A suspension of nitrophenoxy) -2-methylisoindoline-1,3-dione (0.87 g, 2.78 mmol) and 10% Pd / C (0.10 g) in MeOH was stirred in 1 atm. H ₂ (balloon) overnight. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) and filtered through SiO ₂ (60% EtOAc / 40% hexane) to give 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione. as a yellow solid (0.67 g, 86%): TLC (40% EtOAc / 60% hexane) R _f 0.27.

• * ft * · f ^w ft

A10. A basic method for preparing grfHrjvjAVi * ·· * ·, »'· * · is by reacting ω-alkoxycarbocyl precursors with amines.

Synthesis of 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxyaniline

Step 1. Synthesis of 4-chloro-2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridine

To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, step 2; (1.01 g, 4.86 mmol) in THF (20 mL) was added dropwise 4- (2-aminoethyl) morpholine ( 2.55 mL, 19.4 mmol), and the resulting solution was heated at reflux for 20 hours, cooled to room temperature, and treated with water (50 mL). EtOAc (50 mL). The organic layer was dried © (MgSO ₄₎ and concentrated under reduced pressure to give 4-chloro-2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridine, as yellow oil (1.25 g, 95%): TLC (10% MeOH / 90% EtOAc) R _f 0.5 0.

• · · · ·

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

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75 mmol) in DMF (8 mL) was stirred at room temperature for 2 hours, then successively was treated with 4-chloro-2- (N- (2-porpholin-4-ylethyl) carbamoyl) pyridine (1.22 g, 4.52 mmol) and K ₂ CO ₃ (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 ° C overnight, cooled to room temperature, and partitioned between EtOAc (25 mL) and saturated NaCl solution (25 mL). The aqueous layer was re-extracted with EtOAc (25 mL). The combined organic layers were washed with saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure. The brown solids obtained were purified by column chromatography (58 g; gradient from 100% EtOAc to 25% MeOH / 75% EtOAc) to give 4- (2- (N- (2-morpholine-

4-ylethyl) carbamoyl) pyridyloxy) aniline (1.0 g, 65%): TLC (10% MeOH / 90% EtOAc) R _f 0.32;

A11. A basic method for reducing nitroarynes to arylamines.

Synthesis of 4- (3-carboxyphenoxy) aniline

A.

HE ·· ··

Suspension of 4- (3-carboxyphenoxy) -1-nitrobenzene (5.38 g,

20.7 mmol) and 10% Pd / C (0.05 g) in MeOH (120 mL) was stirred under an atmosphere of H ₂ (balloon) for 2 days. The resulting mixture was filtered through a pad of Celite®, then concentrated under reduced pressure to give

4- (3-carboxyphenoxy) aniline, as a brown solid (2.26 g, 48%): TLC (10% MeOH / 90% CH ₂ Cl ₂ ) R _f 0.44 (in strips).

A12. A basic method for synthesizing isoindolinone anilines.

Synthesis of 4- (1-oxoisoindolin-5-yloxy) aniline

Step 1. Synthesis of 5-hydroxyisoindolin-1-one

To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly added portionwise zinc powder (47.6 g, 729 mmol), then the mixture was heated at reflux temperature. refrigerate for 40 minutes, filter hot, and concentrate under reduced pressure. The reaction was repeated in the same scheme, and the combined oily residue was purified by column chromatography (1.1 Kg SiO ₂ ; gradient from 60% EtOAc / 40% hexane to 25% MeOH / 75% EtOAc) to give 5-hydroxyisoindoline -1-he • · • · · • · · · • · • · ···· ·· ·· ..

• ·. · • · ·.

...... .. ·· (3.77 g): TLC (100% EtOAc) R _f 0.17; HPLC £ 3

MS * m / z

250 ((M + H) &lt; ⁺ & gt ^; ).

Step 2. Synthesis of 4- (1-isoindolinone-5-yloxy) -1 nitrobenzene

To a suspension of NaH (0.39 g, 16.1 mmol) in DMF at 0 ° C was added 5-hydroxyisoindolin-1-one (2 g, 13.4 mmol) in portions.

The resulting suspension was allowed to warm to room temperature and stirred for 45 minutes, then 4-fluoro-1-nitrobenzene was added, and then the mixture was heated to 70 ° C for 3 hours. The mixture was cooled to 0 ° C and treated dropwise with water until a precipitate formed.

The solids obtained were collected to give 4- (1-isoindolinone-5-yloxy) -1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100 EtOAc): R _f 0.35.

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

A suspension of 4- (1-isoindolinone-5-yloxy) -1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd / C (0.20 g) in EtOH (50 mL) was stirred in atmosphere of H ₂ (balloon) for 4 hours,

concentrated under reduced pressure yielding 4- (1-oxoisoindolin-5-yloxy) aniline as a dark yellow solid: T1_S (100% EtOAc) R _f 0,15.

A13. Basic Method for Synthesis of ω-Carbamoyl Anilines by Formation of EDCI-Mediated Amide, followed by Nitroarene Reduction

Synthesis of 4- (3-N-methylcarbamoylphenoxy) aniline

OEt

Step 1. Synthesis of 4- (3-ethoxycarbonylethoxy) -1 -1 nitrobenzene

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

Stage 2. Synthesis of 4- (3-carboxyphenoxy) -1-nitrobenzene

To a vigorously stirred mixture of 4- (3-ethoxycarbonylethoxy) -1-1-nitrobenzene (5.14 g, 17.9 mmol) in 3: 1 THF / aqueous solution (75 mL) was added a solution of LiOH * H ₂ O (150 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated to 50 ° C overnight, then cooled to room temperature, concentrated under reduced pressure and adjusted to pH 2 with 1M HCl solution. The brownish-yellow solid obtained was separated by filtration and washed with hexane to give 4- (3-carboxyphenoxy) -1-nitrobenzene (4.40 g, 95%).

Stage 3. Synthesis of 4- (3- (M-methylcarbamoyl) phenoxy) -1nitrobenzene

A mixture of 4- (3-carboxyphenoxy) -1-nitrobenzene (3.72 g,

14.4 mmol), EDCFHCI (3.63 g, 18.6 mmol), N-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in

CH ₂ Cl ₂ , (45 mL) was stirred at room temperature for 3 days, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL). and the resulting mixture was extracted with 1M HCl solution (50 mL). The aqueous layer was re-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with saturated NaCl solution (50 mL), dried (Na ₂ SO 4), and concentrated under reduced pressure to give 4- (3- (N-methylcarbamoyl) phenoxy) -1-nitrobenzene. in the form of oil (1.89 g).

NHMe

Step 4. Synthesis of 4- (3- (1-methylcarbamoyl) phenoxy) aniline

A suspension of 4- (3- (N-methylcarbamoyl) phenoxy) -1-nitrobenzene (1.89 g, 6.95 mmol) and 5% Pd / C (0.24 g) in EtOAc (20 mL) was stirred in atmosphere of H ₂ (balloon) overnight. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH / 95% CH ₂ Cl ₂ ).

The resulting oil was solidified in vacuo overnight to give 4- (3-methylcarbamoyl) phenoxy) aniline as a yellow solid (0.5 g, 56%).

A14. Basic Method for Synthesis of ω-Carbamoyl Anilines by Formation of EDCI-Mediated Amide, followed by Reduction of Nitroaryl · · · · · · · ·

Synthesis of 4-3- (5-methylcarbamoyl) pyridyloxy) aniline

Step 1. Synthesis of 4-3- (5-methylcarbamoyl) pyridyloxy) -

1-nitrobenzene

OK To a suspension of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF. The resulting suspension was added to a solution of 4-fluoro-1-nitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture heated to 70 ° C overnight, cooled to room temperature temperature and treated with MeOH (5 mL), then with water (5 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-methylCarbamoyl) pyridyloxy) -1-nitrobenzene (0.60 g).

Fr.

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

A suspension of 4-3- (5-methyl-carbamoyl) pyridyloxy) -1-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd / C in MeOH / EtOAc were used. · ::: · .. ··. · · · *: · ···.: R ··· ...... · .. · _{ο #} ·::; · Stirred in an atmosphere of H ₂ (balloon) for * 72 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% EtOAc / 90% hexane to 30% EtOAc / 70% hexane, to 50% EtOAc / 50% hexane) to give 4-3- (5-methylcarbamoyl) pyridyloxy) -aniline (0.28 g, 60%): ¹ H-NMR (CDCl ₃ ) δ 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7, 73 (, 1 Η), 8.51 (d, 1 Η), 8.87 (d, 1H).

A15. Synthesis of aniline by electrophilic nitration followed by reduction.

Synthesis of 4- (3-N-methylcarbamoylphenoxy) aniline

Step 1. Synthesis of N-methyl-3-bromobenzenesulfonamide

To a solution of 3-bromobenzenesulfonyl chloride (2.5 g,

11.2 mmol) in THF (15 mL) at 0 ° C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was allowed to warm to room temperature overnight. The resulting mixture was partitioned between EtOAc (25 mL) and 1 M HCl solution (25 mL). The aqueous phase was re-extracted with EtOAc (2 x 25 mL). The combined organic phases were washed sequentially with water (2 x 25 mL), saturated NaCl solution (25 mL), dried (MgBOD), and concentrated under reduced pressure to give N-methyl-3-bromobenzenesulfonam ^ (2.9 & 99%) ·

Step 2. Synthesis of 4- (3- (N-methylsulfamoyl) phenyloxy) benzene

To a suspension of phenol (1.9 g, 20 mmol), K ₂ CO ₃ (6.0 g, 40 mmol) and Cui (4 g, 20 mmol) in THF (25 mL) was added N-methyl-

3-bromobenzenesulfonamide (2.5 g, 10 mmol), and the resulting mixture was stirred at reflux overnight, cooled to room temperature, and partitioned between EtOAc (50 mL). and 1 N HCI solution (50 mL). The aqueous layer was re-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed sequentially with water (2 x 50 mL), saturated NaCl solution (50 mL), dried (MgSO ₄ ), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc / 70% hexane) to give 4- (3- (N-methylsulfamoyl) phenoxy) benzene (0.30 g).

Step 3. Synthesis of 4- (3- (N-methylsulfamoyl) phenoxy) -1nitrobenzene

To a solution of 34- (3- (N-methylsulfamoyl) phenoxy) benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10 ° C was added NaNO ₂

...... * · ·. . · (0.097 g, 1.14 mmol) in portions over 'Aa 5 *' minutes. The resulting solution was stirred at -10 ° C for 1 hour, then allowed to warm to room temperature, and concentrated under reduced pressure. The residue was partitioned between EtOAc (10 mL) and water (10 mL). The organic phase was washed successively with water (10 mL), saturated NaCl solution (10 mL), dried (MgSO ₄ ), and concentrated under reduced pressure to give 4- (3- (M-methylsulfamoyl) ) phenoxy) -1-nitrobenzene (0.20 g). This product is stored for the next step without further purification.

Step 4. Synthesis of 4- (3- (N-methylsulfamoyl) phenoxy) aniline

A suspension of 4- (3- (N-methylsulfamoyl) phenoxy) -1-nitrobenzene (0.30 g) and 10% Pd / C (0.030 mL) in EtOAc (20 mL) was stirred under an atmosphere of H ₂ (balloon). ) overnight.

The resulting mixture was filtered through a pad of Celit®. 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 ω-ketones.

Synthesis of 4- (4- (1- (M-methoxy) iminoethyl) phenoxyaniline HCl salt.

To a suspension of 4- (4-acetylphenoxy) aniline HCl salt (prepared in a manner analogous to method A13, step 4; 1.0 g, N 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0 mL) was added

O-methylhydroxylamine HCl (0.65 g, 7.78 mmol, 2.0 equiv). The resulting solution was heated at reflux for 30 minutes, cooled to room temperature, and concentrated under reduced pressure. The resulting solids were triturated with water (10 mL) and washed with water to give 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt, as a yellow solid (0.85 g): TLC (50% EtOAc / 50% pet ether) R f 0.78; ¹ H-NMR (DMSO-d ₆ ) δ 3.90 (s, 3H), 5.70 (s, 3H); HPLC - MS m / z © 257 ((M + H) ⁺ ).

A17. Synthesis of N- (1S) -silyloxyalkyl) amides.

Synthesis of 4- (4- (2-N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline

P

• ···

Stage 1.

4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2 carboxamide

To a solution of 4-chloro-N- (2-hydroxyethyl) pyridine-2carboxamide (prepared in a manner analogous to method A2, step 3b; (1.5 g, 7.4 mmol) in anhydrous DMF (7 mL) was added triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 eq) and imidazole (1.12 g, 16.4 mmol, 2.2 eq) The yellow solution obtained was stirred for 3 hours at The residue was partitioned between water (10 mL) and EtOAc (10 mL), the aqueous layer was extracted with EtOAc (3x10 mL), and the combined organic phases were dried (MgSO ₄ ), and dried. concentrate under reduced pressure to give 4-chloro-1 N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide, in the form of an orange oil (2.32 g, 88%), This product was used in the next step without further purification.

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

To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in DMF (8 mL) was added potassium t-butoxide (0.67 g, 6.0 mmol, 1.0 eq) in one portion, to cause an exothermic reaction. When this mixture was cooled to room temperature, a solution of 4-chloro-2- (N- (2-triisopropylsilyloxy) ethyl) -pyridinecarboxamide (2.32 g, 6 mmol, 1 eq) in DMF (4 mL) was added. ,

and then K ₂ CO ₃ (0.42 g, 3.0 mmol, 0.50 eq). The resulting mixture was heated at 80 ° C overnight. An additional portion of potassium tert-butoxide (0.34 g, 3 mmol, 0.5 eq) was then added, and the mixture was stirred at 80 ° C for a further 4 hours. The mixture was cooled to 0 ° C in an ice / water bath, then water (approximately 1 ml) was added dropwise slowly. The organic layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with saturated NaCl solution (20 mL), dried (MgSCU), and concentrated under reduced pressure. The brown residual oil was purified by column chromatography (SiO ₂ ; 30% EtOAc / 70% pet ether) to give 4- (4- (2- (N- (2-τρππ3θπροπππsilyloxy) -ethylcarbamoyl) pyridyloxyaniline) as of clear light brown oil (0.99 g, 38%).

A18. Synthesis of 2-pyridinecarboxylate esters by oxidation of 2-methylpyridines.

Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline

Step 1. 4- (5- (2-Methyl) pyridyloxy) -1-nitrobenzene.

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

1-fluoro-4-nitrobenzene (9.8 g, 91.6 mmol), K ₂ CO ₃ (25 g, 183 mmol, 2.0 equiv) in DMF (100 mL) was heated at reflux temperature. refrigerate overnight. The resulting mixture was cooled to room temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed sequentially with water (2 x 100 mL) and saturated NaCl solution (100 mL), dried (MgSO4), and 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) pyridoxy) -

1-nitrobenzene.

A mixture of 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3 equiv) in pyridine , (20 mL) was heated at reflux for 5 hours, then cooled to room temperature. The resulting slurry was filtered, then concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The solution was treated with concentrated HCl solution (7 mL), then heated at reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (50 mL) and 1 N NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed sequentially with water (2 x 50 mL) and saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography (SiO ₂ ; 50% EtOAc / 50% hexane) to give 4- (5- (2-methoxycarbonyl) pyridoxy) -1-nitrobenzene. (0.70 d).

Step 3. Synthesis of 4- (5- (2-methoxycarbonyl) pyridoxy) aniline.

A suspension of 4- (5- (2-methoxycarbonyl) pyridoxy) -1-nitrobenzene (0.50 g) and 10% Pd / C (0.050 mL) in a mixture of EtOAc (20 mL) and MeOH (5 mL) was added in an atmosphere of H ₂ (balloon) overnight. The resulting mixture was filtered through a pad of Celit (R), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ; 70% EtOAc / 30% hexane) to give 4- (5- (2methoxycarbonyl) pyridoxy) aniline (0.40 g).

A19. Synthesis of ω-C.fonylphenyl anilines.

Synthesis of 4- (4-methylsulfonylphenoxy) aniline.

Step 1. 4- (4-Methylsulfonylphenoxy) -1-nitrobenzene:

To a solution of 4- (4-methylthiophenoxy) -1-nitrobenzene (2.0 g, 7.7 mmol) in CH ₂ Cl ₂ (75 mL) at 0 ° C was slowly added m-CPBA (57%, 40 g ), and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was treated with 1 N NaOH solution (25 mL). The organic layers were washed sequentially with 1 N NaOH solution (25 mL), water (25 mL), and saturated NaCl solution (25 mL), dried (MgSO ₄ ), and concentrated under reduced pressure, whereby 4- (4-methylsulfonylphenoxy) -1-nitrobenzene was obtained as a solid (2.1 g).

Step 2. 4- (4-Methylsulfonylphenoxy) aniline:

4- (4-Methylsulfonylphenoxy) -1-nitrobenzene is reduced to aniline in a manner analogous to that described in method A18, step 3.

C. Synthesis of urea precursors

B1. A basic method for synthesizing aniline isocyanates using CDI.

Synthesis of 4-bromo-3- (trifluoromethyl) phenyl isocyanate.

9 ^F 3

Br ·

NH ₂ -HCl

Stage 1. Synthesis of 4-bromo-3- (trifluoromethyl) aniline

HCI salt

A solution of HCl (1M in Et ₂ O; 300 mL) was added dropwise to a solution of 4-bromo-3- (trifluoromethyl) aniline (64 g, 267 mmol) in Et ₂ O (500 mL), and the resulting mixture was added dropwise. stir at room temperature for 16 hours. The resulting pink-white precipitate was separated by filtration. Yg was treated with Q? Et ₂ O ····: ··:. :

(50 mL) to give 4-bromo-3- (trifluoromethyl): aniline HCl salt (73 g, 98%).

Stage 2.

Synthesis of 4-bromo-3- (trifluoromethyl) phenyl

isocyanate

A suspension of 4-bromo-3- (trifluoromethyl) aniline HCl salt (36.8 g, 133 mmol) in toluene (278 mL) was added dropwise with trichloromethyl chloroformate, and the resulting mixture was heated at reflux. for 18 hours. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mL), then concentrated under reduced pressure. The residue was treated with CH ₂ Cl ₂ (500 mL), then concentrated under reduced pressure. The procedure for treatment with CH ₂ Cl ₂ / concentration under reduced pressure was repeated, and the resulting amber oil was kept at -20 ° C for 16 hours to give 4-bromo-3- (trifluoromethyl) phenyl isocyanate, under reddish-brown solid (35.1 g, 86%): GC-MS m / z 265 (M ⁺ ).

C. Methods for urea formation

C1a. A basic method for synthesizing urea by reaction of isocyanate with aniline.

·· .. ·. ·; ··: ·· ·.

Synthesis of N- (4-chloro-3- (trifluoromethyl) ferrites * N ^ (M-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

A solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (14.60 g, 65.90 mmol) in CH ₂ Cl ₂ (35 mL) was added dropwise to a suspension of (4- (2- (N-methylcarbamoyl) ) -4-Pyridyloxy) aniline (Method A2, step 4; 16.0 g, 65.77 mmol) in CH ₂ Cl ₂ (35 mL) at 0 ° C, the resulting mixture was stirred at room temperature for 22 hours. The yellow solids were separated by filtration, then washed with CH ₂ Cl ₂ (2 x 30 mL) and dried under reduced pressure (approximately 1 mm Hg) to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2 (1H-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, in the format and of an off-white solid (28.5 g, 93%): mp 207 - 209 ° C; ¹ H-NMR (DMSO-d ₆ ) δ 2.77 (d, J = 4.8 Hz) , 3H), 7.16 (m, 3H), 7.37 (d, J = 2.5 Hz, 1H), 7.62 (m, 4H), 8.11 (d, J = 2.5 Hz). , 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES MS m / z 465 ((M + H) &lt; ⁺ & gt ^; ).

C1b. A basic method for synthesizing urea by reaction of isocyanate with aniline.

Synthesis of M- (4-bromo-3- (trifluoro-pyrrolidin) .phenyl-1g) -L1 · -; · ·· * ·. ** · * · ** <(4- (2- (M -methylcarbamoyl) -4-pyridyloxy) phenyl) urea '' · *

A solution of 4-bromo-3- (trifluoromethyl) phenyl isocyanate (method B1, step 2; 8.0 g, 30.1 mmol) in CH ₂ Cl ₂ (80 mL) was added dropwise to a solution of (4- ( 2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (Method A2, step 4; 7.0 g, 28.8 mmol) in CH ₂ Cl ₂ (40 mL) at 0 ° C was stirred at room temperature. The yellow solids obtained were removed by filtration, then washed with CH ₂ Cl ₂ (2 x 50 mL) and dried under reduced pressure (approximately 1 mm Hg) at 40 ° C. yields N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) yl) urea as a pale-yellow solid (13.2 g, 90%): m. p. 203-205 ° C; ¹ H - NMR (DMSO - d ₆₎ δ 2,77 (d, J = 4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J = 2.5 Hz, 1H), 7.58 (m, 3H), 7.77 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.77 (br d, 1H) , 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m / z 509 ((M + H) ⁺ ).

C1c.

A basic method for synthesizing urea by reaction of isocyanate with aniline.

• · · · ·

Synthesis of N- (4-chloro-3- (trifluoromethyl-4H-eneg-1H) - (4 -: ;;

Methyl-4- (2- (M-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea '

A solution of 2-methyl-4- (2- (N-methylcarbamoyl) (4-pyridyloxy) aniline isocyanate (method A5; 0.11 g, 0.45 mmol) in CH ₂ Cl ₂ (1 mL) was treated with Et ₃ N (0.16 mL) and 4-chloro-3- (trifluoromethyl) phenyl) isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temperature for 6 hours, then treated with water (5 mL). The aqueous layer was re-extracted with EtOAc (3x5 mL). The combined organic layers were dried (MgSO ₄ ), and concentrated under reduced pressure to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (2-methyl-4- (2- (M -methylcarbamoyl) (4-pyridyloxy) phenyl) urea as a brown oil (0.11 g, 0.22 mmol): ¹ H-NMR (DMSO-de) δ 2.27 (s, 3H), 2 , 77 (d, J = 4.8 Hz, 3H), 7.03 (dd, J = 8.5, 2.6 Hz, 1H), 7.11 (d, J = 2.9 Hz, 1H) , 7.15 (dd, J = 5.5, 2.6 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H), 7.62 (approx. D, J = 2.6 Hz, 2H), 7.84 (d, J = 8.8 Hz, 1H), 8.17 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.78 ( q, J = 5.2 Hz, 1H), 9.52 (s, 1H); HPLC ES-MS m / z 479 ((M + H) ⁺ ).

C1 d. A basic method for synthesizing urea by reaction of isocyanate with aniline.

Synthesis of N- (4-chloro-3- (trifluoromethanol) N '- (4 · _:: ; · · · · · · · <

aminophenyl) urea * ·· ”···

CF ₃

To a solution of 4-chloro-3- (trifluoromethyl) phenyl) isocyanate (2.27 g, 10.3 mmol), in p ₂ Cl ₂ (308 mL) was added p-phenylenediamine (3.32 g, 30, 7 mmol). The resulting mixture was stirred at room temperature for 1 hour, then treated with CH ₂ Cl ₂ (100 mL), and concentrated under reduced pressure. The pink solids obtained were dissolved in a mixture of EtOAc (3x5 mL). The aqueous layer was re-extracted with EtOAc (110 mL) and MeOH (15 mL), and the clear solution was washed with 0.05 N HCl solution. The organic layer was concentrated under reduced pressure to give impure N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4-aminophenyl) urea (3.3 g): TLC (100% EtOAc) R _f 0.72.

C1e. A basic method for synthesizing urea by reaction of isocyanate with aniline.

Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4ethoxycarbonylphenyl) urea

. ···· · ·. ··.

To a solution of ejr. 4-izotsianatobZnady- '(HM: ^{g,: ·· · · · * ·} · mmol), in CH2CI2 (30 mL) was added (4-chloro-Z- * (trifluoromethyl) aniline (3.21 g, 16 4 mmol) and the solution was stirred at room temperature overnight The resulting suspension was diluted with CH ₂ Cl ₂ (50 mL) and filtered to give N- (4-chloro-3- (Trifluoromethyl) phenyl) -N '- (4-ethoxycarbonylphenyl) urea as a white solid (5.93 g, 97%): TLC (40% EtOAc / 60% hexane) R _f

A basic method for synthesizing urea by reaction of isocyanate with aniline.

Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3carboxyl phenyl) urea

C1f.

To a solution of 4-chloro-3- (trifluoromethyl) phenyl) isocyanate (1.21 g, 5.46 mmol), in CH ₂ Cl ₂ (8 mL) was added 4- (3-carboxyphenoxy) aniline (method A 11 0.81 g, 5.76 mmol), and the resulting mixture was stirred at room temperature overnight, then treated with MeOH (8 mL), and further stirred for 2 hours. The resulting mixture was concentrated under reduced pressure. The brown solid obtained was triturated with 1: 1 EtOAc / hexane to give N- (4-chloro-3- (trifluoromethyl) -phenyl) -N'70 (4-carboxylphenyl) urea, product (1.21 g , 76%).

in the form of nails ^ Ya hard ···· · .. · ':

- ·· '· .. ·' ··:

C2a. A basic method for synthesizing urea by reaction of aniline with N, N-carbonyl diimidazole, followed by addition of a second aniline.

Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N- (4- (2 (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

QF ₃

OMe

N N

To a solution of 2-methoxy-5- (trifluoromethyl) aniline (0.15 g) in anhydrous CH ₂ Cl ₂ (15 mL) at 0 ° C was added CDI (0.13 g). The resulting solution was allowed to warm to room temperature for 1 hour, stirred at room temperature for 16 hours, then was treated with 4- (2 - (methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g).

The resulting yellow solution was stirred at room temperature for 72 hours, then treated with H ₂ O (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic products were washed with saturated NaCl solution (100 mL), dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was triturated (90% EtOAc / 10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure, and the axis-zRgnchn ^ ^T0: lFrzo «^ ·· '·· * \ · *'. * Purified by column chromatography (gradient S3% EtOAc / 67% hexane to 50% EtOAc / 50% hexane, to 100% EtOAc) to give N- (2-methoxy-5- (trifluoromethyl) phenyl) -N- (4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) phenyl) urea (0.098 g, 30%) as a light red solid: TLC (100% EtOAc) R _f 0.62; ¹ H NMR (DMSO-d ₆ ) δ 2.76 (d, J = 4.8 Hz, 3H), 3.96 (s, 3H), 7.1- 7.6 and 8.4-8, 6 (m, 1H), 8.75 (d, J = 4.8 Hz, 1H), 9.55 (s, 1H); FAB - MS m / z 461 ((M + H) &lt; ⁺ & gt ^; ).

c C2b. A basic method for synthesizing urea by reaction of aniline with N, N-carbonyl diimidazole, followed by addition of a second aniline.

Symmetrical ureas as by-products of the reaction procedure for N, N'-carbonyl diimidazole.

Synthesis of bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

To a stirred solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH ₂ Cl ₂ (15 mL) at 0 ° C was added CDI (0.13 g). The resulting solution was allowed to warm to room temperature for 1 hour, then stirred at room temperature for 16 hours. The resulting mixture was treated with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at.

room temperature for 72 teas4?

Acting on water (125 mL). The resulting aqueous * cm @ 2 of C * oe ^: ect of L @ 1 hira with EtOAc (2 x 150 mL). The combined organic phases were washed with saturated NaCl solution (100 mL), dried (MgSO ₄ ),

and concentrate under reduced pressure. The residue was triturated (90% EtOAc / 10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis (4- (2- (N-methyl-carbamoyl) -4-pyridyloxy) phenyl) urea (0.081 g, 44%): TLC (100 % EtOAc) R _f 0.50; ¹ H - NMR (DMSO - d ₆ ) δ 2.76 (d, J = 5.1 Hz, 6H), 3.96 (s, 3H), 7.1 - 7.6 (m, 12H), 8 , 48 (d, J = 5.4 Hz, 1H), 8.75 (d, J = 4.8 Hz, 2H), 8.86 (s, 2H), 9.55 (s, 1H); HPLC ES - MS m / z 513 ((M + H) ⁺ ).

C2c. A basic method for synthesizing urea by reaction of isocyanate with aniline.

Synthesis of N- (2-methoxy-5- (trifluoromethyl) -phenyl) N '- (4- (1,3-dioxoisoindolin-5-yloxy) phenyl urea

To a stirred solution of 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.47 mmol) in CH ₂ Cl ₂ (1.5 mL) was added simultaneously 5- (4 aminophenoxy) isoindoline-1,3 -dione (method A 3, step 3; 0.12 g, 0.47 mmol). The resulting mixture was stirred for 12 hours, then treated with CH 2 Cl 2 (10 ^mL ) 2 · and MeOH (5 mL). and stirring up further knowledge of.

···· .. .. · ·; ··· .; · o'clock. The resulting mixture was washed sequentially with 1'hi pd & - * · * .. · 'HCl product (15 mL) n with saturated NaCl solution (15 mL), dried (MgSO ₄ ), and concentrated under reduced pressure. to give N- (2-methoxy-5- (trifluoromethyl) phenyl) -N- (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea as a white solid (0, 2 d, 96%): TLC (70% EtOAc / 30% hexane) R _f 0.50; ¹ H - NMR (DMSO - d ₆ ) δ 3.95 (s, 3H), 7.31 - 7.10 (t, 6H), 7.57 (d, J = 9.3 Hz, 2H), 7 , 80 (d, J = 8.7 Hz, 1 Η), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES - MS m / z 472.0 ((M + H) ⁺ , 100%).

c

C2d. A basic method for the synthesis of urea by reaction of aniline with N, N'-carbonyl diimidazole, followed by the addition of a second aniline.

Synthesis of N- (5-tert-butyl) -2- (2,5-dimethylpyrrolyl) -enyl) N- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

To a stirred solution of CDI (0.21 g, 1.30 mmol) in CH ₂ Cl ₂ (2 mL) was added at the same time 5- (tert-butyl) -2- (2,5-dimethylpyrrolyl) aniline (method A 4 , step 2; 0.30 g, 1.24 mmol). The resulting mixture was stirred at room temperature for 4 hours, then 4- (2- (Ν-Μβτππ74 ··) was added at once.

. · * ··· '. · '::. . · ..

carbamoyl) -4-pyridyloxy) aniline (0.065 g7 * 0, W7 'riytiol):

The mixture was heated at 36 ° C overnight, then cooled to room temperature and diluted with EtOAc (5 mL). The resulting mixture was washed successively with water (15 mL) and 1 N HCl solution (15 mL), dried (MgSO ₄ ), and filtered through a pad of silica gel (50 mL) to give M- ( 5-tert-butyl) -2- (2,5-dimethylpyrrolyl) phenyl) -N '- (4 (2- (1H-methylcarbamoyl) -4- (pyridyloxy) phenyl) urea, as a yellowish solid (0.033 d, 24%): TLC (40% EtOAc F / 60% hexane) R _f 0.24; ¹ H-NMR (acetone-d ₆ ) δ 1.37 (s, 9H), 1.89 (S, 6H) ), 2.89 (d, J = 4.8 Hz, 3H), 5.83 (s, 2H), 6.87 - 7.20 (m, 6H), 7.117 (dd, 1H), 7.51 - 7.58 (m, 3H), 8.43 (d, J = 5.4 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.80 (br s, 1H) ); HPLC ES - MS m / z 515 ((M + H) ⁺ , 100%).

C3. Combined method for the synthesis of diphenyl ureas using triphosgene

One of the anilines to be attached was dissolved in dichloroethane (0.10 M). This solution was added to an 8 mL © vial (0.5 mL) containing dichloroethane (1 mL). To this was added a solution of bis (trichloromethyl) carbonate (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv), then diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1, 2 equiv.). The vial was closed and heated at 80 ° C for 5 hours, then allowed to cool to room temperature for approximately 10 hours. Second aniline (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv) was added, followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv). The resulting mixture was heated at 80 ° C for 4 hours, cooled to room temperature, and was treated with MeOH (0 · 5: rial,): Injected. * ··· * ·· * ·! ··· · J »t ..

the mixture is concentrated under reduced pressure and the products.'is purified by reverse phase HPLC.

C4. A basic method for the synthesis of urea by reaction of aniline with phosgene, followed by the addition of a second aniline.

Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2 (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

Anhydrous pyridine (0.32 mL) was then added to a stirred solution of phosgene (1.9 M in toluene; 2.07 g, 1.30 mmol) in CH ₂ Cl ₂ (20 mL) at 0 ° C, and then and 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, then concentrated under reduced pressure. The obtained solids were treated with anhydrous toluene (20 mL), then with 4- (2 (N-methylcarbamoyl) -4-pyridyloxy) aniline (prepared as described in method A2; 0.30 g), and the resulting suspension was heated at 80 ° for 20 hours, then allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL), then basified with saturated NaHCO ₃ solution (2 - 3 mL). The alkaline solution was extracted with EtOAc (2 x 250 mL). The organic layers were washed weekly. · '*.

NaCl solution, combined, dried (MgSO ₄ ), and concentrated under reduced pressure. The resulting pink-brown residue was dissolved in MeOH and absorbed in SiO ₂ (100 g). After purification by column chromatography (300 g SiO ₂ ; gradient from 1% EtsN / 33% EtOAc / 66% hexane, to 1% EtaN / 99% EtOAc, to 1% Et ₃ N / 20% MeOH / 79% EtOAc), followed by concentration under reduced pressure at 45 ° C to give a hot concentrated solution in EtOAc, which is treated with hexane (10 mL) to weakly form crystals of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2- (Nmethyl-carbamoyl) -4- (pyridyloxy) phenyl) urea (0.44g); TLC (1% EtsN / 99% EtOAc) R _f 0.40.

D. Mutual conversion of ureas

D1a. Conversion of ω-aminophenyl ureas to N- (aroylamino) phenyl ureas.

Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4- (3methoxycarbonylphenyl) carboxyaminophenyl) urea

To a solution of N (4-chloro-3 - ((trifluoromethyl) phenyl) -N (4-aminophenyl) urea (method C1d; 0.050 g, 1.52 mmol), monomethyl isophthalate (0.25 g, 1.38 mmol) ), ΗΟΒΤ · Η ₂ Ο (0.41 d, ·· · • · · · _

3.03 mmol) and> N-methylmorpholine (0.33 mL, '3', b 3 * rnmo'l) * e ^; Hmg.7 ^: (8 mL) was added EDCFHCI (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temperature overnight, diluted with EtOAc (25 mL) and washed sequentially with water (25 mL) and saturated NaHCO ₃ solution (25 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The solids obtained are triturated with

EtOAc solution (80% EtOAc / 20% hexane) to give N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea (0.27 g , 43%): mp 121 - 122; TLC (80% EtOAc / 20% hexane) R _f 0.75;

D1 b. Conversion of ω-carboxyphenyl ureas to N- (arylcarbamoyl) phenyl ureas.

Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea

To a solution of No. (4-chloro-3 - ((trifluoromethyl) phenyl) -N (4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0 , 53 mmol), ΗΟΒΤ · ₂ Ο (0.14 g, 1.07 mmol) and N-methylmorpholine (0.5 mL, 1.07 mmol) in DMF (3 mL) at 0 ° C were added EDCI- HCI (0,10 g, 0,53 mmol). The resulting mixture was allowed to warm to room • · ·· _ _l -T: ·:; ** .. · temperature and stirred ** Ia · a The resulting mixture was treated with water (10 mL) and extracted with EtOAc (25 mL). The organic phase was concentrated under reduced pressure. The yellow solids obtained were dissolved in EtOAc (3 mL). next e is filtered through a pad of silica gel (17 g, gradient from 70% EtOAc / 30% hexane, to 10% MeOH /% EtOAc) to give N- (4-chloro-3 - ((trifluoromethyl) phenyl) ) -N '- (4- (3-methylcarbamoylphenyl) -carbamoylphenyl) urea as a white solid (0.097 g, 41%): mp 225-222; TLC (100% EtOAc) R _f 0.23 ;

D1c. Combined conversion of ω-carboxyphenyl ureas into N- (arylcarbamoyl) phenyl ureas.

Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (L1 (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea

On a mixture of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (3carboxyphenyl) urea (method C1f; (0.030 g, 0.67 mmol) and N-cyclohexyl-N' - (methylpolystyrene) carbodiimide (55 mg) in 1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CH ₂ Cl ₂ , (1 M; 0.074 mL, 0.074 mmol). (In case of insolubility or turbidity, also added a small amount of DMSO) The resulting mixture was heated at 36 [deg.] C. overnight, then the broth was treated with THE (1 mL) and heated for 18 hours. poly (4-isocyanatemethyl) styrene (0.040 g) and the resulting mixture was diluted The oven was cooled to room temperature and filtered, and the resulting solution was filtered through a pad of silica gel (1 g). After concentration under reduced pressure, Ν- (4-χπορο) was obtained. -3 ((trifluoromethyl) phenyl) -N '- (4- (N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea (0.024 g, 59%): TLC (70% EtOAc / 30% hexane) Rf 0.12;

D2. Conversion of ω-carboalkoxyaryl ureas to ω-carbamoyl ureas.

Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea

Methylamine (1 Mb THF) was added to a sample of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4 (3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol). 1 mL, 1.7 mmol) and the resulting mixture was stirred at room temperature overnight, then concentrated under reduced pressure to give N- (4-chloro-3 - ((trifluoromethyl) phenyl); -N '- (4- (3-methylcarbamoylphenyl) -carboxyaminophenyl) ^w · ^w urea, as a white solid; mp 247; TLC' (100 * ·% * .. · 'EtOAc) R _f 0 , 35.

D3. Conversion of ω-carboalkoxyaryl ureas to ω-carboxyaryl ureas.

Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4carboxyphenyl) urea

To a suspension of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '(4-ethoxycarbonylphenyl) urea (method C1; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added aq. KOH solution (2.5 N, 10 mL, 23 mmol) The resulting mixture was heated at reflux for 12 hours, cooled to room temperature, and concentrated under reduced pressure. with water (50 mL), then treated with 1 N HCl solution to pH 2 to 3. The resulting solids were collected and dried under reduced pressure to give N- (4-chloro-3- ( (trifluoromethyl) phenyl) -N '- (4 carboxyphenyl) urea as a white solid (5.05 g, 92%).

• · • · · · · · ..

· · · ·

D4. A basic method for converting ω-alkoxy ester alkyl alkyl amides.

Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxy-phenyl) urea

Step 1. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5-carboxypyridyl) oxyphenyl) urea

N- (4-Chloro-3 - ((trifluoromethyl) phenyl) -N '- ((4 (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea) from 4-chloro-3 (trifluoromethyl) phenyl isocyanate and 4- ( 3- (5-methoxycarbonylpyridyl) oxyaniline (method A14, step 2) in a manner analogous to method C1a. To a suspension of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3 - (5-methoxycarbonylpyridyl) oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with KOH solution (0.14 g, 2.5 mmol) in water (1 mL), and stirred at room temperature for 1 hour The resulting mixture was brought to pH 5 with a 1 N HCl solution. The solids obtained were dissolved in EtOH (10 mL), and the resulting solution was concentrated under reduced pressure. The dissolution procedure in EtOH / concentration was repeated twice at при · · ♦ ·· · * : · · · · Which gave N- (4-chloro-3- (trifluoromethyl) phenyl) (N- (6-carboxypyridyl) -oxyphenyl) urea (0.18 g, 71%) .

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

Mixture of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5carboxypyridyl) oxyphenyl) urea (0.050 g, 0.011 mmol), N, N-dimethylethylenediamine (0.22 d, 0.17 mmol), HOBT (0.028 g, 0.17 mmol) and N-methylmorpholine (0.035 mL, 0.28 mmol) and EDCI-HCl (0.10 g, 0.53 mmol) in DMF (2 , 5 mL) was stirred at room temperature overnight The resulting solution was partitioned between EtOAc (50 mL) and water (50 mL) The organic phase was washed with water (35 mL), dried (MgSO ₄ ). and concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (approximately 2 mL) .The resulting solution was treated with Et ₂ O dropwise to give M- (4-chloro-3 - (trifluoromethyl) phenyl) -N '- ((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea (0.48 g, 84% ¹ H - NMR (DMSO - bb) δ 2.10 (s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (t, 3H), 8.05 (s , 1H), 8.43 (S, 1H), 8.58 (t, 1H), 8.69 (s, 1H), 8.90 (s, 1H), 9.14 ($, 1H), HPLC ES - MS m / z 522 ((M + H) ⁺ ).

D5.

· *; ·· j · * · · * · * ·

A basic method for the conversion of N- (1H-sipY10xy ^ lk11l / 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-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea (prepared in a manner analogous to method C1a; 0.25 g, 0.37 mmol), tetrabutylammonium fluoride (1.0 M in THF; 2 mL) was added in anhydrous THF (2 mL), and the mixture was stirred at room temperature for 5 minutes, then The aqueous mixture was extracted with EtOAc (3x10 mL), the combined organic layers were dried (MgSO ₄ ), © and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ; gradient). from 100% hexane to 40% EtOAc / 60% hexane) to give N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (2- (M- (2 -hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).

The following are the compounds listed in the tables below that have been synthesized according to the detailed experimental procedures given below:

l * ··· * ·· · · ί ···

Synthesis of Example Compounds ····· (See Compound Characterization Tables)

Description 1: 4- (3-N-methylcarbamoylphenoxy) aniline is prepared according to method A 13. According to method C3, 3-tert-butylaniline is reacted with bis (trichloromethyl) carbonate, followed by 4- (3-N-methylcarbamoylphenoxy) aniline, until received

then urea.

Description 2: 4-fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to method A13, step 1, to give 4- (4-acetylphenoxy) -1-nitrobenzene. 4- (4-acetyl-phenoxy) -1-nitrobenzene was reduced according to method A13, step 4, to give 4- (4-acetylphenoxy) aniline. According to the C3 method, 3-tert-butylaniline was reacted with bis (trichloromethyl) carbonate, followed by 4- (4-acetylphenoxy) aniline to give urea.

Description 3: According to method C2d, 3-tert-butylaniline is reacted with CDI, followed by 4- (3-N-methylcarbamoyl) 4-methoxyphenoxy) aniline, which was prepared according to method A8 to give urea.

Description 4: 5-tert-Butyl-2-methoxyaniline is converted to 5-tert-butyl-2-methoxyphenyl isocyanate according to method B1. The 4- (3-N-methylcarbamoylphenoxy) aniline obtained according to method A13 is reacted with isocyanate according to method C1a to give urea.

Description 5: According to method C2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI, followed by 4- (3-N-methylcarbamoyl) -4-methoxyphenoxy) aniline, which was obtained according to method A8 to give urea.

Description 6:

• · ·· f:: C :.

5- (4-aminophenoxy) izoindolyn-1 H ^l dioate 'prepared according to Method AH. According to method 2d, 5-tert-butyl-2 methoxyaniline was reacted with CDI followed by 5- (4-amino phenoxy) isoindoline-1,3-dione to give urea.

Description 7: 4- (1-Oxoisoindolin-5-yloxy) aniline was synthesized according to method A12. According to method 2d, 5-tert-butyl-2methoxyaniline is reacted with CDI followed by 4- (1-oxo

isoindolin-5-yloxy) aniline to give urea.

Description 8: 4- (3-N-methylcarbamoylphenoxy) aniline was synthesized according to method A13. According to method C2a, 2-methoxy-

5- (Trifluoromethyl) aniline was reacted with CDI followed by 4- (3-N-methylcarbamoylphenoxy) aniline to give urea.

Description 9: 4-hydroxyacetophenone interacts with

2-chloro-5-nitropyridine to give 4- (4-acetylphenoxy) -

5-nitropyridine according to method A3, step 2. According to method A8, step 4, 4- (4-acetylphenoxy) -5-nitropyridine is reduced to 4- (4-acetylphenoxy) -5-aminopyridine. 2-Methoxy-5- (trifluoromethyl) -aniline was converted to 2-methoxy-5- (trifluoromethyl) -phenyl isocyanate according to method B1. The isocyanate is reacted with 4- (4-acetylphenoxy) -5-aminopyridine according to method C1a to give urea.

Description 10: 4-fluoro-1-nitrobenzene and p-hydroxyacetophenone are reacted according to method A13, step 1, to give 4- (4-acetylphenoxy) -1-nitrobenzene. 4- (4-acetylphenoxy) -1-nitrobenzene was reduced according to method A13, step 4, to give 4- (4-acetylphenoxy) aniline. According to method C3, 5- (trifluoromethyl) -2-methoxybutylaniline is reacted with bis (trichloromethyl) carbonate, followed by 4- (4acetylphenoxy) aniline to give urea.

Description 11: 4-Chloro-N-methyl-2-pyridinecarboxamide * ·· 'which is synthesized according to method A2, step 3a, is reacted with 3-aminophenol according to method A2, step 4, using DMAC instead of DMF to give 3 - (- 2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. According to method C4, 2-methoxy-5- (trifluoromethyl) aniline is reacted with phosgene followed by

3 - (- 2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 12: 4-Chloropyridine-2-carbonyl chloride HCl salt is reacted with ammonia according to method A2, step 3b, to give 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to method A2, step 4, using DMAC instead of DMF to give 3- (2-carbamoyl-4-pyridyloxy) aniline. According to method C2a, 2-methoxy-5- (trifluoromethyl) aniline is reacted with phosgene followed by 3- (2-carbamoyl) -4-pyridyloxy) aniline to give urea.

Description 13: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to method A2, step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, using DMAC instead of DMF to give 4 - (- 2- (N-methylcarbamoyl) -4-pyridyloxy) -aniline. According to method C2a, 2-methoxy-5- (trifluoromethyl) -aniline was reacted with CDI, followed by 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 14:: 4-Chloropyridine-2-carbonyl chloride HCl salt is reacted with ammonia according to method A2, step 3b, to give 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide is reacted with 4-aminophenol, according to .87 ·· ·. ··: ··. ·: ····. · · · · · · · ·; ··:.: But method A2, step 4, using DMAC instead of DMF, 'which gives 4- (2-carbamoyl-4-pyridyloxy) aniline. According to method C4, 2-methoxy-5- (trifluoromethyl) aniline is reacted with phosgene followed by 4- (2-carbamoyl) -4-pyridyloxy) aniline to give urea.

Description 15: According to method C2d, 6- (trifluoromethyl)

2-Methoxyaniline was reacted with CDI, followed by 4- (3-Nmethylcarbamoyl) -4-methoxyphenoxy) aniline, which was prepared according to method A8, to yield urea.

Description 16: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2methylaniline was synthesized according to method A5. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The isocyanate is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2methylaniline according to method C1 to give urea.

Description 17: 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to method A6. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 5- (Trifluoro-methyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (methylmethylcarbamoyl) -4-pyridyloxy) -2-chloroaniline according to method C1a to give urea.

Description 18: According to method A2, step 4, 5-amino-2-methylphenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to method A2, step 3b, to give 3- (2- ( N-methylcarbamoyl) -4-pyridyloxy) 4-methylaniline. 5- (Trifluoromethyl) -2-methoxy-aniline was converted to 5 (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate reacting with stvuva ZCH2CHM- _M is ™ K ap _b ADP) .4-pyridin _D i ^ N ^ a ^ 5 vat according to Method C1a to afford the urea.

Description 19: 4-Chloropyridine-2-carbonyl chloride is reacted with ethylamine according to method A2, step 3b. Received

4-Chloro-N-ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to method A2, step 4, to give

4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxy-aniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (2- (N-

With ethylcarbamoyl) -4-pyridyloxy) aniline according to method C1a, to give urea.

Description 20: According to method A2, step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to method A2, step 3b, to give 4- (2- ( N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 5- (Trifluoromethyl) -2-methoxy-aniline was converted to

5- (Trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate

C is treated with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline according to method C1a to give urea.

Description 21: 4- (4-Methylthiophenoxy) -1-nitrobenzene is oxidized according to method A19, step 1, to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. Nitrobenzene was reduced according to method A19, step 1, to give 4- (4-methylsulfonylphenoxy) -1-aniline. According to method C1a, 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (4-Methylsulfonylphenoxy) -1-aniline to give urea.

· * '.. ·. ·: ··. ·: 1, - ·! *******

Description 22: 4- (3-Carbamoylphenoxy) -1-nitrobenyl &lt; RTI ID = 0.0 &gt; &lt; / RTI &gt; (Trifluoromethyl) -2-methoxy-phenyl isocyanate is reacted with 4- (3-carbamoylphenoxy) aniline to give urea.

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

Description 24: 4-Chloropyridine-2-carbonyl chloride is reacted with dimethylamine according to method A2, step 3b. The resulting 4-chloro-N, N-dimethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to method A2, step 4, to give 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline according to method C1a to give urea.

Description 25: 4- (1-Oxoisoindolin-5-yloxy) aniline was synthesized according to method A12. 5- (Trifluoromethyl) -2-methoxyaniline was treated with CDI, followed by 4- (1-oxoisoindolin-5-yloxy) aniline according to method C2d, to yield urea.

Description 26: 4-Hydroxyacetophenone interacts with

4-fluoronitrobenzene according to method A13, step 1, to give 4- (4-acetylphenoxy) nitrobenzene. Nitrobenzene is reduced according to method A13, step 4, to give

I

...... .. *:

4- (4-acetylphenoxy) aniline which is 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 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with the 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline HCl salt according to method C1 to give urea.

Description 27: 4-Chloro-N-methylpyridinecarboxamide is synCised according to the description of method A2, step 3b. The chloropyridine is reacted with 4-aminothiophenol according to method A2, step 4 to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 5- (trifluoromethyl) -2-methoxyaniline is converted to 5- ( trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (4- (2- (1H-methylcarbamoyl) -phenylthio) aniline according to method C1 to give urea.

Description 28: 5- (4-Aminophenoxy) -2-methylisoindoline-1,30 dione was synthesized according to method A9. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione according to method C1 to give urea.

Description 29: 4-Chloro-N-methylpyridinecarboxamide was synthesized according to the description of method A2, step 3b. Chlorpyridine is reacted with 3-aminothiophenol according to method A2, step 4, to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 5- (trifluoromethyl) -2-methoxyaniline is converted to 5- ( trifluoromethyl) -2-methoxyphenyl isocyanate, cf. Method B1 5- (trifluoromethyl) -2-methoxyphenyl isocyanate interacts with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline according to method C1 to give urea.

Description 30: 2-Chloropyridine-2carbonyl chloride is reacted with isopropylamine according to method A2, step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with method A2, step 4, to give 4- (2- (Nisopropylcarbamoyl) 4-pyridyloxy) aniline. 5- (trifluoromethyl) -

2-Methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (2- (1M-isopropylcarbamoyl) 4-pyridyloxy) aniline according to method C1 to give urea.

Description 31: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to method A14. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxy-phenyl isocyanate according to method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method C1 to give urea. N- (5- (trifluoromethyl) -2-methoxyphenyl) -1H '- (4- (3- (5-methoxycarbonyl-pyridyl) oxy) phenyl) urea was obtained according to method D4, step 1, and the corresponding acid is involved in the 4- (2-aminoethyl) -morpholine coupling reaction to give the amide according to method D4, step 2.

Description 32: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to method A14. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. The 5- (trifluoromethyl) -2-methoxyphenyl isocyanate reacts with 4- (3- (5-methoxy92)

• · · ♦ · • · • · · · • · • · • • · • · · _ · · • · • • • • · · ...... • · · • · ··· · • • • • ··· • • · • · • Λ A • • <

carbonyl) pyridyloxy) aniline according to method C1a to give urea. B1- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (4- (3 (5-methoxycarbonyl-pyridyl) oxy) phenyl) urea was saponified according to method D4, step 1, and the corresponding acid was involved in the addition acid. reaction with methylamine to give the amide according to method D4, step 2, to give the amide.

Description 33: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to method A14. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method C1a to give urea. N- (5- (trifluoromethyl) -2-methoxyphenyl) -N'-4- (3 (5-methoxycarbonyl-pyridyl) oxy) phenyl) urea was saponified according to method D4, step 1, and the corresponding acid was involved in a coupling reaction with N, N-dimethylethylenediamine according to method D4, step 2, to give amide.

Description 34: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method C1f to give N- (5- (trifluoromethyl) -2methoxyphenyl) -N- (3-carboxyphenyl) urea which is involved in the coupling reaction with 3-aminopyridine according to method D1c.

Description 35: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method C1f to give N- (5- (trifluoromethyl) -2methoxyphenyl) -N- (3-carboxyphenyl) urea which is involved in the coupling reaction with N- (4-fluorophenyl) piperazine according to method D1c.

Description 36: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method C1f to give N- (5- (trifluoromethyl) -2methoxyphenyl) -N '- (3-carboxyphenyl) urea involved in the coupling reaction with 4-fluoroaniline according to method D1c.

Description 37: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method C1f to give N- (5- (trifluoromethyl) -2methoxyphenyl) -N '- (3-carboxyphenyl) urea which is involved in the coupling reaction with 4- (dimethylamino) aniline according to method D1c.

Description 38: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method C1f to give N- (5- (trifluoromethyl) -2methoxyphenyl) -N- (3-carboxyphenyl) urea, which is involved in the coupling reaction with 5-amino-2-methoxypyridine according to method D1c.

Description 39: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method C1f to give N- (5- (trifluoromethyl) -2methoxyphenyl) -N- (3-carboxyphenyl) urea which is involved in the coupling reaction with 4-morpholinoaniline according to method D1c.

Description 40: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method B1. 4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to method C1f to give N- (5- (trifluoromethyl) -2methoxyphenyl) -1 N '- (3-carboxyphenyl) urea involved in the reaction of attachment with N- (2-pyridyl) piperazine according to method D1c.

Description 41: 4- (3- (N-Methylcarbamoyl) phenoxy) aniline was synthesized according to method A13. In accordance with Method C3, 4-chloro-3 (trifluoromethyl) aniline is converted to isocyanate, then reacted with 4- (3-carboxyphenoxy) aniline reacted with 4- (3- (N-methylcarbamoyl) phenoxy) aniline, wherein urea is obtained.

* • · • · · • · · ····: · ·: ··;

• ·

Description 42: 4- (2-N-Methylcarbamyl-4-pyridyloxy) aniline was synthesized according to method A2. 4-Chloro-3- (trifluoromethyl) phenylisocyanate was reacted with 4- (2-N-methylcarbamyl-4-pyridyloxy) aniline according to method C1a to give urea.

Description 43: The 4-chloropyridine-2-carbonyl chloride HCl salt is reacted with ammonia according to method A2, step 3b, to give 4-chloro-2-pyridinecarboxamide. The 4-chloro-2-pyridinecarboxamide is reacted with 4-aminophenol according to method A2, step 4 to give 4- (2-carbamoyl) -4-pyridyloxy) aniline. According to method C1, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2-carbamoyl) 4-pyridyloxy) aniline to give urea.

Description 44: 4-Chloropyridine-2-carbonyl chloride HCl salt is reacted with ammonia according to method A2, step 3b, to give 4-chloro-2-pyridinecarboxamide. The 4-chloro-2-pyridinecarboxamide is reacted with 3-aminothiophenol according to method A2, step 4, to give

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 give urea.

Description 45: 4-Chloro-N-methyl-2-pyridinecarboxamide, which is synthesized according to method A2, step 3a, is reacted with

3-aminothiophenol according to method A2, step 4, to give 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

QA · · · · · · · · ·

9b .... \ _e ·. : ·· ..:

·· ·· ·

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

Description 47: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2methylaniline was synthesized according to the description of method A5. According to method C1c, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to give urea.

Description 48: 4- (3-N-Methylsulfamoyl) phenyloxy) aniline was synthesized according to the description of method A15. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-N-methylsulfamoyl) phenyloxy) aniline to give urea.

Description 49: 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to the description of method A6. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate F is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to give urea.

Description 50: According to method A2, step 4, 5-amino-2methylphenol is reacted with 4-chloro-N-2-pyridinecarboxamide, which is synthesized according to method A2, step 3b, to give 3- (2- (M-methylcarbamoyl) ) -4-pyridyloxy) -4-methylaniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to give urea.

Description 51: 4-Chloropyridine-2-carbonyl chloride is reacted with ethylamine according to method A2, step 3b. Received

4-Chloro-N-ethyl-2-pyridinecarboxamide is reacted with

4-aminophenol according to method A2, step 4, to give

4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 52: According to method A2, step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N-2-pyridinecarboxamide, which is synthesized according to method A2, step 3b, to give 4- (2- (1M -methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -

3-chloroaniline to give urea.

Description 53: 4- (4-Methylthiophenoxy) -1-nitrobenzene is oxidized according to method A19, step 1, to give

4- (4-methylsulfonylphenoxy) -1-nitrobenzene. Nitrobenzene was reduced according to method A19, step 2, to give '4- (4-methylsulfonylphenoxy) -1-aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4-methylsulfonylphenoxy) -1-aniline to give urea.

Description 54: 4-Bromobenzenesulfonyl chloride is reacted with methylamine according to method A15, step 1, to give N-methyl-4-bromobenzenesulfonamide. N-methyl-4-bromobenzenesulfonamide is involved in a coupling reaction with phenol according to method A15, step 2, to give 4- (4- (N-methylsulfamoyl) phenoxy) benzene. 4- (4- (N-methylsulfamoyl) -phenoxy) benzene is converted to 4- (4- (N-methylsulfamoyl) -phenoxy) -1-nitrobenzene according to method A15, step 3. 4- (4- (M- methylsulfamoyl) -phenoxy) -1-nitrobenzene is reduced98 •. ·. ·: ·· ·· '··

to 4- (4-N-methylsulfamoyl) phenoxy) aniline according to method A15, step 4. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4-N-methylsulfamoyl) phenoxy). aniline to give urea.

Description 55: 5-hydroxy-2-methylpyridine is involved in a coupling reaction with 1-fluoro-4-nitrobenzene according to method A18, step 1, to give 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene. The methylpyridine is oxidized according to the carboxylic acid, then esterified according to method A18, step 2 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene. Nitrobenzene was reduced according to method A18, step 3 to give 4- (5- (2methoxycarbonyl) pyridyloxy) aniline. The aniline is reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to method C1a to give urea.

Description 56: 5-Hydroxy-2-methylpyridine is involved in a coupling reaction with 1-fluoro-4-nitrobenzene according to method A18, step 1, to give 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene. The methylpyridine is oxidized according to the carboxylic acid, then esterified according to method A18, step 2 to give 4- (5- (2methoxycarbonyl) pyridyloxy) -1-nitrobenzene. The nitrobenzene was reduced according to method A18, step 3 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline. The aniline was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to method C1a to give N- (4-chloro-3- (trifluoromethyl) phenyl) -1 N '- (4- (2- (methoxycarbonyl)) -5-pyridyloxy) phenyl) urea. The methyl ester is reacted with methylaniline according to method D2 to give N- (4-chloro-3- (trifluoromethyl) phenyl) -1T- (4- (2- (N-methylcarbamoyl) -5- pyridyloxy) phenyl) urea.

Description 57: N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4-aminophenyl) urea is prepared according to method C1d.

3- (Trifluoromethyl) phenyl-N '- (4-aminophenyl) urea is involved in a coupling reaction with mono-methyl isophthalate according to method D1a to give urea.

Description 58: N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4-aminophenyl) urea is prepared according to method C1d.

3- (Trifluoromethyl) phenyl-N '- (4-aminophenyl) urea is involved in a coupling reaction with mono-methyl isophthalate according to method D1a to give N- (4-chloro-3- (trifluoromethyl) phenyl-N' - (4- (3-Methoxycarbonylphenyl) -carboxyaminophenyl urea. According to method D2, N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4- (3-methoxycarbonylphenyl) -carboxyaminophenyl urea is reacted with methylamine, reacted with methylamine) to give the corresponding methyl amide.

Description 59: 4-Chloropyridine-2-carbonyl chloride is reacted with diethylamine according to method A2, step 3b. The resulting 4-chloro-N, N-diethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to method A2, step 4, to give 4- (2- (N, N-diethylcarbamoyl) -4-pyridyloxy) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N, N-diethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 60: 4-Hydroxyacetophenone interacts with

4-fluoronitrobenzene according to method A13, step 1, to give 4- (4-acetylphenoxy) nitrobenzene. Nitrobenzene was reduced according to method A13, step 4, to give • 4

100

4- (4-acetylphenoxy) aniline, which is converted to 4- (4- (1- (Nmethoxy) iminoethyl) phenoxyaniline HCl salt according to method A16. In accordance with method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4-acetylphenoxy) aniline to give urea.

Description 61: 4- (3-Carboxyphenoxy) -1-nitrobenzene is synthesized according to method A13, step 2. 4- (3-carboxyphenoxy) -1nitrobenzene is involved in a coupling reaction with 4- (2-amifoethyl) morpholine according to method A13 Step 3 to give 4- (3-N- (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene. According to method A13, step 4, 4- (3-N- (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3-N (2-morpholinylethyl) carbamoyl) phenoxy) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl) -isocyanate is reacted with 4- (3-N- (2-morpholinylethyl) -carbamoyl) phenoxy) aniline to give urea.

Description 62: 4- (3-Carboxyphenoxy) -1-nitrobenzene synthesized according to method A13, step 2. 4- (3-carboxyphenoxy) -1nitrobenzene is involved in the addition reaction with 1- (2-aminoethyl) piperidine according to method A13, step 3 to give 4- (3 (-N- (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene. According to method A13, step 4, 4- (3- (N- (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (N (2-piperidylethyl) carbamoyl) phenoxy) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl) isocyanate is reacted with 4- (3- (N- (2-piperidylethyl) carbamoyl) phenoxy) aniline to give urea.

Description 63: 4- (3-Carboxyphenoxy) -1-nitrobenzene was synthesized according to ether-EAE, step 2. 4- (3-carboxyphenoxy) -1 a> _

101 Nitrobenzene is involved in a coupling reaction with tetrahydrofurfurylamine according to method A13, step 3, to give 4- (3- (N- (tetrahydrofurylmethyl) carbamoyl) phenoxy) 1-nitrobenzene. According to method A13, step 4, 4- (3- (N- (tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (N- (tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (N- (tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline to give urea.

Description 64: 4- (3-Carboxyphenoxy) -1-nitrobenzene is synthesized according to method A13, step 2. 4- (3-carboxyphenoxy) -1nitrobenzene is involved in a coupling reaction with 2-aminomethyl-1-ethylpyrrolidine according to method A13, step 3 to give 4- (3- (14 - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene. According to Method A13, Step 4, 4- (3- (N - ((1methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy)) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy)) aniline to give urea.

Description 65: 4-Chloro-N-methylpyridinecarboxamide was synthesized according to the procedure described in method A2, step 3b. Chloropyridine is reacted with 4-aminophenol according to method A2, step 4 to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline to give urea.

• ·

102

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

Description 67: N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4-ethoxycarbonylphenyl) urea is synthesized according to method Cl e. N- (4-chloro-3- (trifluoromethyl) phenyl-N' - (4- ethoxycarbonylphenyl) urea was soaped according to method D3 to give N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4-carboxylphenyl) urea. N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4-carboxylphenyl) urea is involved in a coupling reaction with 3methylcarbamoylaniline according to method D1b to give N- (4-chloro-3- (trifluoromethyl) phenyl-N' - (4- (3-methylcarbamoylphenyl) ) urea carbamoylphenyl.

Description 68: 5- (4-Aminophenoxy) -2-methylisoindoline-1,3dione is synthesized according to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 5- (4-aminophenoxy) -

2-methylisoindoline-1,3-dione to give urea.

Description 69: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in method A2, step 3b. Chloropyridine is reacted with 3-aminophenol according to method A2, step 4, to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline to give urea.

103 ··· .. ·. · ···

Description 70: 4- (2- (1 N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was synthesized as described in method A10. according to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to give urea.

Description 71: 4- (3- (5-Methoxycarbonyl) pyridyloxy) -aniline was synthesized according to method A14. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method C1a to give urea. N- (4-chloro-3- (trifluoromethyl) phenyl-N '- (4- (3- (5methoxycarbonylpyridyl) oxy) phenyl urea) was saponified according to method D4, step 1, and the corresponding acid was involved in a 4- (2-aminoethyl) morpholine to give the amide.

Description 72: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to method A14. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method C1a to give urea. N- (5- (trifluoromethyl) -2-methoxyphenyl) -1H '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl urea is saponified according to method D4, step 1, and the corresponding acid is involved in a coupling reaction with methylamine according to method D4, step 2, to give the amide.

Description 73: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to method A14. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method C1a to give urea. N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (4- (3- (5-methoxycarbonylylridyl) oxy) phenyl urea was saponified according to the meth-

104 then D4, step 1, and the corresponding acid is involved in the coupling reaction with N, N-dimethylethylenediamine according to method D4, step 2 to give the amide.

Description 74: 4-Chloropyridine-2-carbonyl chloride HCl salt is reacted with 2-hydroxyethylamine according to method A2, step 3b, to give 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide. 4-Chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide is reacted with triisopropylsilyl chloride followed by 4-aminophenol according to method A17 to give 4- (4- (2- (Ν- (2- τρπisopropylsilyloxy) ethylcarbamoyl) pyridyloxy-aniline According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (N- (2-triisopropyl-silyloxy) ethylcarbamoyloxy) pyridinyl) pyridinyl-pyridoyl) pyridinyl-pyridinyl-pyridoxy-pyridinyl-pyridoxy-pyridinyl-pyridinyl-pyridin-3-yl yields Ν (4chloro-3 - ((trifluoromethyl) phenyl-N '- (4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea.

C Description 75: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to method C1f to give urea which is involved in the coupling reaction with 3-aminopyridine according to method D1c.

Description 76: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to method C1f to give urea, which is involved in the addition reaction of N- (4-acetylphenyl) piperazine according to method D1c.

105 ····

Description 77: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to method C1f to give urea which is involved in the coupling reaction with 4-fluoroaniline according to method D1c.

Description 78: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to method C1f to give urea which is involved in a coupling reaction with 4- (dimethylamino) aniline according to method D1c .

Description 79: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to method C1f to give urea which is involved in the coupling reaction with N-phenylethylenediamine according to 0 method D1c.

Description 80: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to method C1f to give urea which is involved in the coupling reaction with 2-methoxyethylamine according to method D1c.

Description 81: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to C1f 'to give urea which is involved in

106 · The coupling reaction with 5-amino-2-methoxypyridine according to method D1c.

Description 82: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to method C1f to give urea which is involved in a coupling reaction with 4-morpholinoaniline according to method D1c.

C Description 83: 4- (3-Carboxyphenoxy) aniline was synthesized according to method A11. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to method C1f to give urea which is involved in the coupling reaction with N- (2-pyridyl) piperazine according to method D1c.

Description 84: 4-Chloropyridine-2-carbonyl chloride HCl salt is reacted with 2-hydroxyethylamine according to method A2, step 3b, to give 4-chloro-N- (2-triisopropylF silyloxy) ethylpyridine-2-carboxamide. 4-Chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide is reacted with triisopropylsilyl chloride followed by 4-aminophenol according to method A17 to give 4- (4- (2- (N- (2-triisopropylyloxy)) ethylcarbamoyl) pyridyloxyaniline.

According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline) to give N- (4-chloro-3- ( (trifluoromethyl) phenyl) -N '- (4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea).

107 gave 1 N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (4- (2- (N- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea.

Description 85: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -aniline was synthesized according to method A2. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-bromo-3 (trifluoromethyl) phenyl isocyanate is reacted with 4- (2 (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

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

Description 87: According to method A2, step 4, 4-amino-2 © chlorophenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which is synthesized according to method A2, step 3b, to give 4- (2- (M-methylcarbamoyl) -4-pyridyloxy) -

3-chloroaniline. 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 is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to give urea.

Description 88: 4-Chloropyridine-2-carbonyl chloride is reacted with ethylamine according to method A2, step 3b. Received

4-Chloro-N-ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to A2, step 4, to give

108

4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. 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 is reacted with 4- (2- (1H-ethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 89: 4-Chloro-N-methyl-2-pyridinecarboxamide, which is synthesized according to method A2, step 3a, is reacted with 3-aminophenol according to method A2, step 4, to give 3- (2- (M- methylcarbamoyl) -4-pyridyloxy) aniline. 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 is reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -anil to give urea.

Description 90: According to method A2, step 4, 5-amino-2-chlorophenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which is synthesized according to method A2, step 3b, to give 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-methylaniline. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to give urea.

Description 91: 4-Chloropyridine-2-carbonyl chloride is reacted with dimethylamine according to method A2, step 3b. The resulting 4-chloro-N, N-dimethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to method A2, step 4 to give 4- (2- (N, N-dimethylcarbamoyl) -4- pyridyloxy) aniline.

109

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 is reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 92: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in method A2, step 3b. The chloropyridine is reacted with 3-aminophenol according to method A2, step 4 to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 4-bromo-3- (trifluoromethyl) -aniline is converted to 4 -bromo-3- (trifluoromethyl) phenyl isocyanate according to method B. According to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-methylcarbamoyl) phenylthio) aniline to give urea.

Description 93: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in method A2, step 3b. The chloropyridine is reacted with 3-aminophenol according to method A2, step 4 to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 4-bromo-3- (trifluoromethyl) -aniline is converted to 4 -bromo-3- (trifluoromethyl) phenyl isocyanate according to method B. According to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (4- (2- (N-methylcarbamoyl) -phenylthio) aniline, producing urea.

Description 94: 4- (2- (N-2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was synthesized according to method A10. 4-Bromo 3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1d, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to give urea.

Description 95: 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to method A2. 4-Chloro-2-methoxy-5 (trifluoromethyl) aniline was synthesized according to method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (Nmethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 96: 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to method A6. 4-Chloro-2-methoxy-5 (trifluoromethyl) aniline was synthesized according to method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (Nmethylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to give urea.

Description 97: According to method A2, step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which is synthesized according to method A2, step 3b, to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate

111

reacts with 4- (2- (1M-methylcarbamoyl) -4-pyridyloxy) -

2-chloroaniline to give urea.

Description 98: 4-Chloro-N-methyl-2-pyridinecarboxamide, which is synthesized according to method A2, step 3a, is reacted with

3-aminophenol according to method A2, step 4, to give

3- (2- (N-methylcarbamoyl) -4H-pyridyloxy) aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) -aniline was synthesized according to method A7.

4- Chloro-2-methoxy-5- (trifluoromethyl) -aniline is converted to 4-

With chloro-3-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-chloro-3-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

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

Description 100: 4-Chloropyridine-2-carbonyl chloride is reacted with dimethylamine according to method A2, step 3b. The resulting 4-chloro-N, N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4 to give 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) -anidine . 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline is synthesized.

112

according to method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 101: 4-Chloro-N-methyl-2-pyridinecarboxamide, which is synthesized according to method A2, step 3a, is reacted with 3-aminophenol according to method A2, step 4 to give 3- (2- (M -methylcarbamoyl) -4-pyridyloxy) aniline. 2-Amino-3-methoxynaphthalene was synthesized according to the description of method A1. According to the C3 method, 2-amino-3-methoxynaphthalene is reacted with bis (trichloromethyl) carbonate, followed by 3 (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Description 102: 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to method A2. 5-tert-Butyl-2- (2,5C dimethylpyrrolyl) aniline was synthesized according to method A4.

5-tert-Butyl-2- (2,5-dimethylpyrrolyl) aniline was reacted with CDI, followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline according to method C2d to give urea.

Description 103: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to method A2, step 3b. 4-Chloro-1M-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to method A2, step 4, using DMAC instead of DMF to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. According to method C2b, the interaction of 3-amino-2-methoxyquinoline with CDI followed by 4- (2- (M-methylcarbamoyl) -4 ···

113 Pyridyloxy) aniline produces 4- (2- (1-methylcarbamoyl) -4-pyridyloxy) phenyl urea.

The following table lists the compounds that have been synthesized according to the detailed experimental procedures given above:

TABLES

The compounds listed in Tables 1-6 below are synthesized according to the basic methods mentioned above, and more detailed exemplary procedures are in the descriptions listed above and the characteristics are listed in the tables.

T able 1. 3-tert-butylphenyl urea

Description <we R M.P. (° C) HPLC (min.) TLC Rt TLC Solution System Mac Spec. (source) Synthet. method 1 Fr. NH r = \ Me 0.22 50% EtOAc / 50% hexane 418 (M + H) + (HPLC ES-MS) A13 NW

• ·

114

2 —O- 0 Me 0.58 50% EtOAc / 50% hexane 403 (M + H) + (HPLC ES-MS A13 NW 3 Fr. -3 -NH Me - OMe 133- 135 0.68 100% EtOAc 448 (M + H) + (FAB) A8 C2d

Table 2. 5-tert-butylphenyl ureas

We are intoxicated R M.P. (° C) HPLC (min.) TLC Rf TLC Solution System Mac Spec. (source) Synthet. Method 4 - £ V-o Fr. V-NH · 5.93 448 (M + H) + (HPLC ES-MS) A13 B1 C1a 5 ———— 0 V-NH 4θ- ° Μ _θ 120- 122 0.67 100% EtOAc 478 (M + H) + (FAB) A8 C2d

6 -in ₃ , · D 0.40 50% EtOAc / 50% hexane 460 '··· (MH) + (HPLC ES-MS) AZ C2d 7 О „ ^о_ С ^ ^с 0.79 50% EtOAc / 50% hexane 446 (M + H) + (HPLC ES-MS) A12 C2d

Table 3. 5- (Trifluoromethyl) -2-methoxyphenyl ureas

We stretched R M.P. (° C) HPLC (min.) TLC Rf TLC Solution System Mac Spec. (source) Synthet. method 8 0 NH 250 (dec) 460 (M + H) + (FAB) A13 C2a 9 206- 208 0.54 10% MeOH / 90% CH ₂ CI ₂ 446 (M + H) + (HPLC ES-MS I stage 2, A8 step4 B1,

116 ♦ · J J · ♦ * ··

C1a 10 Μ 0.33 50% EtOAc / 50% petr. ether 445 (M + H) + (HPLC ES-MS A13 C3 11 -Ο U ν = / - / Me 0.20 2% Et3N / 98% EtOAc 461 (M + H) + (HPLC ES-MS A2 C4 12 —V-νη ₂ ^σ ~ 0 ^Ν 0.27 2% Et3N / 98% EtOAc 447 (M + H) + (HPLC ES-MS A2 C4 13 0 Υ-ΝΗ / \ / - \ Μβ ΧΖΧ ° ~ G ⁿ 0.62 100% EtOAc 461 (M + H) + (FAB) A2 C2a 14 ο V-nh ₂ ° “C / 114- 117 0.40 1% Et3N / 99% EtOAc 447 (M + H) + (FAB) A2 C4 15 0 V- ΝΗ —— ⁰ —Cr ^0Me 232- 235 0.54 100% EtOAc 447 (M + H) + (FAB) A8 C2d

•. . · ·. ·

: .. ·: · ·: · ·: · · *

117

16 0 X — ΝΗ a θ Me 210- 213 0.29 5%. MeOH / 45% EtOAc / 50% petr. ether 475 ”(M + H) + (HPLC ES-MS A5 B1 C1c 17 ° 'Vnh / - \ / - \ ^Me 187- 188 0.17 50% EtOAc / 50% petr. ether 495 (M + H) + (HPLC ES-MS A6 B1 C1a 18 —7 y — Me y — ΝΗ ₃ 0.48 100% EtOAc 475 (M + H) + (HPLC ES-MS A2 stage 4, B1, C1a 19 0 V-NH 194- 196 0.31 5% MeOH / 45% EtOAc / 50% petr. ether 475 (M + H) + (HPLC ES-MS A2 B1, C1a 20 o Cl \ -NH / - / / = / Me C = / ° A ^ ⁿ 214- 216 0.25 495 (M + H) + (HPLC ES-MS A2 C1a 21 208- 210 0.30 50% EtOAc / 50% hexane 481 (M + H) + (HPLC ES-MS) A19 C2a 22 0 / —NH 2 188- 190 0.30 70% EtOAc / 50% hexane 447 (M + H) + (HPLC ES-MS) A15 step4 C1a

118

23 EGG r 0 0.50 70% EtOAc / 30% hexane 472 ”(M + H) + (FAB) AZ B1 C1a 24 In ^e / = <' ^Me 203- 205 0.13 100% EtOAc 479 (M + H) + (HPLC ES-MS A2 C1 C1a 25 EGGS \ ^ NH 0.09 75% EtOAc / 25% hexane 4458 (M + H) + (HPLC ES-MS A12 C2d 26 MeO I? Me 169- 171 0.67 50% EtOAc / 50% petr. ether 474 (M + H) + (HPLC ES-MS A13 step 1, A13 step4 A16, B1, C1a 27 0 V-NH i = \ ^Me 218- 219 0.40 50% EtOAc / 50% petr. ether 477 (M + H) + (HPLC ES-MS A9 B1, C1a 28 EGGS \ AIMe 0 212- 214 0.30 40% EtOAc / 60% hexane A2 C4 29 I do 0 y — NH .— \ m® w 0.33 50% EtOAc / 50% petr. ether 474 (M + H) + (HPLC ES-MS A2 stage 3b, A2 step4 B1, C1a

119

30 0 V-NH in λ l— \ Pr-i 210- 211 —G. A2 B1 C1a 31 0 V-NH 210- 204 0.43 10% MeOH / CH ₂ CI ₂ A14 B1 C1a d ₄ 32 0 Emh 247- 249 0.57 10% MeOH 1 CH2CI2 A14 B1 C1a d ₄ 33 - \ / - ⁰ —Ά d N — Me ^ = / E_N Me 217- 219 0.07 10% MeOH / CH ₂ CI ₂ A14 B1 C1a d ₄ 34 0 4 — NH -O ~ ° ~ C) o 0.11 70% EtOAc / 30% hexane A11 B1 C1f D1c 35 o \ _N 0.38 70% EtOAc / 30% hexane A11 B1 C1f D1c

36 F— 0.77 70% EtOAc / 30% hexane A11 B1 C1f D1c 37 “VAVnh Me ⁷ 0.58 70% EtOAc / 30% hexane A11 B1 C1f D1c 38 Μ8 ° - 0.58 70% EtOAc / 30% hexane A11 B1 C1f D1c 39 ο (/ ^Ν— 0.17 70% EtOAc / 30% hexane A11 B1 C1f D1c 40 0.21 70% EtOAc / 30% hexane A11 B1 C1f D1c

Table 4

3- (Trifluoromethyl) -4-chlorophenyl ureas

121

We describe R M.P. (° C) HPLC (min.) TLC Rf TLC Solution System Mass Spectrum. (source) Synthet. method 41 Fr. V — NH —CH 163- 165 0.08 50% EtOAc / 50% petr. ether 464 (M + H) + (HPLC ES-MS A13 NW 42 0 V- NH / = \ m® 215 0.06 50% EtOAc / 50% petr. ether 465 (M + H) + (HPLC ES-MS A2 C1a 43 -Ο ^- ' o \ - mn ₂ 0.10 50% EtOAc / 50% petr. ether 451 (M + H) + (HPLC ES-MS A2 C1a 44 0 / —MH ₂ Ό ^ν 0.25 30% EtOAc / 70% petr. ether 451 (M + H) + (HPLC ES-MS A2 C1a 45 0 V-NH / - ( ¹⁷¹⁶ W 0.31 30% EtOAc / 70% petr. ether 465 (M + H) + (HPLC ES-MS A2 C1a 46 ~ Ch ^ ° r 176- 179 0.23 40% EtOAc / 60% hexane 476 (M + H) + (FAB) A3 C1a

122

47 Me 0 V-NH / = (Μθ w 0.29 5% MeOH / 45% EtOAc / 50% petr. ether 465 (M + H) + (HPLC ES-MS A5 C1c 48 v / ^X S-NH A ' 206- 209 A15 C1a 49 Cl 0 NH / = ( ^Me Λ_ / ^Ν 147- 151 0.22 50% EtOAc / 50% petr. ether 499 (M + H) + (HPLC ES-MS A6 C1a 50 —Me ^x ° v o NH = / Me N _ // 0.54 100% EtOAc / 479 (M + H) + (HPLC ES-MS A2 C1a 51 0 V-NH / = / Et w 187- 189 0.33 5% MeOH / 45% EtOAc / 50% petr. ether 479 (M + H) + (HPLC ES-MS A2 C1a 52 Cl Oh NH y— (Me Ό 219 0.18 50% EtOAc / 50% hexane 485 (M + H) + (HPLC ES-MS A19 C1a 53 246- 248 0.30 50% EtOAc / 50% hexane 485 (M + H) + (HPLC ES-MS A19 C1a

123

54 ^λ --- ^f '---' NH Me ^Z 196- 200 0.30 50% EtOAc / 50% hexane 502 (M + H) + (HPLC ES-MS A15 C1a 55 228- 230 0.30 30% EtOAc / 70% CH ₂ CI ₂ 466 (M + H) + (HPLC ES-MS 56 Me ⁷ 57 the totot 221- 222 0.75 80% EtOAc / 20% hexane 492 (M + H) + (HPLC ES-MS C1d D1a 58 exactly 247 0.35 100% EtOAc C1d D1a D2 59 yr -Qr ^ 0 ^Me 198- 200 0.09 100% EtOAc 479 (M + H) + (HPLC ES-MS A2 C1a 60 MeO TO — CH Me 158- 160 0.64 50% EtOAc / 50% petr. ether 61 0 4 — NH toto p 195- 197 0.39 10% MeOH / CH ₂ CI ₂ A13 C1a

124

62 0 V- NH 170- 172 0.52 10% MeOH / CH ₂ CI ₂ A13 C1a 63 , o -d 168- 171 0.39 10% MeOH / CH2Cl2 A13 C1a 64 176- 177 0.35 10% MeOH / CH2Cl2 A13 C1a 65 ο V-NH 1 — Κ? _ '\ Me Ό ~ ISO133 487 (M + H) + (HPLC ES-MS A2 B1 C1a 66 ο V-ΝΗ 155 A2 C1a 67 225- 229 0.23 100% EtOAc C1e D3 D1b 68 -O - '^ Qv ⁰ T 234- 236 0.29 40% EtOAc / 60% hexane A9 C1a 69 - <A V-NH 0.48 50% EtOAc / 50% petr. ether 481 (M + H) + (HPLC ES-MS

125 •. ····; · ··.

'· ·· · .. ·· *:

70 -------------- _σ 0.46 5% MeOH / 95% CH ₂ CI ₂ 564 (M + H) + (HPLC ES-MS A10 C1a _ο- y — ΝΗ Q 71 0 V-NH N 0 199- 201 0.50 10% MeOH / CH ₂ CI ₂ A14 C1a D4 72 -θ- > -7 NH Me 235- 237 0.55 10% MeOH / CH ₂ Cl ₂ A14 C1a D4 73 -θ-ο- 0 V- ΝΗ N ^ -N Me 200- 201 0.21 50% MeOH / CH ₂ Cl ₂ A14 C1a D4 74 -ο- \) Si (Pr-i), 145- 148 75 ^_cy ~ Oh b = C 0.12 70% EtOAc / 30% hexane 527 (M + H) + (HPLC ES-MS A11 C1f D1c

126

2- ::>

76 D 0.18 70% EtOAc / 30% hexane ·· A1 * 1 C1f D1c 77 _F _ # y _NH ^ = 0 0.74 70% EtOAc / 30% hexane A11 C1f D1c 78 Me on-a N- ^ y-NH Me z C 0.58 70% EtOAc / 30% hexane A11 C1f D1c 79 y-NH -Ο4Ζ> r Oh 0.47 70% EtOAc / 30% hexane 569 (M + H) + (HPLC ES-MS A11 C1f D1c 80 0 \ -ΝΗ - (/ V-o — Z \ OMe 0.18 70% EtOAc / 30% hexane 557 (M + H) + (HPLC ES-MS A11 C1f D1c 81 MeO— # \ -NH 2 = c 0.58 70% EtOAc / 30% hexane 557 (M + H) + (HPLC ES-MS A11 C1f D1c

127

82 c / N-Ct-NH 0.37 70% EtOAc / 30% hexane 611 (M + H) + (HPLC ES-MS A11 C1f D1c 83 Q Ο \ —Ν \ θ 0.19 70% EtOAc / 30% hexane A11 C1f D1c 84 y- ΝΗ ^0.4 179- 183 A2 A17 C1a D5

Table 5 3- (Trifluoromethyl) -4-bromophenyl ureas

F

Description; we R T.t. (° C) HPLC (min.) TLC Solution System Mac Speck. (source) Synthet. method 85 o V-NH / --- </ Μθ 186- 187 0.13 50% EtOAc / 50% petr. ether 509 (M + H) + (HPLC ES-MS A2 C1 C1a

128 • ·

86 ^c l Unh) - < _t - (Me 150- 152 0.31 50% EtOAc / 50% petr. ether 545 (M + H) + (HPLC ES-MS A6 B1 C1a 87 o Cl V- NH 217- 219 0.16 50% EtOAc / 50% petr. ether 545 (M + H) + (HPLC ES-MS A2 B1 C1a 88 0 4 — NH 183- 184 0.31 50% EtOAc / 50% petr. ether 525 (M + H) + (HPLC ES-MS A2 B1 C1a 89 -TS Vnh - / Me 0.21 50% EtOAc / 50% petr. ether 511 (M + H) + (HPLC ES-MS A2 B1 C1a 90 / - \ ° \ —V y — Me y_ NH 0.28 50% EtOAc / 50% petr. ether 525 (M + H) + (HPLC ES-MS A2 B1 C1a 91 yr ^Me 214- 216 0.28 50% EtOAc / 50% petr. ether 522 (M + H) + (HPLC ES-MS A2 B1 C1a 92 0 NH / - \ / - \ Μ® -O ^- Ml ^ ⁿ 0.47 50% EtOAc / 50% petr. ether 527 (M + H) + (HPLC ES-MS A2step 3b, A2step 4, B1

129

C1a 93 -L} V-NH - / me ^S “^ ^N 0.47 50% EtOAc / 50% petr. ether 527 (M + H) + (HPLC ES-MS A2et3b, A2step 4, B1 C1a 94 0 y-NH 145- 150 0.41 5% MeOH / 95% CH ₂ Cl ₂ A10 B1 C1a

Table 6. 5- (Trifluoromethyl) -4-chloro-2-methoxyphenyl ureas

Description «we R M.P. (° C) HPLC (min.) TLC Rf TLC Solution System Mass Spectrum. (source) Synthet. method 95 Fr. y-NH -, / __ / Me ~ O - “- θ ' 140- 144 0.29 5% MeOH / 45% EtOAc / 50% petr. ether 495 (M + H) + (HPLC ES-MS A2 A7 B1 C1a 96 ^with 'Vnh) - · M, Me 244- 245 0.39 5% MeOH / 45% EtOAc / 50% petr. eteo 529 (M + H) + (HPLC ES-MS A6 A7 B1 C1a

: ·: ·:. : ··.

· · .. ·

130

97 0 CI NH / - (r = (Me ~ C = / ^ 41 / 220- 221 0.25 5% MeOH / 45% EtOAc / 50% petr. ether 529 (M + H) + (HPLC ES-MS A2 A7 B1 C1a 98 -LL Vnh - / me 0.27 5% MeOH / 45% EtOAc / 50% petr. ether 495 (M + H) + (HPLC ES-MS A2 A7 B1 C1a 99 Fr. V- ΝΗ 180- 181 0.52 5% MeOH / 45% EtOAc / 50% petr. ether 509 (M + H) + (HPLC ES-MS A2 A7 B1 C1a 100 o V-ΝΗ / -— \ / (Pr-ί ~ Ό ^ ^< ^ 4Ζγ 162- 165 A2 A7 B1 C1a

Table 7

Connected ureas

Inventory, we R M.P. (° C) HPLC (min.) TLC Rt TLC Solution System Mao Spec. (source) Synthet. method 101 T. ^{n n} OMe 162- 165 A1 A2 NW

• · · • ·

131

102 0 A 1 iAATVi m ^{n n Me} hg ^Me 0.10 50% EtOAc / 50% hexane 442 (M + H) + (HPLC ES-MS A2 A4 C2d 103 Ϊ Htr TON It's h. NH-Me Me — NH 125- 130 0.24 40% EtOAc / 60% hexane 512 (M + H) + (FAB A2 C2b

The above examples can be repeated with similar success by replacing the common or specifically described reagents and / or operating conditions of this invention.

From the foregoing description, a person skilled in the art can easily ascertain the main features of this invention without departing from its scope, may make various changes and modifications to the invention in order to adapt it to different uses and conditions.

Claims (67)

1 Compound of Formula I: A-D-B or a pharmaceutically acceptable salt thereof, wherein De -NH-C (O) -NH-, A is a substituted moiety of up to 40 carbon atoms of the formula: -L- (ML ¹ ) _q , where L is a 5 to 6 membered cyclic structure bonded directly to D, L ¹ contains a substituted cyclic moiety having at least 5 members , M is a group that realizes a bridge having at least one atom, q is an integer in the order of 1 - 3; and each of the cyclic structures of L and L ¹ consists of 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and B is substituted or unsubstituted to a tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms, with at least one 6-membered structure bonded directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, where L ¹ is substituted by at least one substituent selected from the group consisting of -SO ₂ R _X , -C (O) R _X, and -C (NR _y ) R _z , R _y is hydrogen, or a carbon-based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally halogen substituted, to halogen, R _z is hydrogen or a carbon-based residue of up to 30 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen, hydroxy and carbon-based substituents of up to 24 carbon 133 atoms, which optionally contain a hetdate Sh *, .'from a game * · ·· * pathway consisting of N, S, and 0 and optionally substituted with halogen; R _x is R _z , or NR _a R b, wherein R _a and R _b are ca a) independently hydrogen, a carbon-based residue of up to 30 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and 0 and optionally substituted by halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen, or -0Si (Rf) 3 where R _f is hydrogen, or a radical of the carbon-based to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen, hydroxy and substituents up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and 0 and optionally substituted with halogen; or b) R _a and R _b together form a 5-7 membered heterocyclic structure with 1-3 heteroatoms selected from the group consisting of N, S and 0, or a substituted 5-7 membered heterocyclic structure with 13 heteroatoms selected from the group, consisting of N, S and O, halogen substituted, hydroxy, or carbon-based substituents of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen; or c) one of R _a and R _b is -C (O) -, a C 1 -C 5 divalent alkylene group, or a substituted C 1 -C ₅ divalent alkylene group attached to the residue L, forming a cyclic structure with at least 5 members; where the substituents of the substituted C! - With ₅ 134 ·· The divalent alkylene group is selected from the group consisting of halogen, hydroxy, and carbon-based substituents of up to 24 carbon atoms, which optionally contain heteroatoms, Y selected from the group consisting of N, S and 0, and halogen-substituted choice; , where B is substituted, L is substituted, or L ¹ is further substituted, the substituents are selected from the group consisting of halogen, to perhalo, and Wn, where η is 0 - 3; wherein each W is independently selected from the group consisting of Q is -CN, -CO ₂ R ⁷ , -C (O) NR ⁷ R ⁷ , -C (O) -R ⁷ , -NO 2, - OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) OR ⁷ , -NR ⁷ C (O) R ⁷ , -Q-Ar, and carbon-based residues of up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and 0 and optionally substituted with one or more substituents independently selected from the group consisting of -CN, -CO2R ^7, -C (O) -R ^7, -C (O) NR ⁷ R ⁷ , -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NO 2, NR ⁷ C (O) R ⁷ , -NR ⁷ C (O) OR ⁷ , and halogen to per-halo; each R ⁷ being independently selected from H or a carbon-based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen; wherein Q is -O-, -S-, -N (R ⁷⁾ -, - (CH2) m- , -C (0) -, -CH (OH) -, - (CH2) mO- , - (CH2 ) mS-, - (CH2) mN (R _{⁷⁾ -, -O (CH2) m} - SNH ^a -, -CX ^a 2-, -S- (CH2) m-, and -N (R ⁷⁾ (CH2 ) _m -, where pp = 1-3, and X ^a is halogen; and Ar is a 5- or 6-membered aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen to per-halogen, and optionally substituted by Ζ _η ι, where n1 is 0 to 3, and each Z is independently selected from the group consisting of -CN, -CO ₂ R ⁷ , -C (O) R ⁷ , -C (O) NR ⁷ R ⁷ , -NO ₂ , -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) OR ⁷ , -NR ⁷ C (O) R ⁷ , 135. '. ··· ··· .. and a carbon-based residue of up to 24 carbon * atoms optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by one or more substituents selected from the group consisting of -CN, -CO ₂ R ⁷ , -COR ⁷ , -C (O) NR ⁷ R ⁷ , -OR ⁷ , -SR ⁷ , -NO ₂ , -NR ⁷ R ⁷ , -NR ⁷ C (O) R ⁷ , and -NR ⁷ C (O) OR ⁷ , wherein R ⁷ is as defined above. A compound according to claim 1, characterized in that: R _y is hydrogen, C 1 -C 10 alkyl, C 1 -C ₁₀ alkoxy, C ₃ -C ₁₀ cycloalkyl having 0-3 heteroatoms, C ₂ -C 10 alkenyl, C 1 -C 10 alkenyl, C ₆ -C ₁₂ aryl, C ₃ - C 10 Hetaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, C ₇ - C ₂₄ aralkyl, C ₇ - C ₂₄ alkaryl, substituted C 1 -C ₁₀ alkyl, substituted C 1 -C 10 alkoxy, substituted C ₃ -C ₁₀ cycloalkyl having 0-3 heteroatoms selected from the group consisting of N, S and 0 substituted C 6 -C ₁₄ aryl substituted C ₃ -C 10 hetero atoms having 1-3 heteroatoms selected from the group consisting of N, S and 0, substituted C ₇ - C ₂₄ alkaryl or substituted C ₇ - C ₂₄ aralkyl, where R _y is substituted a group, it is substituted by halogen up to per-halo, R _z is hydrogen, Ci - Cio alkyl, Ci - Cio alkoxy, _C3 - Cio cycloalkyl having 0-3 heteroatoms, C ₂ - Cio alkenyl, Ci - Cio alkenoyl, C ₆ - C _i2 aryl, C ₃ - Ci ₂ hetaryl having 1 to 3 heteroatoms selected from the group consisting of S, N, and O, C ₇ -C ₂₄ alkaryl, C ₇ -C ₂₄ aralkyl, substituted C 1 -C ₁₀ alkyl, substituted C 1 -C 10 alkoxy, substituted C ₆ -C ₄ aryl substituted C ₃ -C 10 cycloalkyl having 0-3 heteroatoms selected from the group consisting of S, N, and O substituted C ₃ -Ci ₂ hetaryl having 1-3 heteroatoms selected from the group consisting of S, N, and 0, substituted C ₇ - C ₂₄ 136 ....... · · ··· · * · J ·· · ♦ *. Alkaryl, or substituted C ₇ -C 24 aralkyl, where R _z is a substituted group, it is substituted by halogen to per-halo, hydroxy, C 1 -C ₁₀ alkyl, C ₃ -C 12 cycloalkyl having 0-3 heteroatoms selected from the group consisting of 0, S, and N, C ₃ - C ₁₂ heteroatoms having 1 - 3 heteroatoms selected from the group consisting of N, S, and 0, C- | - C _1-6 alkoxy, C ₆ -C 12 aryl, C 1 -C ₆ halo substituted alkyl, to per-halo alkyl, C ₆ - C 12 halo substituted aryl, to per-halo aryl, C ₃ - C ₁₂ halo substituted cycloalkyl, to per- halo cycloalkyl having 0-3 heteroatoms selected from the group consisting of N, S, and O, halo substituted C ₃ - C ₁₂ hetaryl, to per-halo heteryl, halo substituted aryl having 1-3 heteroatoms selected from the group consisting of O, N, and S, halogen substituted C ₇ - C ₂ 4 aralkyl, to per-halo aralkyl, halogen substituted C ₇ - C ₂ 4 alkaryl, to per-halo alkaryl, and -C (O) R _g , R _a and R _b are, a) independently hydrogen, a residue of a carbon-based selected from the group consisting of Ci - Cio alkyl, Ci - C ₁₀ alkoxy, C ₃ - C ₁₀ cycloalkyl, C ₂ - C ₁₀ alkenyl, Ci - C ₁₀ alkenoyl, C ₆ - C ₁ -aryl, C ₃ - Ο _{Ί 2} hetaryl having 1 - 3 heteroatoms selected from the group consisting of Ο, N, and S, C ₃ - C 12 cycloalkyl having 0-3 heteroatoms selected from the group consisting of N, S and O, C ₇ -C ₂ 4 aralkyl, C ₇ -C ₂ 4 alkyl, substituted C 1 -C ₁₀ alkyl, substituted C ₁ -C ₁₀ alkoxy, substituted C ₃ -C 10 cycloalkyl having 0-3 heteroatoms selected from the group consisting of N, S and O, substituted C ₆ - C 12 aryl, substituted C ₃ - C ₁₂ hetaryl Having 1-3 heteroatoms selected from the group consisting of N, S and 0, substituted C ₇ - C ₂ 4 aralkyl, substituted C ₇ - C ₂ 4 alkaryl, where R _a and R _b are a substituted group, it is halogen to per-halogen, hydroxy, C 1 -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl having 0-3 heteroatoms selected from the group consisting of O, S, and N, C ₃ -C 10 heteroaryl, having 1 - 3 heteroatoms selected from the group consisting of N, S, and O, C 1 -C 10 alkoxy, C ₆ -C 12 aryl, C 1 -C ₆ halogen substituted alkyl, to per-halo alkyl, C _s - C _{1 2} halo substituted aryl up to per-halo aryl, C ₃ - Ci ₂ halo substituted cycloalkyl having 0-3 heteroatoms selected from the group consisting of N, S, and O, to per-halo cycloalkyl, halogen substituted C ₃ -C 10 heteroaryl, to per-halo heteryl, halo substituted C 7 - C ₂₄ aralkyl, to per-halo aralkyl, halogen substituted C ₇ -C ₂₄ alkaryl, to per-halo alkaryl, and -C (O) R _g ; or -OSi (R _f ) ₃ , where R _f is hydrogen, C 1 -C 10 alkyl, C 1 -C ₁₀ alkoxy, C ₃ -C 10 cycloalkyl having 0-3 heteroatoms selected from the group consisting of 0, S, and N , C ₆ -Svaryl, C ₃ -Suhetaryl having 1 - 3 heteroatoms selected from the group consisting of 0, S, and N, C ₇ -C ₂₄ aralkyl, substituted C 1 -C ₁₀ alkyl, substituted C 1 -C 10 alkoxy , C ₃ - C ₁₂ cycloalkyl having 0-3 heteroatoms selected from the group consisting of O, S, and N substituted C ₃ - C ₁₂ heteroatoms having 1 - 3 heteroatoms selected from the group consisting of O , S, and N, substituted _C6 - Cio aryl, and substituted C ₇ - C ₂₄ alkaryl, where Rf is a substituted group, it is substituted hal gene to perhalo, hydroxy, Cf - Cio alkyl, _C3 - _C12 cycloalkyl having 0-3 heteroatoms selected from the group consisting of 0, S, and N, C ₃ - Cio hetaryl having 1-3 heteroatoms, selected from the group consisting of N, S, and O, Cf - C ₁₀ alkoxy, C ₆ - C 10 aryl, C ₇ - C ₂₄ alkaryl, C ₇ - C ₂₄ aralkyl, Cf - C ₆ halogen substituted alkyl, -haloalkyl, C ₆ - C ₁₂ halo substituted aryl, to perhalogen aryl, C ₃ - C ₁₂ halo substituted cycloalkyl having 138 0-3 heteroatoms selected from the group consisting of N, S, and 0, to per-halo cycloalkyl, and -C (O) R _g , halogen substituted C ₃ - C ₁₂ Hetaryl to Per-halo heteroaryl Halo substituted C ₇ - C ₂₄ aralkyl, to per-halo aralkyl, halo substituted C ₇ - C ₂₄ alkaryl, to per-halo alkaryl, and -C (O) R _g , or b) R _a and R _b together form a 5-7 membered heterocyclic © structure with 1-3 heteroatoms selected from the group consisting of N, S and 0, or substituted 5-7 membered heterocyclic structure with 1-3 heteroatoms selected from the group consisting of N, S and O, with substituents selected from the group consisting of halogen to per-halo, hydroxy, C 1 -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl having 0-3 heteroatoms selected from the group consisting of 0, S, and N, C ₃ -Ci ₂ hetaryl having 1 - 3 heteroatoms selected from the group consisting of N, S, and O, C 1 -C ₁₀ alkoxy, C ₆ - C ₁₂ aryl, C ₇ - C ₂₄ alkaryl, C ₇ - C ₂₄ aralkyl, halogen but substituted Ci - C ₆ alkyl, up to per-halo alkyl, halo substituted C ₆ - C | ₂ aryl to 1-per-halo aryl, halogen substituted C ₃ -C ₁₂ cycloalkyl having 0-3 heteroatoms selected from the group consisting of N, S, and O, to per-halo cycloalkyl halogen substituted C ₃ -Ci ₂ hetaryl, to per-halo heteroaryl, halogen substituted C ₇ -C ₂₄ aralkyl, to per-halo aralkyl, halo substituted C ₇ -C ₂₄ alkaryl, to per-halo alkaryl, and -C (O) R _g , or c) one of R _a and R _b is -C (O) -, a C 1 -C ₅ divalent alkylene group, or a substituted C 1 -C ₅ divalent alkylene group attached to the residue L, forming a cyclic structure with at least 5 members , 139 wherein the substituents of the substituted C 1 -C 5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, C 1 -C ₁₀ alkyl, C ₃ -C 12 cycloalkyl having 0-3 heteroatoms selected from the group consisting of O, S, and N, C ₃ -C ₁₂ hetaryl having 1-3 heteroatoms selected from the group consisting of N, S, and O, C 1 -C 10 alkoxy, C ₆ -C ₁₂ aryl, C ₇ -C ₂₄ alkaryl, C ₇ - C ₂₄ aralkyl, C 1 - C ₆ halo substituted alkyl, to per-halo alkyl, C 6 - C ₁₂ halo substituted aryl to per halo aryl, C ₃ - C ₁₂ halo substituted cycloalkyl having 0-3 heteroatoms selected by the group, co consisting of N, S, and 0, up to per-halo cycloalkyl, halo substituted C ₃ - Ci ₂ hetaryl up to per-hetaryl, halo substituted C ₇ - C ₂₄ aralkyl, up to per-halo aralkyl, halo substituted C ₇ - C ₂₄ alkaryl, to per-halo alkaryl, and -C (O) R _g , where R 8 is C 1 -C 10 alkyl; -CN, -CO ₂ R _d , -OR _d , -SR _d , -NO ₂ , -C (O) R _e , -NR _d R _e , -NR _d C (O) OR _e , and -NR _d C (O) R _e, and R _d and R _e are independently selected from the group consisting of hydrogen, alkyl WMO, WMO alkoxy, C ₃ .yu cycloalkyl having 0-3 heteroatoms selected from the group consisting of Ο, N, and S, C ₆ . ₁₂ aryl, C ₃ - C ₁₂ hetaryl having 1 - 3 heteroatoms selected from the group consisting of Ο, N, and S, and C ₇ - C ₂₄ aralkyl, C ₇ - C ₂₄ alkaryl, to per-halo substituted C 1 -C 10 alkyl, to per-halo substituted C ₃ -C ₁₀ cycloalkyl having 0-3 heteroatoms selected from the group consisting of Ο, N, and S, to per-halo substituted C ₆ -C ₁₄ aryl, to per-halo substituted C ₃ -C ₁₂ hetaryl selected from the group consisting of Ο, N, and S, halo substituted C ₇ -C ₂₄ alkyl, to per-halo alkaryl, and to per-halo substituted C ₇ -C ₂₄ aralkyl, 140 -: · W is independently selected from the group consisting of -CN, -CO ₂ R ⁷ , -C (O) NR ⁷ R ⁷ , -C (O) -R ⁷ , -NO 2, -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) OR ⁷ , -NR ⁷ C (O) R ⁷ , C, -C 10 alkyl, C ₁ -C 10 alkoxy, C ₂ -C ₁₀ alkenyl, C 1 -C 10 alkenyl, C ₃ -C ₁₂ cycloalkyl having 0-3 heteroatoms selected from the group consisting of O, S, and N, C ₆ -C 10 aryl, C 7 -C ₂ 4 alkaryl, C 7 -C ₂₄ aralkyl, C ₃ - C 10 heteroaryl having 1 to 3 heteroatoms selected from the group consisting of 0, N, and S, C ₄ - C ₂ 3 alkheteroaryl having 1 to 3 heteroatoms selected from the group consisting of Ο, Ν, and S, substituted Ci - _C10 alkyl, substituted Ci - Cio alkoxy, substituted C ₂ - C ₁₀ alkenyl, substituted St - ₁₀ and Keno, _C3 - Cio cycloalkyl having 0-3 heteroatoms selected from the group consisting of Ο, N, and S, substituted C ₆ - C ₁₂ aryl, substituted C ₃ - Cio hetaryl having 1-3 heteroatoms selected of the group consisting of Ο, N, and S, substituted C ₇ -C ₂₄ aralkyl, substituted C 7 - C ₂₄ alkaryl, substituted C ₄ - C ₂₃ alkheteroaryl having 1 - 3 heteroatoms selected from the group consisting of 0 , N, and S, and -Q-Ar; © R ⁷ is selected independently of the group consisting of H, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C ₂ -C 10 alkenyl, C 1 -C 10 alkenoyl, C ₃ -C ₁₂ cycloalkyl having 0-3 heteroatoms selected from the group consisting of O, S, and N, C ₆ - C ₁₄ aryl, C ₃ - C ₁₃ heteryl having 1 - 3 heteroatoms selected from the group consisting of O, N, and S, C ₇ -C 14 alkaryl, C ₇ - C ₂₄ aralkyl, C ₄ - C ₂₃ alkheteroaryl having 1 - 3 heteroatoms selected from the group consisting of O, N, and S to per-halo substituted C 1 -C ₁₀ alkyl, to per-halo substituted C ₃ -C 10 cycloalkyl having 0-3 heteroatoms selected from the group consisting of Ο, N, and S, to per-halo substituted C ₆ -C ™ aryl, to per-halo it is substituted with C ₃ - C ₁₃ hetaryl having 1 - 3 heteroatoms selected from the group consisting of 141 from Ο, Ν, and S, to per-halo substituted C ₇ -C ₂₄ aralkyl, to perhalo-substituted C ₇ -C ₂₄ alkaryl, to per-halo substituted C ₄ -C ₂₃ alkheteroaryl; and Each Z is selected independently of the group consisting of -CN, -CO ₂ R ^{3 * * * 7} , -C (O) -R ⁷ , -C (O) NR ⁷ R ⁷ , -Mag, -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) OR ⁷ , -NR ⁷ C (O) R ⁷ , C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 10 alkenyl, C 1 -C 10 alkenyl, C 3 - C 10 cycloalkyl having 0-3 heteroatoms selected from the group consisting of Ο, N, and S, C 6 -C 6 aryl, C 3 - C 10 hetero atoms having 1 - 3 heteroatoms selected from the group consisting of Ο, N, and S, C7-C24 alkaryl, C7-C24 aralkyl, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from the group consisting of Ο, N, and S, substituted Cf-C10 alkyl, substituted C1-C10 alkoxy substituted C 2 -C 10 alkenyl substituted C 1 -C 10 alkenyl l, C3-C10 cycloalkyl having 0-3 heteroatoms selected from the group consisting of Ο, N, and S, substituted C6-C12 aryl, substituted C7-C24 alkaryl, C7-C24 aralkyl, and substituted C4-C23 alkheteroaryl having 1 - 3 heteroatoms selected from the group consisting of Ο, N, and S; where, if Z is a substituted group, one or more substituents are selected from the group consisting of-CN, -CO 2 R ⁷ , -C (O) R ⁷ , -C (O) NR ⁷ R ⁷ , -OR ⁷ , -SR ⁷ , -NO2, -NR ⁷ R ⁷ , -NR ⁷ C (O) OR ⁷ , and -NR ⁷ C (O) R ⁷ . Compound according to claim 1, characterized in that M is one or more bridging groups selected from the group consisting of -O-, -S-, -N (R ⁷ ) -, - (CH ₂ ) _m -, -C (O) -, -CH (OH) -, - (CH ₂ ) _m O-, - (CH ₂ ) _m S-, - (CH ₂ ) _m N (R ⁷ ) -, -O (CH 2) m CHX ^a -, -CX ^a 2-, -S- (CH ₂ ) m-, and -N (R ⁷ ) (CH ₂ ) _m -, where m = 1 - 3 and X ^a is halogen, and R ⁷ is as defined in claim 1. 142 Compound according to claim 1, characterized in that the cyclic structures with B and L bonds directly to D are not substituted in the ortho position with -OH. A compound according to claim 1, characterized in that the cyclic structures with B and L bonds directly to D are not substituted in ortho position with a residue having ionizing hydrogen and pKa 10 or lower. A compound according to claim 1, characterized in that B of formula I is a substituted or unsubstituted six membered aryl residue or six membered hetaryl residue, said hetaryl residue having from 1 to 4 members selected from the group of hetary atoms, consisting of nitrogen, oxygen and sulfur, the stabilizer of the hetaryl residue being carbon. A compound according to claim 1, wherein B of formula I is an unsubstituted phenyl group, an unsubstituted pyridyl group, an unsubstituted pyrimidinyl group, a phenyl group substituted with a substituent selected from the group consisting of halogen and Wn, where W and η are as defined in claim 1, a pyrimidinyl group substituted with a substituent selected from the group consisting of halogen and Wn, where W and η are as defined in claim 1, or a substituted pyridyl group substituted with a substituent selected from the group consisting of from halo n and Wn, wherein W and η are as defined in claim 1. A compound according to claim 6, characterized in that B of formula I is a substituted phenyl group, a substituted pyrimidinyl group, or a substituted pyridyl group substituted by 1 to 3 times with 1 or more substituents, 143 • · • ·· • · ♦ · selected from the group consisting of -CN, halogen, Ci - _C10 alkyl, Ci - Cio alkoxy, -OH, up to per halo substituted Ci - Cio alkyl, up to per halo substituted Ci - C 1-4 alkoxy or phenyl substituted by halogen to per halo. A compound according to claim 1, characterized in that the L, six membered cyclic structure linked directly to D is a substituted or unsubstituted 6 membered aryl moiety, or a substituted or unsubstituted 6 membered hetaryl moiety, wherein said hetaryl moiety is from 1 to 4 members selected from the group consisting of nitrogen, oxygen and sulfur, the stabilizer of said hetaryl residue being carbon, where one or more substituents are selected from the group consisting of halogen and Wn, where W and η are as defined in claim 1. A compound according to claim 8, characterized in that L, a six-membered cyclic structure linked directly to D, is a substituted phenyl, unsubstituted phenyl, substituted pyrimidinyl, unsubstituted pyrimidinyl, substituted pyridyl or unsubstituted pyridyl group. A compound according to claim 1, characterized in that L ¹ contains a 5 to 6 membered aryl moiety, or a hetaryl moiety, wherein said hetaryl moiety contains from 1 to 4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur. A compound according to claim 1, wherein said substituted cyclic moiety L ¹ is phenyl, pyridinyl or pyrimidinyl. 144 • · A compound according to claim 3, wherein said substituted cyclic moiety L ¹ is phenyl, pyridinyl or pyrimidinyl. A compound according to claim 6, wherein said substituted cyclic moiety L ¹ is phenyl, pyridinyl or pyrimidinyl. A compound according to claim 8, wherein said substituted cyclic moiety L ¹ is phenyl, pyridinyl or pyrimidinyl. A compound according to claim 9, wherein said substituted cyclic moiety L ¹ is phenyl, pyridinyl or pyrimidinyl. A compound according to claim 10, wherein said substituted cyclic moiety L ¹ is phenyl, pyridinyl or pyrimidinyl. A compound according to claim 14, characterized in that M is one or more bridging groups selected from the group consisting of -O-, -S-, -N (R ⁷ ) -, - (CH 2 ) m-, -C (0) -, -CH (OH) -, - (CH2) mO- , - (CH2) mS-, - (CH2) mN (R ⁷⁾ -, -O (CH2) _m SNH ^a -, -CX ^a 2-, -S- (CH 2) m -, and -N (R ⁷ ) (CH 2) _m -, where m = 1 - 3, X ^a is halogen and R ⁷ is hydrogen, or a carbon-based residue of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O, and optionally substituted by halogen to per halo. A compound according to claim 15, characterized in that M is one or more bridging groups selected from the group consisting of -O-, -S-, -N (R ⁷ ) -, - (CH 2 ) m-, -C (0) -, -CH (OH) -, - (CH2) mO- , - (CH2) mS-, - (CH2) mN (R ⁷⁾ -, -O (CH 2) _m - CHX ^a -, -CX ^a 2-, -S- (CH 2) m -, and -N (R ⁷ ) (CH 2) _m -, where m = 1 - 3, X ^a is 145 is halogen, and R ⁷ is hydrogen, or a carbon-based residue of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O, and optionally substituted by halogen to per halo. A compound according to claim 16, characterized in that M is one or more bridging groups selected from the group consisting of -O-, -S-, -N (R ⁷ ) -, - (CH 2 ) m-, -C (O) -, -CH (OH) -, - (CH2) mO- , - (CH2) mS-, - (CH2) mN (R _{⁷⁾ -, -O (CH2) m} - CHX ^a -, -CX ^a 2-, -S- (CH2) m-, and -N (R ⁷ ) (CH 2) _m -, where m = 1 - 3, X ^a is halogen and R ⁷ is hydrogen, or a carbon-based residue of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and 0, and optionally substituted by halogen to per halo. A compound according to claim 17, wherein M is one or more bridging groups selected from the group consisting of -O-, -S-, -N (R ⁷ ) -, - (CH 2 ) m-, -C (0) -, -CH (OH) -, - (CH2) "O-, - (CH2) mS-, - (CH2) mN (R ⁷⁾ -, -O (CH2) _m -SNH ^a -, -CX ^a 2-, -S- (CH2) m-, and -N (R ⁷⁾ (CH2) _m -, where m = 1-3, X ^a is halogen, a R ⁷ is hydrogen , or a carbon-based residue of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O, and optionally substituted by halogen to per halo. A compound according to claim 1, characterized in that L ¹ is further substituted by 1 to 3 times with one or more substituents selected from the group consisting of C ₁ -C 10 alkyl to per halo substituted C 1 -C ™ alkyl, -CN, -OH, halogen, Ci - _C10 alkoxy and up to per halo substituted Ci-Cio alkoxy. 146 A compound according to claim 13, characterized in that L ¹ is further substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -C 10 alkyl to per halo substituted C 1 -C 10 alkyl , -CN, -OH, halogen, C1-C10 alkoxy, and up to per-halo substituted C1-C10 alkoxy. A compound according to claim 18, characterized in that L ¹ is further substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -C 10 alkyl to per halo substituted C 1 -C 10 alkyl , -CN, -OH, halogen, C1-C10 alkoxy, and up to per-halo substituted C1-C10 alkoxy. A compound according to claim 19, characterized in that L ¹ is further substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -C ₁₀ alkyl to per halo substituted C 1 -C 10 alkyl, -CN, -OH, halogen, C1-C10 alkoxy, and to halogen substituted C1-C10 alkoxy. A compound according to claim 20, characterized in that L ¹ is further substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -C 10 alkyl to per halo substituted C 1 -C 10 alkyl , -CN, -OH, halogen, Ci - Cio alkoxy and up to per halo substituted Ci-C ₁₀ alkoxy. A compound according to claim 21, characterized in that L ¹ is further substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -C 10 alkyl to per halo substituted C 1 -C 10 alkyl , -CN, 147 -OH, halogen, C1-C10 alkoxy, and up to per-halo substituted C1-C10 alkoxy. A compound according to claim 1, wherein L ¹ is substituted with -C (O) R _X. A compound according to claim 1, wherein L ¹ is substituted with -SO ₂ R _X. 30. A compound according to claim 1, wherein L ¹ is substituted with -C (O) R _X. A compound according to claim 1, wherein L ¹ is substituted with -SO ₂ R _X. A compound according to claim 1, wherein L ¹ is substituted by -C (O) R _X or -SO ₂ R _X> wherein R _x is NR _a R _b . A compound according to claim 13, wherein L ¹ is substituted with -C (O) R _X , or -SO ₂ R _X , wherein R _x is NR _a R _b , a R _a and R _b are (a) independently hydrogen, a carbon-based residue of up to 30 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O, and optionally substituted with halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and 0 and optionally substituted by halogen, or -Osi (Rf) ₃ , wherein Rf is hydrogen, or a carbon-based residue of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O, and optionally substituted by halogen, hydroxy, and carbon substitutes η l OL mrnannnuu cast pl ιλοΛλο l-l πτηΜ, Ίΐιι νΛτΛΓιΛ • · • · · · 148 atoms selected from the group consisting of N, S and O and optionally substituted with halogen; or * b) R _a and R _b together form a 5-7 membered heterocyclic structure with 1-3 heteroatoms selected from the group consisting of N, S and O, or a substituted 5-7 membered heterocyclic structure with 1-3 heteroatoms, selected from the group consisting of N, S and O, substituted by halogen, hydroxy, or carbon-0 substituents to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O, and choices are halogen substituted; or) c) one of R _a and R _b is -C (O) -, a C 1 -C ₅ divalent alkylene group, or a substituted C 1 -C ₅ divalent alkylene group attached to the residue L, forming a cyclic structure with at least 5 members , wherein the substituents of the substituted C 1 -C ₅ divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon-based substituents of up to 24 carbon atoms, optionally containing heteroatoms, ® selected from the group consisting of N, S and 0 and optionally substituted with halogen. ) A compound according to claim 18, wherein L ¹ is substituted by -C (O) R _{X 1} or -SO ₂ R _X , wherein R _x is NR _a R _b and R _a and R _b are independently hydrogen , or a carbon-based residue of up to 30 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O, and optionally substituted by halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, optionally contain heteroatoms selected from the group consisting of N, S and O and optionally substituted halogen. • · 149 A compound according to claim 19, wherein L ¹ is substituted by -C (O) R _X , wherein R _x is NR _a R _b and R _a and R _b are independently hydrogen or a carbon residue. up to 30 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen, hydroxy and carbon substituents up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and 0, and optionally substituted with halogen. A compound according to claim 20, wherein L ¹ is substituted with -C (O) R _X , or -SO ₂ R _X , wherein R _x is NR _a R _b and R _a and R _b are independently hydrogen or a carbon-based residue of up to 30 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O, and optionally substituted with halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, optionally optionally contain heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen. A compound according to claim 21, wherein L ¹ is substituted with -C (O) R _X , or -SO ₂ R _X , wherein R _x is NR _a R _b and R _a and R _b are independently hydrogen, or a carbon-based residue of up to 30 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S, and 0, and optionally substituted with halogen, hydroxy, and carbon-based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen. 38. Compound of Formula I: 150 A-D-B (I) or a pharmaceutically acceptable salt thereof, characterized in that De -NH-C (O) -NH-, A is a substituted moiety of up to 40 carbon atoms of the formula: -L- (ML ¹ ) _q , where L is a 6 membered aryl moiety, or a 6 membered hetaryl moiety attached directly to D, L ¹ contains a substituted cyclic moiety having the most less than 5 members, M is a group that makes a bridge bond having at least one atom, q is an integer in the order of 1 - 3; and each of the cyclic structures of L and L ¹ consists of 0 - 4 members in the group consisting of nitrogen, oxygen and sulfur, and B is substituted, or unsubstituted, to a tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms, with at least one 6-membered cyclic structure bonded directly to D containing 0-4 members from the group consisting of nitrogen, oxygen and sulfur, where L ¹ is substituted by at least one substituent selected from the group consisting of -SO ₂ R _X , -C (O) R _X, and -C (NR _y ) R ₂ , R _y is hydrogen or a carbon-based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and 0 and optionally halogen substituted, to halogen, R _z is hydrogen or a carbon-based residue of up to 30 carbon atoms, optionally containing heteroatoms selected from Μ O 14 14 PL ΙΙΛ ^ ΛΛ 151 hydroxy and carbon-based substituents of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and 0 and optionally substituted by halogen; R _x is R _z , or NR _a R _b , where R _a and R _b are ca a) independently hydrogen, a carbon-based residue of up to 30 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from the group consisting of N, S and 0 and optionally substituted by halogen, or -OSi (R _f ) ₃ , wherein R _f is hydrogen or a carbon-based residue of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen; or b) R _a and R _b together form a 5-7 membered heterocyclic structure with 1-3 heteroatoms selected from the group consisting of N, S and O, or a substituted 5-7 membered heterocyclic structure with 1-3 heteroatoms selected from the group consisting of N, S and O, substituted by halogen, hydroxy, or carbon-based substituents of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S, and O and optionally substituted by halogen; or c) one of R _a and R _b is -C (O) -, C 1 -C ₅ divalent alkylene rDvna. or a substituted C 1 -C 5 divalent alkylene moiety. 152 bonded to residue L, forming a cyclic structure of at least 5 members, wherein the substituents of the substituted C 1 -C 5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon-based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen; where B is substituted, L is substituted, or L ¹ is further substituted, the substituents are selected from the group consisting of halogen, to perhalo, and Wn, where η is 0 - 3; wherein each W is independently selected from the group consisting of -CN, -CO ₂ R ⁷ , -C (O) NR ⁷ R ⁷ , -C (O) -R ⁷ , -NO2, -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) OR ⁷ , -NR ⁷ C (O) R ⁷ , -Q-Ar, and carbon-based residues of up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R ^7, -C (O) -R ^7, -C (O) NR ⁷ R ⁷ , -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NO _{2 and} NR ⁷ C (O) R ⁷ , -NR ⁷ C (O) OR ⁷ , and halogen to per-halo; each R ⁷ being independently selected from H or carbon residue up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen; wherein Q is -0-, -S-, -N (R ⁷⁾ -, - (CH2) m- , -C (0) -, -CH (OH) -, - (CH2) mO- , - (CH2 ) mS-, - (CH2) mN (R _{⁷⁾ -, -O (CH2) m} - SNH ⁸ -, -CXV, -S- (CH2) m-, and -N (R ⁷⁾ (CH2) m- , where m = 1 - 3, and X ^a is halogen; Ar is a 5- or 6-membered aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen to per-halo, and optionally substituted by Ζ _η ι, where n1 is 0 to 3, and each Z is independently selected from the group consisting of -CN, -CO ₂ R ⁷ , -C (O) R ⁷ , -C (OyNR ⁷ R ⁷ , -NO 2,. -OR ^7; -SR ^{7, -NR?} R ^7, -NR ⁷ C (O) OR ^7, -NR ⁷ C (O) R ^7, and residual carbon-based to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by one or more substituents selected from the group consisting of -CN, -CO2 R ⁷ , -COR ⁷ , ί -C (O) NR ⁷ R ⁷ , -OR ⁷ , -SR ⁷ , -NO ₂ , -NR ⁷ R ⁷ , -NR ⁷ C (O) R ⁷ , and, -NR ⁷ C (O) OR ⁷ , wherein R ⁷ is as defined above; and wherein M is one or more bridging groups selected from the group consisting of -O-, -S-, -N (R ⁷ ) -, - (CH ₂ ) "-. <C (O) -, -CH (OH) -, - (CH ₂ ) _m O-, - (CH ₂ ) _m S-, - (CH 2) _m N (R ⁷ ) -, -O (CH 2) m - CHX ^a -, -CX ^a 27, _{m 5} - (CH 25 _m -, and -N (R ⁷ ) (CH ₂ ) _m -, where m = 1 - 3, and X ^a is halogen. 39. Compound of Formula I: A-D-B (I) or a pharmaceutically acceptable salt thereof, characterized in that De -NH-C (O) -NH-, A is a substituted moiety of up to 40 carbon atoms of the formula: -L- (ML ¹ ) _q , where L is a substituted or unsubstituted phenyl or pyridinyl moiety attached directly to D, L ¹ contains a substituted phenyl, pyridinyl or pyrimidinyl moiety, M is a group that makes a bridge bond having at least one atom, q is an integer in the order of 1 - 3; and. . B is a substituted or unsubstituted phenyl or pyridyl group bonded directly to D. • · 154 where L ¹ is substituted by at least one substituent selected from the group consisting of -SO ₂ R _X , -C (O) R _X, and -C (NR _y ) R _z , R _y is hydrogen or a carbon-based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally halogen substituted, to halogen; and _Rz is hydrogen or a carbon-based residue of up to 30 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen; R _x is R _Z) or NR _a R _b , where R _a n R _b ca a) independently hydrogen, a carbon-based residue of up to 30 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen, or -OSi (R _f ) ₃ , wherein R _f is hydrogen or a carbon-based residue of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen; or ··· • ··· • 9 155 b) R _a and R _b together form a 5-7 membered heterocyclic structure with 1-3 heteroatoms selected from the group consisting of N, S and 0, or substituted 5-7 membered heterocyclic structure with 1-3 heteroatoms selected from the group consisting of N, S and O, substituted by halogen, hydroxy, or carbon-based substituents of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S, and O and optionally substituted with halogen; or c) one of R _a , or R _b is -C (O) -, - a C ₅ divalent alkylene group, or a substituted C 1 -C 5 divalent alkylene group attached to the residue L, forming a cyclic structure with at least 5 members wherein the substituents of the substituted Ci - C ₅ divalent alkylene group are selected from the group consisting of halogen, hydroxy, and substitutes for carbon-based to 24 carbon atoms, which optionally contain heteroatoms selected from the group consisting of N, S and 0 and are optionally substituted by halogen; where B is substituted, L is substituted, or L ¹ is further substituted, the substituents are selected from the group consisting of halogen, to perhalo, and Wn, where η is 0 - 3; wherein each W is independently selected from the group consisting of -CN, -CO ₂ R ⁷ , -C (O) NR ⁷ R ⁷ , -C (O) -R ⁷ , -NO 2, -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) OR ⁷ , -NR ⁷ C (O) R ⁷ , -Q-Ar, and carbon-based residues of up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R ^7, -C (O) R ^7, -C (O) NR ⁷ R ⁷ , -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NO ₂ , NR ⁷ C (O) R ⁷ , -NR ⁷ C (O) OR ⁷ , and halogen to per-halo; each R ⁷ being independently selected from H or a carbon-based residue of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by halogen; wherein Q is -0-, -S-, -N (R ⁷⁾ -, - (CH2) m- , -C (0) -, -CH (OH) -, - (CH2) mO- , - (CH2 ) mS-, - (CH2) mN (R _{⁷⁾ -, -O (CH2) m} - SNH ^a -, -CX ^a 2-, -S- (CH2) m-, and -N (R ⁷⁾ (CH2 ) _m - where m = 1 - 3 and X ^a is halogen; Ar is a 5- or 6-membered aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen to per-halogen, and optionally substituted by Ζ _η ι, where n1 is 0 to 3, and each Z is independently selected from the group consisting of -CN, -CO ₂ R ⁷ , -C (O) R ⁷ , -C (O) NR ⁷ R ⁷ , -NO2 , -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) OR ⁷ , -NR ⁷ C (O) R ⁷ , and a carbon-based residue of up to 24 carbon atoms optionally containing heteroatoms, selected from the group consisting of N, S and 0 and optionally substituted by one or more substituents selected from the group consisting of -CN, - CO2R ⁷ , -C (O) R ⁷ , -C (O) NR ⁷ R ⁷ , -NO2, -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) R ⁷ , and -NR ⁷ C (O) R ⁷ , and a carbon-based residue of up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted by one or more substituents selected from the group consisting of -CN, -CO2R ⁷ , -COR ⁷ , -C (O) NR ⁷ R ⁷ , -OR ⁷ , -SR ⁷ , -NO2, -NR ⁷ R ⁷ , -NR ⁷ C (O ) R ⁷ , and -NR ⁷ C (O) OR ⁷ , and wherein M is one or more groups that make the bridge bond selected from the group consisting of -O-, -S-, -N (R ⁷ ) -, - (CH ₂ ) _m -, -C (O) -, -CH (OH) -, - (CH ₂ ) _m O-, - (CH ₂ ) _m S-, - (CH ₂ ) _m N (R ⁷ ) -, -O (CH ₂ ) _m - CHX ^a -, -CX' ₂ -, -S- (CH ₂ ) _m -, and -N (R ⁷ ) (CH ₂ ) _m - where m = 1 - 3 and X ^a is x & log. 157 A compound according to claim 38, characterized in that the cyclic structures of B and L bound directly to D are not substituted at the ortho position by -OH. A compound according to claim 38, characterized in that the cyclic structures of B and L bonded directly to D are not substituted at the ortho position by a residue having ionizing hydrogen and pKa 10 or lower. A compound according to claim 39, characterized in that the cyclic structures of B and L linked directly to D are not substituted in the ortho position by -OH. A compound according to claim 39, characterized in that the cyclic structures of B and L bound directly to D are not substituted in the ortho position by a residue having ionizing hydrogen and pKa 10 or lower. A compound according to claim 38, wherein the substituents on B and L, and the additional substituents on L ¹ , are selected from the group consisting of C 1 -C 10 alkyl, O to halogen substituted C 1 -C 10 alkyl, CN, OH, halogen, C 1 -C 10 alkoxy, and to per halo substituted C ₁ -C ₁₀ alkoxy. A compound according to claim 39, wherein the substituents for B and L, and the additional substituents for L ¹ , are selected from the group consisting of C 1 -C 10 alkyl, to per halo substituted C 1 -C ₁₀ alkyl, CN , OH, halogen, C 1 -C ₁₀ alkoxy, and up to per halo substituted C 1 -C 10 alkoxy. A compound according to claim 38, wherein L ¹ is substituted with C (O) R _X or SO ₂ R _X. A compound according to claim 39, characterized in that L ¹ is substituted with C (O) R _X or SO ₂ R _X , · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 158 A compound according to claim 46, wherein R _x is NR _a R _b and R _a and R _b are independently hydrogen and a carbon-based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from the group, consisting of N, S and O, and optionally substituted by halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O, and optionally substituted with halogen. A compound according to claim 47, wherein R _x is NR _a R _b and R _a and R _b are independently hydrogen and a carbon-based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from the group, consisting of N, S and 0, and optionally substituted by halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and 0, and optionally substituted with halogen. A compound according to claim 1, which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic and mineral acids, selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid (t-toluene sulfonic acid) naphthalene sulfonic acid, 2-naphthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, iant. acid, fumaric • · • · • « 159 acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and almond acid; and B) acidic salts of organic and mineral bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. A compound according to claim 2, which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic and mineral acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid (1-tosulfonic acid) naphthalic sulfonic acid, 2-naphthalic sulfonic 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 almond acid; and b) acidic salts of organic and mineral bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. • · · · · · · · 160 A compound according to claim 33, characterized in that it is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic and mineral acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid (p-toluene sulfonic acid) -naphthalic sulphonic acid, 2-naphthalic sulphonic 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) acidic salts of organic and mineral bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. A compound according to claim 38, which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic and mineral acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonoric acid, p-toluene sulfonic acid. - \ L · - -1 ------ - - ¹ -------- ~ • · · · • · 161 ca 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 almond acid; and B) acidic salts of organic and mineral bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. 54. A compound according to claim 39, which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic and mineral acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid (1-tosulfonic acid) naphthalic sulfonic acid, 2-naphthalic sulfonic 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 almond acid; and b) acidic salts of organic and mineral bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cation, aliphatic • · 162 substituted ammonium cations and aromatic substituted ammonium cations. 55. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt of a compound of formula I, and a physiologically acceptable carrier. 56. A pharmaceutical composition characterized in that O contains a compound of claim 2, compatible with Formula I, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. 57. A pharmaceutical composition comprising a compound of claim 33, compatible with formula I, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. A pharmaceutical composition comprising a compound of claim 38, compatible with Formula I, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. A pharmaceutical composition comprising a compound of claim 39, compatible with formula I, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. 60. A compound characterized in that it is selected from the group consisting of 3-third butylphenyl ureas of Table 1 above; 5-tert-butyl-2-methoxyphenyl ureas from Table 2 above; 5- (Trifluoromethyl) -2-phenyl ureas qt Table 3 above; 163 3- (trifluoromethyl) -4-chlorophenyl ureas from Table 4 above; 3- (trifluoromethyl) -4-bromophenyl ureas from Table 5 above; 5- (Trifluoromethyl) -4-chloro-2 methoxyphenyl ureas from Table 6 above; and ureas 101 - 103 of Table 7 above. A compound characterized in that it is selected from the group consisting of 3- tert-butylphenyl ureas: N- (3-tert-butylphenyl) -N '- (4- (3- (N-methylcarbamoyl) phenyl) oxy) phenyl urea and N- (3-tert-butylphenyl) -N '- (4- (4-acetylphenoxy) phenyl urea; 5-tert-butyl-2 methoxyphenyl ureas: N- (5-tert-butyl-2-methoxyphenyl) -N '- (4- (1,3-dioxoisoindolin-5-yloxy) phenyl urea, N- (5-tert-butyl-2-methoxyphenyl) -N '- (4- (1-oxoisoindoline- 5-yloxy) phenyl urea, N- (5-tert-butyl-2-methoxyphenyl) -N '- (4- (4-methoxy-3- (Methylcarbamoyl) phenoxy) phenyl urea, and N- (5-tert-butyl-2-methoxyphenyl) -N '- (4- (3- (N-methylcarbamoyl) phenoxy) phenyl urea; 2-methoxy-5-trifluoromethyl) phenyl ureas: N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl- 4- pyridyloxy) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, · · 164 N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (methylmethylcarbamoyl) (4-pyridyloxy)) phenyl) urea, and N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (methylmethylcarbamoyl) (4-pyridyloxy)) phenyl) urea; 4-chloro-3- (trifluoromethyl) phenyl ureas: N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, and N, N-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea. 4-bromo-3- (trifluoromethyl) phenyl ureas: N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -1H '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, · · · · · · · · · · · · · · · · · · · 165 N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (methylmethylcarbamoyl) (4-pyridyloxy)) phenyl) urea, and N- (4-bromo-3- (trifluoromethyl) phenyl) -1 N- (3-chloro-4- (2- (methylmethylcarbamoyl) (4-pyridyloxy)) phenyl) urea; and 2-Methoxy-4-chloro-5- (trifluoromethyl) phenyl ureas: N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (3- (2- (Methylcarbamoyl) -4- pyridyloxy) phenyl) urea, 1- {1- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (Mmethylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, and N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea. Use of a compound of formula I according to claim 1 for the treatment of cancer cell growth mediated by Raf kinase. Use of a compound of formula I according to claim 33 for the treatment of cancer cell growth mediated by Raf kinase. 64. Use of a compound of formula I according to claim 38 for the treatment of cancer cell growth mediated by Raf kinase. Use of a compound of formula I according to claim 39 for the treatment of cancer cell growth mediated by raf kinase. • · • ♦ 9 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 9 · · · · 9 · · · · · · · · · · · · 166 66. Use of a compound for the treatment of cancer cell growth mediated by a raf kinase selected from the group consisting of: 3-third butylphenyl ureas of Table 1 above; 5-tert-butyl-2-methoxyphenyl ureas from Table 2 above; 5- (Trifluoromethyl) -2-phenyl ureas of Table 3 above; 3- (trifluoromethyl) -4-chlorophenyl ureas from Table 4 above; 3- (trifluoromethyl) -4-bromophenyl ureas from Table 5 above; 5- (Trifluoromethyl) -4-chloro-2 methoxyphenyl ureas from Table 6 above; and ureas 101 -103 of Table 7 above. 67. Use of a compound for the treatment of cancerous growth by mediated by a raf kinase selected from the group consisting of: 3-tert-butyl-phenyl urea: N- (3-tert-butylphenyl) -N '- (4- (3- (N-methylcarbamoyl) phenoxy) phenyl urea and N- (3-tert-butylphenyl) -N '- (4- (4-acetylphenoxy) phenyl urea; 5-tert-butyl-2 methoxyphenyl ureas: N- (5-tert-butyl-2-methoxyphenyl) -N '- (4- (1,3-dioxoisoindolin-5-yloxy) phenyl urea, N- (5-tert-butyl-2-methoxyphenyl) -N '- (4- (1-oxoisoindolin-5-yloxy) phenyl urea, N- (5-tert-butyl-2-methoxyphenyl) -N '- (4- (4-methoxy-3- (methylmethylcarbamoyl) phenoxy) phenyl urea, and • · · · · · · · · · · · · · · »• 4 ····· 9 · 9 9 9 9 9 99 99 9 9 9 9 99 167 N- (5-tert-butyl-2-methoxyphenyl) -N '- (4- (3- (N-methylcarbamoyl) phenoxy) phenyl urea; • 2-methoxy-5-trifluoromethyl) phenyl ureas: _l-N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl- 4-pyridyloxy) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) ) phenyl) -N '- (4- (2-carbamoyl- 4-pyridyloxy) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2- (1M-methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (Nmethylcarbamoyl) (4-pyridyloxy)) phenyl) urea, and N- (2-methoxy-5- (trifluoromethyl) phenyl) -N- (3-chloro-4- (2- (methylmethylcarbamoyl) (4-pyridyloxy)) phenyl) urea; f 4-chloro-3- (trifluoromethyl) phenyl ureas: N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, and N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea. 4 · 4 ·· · · · 44 • ·> · · 4 · · · · · • “44 4” · · ·· · ♦ · • · · · · 4 · · · · · · · · · · 4 · 4 44 * 4 • · · · · · · · · · · · · 168 4-bromo-3- (trifluoromethyl) phenyl ureas: N- (4-bromo-3- (trifluoromethyl) phenyl) -N- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (methylmethylcarbamoyl) (4-pyridyloxy)) phenyl) urea, and N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (1Hmethylcarbamoyl) (4-pyridyloxy)) phenyl) urea; and 2-Methoxy-4-chloro-5- (trifluoromethyl) phenyl ureas: N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (3- (2- (Methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (Mmethylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea, and N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea.