SK9882001A3 - Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors - Google Patents

Description

Technical field

The present invention describes the use of aryl ureas in the treatment of raf-related diseases and the use of pharmaceutical compositions for the treatment of this disease.

BACKGROUND OF THE INVENTION

The p21 ^ras oncogene is the major contributor to the development and progression of solid cancers in human subjects and is mutated 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, ras protein is a key element of the growth factor receptor-regulated signal transduction cascade in almost all tissues (Avruch et al., Trends Biochem. Sci. 1994, 19, 279-83). The ras guanine nucleotide binding protein is biochemical and cyclization between the GTP-bound activated form and the GDP-bound resting form is precisely regulated by the activity of the endogenous ras GTPase and other regulatory proteins. In cancer mutant ras cells, endogenous GTPase activity is small, and therefore the protein imparts constitutive growth signals to downstream effectors, e.g. the enzyme rafkinase, resulting in cancerous growth of cells that carry these mutants (Magnuson et al., Semin. Cancer Biol. 1994, 5, 247-53). Inhibiting the effect of active ras by inhibiting the rafkinase signaling pathway by applying inactivated antibodies to rafkinase or by coexpressing dominant negative rafkinase or dominant negative MEK, a rafkinase substrate, has been found to reverse the transformed cells to a normal growth phenotype (see: Daum et al., Trends Biochem. Sci., 1994, 19, 474-80, Fridman et al., J. Biol. Chem., 1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 426-28) further suggests that inhibition In the same way, inhibition of rafkinase (antisense oligodeoxynucleotides) was correlated in vitro and in vivo with growth inhibition of various human tumor types (Monia et al., Nat. Med., 1996, 2). , 668-75).

SUMMARY OF THE INVENTION

The present invention provides compounds that are inhibitors of the enzyme rafkinase. Since the enzyme is a downstream effector of p21 ^ras , inhibitors are effective in pharmaceutical formulations for use in human or veterinary subjects where inhibition of the rafkinase pathway, e.g. in the treatment of tumors and / or cancer cell growth associated with raffinase. In particular, the compounds are useful in the treatment of human or animal cancers, e.g. mouse carcinomas, since the progression of these carcinomas is dependent on the cascade of signal transduction of the ras protein and is therefore prone to treatment by disrupting the cascade, ie by inhibiting raffinase. Thus, the compounds of the invention are effective in the treatment of solid tumors, e.g. carcinomas (e.g., lung, pancreas, thyroid, bladder or colon cancer), myeloid diseases (e.g., myeloid leukemia), or adenoma (e.g., villous colon adenoma).

Therefore, the present invention provides compounds commonly referred to as aryl ureas, including both aryl and heteroaryl analogs that inhibit the rafkinase pathway. The invention also provides a method of treating raf-related diseases in a human or animal subject. Accordingly, the invention is directed to compounds and methods for treating cancer cell growth mediated by rafkinase, comprising administering a compound of Formula I

A-D-B (I) in Formula I, D is -NH-C (O) -NH-,

A is a substituted moiety having up to 40 carbon atoms in the formula: -L- (ML *) -, where L is a 5- or 6-membered cyclic structure bonded directly to D, L ¹ er contains a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of 1-3; and each cyclic structure of L and L ¹ contains 0-4 members of a group consisting of a nitrogen, oxygen or sulfur atom, and

B is a substituted or unsubstituted to tricyclic aryl or heteroaryl moiety having up to 30 carbon atoms with at least one 6-membered cyclic structure bonded directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L ¹ is substituted at least one substituent selected from the group consisting of -SChRx, -C (O) R _X and -C (NR _y ) R _z ,

R _y is a hydrogen atom or a carbon-based moiety having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen, except per halogen,

R ₂ is a hydrogen atom or a carbon-based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur 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 nitrogen, oxygen or sulfur atoms and are optionally substituted with halogen;

R _x is R _z or NR _and R b, wherein the substituents R _a and R b are

(a) independently hydrogen, a carbon-based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur 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 nitrogen, oxygen and sulfur atoms and are optionally substituted with halogen, or

-Si (Rf) 3, wherein Rf is hydrogen or a carbon-based moiety having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen, hydroxy and carbon-based substituents up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen; or

b) R _a and R b together form a 5-7 membered heterocyclic structure containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or a substituted 5-7 membered heterocyclic structure having 1-3 heteroatoms selected from the group consisting of a nitrogen, oxygen and sulfur atom substituted with halogen, hydroxy or carbon-based substituents having up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur and optionally substituted with halogen; or

c) one of the substituents R _a or R b is -C (O) -, a C 1 -C 8 divalent alkylene group or a substituted C 1 -C 8 divalent alkylene group bonded to the L moiety to form a cyclic structure with at least 5 members wherein the substituents of the substituted C 1-6 C 1-4 divalent alkylene groups are selected from the group consisting of halogen, hydroxy and carbon-based substituents having up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen;

wherein B is substituted, L is substituted or L ¹ is additionally substituted and the substituents are selected from the group consisting of halogen, up to total halogen substitution being possible, and Wn, wherein n is 0-3;

wherein each W is independently 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 , -NR ⁷ R ⁷ , NO ₂ , -NR ⁷ C (O) R ⁷ ,

-NR ⁷ C (O) OR ⁷ , -Q-Ar, and carbon-based moieties having up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of re-atom

I of nitrogen, oxygen and sulfur and optionally substituted with one or more substituents independently 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 , -NR ⁷ R ⁷ , NO ₂ , -NR ⁷ C (O) R ⁷ , -NR ⁷ C (O) OR ^7, and halogen, up to total halogen substitution being possible; wherein each R ⁷ is independently selected from hydrogen or a carbon-based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen, wherein Q is -O-, -S -, -N (R ⁷⁾ -, - (CH2) m-, -C (0) -, -CH (OH) -, - (CH 2) n 0-, - (CH 2) m S-, - (CH 2 ) m N (R ⁷⁾ -, -0 (CH 2) _m CHX ^a -, -CX ^a ₂ -, -S- (CH _{2) m} - and

-N (R ⁷ ) (CH ₂ ) _m -, wherein the index m = 1-3 and X ^a is halogen; and

Ar is a 5- or 6-membered aromatic structure containing 0-2 members of the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen except for total halogen substitution and optionally substituted by _Zn i, wherein the index nl is 0-3 and each Z is independently selected from the group consisting of -CN, -CO ₂ R ⁷ , -C (O) NR ⁷ R ⁷ , -NO 2, -OR ⁷ , -SR ⁷ , NR ⁷ R ⁷ , -NR ⁷ C (O) OR ⁷ , -C (O) R ⁷ , -NR ⁷ C (O) R ^7, and carbon-based moieties of up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur and optionally substituted with one or more substituents independently 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 , -NR ⁷ R ⁷ , NO ₂ , - NR ⁷ C (O) R ⁷ and -NR ⁷ C (O) OR ⁷ , wherein R ⁷ is as defined above.

In Formula I, suitable hetaryl groups include, but are not limited to, aromatic rings having 5-12 carbon atoms or cyclic systems having 1-3 rings, of which at least one is aromatic, in which one or more e.g. 1-4 carbon atoms in one or more rings may be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 37 atoms. For example, B may be 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-thienyl

4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or

5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4- pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5 yl,

1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or 5-yl, 1,3,4-thiadiazol-2-or - 5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3-or-5- yl, 1,2,3-thiadiazol-4- or 5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3 or 4-pyridazinyl , pyrazinyl, 2-, 3-, 4-, 5-, 6-, or 7-benzofuryl, 2-, 3-, 4-, 5-, 6-, or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4- , 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5 -, 6- or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benzo-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl , 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5 -, 6-, 7-, 8 or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl or additionally optionally substituted phenyl , 2- or 3-thienyl, 1,3,4-thiadiazolyl, 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- l, 2,4-thiadiazol-2-yl.

Suitable alkyl groups and alkyl moieties, e.g. alkoxy groups, etc., throughout the text include methyl, ethyl, propyl, butyl, etc., including all branched or unbranched isomers such as e.g. isopropyl, isobutyl, sec-butyl, tert-butyl, etc.

Suitable aryl groups that do not contain heteroatoms include e.g. phenyl and 1- and 2-naphthyl.

The term "cycloalkyl" as used herein refers to a cyclic structure with or without alkyl substituents such that e.g. "C 4 cycloalkyl" includes methyl substituted cyclopropyl groups as well as cyclobutyl groups. The term "cycloalkyl" also includes saturated heterocyclic groups.

Suitable halogen groups include F, Cl, Br and / or I, one to persubstitution is possible (all H atoms in the group replaced by halogen atoms), wherein the alkyl group is halogen substituted, with mixed substitution possible.

The invention also relates to the compounds of formula I per se (per se).

The present invention also discloses pharmaceutically acceptable salts of Formula I. Suitable pharmaceutically acceptable salts are well known to the skilled artisan and include basic salts of inorganic and organic acids, including e.g.

hydrochloric, hydrobromic, sulfuric, trifluoromethanesulfonic, benzenesulfonic, sulfonic, 2-naphthalenesulfonic, acetic, lemon, milk, oxalic, succinic, salicylic, phenylacetic, phenylglycolic, orthophosphoric, methanesulfonic, methanesulfonic, methanesulfone, , benzoic acid. In addition, pharmaceutically acceptable salts include the acid salts of inorganic bases, e.g. salts containing alkali metal cations (e.g. Li ⁺ , Na ⁺ or K ⁺ ), alkaline earth metal cations (e.g. Mg ^2+,, Ca ²⁺ or Ba ²⁺ ), ammonium cation, as well as acid salts of organic bases including aliphatic and an aromatic group substituted with ammonia; and quaternary ammonium cations, e.g. resulting from protonation or peralkylation of triethylamine, N, N -diethylamine, N, N -dicyclohexylamine, lysine, pyridine, N, N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1 , 5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).

Many of the compounds of formula 1 have asymmetric carbon atoms and can therefore exist in racemic and optically active forms. Methods for separating enantiomeric and diastereomeric mixtures are well known in the art. The present invention encompasses any isolated racemic or optically active form of the compounds of Formula I having rafkinase inhibitory activity.

General methods of preparation

Compounds of formula I may be prepared by known chemical reactions and procedures, some of which may be prepared from starting materials that are commercially available. However, the following general methods of preparation are set forth below and are intended to serve as a guide for the skilled artisan in synthesizing these compounds. Methods of preparation are provided with more detailed examples described in the experimental section.

»P

Substituted anilines can be prepared by standard methods (March. Advanced Organic Chemistry, 3 ^rd Ed .; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations, VCH Publishers: New York (1989)). According to Scheme I, arylamines are generally synthesized by reducing nitroaryls with catalysts (metals), e.g. Ni, Pd or Pt and H2, or hydride transfer agents such as e.g. formate, cyclohexadiene or borohydride (Rylander. Hydrogenation Metods, Academic Press: London, UK (1985)). Nitroaryls can also be directly reduced by a strong hydride source, e.g. LiAlH4 (Seyden-Penne. Reductions by Alumino- and Borohydrides in Organic Synthesis \ VCH Publishers: New York (1991)) or zero-charge metals, e.g. Fe, Sn, or Ca, usually in acidic medium. There are many methods for nitroaryl synthesis (March. Advanced Organic Chemistry, 3 ^rd Ed .; John Wiley, New York (1985). Larock. Comprehensive Organic Transformations, VCH Publishers: New York (1989)).

ArNO ₂

H ₂ (catalyst) (e.g. Ni, Pd, Pt) ΜΊ

ArNH ₂ \ M (0)> X (eg Fe, Sn, Ca)

Scheme I Reduction of nitroaryls to arylamines

Nitraryls are commonly prepared by electrophilic aromatic nitration with HNO3 or alternatively by a NO2 ⁺ source. The nitroaryls may be further processed prior to reduction. Thus substituted nitroaryls

Ar-H

HNO ₃

ArNO _{2 with a} strong leaving group (e.g., F, Cl, Br, etc.) may undergo substitution reactions when reacting with nucleophiles, e.g. thiolate (shown in the examples in Scheme II) or phenoxide. Nitroaryls may also be subject to Ullman-type coupling reactions (Scheme II).

Br-Ar

CuO / base

ArSH base

Selected nucleophilic aromatic substitution by nitroaryl

Nitroaryls may also undergo metal-mediated cross-coupling reactions in transit. For example, nitroaryl electrophiles, e.g. nitroaryl bromides, iodides or triflates are subject to cross-coupling reactions with palladium-mediated aryl nucleophiles, e.g. with aryl boronic acids (Suzuki reaction, shown below), arylcines (Stille reaction) or arylzines (Negishi reaction) to obtain biaryls (5).

ArB (OR ') ₂ --------> Pd (0)

Either nitroaryls or anilines can be converted to the corresponding arenesulfonyl chlorides (7) by reaction with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source, e.g. KF, provides sulfonyl fluoride (8). Reacting the sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, e.g. tris (dimethylamino) sulfonium difluorotrimethylsiliconate (TASF) to give the corresponding trifluoromethylsulfone (9). Alternatively, the sulfonyl chloride 7 can be reduced to arenethiol (10) e.g. zinc amalgam. Treatment of thiol 10 with CHCIF 2 in the presence of a base gives difluoromethylmercaptan (11), which can be oxidized to sulfone (12) by any of various oxidants, including a mixture of CrCl 2 and acetic anhydride (Sedova et al., Zh. Org. Khim. (568).

r r

(MyNfoS M63S1F2 MagSICFa

Scheme III Selected Methods for Synthesis of Fluorinated Arylsulfones

According to Scheme IV, the unsymmetrical preparation of urea involves the reaction of an arylisocyanate (14) with an arylamine (13). The heteroaryl isocyanate can be synthesized from heteroarylamine by reaction with phosgene or phosgene equivalent, such as e.g. trichloromethylchloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene) or N, N'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, e.g. an ester, an acid halide or an anhydride by Curtius rearrangement. Thus, reaction of the acid derivative 16 with an azide source and subsequent rearrangement affords an isocyanate. The corresponding carboxylic acid (17) can be subjected to Curtius rearrangements using diphenylphosphoryl azide (DPPA) or similar agents.

ABOUT

Ar ^{1 —} NH1 13

COCI ₂ . HjN-Ar ²

Ar'-NCO ------- * 14

N ₃ DPPA

O O

ABOUT

Scheme IV Selected methods for the preparation of unsymmetrical urea

In the final step, the ureas may be further processed by methods known to the skilled artisan.

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 spray, or rectally in dosage unit formulations. The term "injected" includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as the use of infusion techniques. The one or more compounds may be together one or more non-toxic pharmaceutically acceptable carriers and, if desired, other active ingredients.

Formulations intended for oral use may be prepared according to any suitable processing methods for pharmaceutical preparations. Such compositions may contain one or more agents selected from the group consisting of diluents, sweeteners, flavoring agents, coloring agents and preservatives to provide readily digestible compositions. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be e.g. inert diluents, e.g. calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and tablet disintegrants, e.g. corn starch or alginic acid; and binders, e.g. magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby prolong the effect. For example, retardants, e.g. glyceryl monostearate or glyceryl distearate. These compounds may also be prepared in a solid, rapid release form.

Formulations for oral use may be solid gelatin capsules, wherein the active ingredient is admixed with an inert solid diluent, e.g. calcium carbonate, calcium phosphate or kaolin, or they may be soft gelatin capsules, wherein the active ingredient is admixed with water or an oil medium such as e.g. peanut oil, mineral oil or olive oil.

Aqueous suspensions containing the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used. Such excipients are suspending agents, e.g. sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia; dispersants or detergents may be natural phosphatides, e.g. lecithin or condensation products or an alkene oxide with fatty acids, e.g. polyoxyethylene stearate, or the condensation products of ethylene oxide with long-chain aliphatic alcohols, e.g. heptadecaethyleneoxycethanol, or the condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, e.g. polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, e.g. , polyethylene. Aqueous suspensions may also contain one or more preservatives, e.g. ethyl or H-propyl (N-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersant or detergent, a suspending agent and one or more preservatives. Suitable dispersants or detergents and suspending agents are illustrated in the above examples. Other excipients, e.g. sweeteners, flavorings and coloring agents.

The compounds may also be in the form of anhydrous liquid preparations, e.g. as oily suspensions, which may be prepared by suspending the active ingredients in a vegetable oil, e.g. peanut oil, olive oil, sesame oil or peanut oil, or in mineral oil, e.g. in paraffin oil. The oily suspensions may contain a thickening agent, e.g. beeswax, hard paraffin or cetyl alcohol. Sweeteners, e.g. as mentioned above, and flavorings may be added to provide readily digestible oral preparations. These compositions may be protected by the addition of an antioxidant, such as e.g. ascorbic acid.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, e.g. olive oil or peanut oil or mineral oil, e.g. paraffin oil or mixtures thereof. Suitable emulsifiers may be natural gums, e.g. gum arabic or tragacanth, natural phosphatides, e.g. soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, e.g. sorbitan monooleate and condensation products of said partial esters with ethylene oxide, e.g. polyoxyethylene. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, e.g. glycerol, propylene glycol, sorbitol or sucrose. Such formulations may contain a soothing agent, a preservative and a flavoring and coloring agent.

The compounds may also be administered in the form of suppositories for rectal administration of the drug. These formulations can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at normal temperature but liquid at rectal temperature and therefore dissolves in the rectum to release the drug. Such materials include cocoa oil and polyethylene glycols.

f r

For all of the treatment regimens used herein, the compounds of formula I will preferably be from 0.01 to 200 mg / kg of total body weight per day. The daily dose administered by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and the use of infusion techniques will preferably be from 0.01 to 200 mg / kg of total body weight. The daily dose for rectal administration will preferably be from 0.01 to 200 mg / kg of total body weight. The daily topical dosage will preferably be from 0.1 to 200 mg, which will be administered one to four times daily. The daily dose for inhalation will preferably be from 0.01 to 10 mg / kg of total body weight.

However, it will be clear to the professional public that the various routes of administration will depend on various factors, i. from all those commonly considered when therapeutic agents are applied. It will be appreciated that the specific dosage level for any individual patient will depend on various factors including the activity of the specific compound used, the patient's age, the patient's body weight, the general health of the patient, the sex and lifestyle of the patient. Time of administration, route of administration and rate of excretion, drugs used in combination, and severity of the status of ongoing therapy. Nevertheless, it will be further clear to the professional public that the optimal course of the treatment, i.e., the treatment, can be achieved. the method of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof administered over a specified number of days can be ascertained by persons skilled in the art using conventional treatment tests.

Obviously, the specific dose level for any patient will depend on various factors, including the activity of the specific compound used, age, body weight, general health, sex, eating habits, time and mode of administration, excretion rate, drug combination and other conditions throughout therapy.

All data of all applications, patents and publications cited above and below are hereby incorporated by reference, including provisional application no. 50/1 15,877, filed Jan. 13, 1999, and provisional application no. No. 09 / 257,266, filed

February 25, 1999.

Compounds of formula I may be prepared from known compounds (or starting materials which may be prepared from known compounds), e.g. using the general preparation methods described above. The activity of the provided compound for inhibiting rafkinase can be routinely determined, e.g. procedures below. The following examples are for illustrative purposes only and are not intended to limit the present invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

All reactions are carried out in glass containers which have been previously flame-dried or in an oven under dry argon or dry nitrogen pressure. Stirring was performed magnetically unless otherwise indicated. Appropriate liquid substances and solutions were operated via syringe or cannula and introduced into reaction vessels through a rubber septum.

Unless otherwise stated, the term "concentrated under reduced pressure" refers to the use of a Buchi rotary evaporator at about 15 mmHg. Unless otherwise stated, the term "under high vacuum" refers to a vacuum of 0.4 - 1.0 mm Hg.

All temperatures are uncorrected in degrees Celsius (° C). Unless otherwise indicated, all proportions and percentages are by weight.

Technically pure reagents and solvents were used without further purification. N -cyclohexyl-N '- (methylpolystyrene) carbodiimide was purchased from Calbiochem-Novabiochem Corp. The following were purchased: 3-tert-butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-3- (trifluoromethyl) aniline, 4-chloro-3- (trifluoromethyl) aniline, 2-methoxy-5- (trifluoromethyl) aniline, 4- tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-5- (trifluoromethyl) aniline and 4-chloro-3- (trifluoromethyl) ) phenyl isocyanate, and were used without further purification. Synthesis of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A.

• 9

Cordi et al. EP 542,609; IBID Bioorg. Med. Chem., 3, 1995, 129), 4- (3-carbamoylphenoxy) -1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-tert-butylphenylisocyanate (O. Rohr et al. DE 2,436,108) and 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491) have been described above.

Thin layer chromatography (TLC) was performed on a glass plate coated with Whatman® silica gel, 60A F-254 silica gel, 250 µm thick. Visualization was performed by one or more of the following techniques: (a) ultraviolet radiation, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of molybdophosphoric acid in ethanol and subsequent heating, (d) immersion of the plate in cerium sulfate solution; followed by heating and / or (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine and subsequent heating. Column chromatography (flash chromatography) was performed using EM Science® 230-400 mesh silica gel.

Melting points were determined using a Thomas-Hoover instrument or a Mettler FP 66 automated to determine the melting point, and these melting points are not corrected. Fourier transform infrared spectroscopy spectra were obtained from a Mattson 4020 Galaxy Serie spectrophotometer. 1 H NMR spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with a standard of either Me. Si (δ 0.00) or residual protonated solvent (CHCl 3 δ 7.26; MeOH δ 3.30; DMSO δ 2 , 49). ¹³ C NMR spectra were measured with a General Electric GNOmega 300 (75 MHz) spectrometer with solvent (CDCl 3 δ 77.0; MeOD-d3; δ 49.0; DMSO d 6 Ô 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra were obtained either as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact ionization mass spectra (EI-MS) were obtained from a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics desorption chemical ionization probe for sample introduction. The ion source was maintained at 250 ° C. Electron ionization surges were performed by a rrs of 70 eV electron energy and a 300 μΑ flux trap. Liquid cesium ionization secondary mass spectra (FABMS), the latest version of the fast atom bombardment mass spectrum, were obtained from a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained from a Hewlett Packard MS-Engine (5989A) spectrometer with methane or ammonia gas reagent (1 x 10 ^-4 torr to 2.5 x 10 ^-4 torr). The Direct Advertising Desorption Chemical Ionization (DCI) probe (Vaccumetrics, Inc.) was ramped with 0-1.5 amps in 10 sec and held at 10 amps until all traces of samples had disappeared (~ 1-2 min). Spectra were taken from 50-800 amu at 2 sec per image. HPLC electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. 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 using a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM surface layer; 25 mx 0.2 mm) and a Hewlett Packard 5971 selective mass detector (ionization) energy 70 eV). Elemental analysis was performed by Robertson Microlit Labs, Madison NJ.

All compounds shown by NMR spectra, LRMS and either elemental analysis or HRMS are consistent with the assigned structure.

List of abbreviations and acronyms

AcOH acetic acid anh without water atm atmosphere BOC / Crc-butoxycarbonyl CDI 1,1'-carbonyldiimidazole conc concentrated D day (s) dec degradation

DMAC N, N-dimethylacetamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1 H) -pyrimidinone DMF N, N-dimethylformamide i DMSO dimethyl sulfoxide DPPA diphenylphosphoryl EDCI l- (3-dimethylaminopropyl) -3-ethylcarbodiimide EtOAc acetate EtOH ethanol (100%) Et ₂ O diethyl ether Et ₃ N triethylamine h lesson HOBT 1-hydroxybenzotriazole ZM-CPBA 3-chloroperoxybenzoic acid MeOH methanol pet. ether THF petroleum ether (boiling range 30-60 ° C) tetrahydrofuran TFA trifluoroacetic acid tf trifluoromethanesulfonyl

DETAILED DESCRIPTION OF THE INVENTION

A. General Methods for Synthesis of Substituted Anilines

Al. General process for the preparation of arylamine, including ether formation, ester saponification, Curtius rearrangement, and deprotection of the carbamate.

Synthesis of 2-amino-3-methoxynaphthalene

·· P

Step 1. Methyl 3-methoxy-2-naphthoate

A slurry 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 min, 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 (about 0.4 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10.30 g): 1 H NMR (DMSO-d6) 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, 1 H).

Step 2. 3-Methoxy-2-naphthoic acid

A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room temperature was treated with a solution of 1 N NaOH (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 hexanes then washed several times with hexanes 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), 7.91 (d, J = 8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (br s, 1H).

• ·

Step 3. 2- (N - (carbobenzyloxy) amino-3-methoxynaphthalene)

A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et ₃ N (2.59 mL, 18.6 mmol) in anhydrous toluene (70 mL) was stirred at room temperature for 15 min. The reaction mixture was then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) by pipetting into the reaction mixture. The resulting mixture was heated at 80 ° C for 2 hours. After the mixture was cooled to room temperature, benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was then heated to 80 ° C overnight. The resulting mixture was cooled to room temperature, quenched with 10% 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 on silica gel using 14% EtOAc and 86% hexane to give 2- (N- (carbobenzyloxy) amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%); ^H NMR (DMSO- -d ₆ ) δ 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 5H), 7.72-7.75 (m, 2H), 8 20 (s, 1H), 8.76 (s, 1H).

OMe

Step 4. 2-Amino-3-methoxynaphthalene

A slurry of 2- (N - (carbobenzyloxy) amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd / C (0.5 g) in EtOAc (70 mL) was kept at room temperature overnight . nitrogen (using a balloon) at room temperature. the mixture was filtered through a pad of Celite and concentrated under reduced pressure to give 2-amino-3metoxynaftalén as a pale pink powder (2.40 g, 85%): ^H NMR (DMSO- - (d) δ 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H) 7.56 (d, J = 8.0 Hz, 1H) EI-MS m / z 173 (M < ^{+ >} ).

A2. Ω-Carbamylaniline synthesis involving the preparation of carbamylpyridine and nucleophilic coupling with arylamine.

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

ABOUT

Step 1a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide by Menisci reaction

Warning: this reaction is very dangerous and potentially explosive. To a stirred solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temperature was added concentrated H 2 SO 4 (3.55 mL) to form an exothermic reaction. To this mixture was added H 2 O 2 (30 wt% in H 2 O, 17 mL) followed by FeSO 4 .7H 2 O (0.56 g) to form another exothermic reaction. The resulting mixture was stirred in a dark room at room temperature for 1 hour, then slowly warmed at 45 ° C for 4 hours. After bubbling is complete, the reaction is heated at 60 ° C for 16 hours. The resulting cloudy brown solution was diluted with H 2 O (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with saturated NaCl solution (3 x 150 mL), then combined, dried (MgSO 4) and filtered through a pad of silica gel and washed with EtOAc. The resulting brown oil was purified by silica gel column chromatography with a gradient of 50% EtOAc / 50% hexanes to 80% EtOAc / 20% hexanes). The resulting yellow oil crystallized at 0 ° C after 72 hours to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc / 50% hexane) R f = 0.50 ;

1 H NMR (CDCl 3) δ 3.04 (d, J = 5.1 Hz, 3H), 7.43 (dd, J = 5.4, 2.4 Hz, 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 hydrochloride via picolinic acid

Anhydrous DMF (6.0 mL) was slowly added to SOCl 2 (180 mL) over a temperature range of 40 ° to 50 ° C. The solution was stirred in this temperature range for 10 min, then picolinic acid (60.0 g, 487 mmol) was added portionwise over 30 min. The resulting solution was heated at 72 ° C (vigorous SO 2 release) for 16 hours to form a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. Addition of toluene and subsequent concentration was done twice more. The resulting almost dry residue was filtered 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 hydrochloride as a yellow to orange solid (92.0 g, 89%). ).

ABOUT

OMe Dl

Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate hydrochloride

Anhydrous DMF (10.0 mL) was slowly added to SOCl 2 (300 mL) at 40-48 ° C. Stir the solution at this temperature range for 10 min, then add picolinic acid (100 g, 812 mmol) over 30 min. The resulting solution was heated at 72 ° C (vigorous SO 2 release) for 16 hours to give a yellow solid. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. Addition of toluene and subsequent concentration was done twice more. The resulting almost dry residue was filtered and the solid was washed with toluene (50 mL) and dried under high vacuum for 4 hours to give 4-chloropyridine-2-carbonyl chloride hydrochloride as a white solid (27.2 g, 16%). This substance is set aside.

The red filtrate was added to a solution of MeOH (200 mL) to maintain the temperature of the mixture below 55 ° C. The mixture was stirred at room temperature for 45 min, cooled to 5 ° C and treated dropwise with Et 2 O (200 mL). The resulting solid was filtered, washed with EtaO (200 mL), and dried under reduced pressure at 35 ° C to give methyl 4-chloropyridine-2-carboxylate hydrochloride as a white solid (110 g, 65%): mp 108 -112 ° C; H

9 r 23

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) < ^{+ >} ).

Step 3a. Synthesis of ^4-chloro-N- methyl-2-pyridinecarboxamide from methyl 4chlórpyridín-2-carboxylate

A suspension of methyl 4-chloropyridine-2-carboxylate hydrochloride (89.0 g, 428 mmol) in MeOH (75 mL) at 0 ° C was treated with a 2.0 M solution of methylamine in THF (1 L) to such an extent to maintain the temperature of the mixture below 5 ° C. The resulting mixture was stored at 3 ° C for 5 hours, then concentrated under reduced pressure. The resulting solid was suspended in EtOAc (1 L) 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-2-pyridinecarboxamide as pale yellow crystals (71.2 g, 97%): mp 4143 ° C; 1 H 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) 1 H, 8.61 (d, J = 5.1 Hz, 1H), 8.85 (br d, 1H); CI-MS m / z 171 ((M + H) < ^{+ >} ) ·

ABOUT

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

4-Chloropyridine-2-carbonyl chloride hydrochloride (7.0 g, 32.95 mmol) was added portionwise to a mixture of a 2.0 M solution of methylamine in THF (100 mL) and MeOH (20 mL) at 0 ° C. The resulting mixture was stored at 3 ° C for 4 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.

ABOUT

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

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anhydrous DMF (150 mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol) and the red to brown mixture was stirred at room temperature. temperature for 2 hours. The mixture was treated with 4-chloro-07-methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and K 2 CO 3 (6.50 g, 47.0 mmol), then heated at 80 ° C for 8 hours. The mixture was cooled to room temperature and partitioned between EtOAc (500 mL) and saturated NaCl (500 mL). The aqueous phase was re-extracted with EtOAc (300 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 to give 4- (2- (7-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 ¹ quartet, J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J 2.5 Hz, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m / z 244 ((M + H) < ⁺ >)^>

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

Step 1.

Synthesis of 5-hydroxyisoindoline-1,3-dione et

To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in concentrated 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 min, then the clear, light yellow mixture was heated at 160 ° C for 2 hours. The resulting mixture was kept at 160 ° C and concentrated to approximately 15 mL, then cooled to room temperature and the pH was adjusted to 10 with NaOH solution. The mixture was cooled to 0 ° C and slowly acidified to pH 5 with 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 Hz, 1H).

ABOUT

Step 2.

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

To a stirred slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 ° C was added dropwise a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL). The pale yellow to green mixture was allowed to warm to room temperature on standing and stirred for 1 hour, then 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe three to four times. The resulting mixture was heated at 70 ° C overnight, then cooled to room temperature and diluted slowly with water (150 mL), 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%): TLC (30 % EtOAc / 70% hexane) _Rf = 0.28; ¹ H NMR (DMSO-d ₆ ) δ 7.32 (d, J = 12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 9Hz, 2H), 11.43 (brs, 1H); CI-MS m / z 285 ((M + H) < ^{+ &gt};, 100%).

ABOUT'

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

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 under atm. Argon and slowly add iron as a powder (0.59 g, 55.9 mmol). The 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 under reduced pressure to give 5- (4-aminophenoxy) isoindoline-1,3-dione as a brownish solid (0.4 g, 75%): TLC (50% EtOAc / 50% hexane) Rf = 0.27; H NMR _(DMSO-d) 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, 1 H), 7.23 (dd, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 11.02 (s, 1 H); HPLC ES-MS m / z 255 ((M + H) < ^{+ &gt};, 100%).

A4. General method for the synthesis of pyrolylanilines.

Synthesis of 5-tert-butyl-2- (2,5-dimethylpyrolyl) aniline

N

Step 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 via syringe AcOH (0.1 mL) and acetonylacetone (0.299 g, 2.63 mmol). ). The reaction mixture is heated at 120 ° C for 72 hours while removing the volatiles in an azeotropic manner. The reaction mixture was cooled to room temperature, diluted with CH 2 Cl 2 (10 mL) and washed successively with 1 N HCl (15 mL) and 1 N NaOH (15 mL) and saturated NaCl (15 mL), dried (MgSO 4) and concentrated under reduced pressure. pressure. The resulting orange to brown solid was purified by silica gel column chromatography (60 g SiO 2; gradient of 6% EtOAc / 94% hexane to 25% EtOAc / 75% ether / hexane) to give 1- (4-tert-butyl) -2-nitrophenyl) -2,5-dimethylpyrrole as an orange to yellow solid (0.34 g, 49%): TLC (15% EtOAc / 85% hexane) R _f 0.67; 1 H NMR (CDCl ₃ ) δ 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H), 7, 62 (dd, 1H); 7.88 (d, J = 2.4Hz, 1H); CI-MS m / z 273 ((M + H) < ^{+ &gt};, 50%).

Step 2. Synthesis of 5- (e) x-butyl-2- (2,5-dimethylpyrolyl) aniline

A slurry of 1- (4- tert -butyl-2-nitrophenyl) -2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10% Pd / C (0.056 g) and EtOAc (50 mL) under atm. The hydrogen (balloon) was stirred for 72 hours, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give 5- tert -butyl-2- (2,5-dimethylpyrolyl) aniline as a yellowish solid (0.30 g, 99%): TLC (10% EtOAc / 90% hexane) Rf = 0.43; 1 H NMR (CDCl 3) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H) 7.28 (br s, 1H).

A5. General method for the synthesis of anilines by nucleophilic aromatic substitution of anilines.

Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline hydrochloride

A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert -butoxide (10.86 g, 96.77 mmol) and the black mixture Stir at room temperature until r

PP temperature in the flask will not reach room temperature. The mixture was then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 ° C for 8 hours. The mixture was cooled to room temperature and diluted with water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with saturated NaCl solution (200 mL), dried (MgSO 4) and concentrated under reduced pressure. The remaining 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 resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration from solution and stored before use, with exclusion of air at 0 ° C: Ή NMR _(DMSO-D) δ 2.41 (s, 3 H ), 2.78 (d, J = 4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J = 8.5, 2.6 Hz, 1H), 7, 23 (dd, J = 5.5, 2.6 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1 H), 8.55 (d, J = 5.9 Hz, 1 H), 8.99 (q, J = 4.8 Hz, 1 H) ).

A6. A general method for the synthesis of anilines from hydroxyanilines by introducing a protecting group on nitrogen, by nucleophilic aromatic substitution and by removing the protecting group.

Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline

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

Iron (3.24 g, 58.00 mmol) was added to a stirred solution of TFA (200 mL). To this slurry was added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 mL). The gray slurry was stirred at room temperature for 6 days. The iron is filtered from the solution and the remaining substance is concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To this yellow solution was added saturated NaHCO 3 solution (50 mL). The solid which precipitated from solution was removed. The filtrate was slowly quenched with sodium bicarbonate solution until the product was visibly separated from the solution (a small flask was chosen for determination). The slightly dark yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with saturated NaCl solution (125 mL), dried (MgSO 4) and concentrated under reduced pressure. According to 1 H NMR (DMSO-d 6), the starting nitrophenol and the desired 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol were 1: 1. The crude material was used in the next step without further purification.

Step 2. Synthesis of 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl (2,2,2-trifluoro) acetamide

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 mixture was stirred at room temperature until the reaction mixture was cooled to room temperature in the flask. 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 atm. argon for 4 days. The black reaction mixture was cooled to room temperature and poured into cold water (100 mL). Extract the mixture with EtOAc (3 x 75 mL) and concentrate the combined organic layers under reduced pressure. The remaining brown oil was purified by silica gel column chromatography with a gradient of 20% EtOAc / petroleum ether to 40% EtOAc / petroleum ether to give 4- (2- (7-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl- (2,2,2- trifluoro) acetamide as a yellow solid (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 (2,2,2-trifluoro) acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) ) was treated with 1N NaOH solution (20 mL). The brown solution was stirred for 8 hours. To this solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x 40 mL) and concentrated to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline as a green oil that solidified on standing (2.86 g, 10 mL). , 30 mmol): H NMR (DMSO- d _d) δ 2.77 (d, J = 4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J = 8, Δ, 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 (d, q, J = 4.8, 1H).

A7. General method for deprotecting from acylated aniline.

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

OMe

A suspension of 3-chloro-6- (N-acetyl) -4- (trifluoromethyl) anisole (4.00 g, 14.95 15 mmol) in 6M HCl solution (24 mL) was heated at reflux for 1 hour. The resulting solution was cooled to room temperature, solidifying a little. The resulting mixture was diluted with water (20 mL), then treated with a mixture of solid NaOH and saturated NaHCO 3 solution until the solution was basic. The organic layer was extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic layers 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, 14.2 mmol): 1 H NMR ( DMSO-d6 δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

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

Synthesis of 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline.

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

To a solution of 4- (3-carboxy-4-hydroxyphenoxy) -1-nitrobenzene (prepared from 2,5-dihydroxybenzoic acid by the method of Example 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, cooled to room temperature and filtered through a pad of Celite®. The resulting solution was concentrated under reduced pressure, absorbed onto silica gel, and purified by silica gel column chromatography using 50% EtOAc and 50% hexane to give 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene as a yellow powder (3 g). Melting point 115118 ° C.

ABOUT

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 overnight, then heated at reflux for 4 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50 mL) and the aqueous mixture 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- (3-carboxy-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 portionwise SOCl 2 (0.64 mL, 8.77 mmol). . The resulting solution was heated at reflux for 18 hours, cooled to room temperature and concentrated under reduced pressure. The resulting yellow solid was dissolved in CH 2 Cl 2 (3 mL), then the resulting solution was treated portionwise with methylamine solution (2.0 M in methylene chloride). THF, 3.5 mL, 7.02 mmol) (cautiously evolving gas) and stirred at room temperature for 4 hours. The resulting mixture was treated with 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- (N -methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene as a yellow solid (0.50 g, 95%).

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

A slurry of 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd / C (0.20 g) in EtOH (55 mL) ) is stirred under 1 atm. H ₂ (balloon) for 2.5 days, then filtered through a pad of Celite ®. The resulting solution was concentrated under reduced pressure to give 4- (3- (77-methylcarbamoyl) -4-methoxyphenoxy) aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et ₃ N / 99) , 9% EtOAc) _Rf = 0.36.

A9. General process for the preparation of ω-alkylphthiimide-containing anilines.

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

Step 1.

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

> R f «« «« e e e e e e

A slurry of 5- (4-nitrophenoxy) isoindoline-1,3-dione (A3 step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) The reaction mixture was stirred at room temperature for 1 hour, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temperature overnight, cooled to ° C and treated with water (10 mL). The resulting solids were combined and dried under reduced pressure to give 5- (4-nitrophenoxy) -2-methyl-isoindoline-1,3-dione as a light 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 slurry of 5- (4-nitrophenoxy) -2-methylisoindoline-1,3-dione (0.87 g, 2.78 mmol) and 10% Pd / C (0.10 g) in MeOH was stirred under 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 a pad of silica gel (60% EtOAc / 40% hexane) to give 5- (4-aminophenoxy) -2-methyl-isoindoline-1,3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc / 60% hexane) R f = 0.27.

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

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

To a solution of methyl 4-chloropyridine-2-carboxylate hydrochloride (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 h, Cool to room temperature and react with water (50 mL). The resulting mixture was extracted with 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 a yellow oil (1.25 g, 95%); TLC (10% MeOH / 90% EtOAc) _Rf = 0.50.

ABOUT

Step 2. Synthesis of 4- (2- (N ^' - (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline.

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temperature for 2 hours, then gradually reacted with 4-chloro-2- (N - (2-morpholin-4-yl-ethyl) -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 (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 resulting brown solid was purified by silica gel column chromatography (58 g) with a gradient of 100% EtOAc to 25% MeOH / 75% EtOAc) to give 4- (2- (N- (2-morpholin-4-ylethyl)) carbamoyl) pyridyloxy) aniline (1.0 g, 65%): TLC (10% MeOH / 90% EtOAc) _Rf = 0.32.

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

OH .0 r f

A slurry of 4- (3-carboxyphenoxy) -1-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd / C (0.50 g) in MeOH (120 mL) was stirred under atm. H2 (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 C1 ₂₎ R f = 0.44 (elongated period).

A12. General method for the synthesis of isoindolinone-containing 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 for 40 min. hot filtered and concentrated under reduced pressure. Further work-up to the same scale was performed and the combined oily residue was purified by column chromatography in a gradient of 60% EtOAc / 40% hexane to 25% MeOH / 75% EtOAc to give 5-hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) _Rf = 0.17; HPLC ES-MS m / z 150 ((M + H) < ^{+ >} ).

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

To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 ° C was added portionwise 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol). The resulting slurry was warmed to room temperature and stirred for 45 minutes, then 4-fluoro-1-nitrobenzene was added and the mixture was heated at 70 ° C for 3 hours.

The mixture was cooled to 0 ° C and treated dropwise with water until a precipitate formed. The resulting solid was combined to give 4- (isoindolinon-5-yloxy) -1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf = 0.35.

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

A slurry of 4- (1-isoindolinon-5-yloxy) -1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd / C20 (0.20 g) in EtOH (50 mL) was stirred under atm. H ₂ (balloon) for 4 hours, then filtered through a pad of Celite ®. The filtrate was concentrated under reduced pressure to give 4- (l-oxoisoindolin-5-yloxy) aniline as a dark yellow solid: TLC (100% EtOAc) _Rf = 0.15.

A13. General method for synthesis of ω-carbamoylanilines via amide prepared by EDCI and nitroarene reduction. Synthesis of 4- (3H-methylcarbamoylphenoxy) aniline.

ABOUT

Step 1. Synthesis of 4- (3-ethoxycarbonylphenoxy) -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) is heated at reflux through 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 successively 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 silica gel column chromatography using 10% EtOAc and 90% hexane to give 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene as an oil (38 g).

e r «e r r

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

To a vigorously stirred mixture of 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene (5.14 g, 17.9 mmol) in a mixture of THF and water (3: 1) (75 mL) was added L1OH.H2O solution (1.50). g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50 ° C overnight, then cooled to room temperature, concentrated under reduced pressure, and acidified to pH = 2M with HCl solution. The resulting light yellow solid was removed by filtration and washed with hexane to give 4- (3-carboxyphenoxy) -1-nitrobenzene (4.40 g, 95%).

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

A mixture of 4- (3-carboxyphenoxy) -1-nitrobenzene (3.72 g, 14.4 mmol), EDCI.HCl (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 as an oil. (1.89 g).

Step 4.

Synthesis of 4- (3- (N-methylcarbamoyl) phenoxy) aniline

A slurry 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 under atm. H2 (balloon) overnight. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH and 95% CH 2 Cl 2. The resulting oil solidified under vacuum overnight to give 4- (3- (N-methylcarbamoyl) phenoxy) aniline as a yellow solid (0.95 g, 56%).

A14. General method for synthesis of ω-carbamoylanilines via amide prepared by EDCI and nitroarene reduction. Synthesis of 4-3- (5-methylcarbamoyl) pyridyloxy) aniline

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

To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated at 70 ° C overnight, cooled to room temperature and treated with MeOH. (5 mL), followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase is concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 30% EtOAc and 70% hexane to give 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.60 g).

p r

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

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

A15. Synthesis of aniline by electrophilic nitration and reduction.

Synthesis of 4- (3-methylsulfamoylphenoxy) aniline.

BRQ. 0

NHMe

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 warmed to room temperature and stirred at room temperature overnight. The resulting mixture was partitioned between EtOAc (25 mL) and 1 M HCl (25 mL). The aqueous phase was re-extracted with EtOAc (2 x 25 mL). The combined organic phases were washed successively with water (2 x 25 mL) and saturated NaCl solution (25 mL), dried (MgSO ₄ ), and concentrated under reduced pressure to give N-methyl-3-bromobenzenesulfonamide as a white solid (2, 8 g, 99%).

Q., O

NHMe

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

To a slurry of phenol (1.9 g, 20 mmol), K 2 CO 3 (6.0 g, 40 mmol) and CuI (4 g, 20 mmol) in DMF (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 HCl (50 mL). The aqueous phase was re-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed successively with water (2 x 50 mL) and saturated NaCl solution (50 mL), dried (MgSO 4), and concentrated under reduced pressure. The residual oil was purified by column chromatography on silica gel using 30% EtOAc and 70% hexane to give 4- (3- ^(N -metylsulfamoyl) phenyloxy) benzene (0.30 g).

NHMe

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

To a solution of 4- (3- (N-methylsulfamoyl) phenyloxy) benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10 ° C was added portionwise NaNO ₂ (0.097) over 5 minutes. g, 1.14 mmol). The resulting solution was stirred at -10 ° C for 1 hour, then warmed 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) and saturated NaCl solution (10 mL), dried (MgSO 4) and concentrated under reduced pressure to give 4- (3 (N-methylsulfamoyl) phenyloxy) -1-nitrobenzene (0). , 20 g). This material was used in the next step without further purification.

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

4- (3- (N-methylsulfamoyl) phenyloxy) -1-nitrobenzene slurry (0.30

g) and 10% Pd / C (0.030 g) in EtOAc (20 mL) was stirred under atm. H ₂ (balloon) overnight. The resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography

e r e r p p p

P r r · · r r

30% EtOAc and 70% hexane to give 4- (3- (N-methylsulfamoyl) phenyloxy) aniline (0.070 g).

A16. Modification of ω-ketones. Synthesis of 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline hydrochloride)

To a slurry of 4- (4-acetylphenoxy) aniline hydrochloride (prepared analogously to Example A13, Step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0 mL) was added. Omethylhydroxylamine hydrochloride (0.65 g, 7.78 mmol, 2.0 equiv) was added. The resulting solution was heated at reflux for 30 minutes, cooled to room temperature, and concentrated under reduced pressure. The resulting solid was triturated with water (10 mL) and washed with water to give 4- (4- (1- (7-methoxy) iminoethyl) phenoxyaniline hydrochloride as a yellow solid (0.85 g): TLC (50% EtOAc / 50 mL). % petroleum 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 - ((D-silyloxyalkyl) amides) Synthesis of 4- (4- (2- (β- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline).

Step 1. 4-Chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide

To a solution of 4-chloro-N- (2-hydroxyethyl) pyridine-2-carboxamide (prepared analogously to Example 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 equiv) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv). The resulting yellow solution was stirred for 3 hours at room temperature, then concentrated under reduced pressure. The residue was partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried (MgSO 4) and concentrated under reduced pressure to give 4-chloro-2- (N - (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide as an orange oil (2.32 g, 88%). This material was used in the next step without further purification.

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

To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anhydrous DMF (8 mL) was added potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv) in one portion. The reaction is exothermic. After cooling to room temperature, a solution of 4-chloro-2- (N- (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) In DMF (4 mL) was added followed by K 2 CO 3 (0.42 g). , 3.0 mmol, 0.50 equiv). The resulting mixture was heated at 80 ° C overnight. Another portion of potassium tert -butoxide (0.34 g, 3 mmol, 0.5 equiv.) Was added and the mixture was stirred at 80 ° C for an additional 4 hours, cooled to 0 ° C in an ice bath. then water (about 1 mL) is slowly added dropwise. The organic layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with saturated NaCl solution (20 mL), dried (MgSO 4) and concentrated under reduced pressure. The brown oily residue was purified by silica gel column chromatography using 30% EtOAc and 70% petroleum ether to give 4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline) as a 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.

r r

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 mL, 91.6 mmol, 1.0 equiv), K 2 CO 3 (25 g, 183 mmol) , 2.0 equiv) in DMF (100 mL) was heated at reflux 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 successively with water (2 x 100 mL) and saturated NaCl solution ((100 mL), dried (MgSO 4), and concentrated under reduced pressure to afford 4- (5- (2-methyl)). pyridyloxy) -1-nitrobenzene as a brown solid (12.3 g).

OMe

ABOUT

Step 2. Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) -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 minol, 3.0 equiv) in pyridine (20 mL) was heated at reflux for 5 hours, then cooled to room temperature. The resulting slurry was filtered and 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 (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed successively with water (2 x 50 mL) and saturated NaCl solution (50 mL), dried (MgSO 4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% EtOAc and 50% hexane to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.70 g).

r r

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

ABOUT

A slurry of 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.50 g) and 10% Pd / C (0.050 g) in EtOAc (20 mL) and MeOH (5 mL) was left under atm. H2 (balloon) overnight. The resulting mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 70% EtOAc and 30% hexane to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline (0.40 g).

A19. Synthesis of ω-sulfonylphenylanilines.

Synthesis of 4- (4-methylsulfonylphenyoxy) 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 (57-86%, 4.0 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 layer was washed successively with 1N NaOH solution (25 mL), water (25 mL) and saturated NaCl solution (25 mL), dried (MgSO ₄ ), and concentrated under reduced pressure to give 4- (4-methylsulfonylphenoxy) - 1-nitrobenzene as a solid (2.1 g).

Step 2.

4- (4-Methylsulfonylphenoxy) -1-aniline:

e r

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

B. Synthesis of urea precursors

BI. General method for the synthesis of isocyanates from anilines by CDI. synthesis

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

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

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

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

A suspension of 4-bromo-3- (trifluoromethyl) aniline hydrochloride (36.8 g, 133 mmol) in toluene (278 mL) was treated 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 residue was re-treated with CH ₂ Cl ₂ and concentrated to give a yellow oil, which was stored at -20 ° C for 16 hours. The obtained 4-bromo-3- (trifluoromethyl) phenyl isocyanate is a brown solid (3.1 g, 86%): GC-MS m / z 265 (M < ^{+ >} ).

C. Methods for the preparation of ureas

Duty. General method for the synthesis of ureas by reaction of isocyanate with aniline.

Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -. ^M - (4- (2 - (/ V-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

NHMe

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 resulting yellow solid was removed by filtration, washed with CH 2 Cl 2 (2 x 30 mL) and dried under reduced pressure (about 1 mm Hg) to give N - (4-chloro-3 (trifluoromethyl) phenyl) -? - (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as 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) < ^{+ >} ).

Clb. General method for the synthesis of ureas by reaction of isocyanate with aniline.

Synthesis of ^N - (4-bromo-3- (trifluoromethyl) phenyl) - / ^V, - (4- (2 - (/ V-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

N r r

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- (27-methylcarbamoyl) -4 -pyridyloxy) aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH 2 Cl 2 (40 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 16 hours. The resulting yellow solid was removed by filtration, washed with CH 2 Cl 2 (2 x 50 mL) and dried under reduced pressure (about 1 mm Hg) at 40 ° C to give 27- (4-bromo-3- (trifluoromethyl) phenyl ) -27 '- (4- (2- (27-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as a pale yellow solid (13.2 g, 90%): mp 203-205 ° C; 1 H NMR (DMSO-d ₆ ) δ 2.77 (d, J = 4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, 25 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), 8.19 (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) < ^{+ >} ).

CIC. General method for the synthesis of ureas by reaction of isocyanate with aniline.

Synthesis of 27- (4-chloro-3- (trifluoromethyl) phenyl) -27 '- (2-methyl-4- (2- (27-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea

Cl

H

NHMe

A solution of 2-methyl-4- (2- (27-methylcarbamoyl) (4-pyridyloxy)) aniline (Method A5; 0.1 µg, 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 (10 g, 0.45 mmol). The resulting brown solution was stirred at room temperature for 6 days, treated with water (5 mL). The aqueous phase was re-extracted with EtOAc (3 x 5 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure to give 27 (4-chloro-3- (trifluoromethyl) phenyl) -27 '- (2-methyl-4- (2- (27-methylcarbamoyl) (4-pyridyloxy) phenyl) urea as a brown oil (0.11 g, 0.22 mmol): 1 H NMR (DMSO-d 6) δ 2.27 (s, 3H), 2.77 (d, J = 4) 8 Hz, 3H), 7.03 (dd, J = 8.5, 2.6 Hz, 1H), 7.11 (d, J = 2.9 Hz, 1H), 7.15 (dd, J = 5.5, 2.6, Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H), 7.62 (app d, J = 2.6 Hz, 2H), 7.84 (d, J = 8.8 Hz, 1 H), 8.12 (s, 1 H), 8.17 (s,

1H); 8.50 (d, J = 5.5 Hz, 1H), 8.78 (q, J = 5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m / z 479 ((M + H) < ^{+ >} ).

Cld. General method for the synthesis of ureas by reaction of isocyanate with aniline. AA Synthesis of (4-chloro-3- (trifluoromethyl) phenyl) -. ^V, - (4-aminophenyl) urea

H H

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (2.27 g, 10.3 mmol) in CH 2 Cl 2 (308 mL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one portion. The resulting mixture was stirred at room temperature for 1 hour, treated with CH 2 Cl 2 (100 mL), and concentrated under reduced pressure. The resulting pink solid was dissolved in a mixture of EtOAc (110 mL) and MeOH (15 mL) and the clear solution was washed with 0.05 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.

Cle. General method for the synthesis of ureas by reaction of isocyanate with aniline.

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

To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH 2 Cl 2 (30 mL) was added 4-chloro-3- (trifluoromethyl) aniline (3.21 g, 16.4 mmol) and Stir at room temperature overnight. The resulting slurry was diluted with CH 2 Cl 2 (50 mL) and filtered to give N - (4-chloro-3- (trifluoromethyl) phenyl) - N '- (4β-ethoxycarbonylphenyl) urea as a white solid (5.93 g, 97%): TLC (40% EtOAc / 60% hexane) R f = 0.44.

CLF. General method for the synthesis of ureas by reaction of isocyanate with aniline. Synthesis of N - (4-chloro-3- (trifluoromethyl) phenyl) - N - (3-carboxyphenyl) urea

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (1.21g, 5.46 mmol) in CH 2 Cl 2 (8 mL) was added 4- (3-carboxyphenoxy) aniline (Method A1); 16 mmol) and the resulting mixture was stirred at room temperature overnight, then treated with MeOH (8 mL) and stirred for an additional 2 hours. The resulting mixture was concentrated under reduced pressure. The resulting brown solid was triturated with EtOAc / hexane (1: 1) to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3-carboxyphenyl) urea as an off-white solid (1, 1, 2). 21 g, 76%).

C2a. General method for the synthesis of urea by reacting aniline with N ', N'carbonyldiimidazole and adding a second aniline. Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

NHMe

To a solution of 2-methoxy-5- (trifluoromethyl) aniline (0.15 g) in anhydrous form

CH 2 Cl 2 (15 mL) at 0 ° C was added CDI (0.13 g). The resulting solution was warmed to room temperature for 1 hour, stirred at room temperature for 16 hours, treated with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 72 hours, treated with H ₂ O (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases 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 solid was collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the remaining oil was purified by silica gel column chromatography in a gradient of 33% EtOAc / 67% hexane, 50% EtOAc / 50% hexane to 100% EtOAc to give N (2-methoxy-5- (trifluoromethyl) (phenyl) -N- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as a light brown solid (0.098 g, 30%): 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, 11H), 8.75 (d, J = 4.8Hz, 1H), 9.55 (s, 1H); FAB-MS m / z 461 ((M + H) < ^{+ >} ).

C2B. General method for the synthesis of urea by reacting aniline with N, N'-carbonyldiimidazole and adding a second aniline. Symmetrical ureas as by-products of the reaction of 2 \ /, ^N '-carbonyldiimidazole. Synthesis of bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

MeHN-

NHMe

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 warmed to room temperature for 1 hour, stirred at room temperature for 16 hours. The resulting mixture was treated with 4- (2- (1H-methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temperature for 72 hours, treated with water (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with saturated NaCl solution (100 mL), dried (MgSO 4) and concentrated under reduced pressure. The residue was triturated in a mixture of 90% EtOAc and 10% hexane. The resulting white solid was collected by filtration and washed with EtOAc to give bis (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.081 g, 44%); TLC (100%)

EtOAc) Rf = 0.50; 1 H NMR (DMSO-d ₆ ) δ 2.76 (d, J = 5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J = 5.4 Hz) (1H), 8.75 (d, J = 4.8Hz, 2H), 8.86 (s, 2H); HPLC ESMS m / z 513 ((M + H) < ^{+ >} ).

C2c. General method for the synthesis of ureas by reaction of isocyanate with aniline.

Synthesis of A / - (2-methoxy-5- (trifluoromethyl) phenyl-.V ^- (4- (l, 3-dioxoizoindolin5-yloxy) phenyl) urea

CF ₃

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 5- (4-aminophenoxy) isoindoline-1,3-dione (Method A3) at once. Step 3 (0.12 g, 0.47 mmol). The resulting mixture was stirred for 12 hours, treated with CH 2 Cl 2 (10 mL) and MeOH (5 mL). The resulting mixture was washed sequentially with 1N HCl solution (15 mL) and saturated NaCl solution (15 mL), dried (MgSO 4), 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 g, 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 (m, 6H), 7.57 (d, J = 9.3Hz, 2H), 7, 80 (d, J = 8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS 472.0 ((M + H) ⁺ , 100%).

C2d. General method for the synthesis of urea by reacting aniline with N, N'carbonyldiimidazole and adding a second aniline. Synthesis of N- (5- (tert-butyl) -2- (2,5-dimethylpyrrolyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4pyridyloxy) phenyl) urea

To a stirred solution of CDI (0.21g, 1.30 mmol) in CH 2 Cl 2 (2 mL) was added 5 - (tert -butyl) -2- (2,5-dimethylpyrolyl) aniline (Method A4, Step 2) all at once. 0.30 g, 1.24 mmol). The resulting mixture was stirred at room temperature for 4 hours, then 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (0.065 g, 0.267mmol) was added in one portion. The resulting mixture was heated at 36 ° C overnight, cooled to room temperature and diluted with EtOAc (5 mL). The resulting mixture was washed sequentially with water (15 mL) and 1N HCl solution (15 mL), dried (MgSO 4), and filtered through a pad of silica gel (50 g) to give N - (5 - (tert -butyl) - 2- (2,5-methylpyrrole) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyl oxy) phenyl) urea as a yellowish solid (0.033 g, 24%) TLC (40% EtOAc / 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 = 4.8Hz, 3H), 5.83 (s, 2H) ), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J = 5.4Hz, 1H) ), 8.57 (d, J = 2.1 Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M + H) < ^{+ &gt};, 100%).

C3. Combination method of diphenylurea synthesis using triphosgene

One of the anilines with which the coupling reaction is to be carried out is dissolved in dichloroethane (0.10 M). This solution was added to an 8 mL flask (0.5 mL) containing dichloroethane (1 mL). To this flask was added a solution of bis (trichloromethyl) carbonate (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv) .). Seal the flask and heat at 80 ° C for 5 hours, warm to room temperature for 10 hours, then add the second aniline (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.), Diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv). The resulting mixture was heated at 80 ° C for 4 hours, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.

C4. General method for the synthesis of urea by reacting aniline with phosgene and adding a second aniline. Synthesis of AL (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

To a stirred solution of phosgene (1.9 M in toluene; 2.07 mL 0.21g, 1.30 mmol) in CH 2 Cl 2 (20 mL) at 0 ° C was added anhydrous pyridine (0.32 mL) then 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 resulting solid was treated with anhydrous toluene (20 mL) followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline (prepared according to Method A2; 0.30 g) and the resulting suspension was heated at 80 ° C for 20 hours and then cooled to room temperature. The resulting mixture was diluted with water (100 mL), basified with saturated NaHCO 3 (2-3 mL). The basified solution was extracted with EtOAc (2 x 250 mL). The organic layers were washed separately with saturated NaCl solution, combined, dried (MgSO ₄ ) and concentrated under reduced pressure. The resulting pink to brown residue was dissolved in MeOH and absorbed onto silica gel (100 g). Purification by silica gel column chromatography (300 g) with a gradient of 1% Et 3 N / 33% EtOAc / 66% hexane, 1% Et 3 N / 99% EtOAc to 1% Et 3 N / 20% MeOH / 79 ° / o EtOAc, then concentrated under reduced pressure at 45 ° C to give a hot concentrated solution in EtOAc, which was washed with hexane (10 mL) to slowly form crystals of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N ^&apos' - (4- (2- (N (methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.44 g): TLC (1% Et 3 N / 99% EtOAc) R _t = 0.40.

D. Interconversion of ureas

DLA. Conversion of ω-aminophenylureas to (β- (aroylamino) phenylureas).

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

Cl

OMe

To a solution of N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N - (4-aminophenyl) urea (Method Cld; 0.050 g, 1.52 mmol), obtained methyl isophthalate (0.25 g, 1). , 38 mmol), HOBT.H2O (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) were added EDCI.HCl (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 (25 mL) .The organic layer was dried (Na ₂ SO ₄ ). and concentrated under reduced pressure. The resulting solid was triturated with EtOAc (80% EtOAc / 20% hexane) to give ΛΓ- (4-chloro-3 - ((trifluoromethyl) phenyl) - N 4 - (4- (3- methoxycarbonylphenyl) carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122 ° C; TLC (80% EtOAc / 20% hexane) R f = 0.75.

DLB. Conversion of ω-carboxyphenylureas to (o- (arylcarbamoyl) phenylureas).

Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -7 '- (4- (3-methylcarbamoylphenyl) carbamoy Ifenyl) urea

Cl

NHMe

To a solution of N- (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), HOBT.H 2 O (0.14 g, 1.07 mmol) and N e methyl methylmorpholine (0.5 mL, 1.07 mmol) in DMF (3 mL) at 0 ° C were added EDCI HCl (0.10 g, 0.53 mmol) The resulting mixture was warmed to room temperature and stirred overnight The reaction mixture was treated with water (10 mL) and extracted with EtOAc (25 mL). The resulting yellow solid was dissolved in EtOAc (3 mL), filtered through a pad of silica gel (17 g) with a gradient of 70% EtOAc / 30% hexane to 10% MeOH / 90% EtOAc to give γ- ( 4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea as a white solid (0.097 g, 41%); mp 225-229 ° C; TLC (100 % EtOAc) Rf = 0.23.

Dl c. Combination method for the conversion of ω-carboxyphenylureas to α- (arylcarbamoyl) phenyl urea. Synthesis of AL (4-chloro-3 - ((trifluoromethyl) phenyl) -7 ' ^, - (4- (N - (3- (N - (3-pyridyl) carbanioyl) phenyl) carbamoyl) phenyl) urea

A mixture of N - (4-chloro-3 - ((trifluoromethyl) phenyl) -7 '- (3-carboxyphenyl) urea (Method C1f; 0.030 g, 0.067 mmol) and N' - cyclohexyl - N '- ( methyl polystyrene) carbodiimide (55 mg) in 1,2-dichloroethane (1 mL) was treated with a solution of 3 aminopyridine in CH 2 Cl 2 (1 M; 0.074 mL, 0.074 mmol) (in case of insolubility or turbidity, a small amount of DMSO was added). The mixture was heated at 36 ° C overnight The turbid reaction mixture was then treated with THF (1 mL) and heating continued for 18 hours. The resulting mixture was treated with poly (4- (isocyanatomethyl) styrene) (0.040 g). ) and the resulting mixture was stirred at 36 ° C for 72 hours, then cooled to room temperature and filtered, and the resulting solution was filtered through a pad of silica gel (1 g), and concentrated under reduced pressure to give A- (4-chloro-3). ((trifluoromethyl) phenyl) - N - (4 - (N - (3- (N - (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea (0.024 g, 59%): TLC (70 % EtOAc / 30% hexane) Rf = 0.12.

D2. Conversion of ω-carboalkoxyarylureas to ω-carbamoylarylureas.

Synthesis of 7V- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4 _(m 3 is ethylcarbamoylphenyl) carboxyaminophenyl) urea

H H

To a sample of ^N - (4-chloro-3 - ((trifluoromethyl) phenyl) -V '- (4- (3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 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) -? 1- (4- (3-methylcarbamoyl phenyl) carboxyaminophenyl) urea as a white solid: mp 247 ° C; TLC (100% EtOAc) R f = 0.35.

D3. Conversion of ω-carboalkoxyarylureas to ω-carboxyarylureas.

Synthesis of N - (4-chloro-3 - ((trifluoromethyl) phenyl) -7 N - (4-carboxyphenyl) urea

To a slurry of N ¹ - (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4-ethoxycarbonylphenyl) urea (Method Cl; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added aqueous KOH (2.5 N, 10 mL, 23 mmol) was added and the resulting mixture was heated at reflux for 12 h, cooled to room temperature and concentrated under reduced pressure. The resulting solid was combined 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. General method for the conversion of ω-alkoxy esters to ω-alkylamides. synthesis

77- (4-chloro-3 - ((trifluoromethyl) phenyl) -77 - ((4- (3- (5- (2-diinetylaminoetyl) carbamoyl) pyridyl) oxyphenyl) urea

Step 1. Synthesis of 77- (4-chloro-3- (tri-fluoromethyl) phenyl) -77 '- ((4- (3- (5-carboxypyridyl) oxyphenyl) urea)

77- (4-Chloro-3- (trifluoromethyl) phenyl) -77 '- ((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea) is prepared from 4-chloro-3- (trifluoromethyl) phenyl isocyanate and 4- (3- (5-methoxycarbonylpyridyl) oxyariiline (Method A14, Step 2) analogously to Method Cla. Suspension 77- (4-chloro-3- (trifluoromethyl) phenyl) -77 '- ((4- (3- ( 5-methoxycarbonylpyridyl) oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and stirred at room temperature The resulting mixture was adjusted to pH 5 with 1 N HCl solution, the resulting precipitate was removed by filtration and washed with water, the resulting solid was dissolved in EtOH (10 mL), and the resulting solution was concentrated under reduced pressure. it was repeated twice to give 77- (4-chloro-3- (trifluoromethyl) phenyl) -77 ^, - ((4- (3- (5-carboxypyridyl) oxyphenyl)) urea (0.18 g, 71%).

Step 2. Synthesis of 77- (4-chloro-3- (trifluoromethyl) phenyl) -77 '- ((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea

A mixture of 77- (4-chloro-3- (trifluoromethyl) phenyl) -77 '- ((4- (3- (5-carboxypyridyl) oxyphenyl) urea (0.050 g, 0.011 mmol), 77) , 77-dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), 77-methylmorpholine (0.035 g, 0.28 mmol) and EDCI.HCl (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room temperature overnight The resulting solution was partitioned between EtOAc (50 mL) and water (50 mL), and the organic phase was washed with water (35 mL), dried (50 mL). The residue was dissolved in a minimum amount of CH ₂ Cl ₂ (about 2 mL) and the resulting solution was treated dropwise with Et ₂ O to give? - (4-chloro- 3- (trifluoromethyl) phenyl) - N - ((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea as a white precipitate (0.48 g, 84%: * H)

NMR (DMSO-d ₆ ) δ 2.10 s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H) ), 8.05 (s, 1H), 8.43 (s, 1H), 8.58 (t, 1H), 8.69 (s, 1H), 8.90 (s, 1H),

9.14 (s, 1H); HPLC ES-MS m / z 522 ((M + H) < ^{+ >} ).

D5. General method for deprotecting from Ν- (ωsilyloxyalkyl) amides. Synthesis of N - (4-chloro-3 - ((trifluoromethyl) phenyl) -7 '- (4 (4- (2- (N - (2-hydroxy) ethylcarbamoyl) pyridyloxy phenyl) urea).

To a solution of N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N - (4- (4- (2- (N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea (prepared analogously to Example Cla) 0.25 g, 0.37 mmol) in anhydrous THF (2 mL) was added tetrabutylammonium fluoride (1.0 M in THF; 2 mL), and the mixture was stirred at room temperature for 5 minutes, treated with water (10 mL). The aqueous mixture was extracted with EtOAc (3 x 10 mL), the combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with a gradient of 100% hexane to 40% EtOAc / 60. % hexane to give N - (4-chloro-3 - ((trifluoromethyl) phenyl) -77 '- (4- (4- (2- (77- (2-hydroxy)) ethyl) carbamoyl) 1) pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).

The compounds listed in the tables below are synthesized according to the above detailed examples:

Synthesis of compounds according to the invention (for individual characteristics see tables)

Example 1: 4- (3-N-methylcarbamoylphenoxy) aniline was prepared according to Method A13. And according to Method C3, S-tert-butylaniline is reacted with bis (trichloromethyl) carbonate, followed by 4- (3- N -methylcarbamoylphenoxy) aniline to give urea.

Example 2: 4-Fluoro-1-nitrobenzene and 4-hydroxyacetophenone were reacted according to Method A13, Step 1 to give 4- (4-acetylphenoxy) -1-nitrobenzene. 4- (4-Acetylphenoxy) -1-nitrobenzene is reduced according to Method A 13, Step 4 to give 4- (4-acetylphenoxy) aniline. And according to Method C3, 3- tert -butylaniline is reacted with bis (trichloromethyl) carbonate followed by 4- (4-acetylphenoxy) aniline to give urea.

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

Example 4: 5- tert -Butyl-2-methoxyaniline is converted to 5-tert-butyl-2-methoxyphenylisocyanate according to Method B1. The 4- (3-N-methylcarbamoylphenoxy) aniline, prepared according to Method A13, was reacted with an isocyanate according to Method Cla to give urea.

Example 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 prepared according to Method A8 to give urea.

Example 6: 5- (4-Aminophenoxy) isoindoline-1,3-dione was prepared according to Method A3. According to Method 2d, 5- tert -butyl-2-methoxyaniline is reacted with CDI, followed by 5- (4-aminophenoxy) isoindoline-1,3-dione to give urea.

Example 7: 4- (1-Oxoisoindolin-5-yloxy) aniline was prepared according to Method A12. And according to method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI, followed by 4- (1-oxoisoindolin-5-yloxy) aniline to give urea.

Example 8: 4- (3-N-Methylcarbamoylphenoxy) aniline was prepared according to Method A13. And according to method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI, followed by 4- (3-N-methylcarbamoylphenoxy) aniline to give urea.

Example 9: 4-Hydroxyacetophenone is reacted with 2-chloro-5-nitropyridine to give 4- (4-acetylphenoxy) -5-nitropyridine according to Method A3, Step 2. A according to Method A8, Step 4, 4- (4-acetylphenoxy) -5-nitropyridine reduces to 4- (4-acetylphenoxy) -5-aminopyridine. 2-Methoxy-5- (trifluoromethyl) aniline is 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 Cla to give urea.

Example 10: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to give 4- (4-acetylphenoxy) -1-nitrobenzene. 4- (4-Acetylphenoxy) -1-nitrobenzene is 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- (4-acetylphenoxy) aniline to give the urea.

Example 11: 4-Chloro-7-methyl-2-pyridinecarboxamide, prepared according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to give 3 - (- 2- (7 / methylcarbamoyl) -4-pyridyloxy) aniline. And according to Method C4, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene, followed by 3 - (- 2- (77-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 12: 4-Chloropyridine-2-carbonyl chloride hydrochloride was reacted with ammonia according to Method A2, Step 3b to give 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide is reacted with 3aminophenol according to Method A2, Step 4 using DMAC instead of DMF to give 3- (2-carbamoyl-4-pyridyloxy) aniline. And, according to Method C2a, is

2-Methoxy-5- (trifluoromethyl) aniline is reacted with phosgene followed by 3- (2-carbamoyl-4-pyridyloxy) aniline to give urea.

Example 13: 4-Chloro-N-methyl-2-pyridinecarboxamide was prepared according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide is reacted with 4aminophenol according to Method A2, Step 4, using DMAC instead of DMF to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. And according to method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI, followed by 4- (2- (7-methylcarbamoyl) -4-pyridyloxy) aniline to obtain urea.

Example 14: 4-Chloropyridine-2-carbonyl chloride hydrochloride was 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 Method A2, Step 4, using DMAC instead of DMF to give 4- (2-carbamoyl-4-pyridyloxy) aniline. And according to Method C4, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene followed by 4- (2-carbamoyl-4-pyridyloxy) aniline to give urea.

Example 15: According to Method C2d, 5- (trifluoromethyl) -2-methoxyaniline was reacted with CDI followed by 4- ^{(3-A-methylcarbamoyl)} -4-methoxyphenoxy) aniline, prepared according to Method A8, to afford urea.

Example 16: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was prepared 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) -2-methylaniline according to Method Cic to give the urea.

Example 17: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was prepared according to Method A6. 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-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline according to Method Cla to give urea.

Example 18: According to Method A2, Step 4, 5-amino-2-methylphenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which is prepared according to Method R-Step

P t r r

A2, Step 3b, to give 3- (2- ^{(N-methylcarbamoyl)} -4-pyridyloxy) -4metylanilín. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2metoxyfenylizokyanát was reacted with 3- (2- (N-methylcarbamoyl ^{I ')} -4pyridyloxy) -4-methylaniline according to Method Cla to give the urea.

Example 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-ethylcarbamoyl) -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- (7-ethylcarbamoyl) -4-pyridyloxy) aniline according to Method Cla to give urea.

Example 20: According to Method A2, Step 4, 4-Amino-2-chlorophenol was reacted with 4-chloro- / 7-methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 4- ( 2 - (/ 7-methylcarbamoyl) -4-pyridyloxy) -3chlóranilín. 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- (7-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline according to Method Cla to give urea.

Example 21: 4- (4-Methylthiophenoxy) -1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. The nitrobenzene is reduced according to Method A19, Step 2 to give 4- (4-methylsulfonylphenoxy) -1-aniline. According to method Cla, 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (4-methylsulfonylphenoxy) -1-aniline to give urea.

Example 22: 4- (3-carbamoylphenoxy) -1-nitrobenzene is reduced to 4- (3-carbamoylphenoxy) aniline according to method A15, step 4. And according to method C a 5- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- ( 3-carbamoyl-phenoxy) -amine, to give the urea.

Example 23: 5- (4-Aminophenoxy) isoindoline-1,3-dione was prepared according to the method

A3. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -263 methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione according to Method Cla to give urea.

Example 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro- N, N -dimethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N, N -dimethylcarbamoyl) -4-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-dimethyicarbamoyl) -4-pyridyloxy) aniline according to Method Cla to provide urea.

Example 25: 4- (1-Oxoisoindolin-5-yloxy) aniline was prepared according to Method A12. 5- (Trifluoromethyl) -2-methoxyaniline was reacted with CDI followed by 4- (loxoisoindolin-5-yloxy) aniline according to Method C2d to give the urea.

Example 26: 4-Hydroxyacetophenone was reacted 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 4- (4-acetylphenoxy) aniline which is converted to 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline hydrochloride according to Method A16. 5- (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (4- (1- (AAmethoxy) iminoethyl) phenoxyaniline hydrochloride according to Method Cla), to obtain urea.

Example 27; 4-Chloro-N-methylpyridinecarboxamide was prepared according to 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 was reacted with 4- (4- (2- (N'-methylcarbamoyl) phenylthio) aniline according to Method Cla to give urea).

Example 28: 5- (4-Aminophenoxy) -2-methyl-isoindoline-1,3-dione was prepared according to Method A9. 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) -2-methylisoindoline-1,3-dione according to Method Cla to give urea.

Example 29: 4-Chloro- N -methylpyridinecarboxamide was prepared according to Method A2, Step 3b. The chloropyridine is reacted with 3-aminothiophenol according to the method

A2, step 4 to obtain

5- (Trifluoromethyl) -2-methoxyaniline methoxyphenyl isocyanate according to

3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline) is converted to 5- (trifluoromethyl) -2-method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 3- (4- (2- With (N-methylcarbamoyl) phenylthio) aniline according to Method Cla to give urea.

Example 30: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline. 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-isopropylcarbamoyl) -4-pyridyloxy) aniline according to Method Cla to provide urea.

Example 31: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared 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 Cla to give urea. N- (5 (Trifluoromethyl) -2-methoxyphenyl) -N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea saponifies according to Method D4, Step 1, and the corresponding acid is coupled according to Method D4, Step 2, with 4- (2-aminoethyl) morpholine to give the amide.

Example 32: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to Method A14. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 565 (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 Cla to give urea. N - (5- (Trifluoromethyl) 2-methoxyphenyl) -N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid is coupled with methylamine according to Method D4, Step 2 to give the amide.

Example 33: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared 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 Cla to give urea. N- (5- (Trifluoromethyl) 2-methoxyphenyl) -N '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with Ύ with N, N-dimethylethylenediamine according to Method D4, Step 2 to give the amide.

Example 34: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A1. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) urea, which according to Method D1c is coupled with 3-aminopyridine.

Example 35: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N - (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) ) urea which, according to Method D1c, is coupled with N - (4-fluorophenyl) piperazine.

Example 36: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A11.

5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3- carboxyphenyl) urea which is coupled with 4-fluoroaniline according to Method D1c.

Example 37: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A11. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) - N - (3-carboxyphenyl) ) urea which is coupled with 4- (dimethylamino) aniline according to Method D1c.

Example 38: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) urea which is coupled with 5-amino-2-methoxypyridine according to Method D1c.

Example 39: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N- (3-carboxyphenyl) urea which is coupled with 4-morpholinoaniline according to Method Dc.

Example 40: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N - (5- (trifluoromethyl) -2-methoxyphenyl) - N - (3- carboxyphenyl) urea which is coupled with N - (2-pyridyl) piperazine according to Method D1c.

Example 41: 4- (3- (N-Methylcarbamoyl) phenoxy) aniline was prepared according to the method

A13. And according to Method C3, 4-chloro-3- (trifluoromethyl) aniline is converted to an isocyanate and reacted with 4- (3- (N-methylcarbamoyl) phenoxy) aniline to give urea.

¾ P

Example 42: 4- (2-AAMethylcarbamyl-4-pyridyloxy) aniline was prepared according to Method A2. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- N -methylcarbamyl-4-pyridyloxy) aniline according to Method Cla to give urea.

Example 43: 4-Chloropyridine-2-carbonyl chloride hydrochloride was 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 Method A2, Step 4 to give 4- (2-carbamoyl-4-pyridyloxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2-carbamoyl-4-pyridyloxy) aniline to give urea.

Example 44: 4-Chloropyridine-2-carbonyl chloride hydrochloride was treated with ammonia according to Method A2, Step 3b, to give 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide is reacted with 3aminophenol according to Method A2, Step 4, to give 3- (2-carbamoyl-4-pyridyloxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2-carbamoyl-4-pyridyloxy) aniline to give urea.

Example 45: 4-Chloro-R / ^{r-methyl-2-pyridinecarboxamide,} which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3 - (- 2- ( N-methylcarbamoyl) -4-pyridyloxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 46: 5- (4-Aminophenoxy) isoindoline-1,3-dione was prepared according to Method A3. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to give urea.

Example 47: 4- (2- (7V ^r: methylene) -4-pyridyloxy) -2-methylaniline was synthesized according to Method A5. And according to Method C18, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to give urea.

Example 48: 4- (3-N-Methylsulfamoyl) phenyloxy) aniline was prepared according to Method A15. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-7 N-methylsulfamoyl) phenyloxy) aniline to give urea.

Example 49: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was prepared according to Method A6. And, according to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to afford the urea.

Example 50: Following Method A2, Step 4,5, 5-amino-2-methylphenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 3- (2). - (./ V-methylcarbamoyl) -4-pyridyloxy) -4metylanilín. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to give urea.

Example 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-7'-ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 52: According to Method A2, Step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N ¹ -methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 4- ( 2- (AAmetylkarbamoyl) -4-pyridyloxy) -3chlóranilín. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to afford the urea.

Example 53: 4- (4-Methylthiophenoxy) -1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. The nitrobenzene is reduced according to Method A19, Step 2 to give 4- (4-methylsulfonylphenoxy) -1-aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4-methylsulfonylphenoxy) -1-aniline to give urea.

* r à r

Example 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to give N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-bromobenzenesulfonamide is coupled with phenol according to Method A15, Step 2 to give 4- (4- (N-methylsulfamoyl) phenoxy) benzene. 4- (4- (N-Methylsulfamoyl) phenoxy) benzene was converted to 4- (4- (N-methylsulfamoyl) phenoxy) -1-nitrobenzene according to Method A15, Step 3. 4- (4- (N-Methylsulfamoyl) phenoxy) - The 1-nitrobenzene is reduced to 4- (4-7-methylsulfamoyl) phenyloxy) aniline according to method A15, step 4. And according to method C1 a 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- and ^r -metylsulfamoyl) phenyloxy) aniline to afford the urea.

Example 55: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4- (5- (2-Methyl) pyridyloxy) -1-nitrobenzene. Methylpyridine is oxidized to the carboxylic acid, esterified according to Method A18, Step 2 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) 1-nitrobenzene. The nitrobenzene is reduced according to Method A18, Step 3 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline. The aniline is reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to method Cla to give the urea.

Example 56: 5-Hydroxy-2-methylpyridine is coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4- (5- (2-Methyl) pyridyloxy) -1 nitrobenzene. Methylpyridine is oxidized to the carboxylic acid, esterified according to Method A18, Step 2 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) 1-nitrobenzene. The nitrobenzene is reduced according to Method A18, Step 3 to give 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline. The aniline is reacted with

4-chloro-3- (trifluoromethyl) phenyl isocyanate according to method Cla to give N (4-chloro-3- (trifluoromethyl) phenyl) - N - (4- (2- (methoxycarbonyl) -5- pyridyloxy) phenyl) urea. the methyl ester was reacted with methylamine according to method D2 to give N- (4-chloro-3- (trifluoromethyl) phenyl) -7V ^- (4- (2 - (/ V-methylcarbamoyl) -

5-pyridyloxy) phenyl) urea.

Example 57: N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4-aminophenyl) urea was prepared according to Method C, N- (4-Chloro-3- (trifluoromethyl) phenyl-N- ⁾ - (4'-aminophenyl) urea is coupled with n-OH-methylisophthalate according to Method D1 to give urea.

Example 58: 27- (4-Chloro-3- (trifluoromethyl) phenyl-27 '- (4-aminophenyl) urea was prepared according to Method C. 27- (4-Chloro-3- (trifluoromethyl) phenyl-27' - ( 4aminophenyl) urea is coupled with mono-methylisophthalate according to Method D1 to give 27- (4-chloro-3- (trifluoromethyl) phenyl-27 '- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea). 27- (4-chloro-3 (trifluoromethyl) phenyl-27 '- (4- (3-methoxycarbonylphenyl) carboxy amino phenyl) urea is reacted with methylamine to give the corresponding methylamide.

Example 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-27,27-dimethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (27,27-dimethylcarbamoyl) -4-pyridyloxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (27,27-dimethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4- (4-acetylphenoxy) nitrobenzene. Nitrobenzene is reduced according to Method 13, Step 4 to give 4- (4-acetylphenoxy) aniline, which is converted to 4- (4- (1- (27methoxy) iminoethyl) phenoxyaniline hydrochloride according to Method A16). chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4-acetylphenoxy) aniline to give urea.

Example 61: 4- (3-Carboxyphenoxy) -1-nitrobenzene was prepared according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with 4- (2-aminoethyl) morpholine according to Method A13, Step 3, to give 4- (3- (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene. And, according to method A13, step 4, 4- (3- (27- / 2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4 (3- (27- / 2-morpholinylethyl) carbamoyl) phenoxy) aniline. And, according to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (27- / 2-morpholinylethyl) carbamoyl) phenoxy) aniline to give urea.

Example 62: 4- (3-Carboxyphenoxy) -1-nitrobenzene was prepared according to Method A13, Step 2. 4- (3-carboxyphenoxy) -1-nitrobenzene was coupled with 1- (2-aminoethyl) piperidine according to Method A13 step 3 to give 4- (3- (N, N-piperidyl ethyl) carbamoyl) phenoxy) -1-nitrobenzene. And according to Method A13, Step 4, 4- (3- (N-β-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (3 (N β 2 -piperidylethyl) carbamoyl) phenoxy) aniline. And, according to method C1a, the 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (AA (2-piperidylethyl) carbamoyl) phenoxy) aniline to give urea.

Example 63: 4- (3-Carboxyphenoxy) -1-nitrobenzene was prepared according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4- (3- (7Vftetrahydrofurylmetyl) carbamoyl) phenoxy) -l-nitrobenzene. And according to Method A13 step 4, 4- (3- (N -tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (N - (tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline. And, according to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N - (tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline to give urea.

Example 64: 4- (3-Carboxyphenoxy) -1-nitrobenzene was prepared according to Method A13, Step 2.4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with 2-aminomethyl-1-ethylpyrrolidine according to Method A13, Step 3, to give 4- (3- (Ύ - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene. And, according to method A13, step 4, 4- (3- (N-f (1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -nitrobenzene is reduced to 4- (3- (1H - (1-methylpyrrolidinyl) methyl) carbamoyl) ) phenoxy) aniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (7H - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) aniline to give urea.

Example 65: 4-Chloro-N-methylpyridinecarboxamide was prepared according to Method A2, Step 3b. The chloropyridine is reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4- (4- (2- (N-methylcarbanioyl) phenylthio) aniline. According to Method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4 (4- (2- (N-methylcarbamoyl) phenylthio) or 1 hline to give urea.

r r

Example 66: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (1H-isopropylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 67: N- (4-Chloro-3- (trifluoromethyl) phenyl-N- (4-ethoxycarbonylphenyl) urea was prepared according to Method Cle. 7 - (4-Chloro-3- (trifluoromethyl) phenyl-N - (4-ethoxycarbonylphenyl) urea was saponified according to Method D3 to give N - (4-chloro-3- (trifluoromethyl) phenyl) -N- (4-carboxyphenyl) urea. -Chloro-3 (trifluoromethyl) phenyl-N '- (4-carboxyphenyl) urea was coupled with 3-methylcarbamoylaniline according to Method Db to give N - (4-chloro-3- (trifluoromethyl) phenyl) -N' - (4- (3-methylcarbamoyl-phenyl) carbamoy [phenyl 1) urea.

Example 68: 5- (4-Aminophenoxy) -2-methyl-isoindoline-1,3-dione was prepared according to Method A9. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione to give urea.

Example 69: 4-Chloro-N-methylpyridinecarboxamide was prepared according to Method A2, Step 3b. The chloropyridine is reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. According to Method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate reacted with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline) to give urea.

Example 70: 4- (2- (N- (2-Morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was prepared according to Method A10. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2 - (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to give urea.

Example 71: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to Method A14. 4-Chloro-3- (trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method Cla to give urea. N - (4-Chloro-3- (trifluoromethyl) phenyl) - N - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4- ( 2-aminoethyl) morpholine to give the amide.

Example 72: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to Method A14. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method Cla to give urea. 77- (5- (Trifluoromethyl) -2-methoxyphenyl) -77 '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea saponifies according to Method D4, Step 1, and the corresponding acid is coupled with methylamine according to Method D4, step 2 to obtain the amide.

Example 73: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was prepared according to Method A14. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method Cla to give urea. N- (5- (Trifluoromethyl) -2-methoxyphenyl) -77 '- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupling with 77,77-dimethylethylenediamine according to Method D4, Step 2 to give the amide.

Example 74: 4-Chloropyridine-2-carbonyl chloride hydrochloride was reacted with 2-hydroxyethylamine according to Method A2, Step 3b, to give 4-chloro-77- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide. 4-Chloro-77- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide was treated with triisopropylsilyl chloride then 4-aminophenol according to Method A17 to give 4- (4- (2- (77 ('2-triisopropylsilyloxy) ethylcarbamoyl)) And according to Method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (77- (2-trisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline) to give 77- (4-chloro-3 - (( trifluoromethyl) phenyl) -77 '- (4- (4- (2- (77- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea).

Example 75: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1f to give the urea which is coupled with 3-aminopyridine according to Method D1c.

F

Example 76: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3 carboxyphenoxy) aniline according to Method C1f to give the urea which is coupled with N- (4-acetylphenyl) piperazine according to Method D1c.

Example 77: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to give urea which is coupled with 4-fluoroaniline according to Method D1c.

Example 78: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to give urea which is coupled with 4- (dimethylamino) aniline according to Method D1c.

Example 79: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to give urea which is coupled with N-phenylethylenediamine according to Method D1c.

Example 80: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to give the urea which is coupled with 2-methoxyethylamine according to Method D1c.

Example 81: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to give the urea which is coupled with 5-amino-2-methoxy-pyridine according to Method D1c.

Example 82: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to give urea which is coupled with 4-morpholinoaniline according to Method D1c.

e *

Example 83: 4- (3-Carboxyphenoxy) aniline was prepared according to Method All. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to give the urea which is coupled with N - (2-pyridyl) piperazine according to Method D1c.

Example 84: 4-Chloropyridine-2-carbonyl chloride hydrochloride was reacted with 2-hydroxyethylamine according to Method A2, Step 3b, to give 4-chloro-77- (2-trisopropylsilyloxy) ethylpyridine-2-carboxamide. 4-Chloro-27- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide is reacted with triisopropylsilyl chloride then 4-aminophenol according to Method A17 to give 4- (4- (2- (77/2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline). And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (77- / 2-trisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline) to give 77- (4-chloro-3 - ((trifluoromethyl) Phenyl 1) -27 '- (4- (4- (2- (77- / 2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl I) urea) The urea was deprotected according to Method D5 to afford 77- (4-chloro-3 - ((trifluoromethyl) phenyl) -27 '- (4- (4 (2- (77- / 2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea.

Example 85: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) aniline was prepared according to Method A2. 4-Bromo-3- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. And, according to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (27-methylcarbamoyl) -4-pyridyloxy) aniline to yield urea.

Example 86: 4- (2- (77-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was prepared according to Method A6. 4-Bromo-3- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. And, according to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (77-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to afford the urea.

Example 87: According to Method A2, Step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-77-methyl-2-pyridinecarboxamide prepared according to Method

A2, step 3b to give 4- (2- (7-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 4-Bromo-3- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. And, according to Method C1a, 4β-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to afford the urea.

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

Example 89: 4-Chloro-N-methyl-2-pyridinecarboxamide, prepared according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to give 3- (- 2- (A ^r) methylcarbamoyl) -4-pyridyloxy) aniline. 4-Bromo-3- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. And, according to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3 - (- 2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give the urea.

Example 90: According to Method A2, Step 4, 5-amino-2-methylphenol is reacted with 4-chloro-N-methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 3- (2). - (N-methylcarbamoyl) -4-pyridyloxy) -4metylanilín. 4-Bromo- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. And, according to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to give urea.

Example 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro- N, N -dimethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline. . 4-Bromo-3- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. And, according to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (1 H, N-dimethylcarbamoyl) 4-pyridyloxy) aniline to give urea.

Example 92: 4-Chloro-2H-methylpyridinecarboxamide was prepared according to 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. 4-Bromo-3 (trifluoromethyl) aniline is converted to 4-bromo A process according to Method B1, and 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline) to afford urea. .

Example 93: 4-Chloro-N-methylpyridinecarboxamide was prepared according to Method A2, Step 3b. The chloropyridine is reacted with 3-aminothiophenol 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 B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (4- (2- (R) -methylcarbamoyl) phenylthio) aniline to give urea.

Example 94: 4- (2- (N- (2-Morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was prepared according to Method A10. 4-Bromo-3- (trifluoromethyl) aniline is converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. And, according to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to afford the urea.

Example 95: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) aniline was prepared according to Method A2. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was prepared according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline is converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. And, according to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 96: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was prepared according to Method A6. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was prepared according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline is 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 was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to afford the urea.

Example 97: According to Method A2, Step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-N ¹ -methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 4- ( 2 - (? / - methylcarbamoyl) -4-pyridyloxy) -3chlóranilín. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was prepared according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline is converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. And, according to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to afford the urea.

Example 98: 4-Chloro-N-methyl-2-pyridinecarboxamide, prepared according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to give 3- (- 2- (7H- methylcarbamoyl) -4-pyridyloxy) aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was prepared according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline is converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. And, according to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 3 - (- 2- (methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was prepared according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline is 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-ethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N, N-dimethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, from step 4 to give 4- (2- (77,77-dimethylcarbamoyl) -4-pyridyloxy) aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was prepared according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline is converted to 4-chloro-2-methoxy-5 (trifluoromethyl) phenyl isocyanate according to Method Bi. And, according to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (77,77-dimethylcarbamoyl) -4-pyridyloxy) aniline to give the urea.

Example 101: 4-Chloro-77-methyl-2-pyridinecarboxamide, prepared according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to give 3 - (- 2- (77- methylcarbamoyl) -4-pyridyloxy) aniline. 2-Amino-3-methoxynaphthalene was prepared according to Method A1. And according to method C3, 2-amino-

3-Methoxynaphthalene is reacted with bis (trichloromethyl) carbonate followed by 3- (2- (77-methylcarbamoyl) -4-pyridyloxy) aniline to form urea.

Example 102: 4- (2- (77-Methylcarbamoyl) -4-pyridyloxy) aniline was prepared according to Method A2. 5-tert-Butyl-2- (2,5-dimethylpyrolyl) aniline was prepared according to Method A4. 5- tert -Butyl-2- (2,5-dimethylpyrolyl) aniline was reacted with CDI followed by 4- (2- (77-methylcarbamoyl) -4-pyridyloxy) aniline according to Method C2d to give the urea.

Example 103: 4-Chloro-77-methyl-2-pyridinecarboxamide was prepared according to Method A2, Step 3b. 4-Chloro-77-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4, using DMAC instead of DMF to give 4- (2- (77-methylcarbamoyl) -4-pyridyloxy) aniline. A, according to Method C2b, reacting 3-amino-2-methoxyquinoline with CDI, then 4- (2- (77-methylcarbamoyl) -

4-Pyridyloxy) aniline gives bis (4- (2- (77-methylcarbamoyl) -4-pyridlyoxy) phenyl) urea.

The compounds listed in the tables below are synthesized according to the methods described in more detail above.

table

The compounds listed in Tables 1-6 below are prepared according to the general methods and more detailed procedures in the examples above. Individual characteristics are listed in the tables.

Table 1

3- tert -butylphenyl urea _r . _n x _h jO

H H

ťľíkhld R Melting point HPLC (min) TLC Rf TLC System MS Ponizicial Synthesis method 1 O _K Vnh 00:22 50% EtOAc / 50% hcxafa 418 (M + H) < + > (HPLC ES-MS) A13 C3 2 -O- -O- ° £ 00:58 50% EtOAc / 50% hexanes 403 (M + H) < + > (HPLC ES-MS) A13 C3 3 o _in SE-NH ~ O ^0H C / “ ^0Me 133- 13S 0.68 100% EtOAc 448 (M + H) < + > (FAB) A8 C2d

Table 2

5-tert-butyl-2-methoxyphenyl urea

Example R Melting point (° C) HPLC (min) TLC ^Rf TLC System MS [ionization] Synthesis method 4 δ _in V-NH 5.5) 3 448 (M + H) < + > (HPLC ES-MS) A13 BI Cla 5 Vnh -Ο- ° -Ο- ^0Μβ 120- 122 0.67 100% EtOAc 478 (M + H) < + > (FAB) A8 C2d 6 Y ABOUT 00:40 50% EtOAc / 50% hexane 460 (ΜΉ) * (HPLC-ES-MS) A3 C2d

r e

7 0.79 50% EtOAc / 50% hexane 446 (M + H) < + > (HPLC ES-MS) A12 C2d

Table 3

5- (Trifluoromethyl) -2-methoxyphenyl urea

ťifkJid R Melting point .C9 HPLC (min) TLC ^R r TLC System MS [Ionization] Method. synthesis 8 O, N-NH 250 (Dec) 460 (M + H) < + > (FAB) A13 C2a 9 CHX 206- 208 00:54 10% MeOH / 90% CH 2 Cl 2 446 (M + H) < + > (HPLC ES-MS) A3 step 2. A8 step 4, BI. Cla 10 00:33 50% EtOAc / 50% pet ether 445 (M + H) < + > (HPLC ES-MS) A13 C3 11 —E 9 y-nh Me ° Ä ^ ^N 00:20 2% Et 3 N / 98% EtOAc 461 (M + H) < + > (HPLC ES-MS) A2 C4 12 —Ť 2 / -nh ₂ 00:27 1% Et 3 N / 99% EtOAc 447 (M + H) < + > (HPLC ES-MS) A2 C4 13 o _K Vnh 0.62 100% EtOAc 461 (M + H) < + > (FAB) A2 C2a 14 0> ^NH 2 -O- ° C ⁿ 114th 117 00:40 1% Et 3 N / 99% EtOAc 447 (M + H) < + > (FAB) A2 C4

r · • »

15 Vnh - \ Zy ° A ^ ° ^Me 232- 235 00:54 100% EtOAc 490 (M + H) &lt; + &gt; (FAB) A8 C2d 16 0 Me> NH - \ / ^o C / ^N 210213 00:29 5% MeOH / 45% EtOAc / 50% pet ether 475 (M + H) &lt; + &gt; (HPLC ES-MS) A5 BI Cic 17 0 Cl-NH > -V / = <Μθ <R ° -v 187- 188 00:17 50% EtOAc / 50% pet ether 495 (M + H) &lt; + &gt; (HPLC ES-MS) A6 BI Cla 18 —F> - Me> -NH ₂ ° —ζ N 00:48 100% EtOAc 475 (M + H) &lt; + &gt; (HPLC ES-MS) A2 step 4. BI Cla 19 O-NH ^Et 194- 196 00:31 5% MeOH / 45% EtOAc / 50% pet ether. 475 (M + H) &lt; + &gt; (HPLC ES-MS) A2 BI Cla 20 Cl - NH - @ 1 ° C / ^N 214- 216 00:25 5% MeOH / 45% EtOAc / 50% pet ether ' 495 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 21 - ^ ° ^ ¾ 208- 210 00:30 50% EtOAc / 50% hexane 481 (M + H) &lt; + &gt; (HPLC ES-MS) A19C2a 22 0> ~ nh ₂ 188190 00:30 70% EtOAc / 50% hexanes 447 (M + H) &lt; + &gt; (HPLC ES-MS) A15. step 4, Cla 23 -O ^ -Of ⁰ ¥ ^NH o 00:50 70% EtOAc / 30% hexane 472 (M + H) &lt; + &gt; (FAB) A3 BI Cla 24 0 Me Vn ^Me 203- 205 00:13 100% EtOAc 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2 BI Cla

r r

25 00:09 75% EtOAc / 25% hexane 458 (M + H) &lt; + &gt; (HPLC ES-MS) A12 C2d 26 MeQ _Me 169- 171 0.67 50% EtOAc / 50% pet ether 474 (M + H) &lt; + &gt; (HPLC ES-MS) A13 step 4, A13 step 4th A16, BI Cla 27 c> Ϋ-ΝΗ 218219 00:40 50% EtOAc / 50% pet ether 477 (M + H) &lt; + &gt; (HPLC ES-MS) A2 step 3b, A2 step 4. BI, Cla 28 X ^ NMe 0 212214 00:30 40% EtOAc / 60% hexane A9 BI Cla 29 Vnh \ = (/ = (Me S - _/? N 00:33 50% EtOAc / 50% pet ether 474 (M + H) &lt; + &gt; (HPLC ES-MS) A2 step 3b, A2 step 4. BI, Cla 30 O _in V NH ^PN 210- 211 A2 BI Cla 31 o _{x 1-} NH-O- ° -Q 210- 204 00:43 10% MeOH / CH 2 Cl 2 A14 BI Cla D4 32 IGB 247249 00:57 10% MeOH / CH 2 Cl 2 A14 BI Cla D4 33 —Ť ~ ^ ~ ° ~ C ~~ ^ '/ ^{N_Mf x = /} ^ -N Me 217219 00:07 10% MeOH / CH 2 Cl 2 A14 BI Cla D4

34 0 V-NH OD b 00:11 70% EtOAc / 30% hexane All BI Clf Dlc 35 b N - \ Q _o 00:38 70% EtOAc / 30% hexane All BI Clf Dlc 36 —O ~ ^0- O 0.77 70% EtOAc / 30% hexane All BI Clf Dlc 37 ^Me ' _NH ry _NH Me' = Q -Ο- ° ~ Ώ 00:58 70% EtOAc / 30% hexane All BI Clf Dlc 38 MeO-N-NH b = z Q = Q 00:58 70% EtOAc / 30% hexane All BI Clf Dlc 39 0 N — ΓΧ- NH X— / \ = / ^ = Q “O ^-0- ® 00:17 70% EtOAc / 30% hexane All BI Clf Dlc 40 NQN-O-O-N ^ o - &> O 00:21 70% EtOAc / 30% hexane All BI Clf Dlc

Table 4.

3- (trifluoromethyl) -4-chIórfenyImočoviny

r *

Example R Melting point (• C) HPLC (min) TLC ^R r TLC System MS (Ionization) Synthesis method ⁴¹ IGB 163- 165 00:08 50%. EtOAc / 50% pet ether 464 (M + H) &lt; + &gt; (HPLC ES-MS) A13 C3 42 0th IGB * 215 00:06 50% EtOAc / 50% pet ether 465 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 43 0 _Vnh ₂ -Ο-θ-Ο · 00:10 50% EtOAc / 50% pet ether 451 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 44 // \ θ \ - \ z / ^NHz ”° ⁿ 1 00:25 30% EtOAc / 70% pet ether 451 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 45 ° A - ( ^NH ) -O 00:31 30% EtOAc / 70% pet ether 465 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 46 -O- ° -Q '° ^{NH NH} 176179 00:23 40% EtOAc / 60% hexanes 476 (M + H) &lt; + &gt; (FAB) A3 Cla 47 0 Me V-NH -Ο ~ ^0Η ΰ ^Ν ** 00:29 5% MeOH / 45% EtOAc / 50% pet ether 478 (M + H) &lt; + &gt; (HPLC ES-MS) A5 Cic 48 ° * S-NH -Qr / i 206209 A15 Cla 49 Cl Cl — NH ' ^Me 147151 00:22 50% EtOAc / 50% pet ether 499 (M + H + (HPLC ES-MS)) A6 Cla 50 —Me V-NH / = / Me ° Λ 7 00:54 100% EtOAc 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla

»R p r r r <r

51 O _K Ynh -Ό — D 187- 189 00:33 5% MeOH / 45% EtOAc / 50% pet ether 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 52 C 0 y-NH, / = (M ® \ / ° "w ^N 219 00:18 5% MeOH / 45% EtOAc / 50% pet ether 499 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 53 246- 248 030 50% EtOAc / 50% hexane 485 (M + H) &lt; + &gt; (HPLC ES-MS) A19, Cla 54 -CY ° -o- \ ° Me 196- 200 030 70% EtOAc / 30% hexane) 502 (M + H) &lt; + &gt; (HPLC ES-MS) A15 Cla 55 228- 230 030 30% EtOAc / 70% CH 2 Cl 2 466 (M + H) &lt; + &gt; (HPLC ES-MS) 56 ^ - <x, Me 238245 57 -O- ^ O " 221- 222 0.75 80% EtOAc / 20% hexanes 492 (M + H) + (FAB) Cld Dla 58 o _in V- NH -OO ^ ^M · 247 035 100% EtOAc Cld Dla D2 59 O Me -0-0 ' 198- 200 00:09 100% EtOAc 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 60 MeO -o-KH 158160 0.64 50% EtOAc / 50% pet ether 61 O-NH '-ABOUT 195- 197 039 10% MeOH / CH 2 Cl 2 A13 Cla

62 O _K 'of ^NH 170- 172 00:52 10% MeOH / CH 2 Cl 2 * A13 Cla 63 0 z-nh P> - <x> 168- 171 00:39 10% MeOH / CH 2 Cl 2 A13 Cla 64 In ^E1 &apos; -NH N ^ -on 176- 177 00:35 10% MeOH / CH 2 Cl 2 A13 Cla 65 about. Vnh -O- ^ * 130133 487 (M + H) &lt; + &gt; (HPLC ES-MS) A2 BI Cla 66 _{x x} Vnh -0- ° ^ ^PH 155 A2 Cla 67 γ-NH-O-α-Q. 225229 00:23 100% EtOAc Cle D3 Dlb 68 -Ο ~ ^0Η Ού ⁰ X ^ NMe 234- 236 00:29 40% EtOAc / 60% hexane A9 Cla 69 / ž ~ \ —epy — nh ^λ = \ / = (Μβ ^p 00:48 50% EtOAc / 50% pet ether f 481 (M + H) &lt; + &gt; (HPLC ES-MS) 70 o _x 1-NH 00:46 5% MeOH / 95% CH 2 Cl 2 $ 64 (M + H) &lt; + &gt; (HPLC ES-MS) A10 Cla

71 V _ν V - NH O'-Q '—ο' 199- 201 00:50 10% MeOH / CH 2 Cl 2 A14 Cla D4 72 ^ -ΝΗ 235- 237 00:55 10% MeOH / CH 2 Cl 2 2 A14 Cla D4 73 5 ~ ^νη - ^ Ν-Μβ 200201 00:21 50% MeOH / CH 2 Cl 2 2 A14 Cla D4 74 ο _ν ΝΗ C C C ~ ^{0 O} -C 3 ' ^- ' bsi (Pr í) ₃ 145- 148 75 (Λ-ΝΗ 00:12 70% EtOAc / 30% hexane 527 (M + H) &lt; + &gt; (HPLC ES-MS) All Clf Dlc 76 0 Me — V Q Q _o 00:18 70% EtOAc / 30% hexane All Clf Dlc 77 ^FH CH = ° 0.74 70% EtOAc / 30% hexane All Clf Dlc 78 ^Μ \ _ ^ _γ ΝΗ Me ^ = / i = 0 O> O 00:58 70% EtOAc / 30% hexane All Clf Dlc

er * * * r * er r **

79 O _in ^NH- O-O-O- ^3nh O 00:47 70% EtOAc / 30% hexane 569 (M + H) &lt; + &gt; (HPLC ES-MS) All Clf dlc 80 o _at 1'-NH ° ^Me 00:18 70% EtOAc / 30% hexane 508 (M + H) &lt; + &gt; (HPLC ES-MS) All Clf dlc 81 MeO "V-NH ^ = 0 0.58 70% EtOAc / 30% hexane 557 (M + H) &lt; + &gt; (HPLC ES-MS) All Clf Dlc 82 0-0 - ^ = o -O ~ ^o- C? 00:37 70% EtOAc / 30% hexAi 611 (M + H) &lt; + &gt; (HPLC ES-MS) All Clf Dlc 83 Q O 'N ^- O O ^{-0 =} 00:19 70% EtOAc / 30% hexane All Clf dlc 84 In ^nh -Ο ^ θ-Ο 179183 A2 A17 Cla D5

Table 5.

3- (trifluoromethyl) -4-bromophenylurea

br

9 y 9 y 9 9 y

r e

Example R .Melting temperature Γ9 HPLC (min) TLC 8 ( TLC System MS (Ionization)! Method i synthase * 85 Q ^ NH 186- 187 00:13 50% EtOAc / 50% pet ether 509 (M + H) &lt; + &gt; (HPLCESMS) A2 BI Cla 85 0 Cl) "NH - \ / °" 4 / ^N 150- 152 00:31 50% EtOAc / 50% pet ether 545 (M + H) &lt; + &gt; (HPLCESMS) A6 BI Cla 87 o Cl y-NH- (C / ^N) 217- 219 00:16 50% EtOAc / 50% pet. ether 545 (M + H) &lt; + &gt; (HPLC ESMS) A2 BI Cla 88 o _in '^ -NH -0-0 ^E ' 183- 184 00:31 50% EtOAc / 50% pet ether 525 (M + H) &lt; + &gt; (HPLC ESMS) A2 BI Cla 89 “O JH; o £ .n 00:21 30% EtOAc / 50% pet ether 511 (M + H) &lt; + &gt; (HPLC ESMS) A2 BI Cla 90 - ^ V-Μθ Λ-ΝΗ ~ ° -O 0J8 50% EtOAc / 50% pet ether · 525 (M + H) &lt; + &gt; (HPLCESMS) A2 BI Cla 91 0 Me -ο- ~ ο " 214- 216 028 50% EtOAc / 50% pet ether 522 (M + H) &lt; + &gt; (HPLC ESMS) A2 BI Cla 92 o _in Vnh -Qr * -O ^M ' 00:47 50% EtOAc / 50% pet ether 527 (M + H) &lt; + &gt; (HPLC ESMS) A2 step 3b. A2 step 4. BI, Cla 93 -q 00:46 50% EtOAc / 50% pet ether 527 (M + H) &lt; + &gt; (HPLC ESMS) A2 step 3b. A2 step 4, BI. Cla 94 0 > -NH ~ 0 ° 145- 150 00:41 5% MeOH / 95% CH 2 Cl 2 A10 BI Cla

Table 6,

5- (trifluoromethyl) -4Tchlór-2-methoxyphenyl urea

Example R Hot Melting (° C) HPLC (min) TLC ^R r TLC System MS. (FAB] Synthesis method 95 0 NH 140- 144 0:29. <az MeOH / 45% EtOAc / 50% pet ether 495 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 BI Cla 96 0 Cl y - NH - \ / ^o_ C // 244245 00:39 5% MeOH / 45% EtOAc / 50% pet ether 529 (M + H) &lt; + &gt; (HPLC ES-MS) A6 A7 BI Cla 97 O Cl P-NH - <Cz ~ ^oH C / 220- 221 00:25 5% MeOH / 45% EtOAc / 50% pet ether 529 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 BI Cla 98 -Q 00:27 5% MeOH / 45% EtOAc / 50% pet ether 495 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 BI Cla 99 y nh - <y </ " 180- 181 00:52 5% MeOH / 45% EtOAc / 50% pet ether 509 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 BI Cla 100 0 NH ^PN 162165 A2 A7 BI Cla

Table 7.

More ureas

Example R Melting point (’C) HPLC (min) TLC Rf TLC System MS [Ionisationjj Synthesis method 101 0Me ^H 162- 165 Al A2 C3 102 00:10 50% EtOAc / 50% hexanes 442 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A4 C2d 103 ° = < W about 125- 130 00:24 40% EtOAc / 60% hex 512 (M + H) + (FAB) A2 C2b

The synthesis of the compound of the above examples may be repeated with similar success when the generic or specifically described reactants and / or reaction conditions of the present invention set forth in the above described examples are replaced.

From the foregoing description, the essential characteristics of the invention can be readily determined, and variations and modifications to the invention can be made therein without departing from the spirit and scope of the invention.

Claims (67)

PATENT CLAIMS 1. Compound of Formula 1: A-D-B (1) or a pharmaceutically acceptable salt thereof, wherein in Formula I, D is -NH-C (O) -NH-, A is a substituted moiety having up to 40 carbon atoms in the formula: -L- (ML ¹ ) _q , wherein L is a 5- or 6-membered cyclic structure bonded directly to D, L ¹ contains a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer ranging from 1 to 3; and each cyclic structure of L and L ¹ contains 0 to 4 members of the group consisting of nitrogen, oxygen and sulfur; and B is a substituted or unsubstituted to tricyclic aryl or heteroaryl moiety having up to 30 carbon atoms with at least one 6-membered cyclic structure bonded directly to D containing 0 to 4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L ¹ is substituted with at least one substituent selected from the group consisting of -SC 1 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 a group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen, except for perhalogen, R _z is hydrogen or a carbon-based moiety having up to 30 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen, hydroxy and carbon-based substituents having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and are optionally substituted with halogen; R _x is R _z or NR _and R b, wherein R _a and R b are (a) independently hydrogen, a carbon-based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur 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 nitrogen, oxygen and sulfur atoms and are optionally substituted with halogen, or -OSi (Rf) 3, wherein Rf is hydrogen or a carbon-based moiety having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen, hydroxy and carbon-based substituents up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen; or b) R _a and R b together form a 5 to 7 membered heterocyclic structure containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or a substituted 5 to 7 membered heterocyclic structure having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms substituted by halogen, hydroxy or carbon-based substituents having up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted by halogen; or e · r ** »** · λ rr · ·· _Γ · 95 c) one of R _a or R b is -C (O) -, a C 1 -C 8 divalent alkylene group or a substituted C 1 -C 8 divalent alkylene group bonded to the L moiety to form a cyclic structure with at least 5 members wherein the substituted C 1 -C 8 divalent alkylene substituents the groups are selected from the group consisting of halogen, hydroxy and carbon-based substituents having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen; wherein B is substituted, L is substituted or L ¹ is additionally substituted, the substituents are selected from the group consisting of halogen, up to total halogen substitution being possible, and Wn, wherein n is 0 to 3; wherein each W is independently 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 , -NR ⁷ R ⁷ , NO ₂ , -NR ⁷ C (O) R ⁷ , -NR ⁷ C (O) OR ⁷ , -Q-Ar and carbon-based moieties having up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and optionally substituted with one or more substituents independently 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 , -NR ⁷ R ⁷ , NO 2, -NR ⁷ C (O) R ^7, -NR ⁷ C (O) OR ⁷ and halogen up to the maximum levels of substitution by halogen; wherein each R ⁷ is independently selected from hydrogen or a carbon-based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen, wherein Q is -O-, -S -, -N (R ⁷⁾ -, - (CH2) m-, -C (0) -, -CH (OH) -, - (CH 2) m0-, - (CH 2) m S-, - (CH 2) m N (R ⁷⁾ -, -0 _(CH2) -CHX ^a, -CX ^a ₂ -, -S- (CH _{2) m} - and -N (R ⁷ ) (CH ₂ ) _m -, wherein the index m = 1-3 and X ^a is halogen; and Ar is a 5- or 6-membered aromatic structure containing 0 to 2 members of the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen except for total halogen substitution and optionally substituted by _Zn i, where the index nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO ₂ R ⁷ , -C (O) NR ⁷ R ⁷ , -NO 2, -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C ( O) OR ⁷ , -C (O) R ⁷ , -NR ⁷ C (O) R ^7, and carbon-based moieties of up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms and optionally substituted one or more substituents 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 , -NR ⁷ R ⁷ , NO ₂ , -NR ⁷ C (O) R ⁷ and -NR ⁷ C (O) OR ⁷ , wherein R ⁷ is defined above. A compound according to claim 1, wherein: R _y is hydrogen, C 1-10 alkyl, C 10 alkoxy, C 3-10 cycloalkyl having 0 to 3 heteroatoms, C 2-10 alkenyl, C 1-10 alkenoyl, C 6-12 aryl, C 3-12 heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, S and O, C7. ₂ 4aralkyl, C 7 _"2 4alkaryl, substituted C. íoalkyl substituted Cj.ioalkoxy, substituted C3.jocykloalkyl having 0 to 3 heteroatoms selected from among N, S and O, substituted C6-Ci4aryl substituted C3.i ₂ hetaryl having 1-3 heteroatoms selected from the group consisting of N , S and O, substituted C 7-24 alkaryl or substituted C 7 -C ₂₄ aralkyl, when R _y is a substituted group, is substituted by halogen up to perhalogen, R _z is hydrogen, C 1-10 alkyl, C ₁₀ alkoxy, C ₃ . íocykloalkyi having 0 to 3 heteroatoms, C ₂ -ioalkenyl, Ci.ioalkenoyl CD. ₁₂ aryl, C 3 -C ₁₂ hetaryl having 1 to 3 heteroatoms selected from the group consisting of, S, N and O, C ₇ . ₂ 4alkaryl, C ₇ . ₂ 4aralkyl, substituted C. íoalkyl substituted CMOalkoxy group, a substituted C ₆ -Ci4aryl, substituted C3-Cjocykloalkyl having 0 to 3 heteroatoms selected from among S, N and O, substituted C ₃ -i ₂ hetaryl having Laz 3 heteroatoms selected from the group consisting of S, N and O, substituted C 7 -C ₂₄ alkaryl or substituted C 7 -C ₂₄ aralkyl, when the R 1 substituent R ₂ is a substituted group, is substituted by halogen up to perhalogen, hydroxy, C 1-10 alkyl, C 3 -C 12 cycloalkyl having 0 to 0 3 heteroatoms selected from the group consisting of O, S and N, C3-C12 hetaryl having 1 to 3 heteroatoms selected from the group consisting of N, S and O, C1-10 alkoxy, C6-Cnaryl, Ci. ehalo-substituted alkyl up to perhaloalkyl, C8-halo substituted aryl up to perhaloaryl, C3-halo substituted cycloalkyl up to perhalocycloalkyl having 0 to 3 heteroatoms selected from the group consisting of N, S and O, halogen-substituted Ca-Cnhetaryl up to perhalohetaryl having 1 to 3 heteroatoms selected from the group consisting of O, N and S, halogen-substituted C7-C24 aralkyl up to perhaloaralkyl, halogen-substituted C7-C24alkaryl up to perhaloalkaryl and -C (C) _g , R _a and R b are (a) independently hydrogen, The carbon-based moiety selected from the group consisting of C 1 -C 10 alkyl, C ₁ -C 10 alkoxy, C 3-10 cycloalkyl, C 2-10 alkenyl, C 1-10 cycloalkyl. loalkenoylu, co-uarylu C ₃ having .i2hetarylu 1 to 3 heteroatoms selected from the group consisting of O, N and S, C ₃ having -i2cykloalkylu 0-3 heteroatoms selected from the group consisting of N, S and O, C7-24aralkylu, C7 -C24 alkaryl, substituted CMOalkyl, CMOalkoxy substituted, substituted C ₃ .iocykloalkylu, having 0 to 3 heteroatoms selected from among N, S and O, substituted C _3.] 2 aryl, substituted having 1 Cj.uhetarylu up to 3 heteroatoms selected from the group consisting of N, S and O, substituted C 7-24 aralkyl, substituted C 7-24 alkaryl, when the substituents R _a and R b are a substituted group, are substituted with halo except perhalogen, hydroxy, C 1-10 alkyl, C ₃ . i2cykloalkylom having 0 to 3 heteroatoms selected from among O, S and N, C ₃ .i2hetarylom having 1 to 3 heteroatoms selected from the group consisting of N, S and O, CMOalkoxy group, a C _6. R 1-12 aryl, C 1-6 halo substituted alkyl up to perhaloalkyl, C 6 -C 4 halo substituted aryl up to perhaloaryl, C 3 -C 10 halo substituted cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of N, S and O, up to perhaloCycloalkyl, up to perhaloCycloalkyl Ci2hetarylomu to the perhalogénheteraryl, halo substituted C7-C24aralkylom to the perhalogénaralkyl, halo substituted C7 -C24 alkaryl and perhalogénalkaryl to the -C (O) R _g; or -OSi (Rf) 3 wherein Rf is hydrogen, C 1-10 alkyl, C 1-10 alkoxy, C ₃ -C ₁₀ cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of O, S and N, C 8 -C 14 aryl, C 3 -C 12 hetaryl having 1 1-3 heteroatoms selected from the group consisting of O, S and N, C7. 24aralkyl, substituted C 1-10 alkyl, substituted C 1 -C 10 alkoxy, substituted C 3 -C 12 cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of O, S and N, substituted C 3 -C 12 heteroaryl having 1 to 3 heteroatoms selected from the group consisting of O, S , and N, substituted C 6 -aryl and substituted C 7-24 alkaryl, when R f is a substituted group, is substituted with halogen other than perhalogen, hydroxy, C 1-10 alkyl, C 3-12 cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of O, S and N, C3. ₂ hetaryl having 1 to 3 heteroatoms selected from the group consisting of N, S and O, C 1-10 alkoxy, C 1-8 aryl, C 7 -C 24 alkaryl, C 7 -C 24 aralkyl, C 1-8 halogen substituted alkyl up to perhaloalkyl, C 6 -C 6 halo substituted aryl up to perhaloaryl, C 3 -C 12 halo substituted cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of N, S, and O, up to perhalocycloalkyl, halo substituted C 3 -C 12 hetaryl up to perhaloheteraryl, halo substituted C 7 -C 24 arhaloalkyl, -C24alkarylom to the perhalogénalkaryl and -C (O) R _g, or b) R _a and R b together form a 5- to 7-membered heterocyclic structure having 1 to 3 heteroatoms selected from the group consisting of N, S and O or a substituted 5- to 7-membered heterocyclic structure having 1 to 3 heteroatoms selected from the group consisting of N, S and O, with substituents selected from the group consisting of halo to perhalogen, hydroxy, C 1-10 alkyl, C 3-12 cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of O, S and N, C 1 -hetaryl having 1 to 3 heteroatoms selected from the group consisting of N, S and O, a C 10-10 alkoxy group; 12 aryl, C 7 -C 24 alkaryl, C 7 -C 24 aralkyl, halogen substituted C 1-6 aryl; alkyl to perhaloalkyl, halo substituted C 6 -C 6 aryl to perhaloaryl, halo substituted C 3 -C 12 cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of N, S and O, to perhalocycloalkyl, halo substituted C 3 -C 12 halo substituted C 3 -C 12 halo; C 7 -C 24 aralkyl to perhaloaralkyl, halogen substituted C 7 -C 24 alkaryl to perhaloalkaryl and -C (O) R _g , or c) one of the substituents R _a or R b is -C (O) - and a C 1 -C 5 divalent alkylene group or a substituted C 1 -C 5 divalent alkylene group bonded to the L moiety to form a cyclic structure with at least 5 members wherein the substituted C 1 substituents The -C -divalent alkylene group is selected from the group consisting of halogen, hydroxy, C 1-6 alkyl. loalkyl, C 3-8 cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of O, S and N, C 1-4 heteroetaryl having 1 to 3 heteroatoms selected from the group consisting of N, S and O, C 1-10 alkoxy, C 6-10 aryl, C 7 -C 24 alkaryl, C 7 -C 24 aralkyl, C 1 -C 6 halo-substituted alkyl to perhaloalkyl, C 6 -C 10 halo-substituted aryl to perhaloaryl, C 3 -C 12 halo-substituted cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of O, S, and O, 100 Ci2hetarylu substituted C 3 to perhalogénheterarylu, halogen substituted C 7 to C24aralkylu perhalogénaralkylu, halo substituted C7 -C24 alkaryl and perhalogénalkarylu and -C (O) R _e, wherein R _g is C-ioalkyl; -CN, -CO ₂ Rd, -OR 1, -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 substituents Rd and R _e are independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of O, N and S, C 6 aryl, C 3 -C ₁₂ hetaryl having 1 to 3 heteroatoms selected from the group consisting of O, N and S, and C 7 -C 24 aralkyl, C 7 -C 24 alkaryl, to perhalo substituted C 1 -C 10 alkyl, to perhalogen substituted C 3 -C 10 cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of O, and S, up to perhalo-substituted C 6 -C 14 aryl, up to perhalo-substituted C 5 -C 18 heteroaryl having 1 to 3 heteroatoms selected from the group consisting of O, N, and S, halogen substituted C ₇ C 1-8 alkenyl to perhaloalkaryl, and up to perhalo substituted C 7 -C 24 aralkyl; 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 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 10 alkenyl, C 3 -C 10 alkenoyl, C 3 -C 10 cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of O S and N, C-Cuarylu, C 7 -C ₂ 4alkarylu, C7C24aralkylu, C 3 Ci2heteroarylu having 1 to 3 heteroatoms selected from the group consisting of O, N and S, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from the group consisting of H , N and S, substituted C 1 -C 10 alkyl, substituted C 1 -C 10 alkoxy, substituted C ₂ -C ₁₀ alkenyl, substituted C 1 -C ₁₀ alkenoyl, substituted C 3 -C 10 cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of O, N and S, substituted C 6 -C 14 aryl substituted C 1 -C 4 hetaryl having 1 to 3 heteroatoms selected from the group consisting of O, N and S, substituted C 7 -C 24 aralkyl u, substituted C 7 -C 24 alkaryl, substituted C 4 -C 23 alkheteroaryl 101 having 1 to 3 heteroatoms selected from the group consisting of O, N and S and -Q-Ar; R ⁷ is independently selected from 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 10 cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of O, S and N, C 6 - Cuarylu, C 3 -C ₃ hetaryl having 1-3 heteroatoms selected from the group consisting of O, N and S, C7Cualkarylu, C 7 C24aralkylu, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from the group consisting of O, N and S, up to per halo substituted C 1 -C 10 alkyl, up to perhalo substituted C 3 -C 10 cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of O, N and S, up to perhalogen substituted C 6 -C 10 aryl, up to perhalo substituted C 3 -C 13 heteroaryl having 1 to 3 heteroatoms selected from the group consisting from O, N and S, up to perhalo-substituted C7-C24 aralkyl, up to perhalo-substituted C7-C24 alkaryl, and up to perhalo-substituted C4C2 ₃ alkheteroaryl u; 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, -NO 2, -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 alkenoyl, C 3 -C 10 cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of O , N and S, Ce-Cuaryl, Cs-Cnhetaryl having 1 to 3 heteroatoms selected from the group consisting of O, N and S, C7-C24alkaryl, C7-C24aralkyl, C4-C23alkheteroaryl having 1 to 3 heteroatoms selected from the group consisting of O , N and S, substituted C 1 -C 10 alkyl, substituted C 1 -C 10 alkoxy, substituted C 2 -C 10 alkenyl, substituted C 1 -C 10 alkenoyl, substituted C 3 -C 10 cycloalkyl having 0 to 3 heteroatoms selected from the group consisting of O, N and S, substituted C 6 -C 10 aryl , substituted C 7 -C 24 alkaryl, substituted C 7 -C 24 aralkyl and substituted C 4 -C 23 alkheteroaryl having 1 to 3 heteroatoms selected selected from the group consisting of O, N and S, and when Z is substituted 102, then one or more substituents is 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 . A compound according to claim 1, wherein 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 ^and -, - CX ^and 2-, -S- (CH 2) m - and -N (R ⁷ ) (CH 2) _m -, wherein the index m - 1 to 3, X ^a is halogen and R ⁷ is as defined in claim 1. The compound of claim 1, wherein the cyclic structures B and L bonded directly to D are not substituted at the ortho position by -OH. The compound of claim 1, wherein the cyclic structures B and L bonded directly to D are not substituted in the ortho position by the moiety having ionizable hydrogen and pK _and 10 or less. The compound of claim 1, wherein B of Formula 1 is a substituted or unsubstituted 6-membered aryl or 6-membered hetaryl moiety, wherein said hetaryl moiety having 1 to 4 members selected from the group of hetaryl atoms consisting of nitrogen, oxygen and sulfur atoms has the remainder of the hetaryl part that is carbon. A compound according to claim 1, wherein B of formula I is unsubstituted phenyl, unsubstituted pyridyl, unsubstituted pyrimidinyl, phenyl substituted with a substituent selected from the group consisting of halogen and Wn, wherein W and n are as defined in claim 1, pyrimidinyl substituted 103 is a substituent selected from the group consisting of halogen and Wn, wherein W and n are as defined in claim 1, or a substituted pyridyl group substituted with a substituent selected from the group consisting of Wn, wherein W and n are as defined in claim 1. A compound according to claim 6, wherein B of formula I is a substituted phenyl group, a substituted pyrimidinyl group or a substituted pyridyl group substituted one to three times with one or more substituents selected from the group consisting of -CN, halogen, C 1-10 alkyl, C 1 -C 10 alkoxy, -OH, up to perhalo-substituted C 1 -C 10 alkyl, up to perhalo-substituted C 1 -C 10 alkoxy, or phenyl substituted by halogen up to perhalogen. The compound of claim 1, wherein the L 6-membered cyclic structure bonded 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 having 1 to 4 members selected from the heteroatom group consisting of a nitrogen, oxygen and sulfur atom has a hetaryl moiety that is carbon, wherein one or more substituents are selected from the group consisting of halogen and Wn, wherein W and n are as defined in claim 1. The compound of claim 8, wherein the L, 6-membered cyclic structure bonded directly to D is a substituted phenyl, unsubstituted phenyl, substituted pyrimidinyl, unsubstituted pyrimidinyl, substituted pyridyl or unsubstituted pyridyl group. The compound of claim 1, wherein said substituted cyclic moiety L ¹ comprises a 5 to 6-membered aryl moiety or a hetaryl moiety, wherein said r The 104 hetaryl moiety contains 1 to 4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur. The compound of claim 1, wherein said substituted cyclic moiety L ¹ is phenyl, pyridinyl or pyrimidinyl. The compound of claim 3, wherein said substituted cyclic moiety L 'is phenyl, pyridinyl or pyrimidinyl. The compound of claim 6, wherein said substituted cyclic moiety L ¹ is a phenyl, pyridinyl or pyrimidinyl group. The compound of claim 8, wherein said substituted cyclic moiety L ¹ is phenyl, pyridinyl or pyrimidinyl. The compound of claim 9, wherein said substituted cyclic moiety L ¹ is phenyl, pyridinyl or pyrimidinyl. The compound of claim 10, wherein said substituted cyclic moiety L ¹ is phenyl, pyridinyl or pyrimidinyl. The compound of claim 14, wherein 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} -0-, - (CH _{2) and} -S-, - (CH ₂ ) _m -N (R ⁷ ) -, -O (CH ₂ ) _m -CHX ^and -, -CX ^and 2-, -S- (CH 2) m - and -N (R ⁷ ) (CH 2) _m -, 105 wherein m = 1 to 3, X ^a is halogen and R ⁷ is hydrogen or a carbon-based moiety having up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen up to perhalo. A compound according to claim 15, wherein 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} -0-, - (CH _{2) m} -S-, - (CH ₂ ) _m -N (R ⁷ ) -, -O (CH ₂ ) _m -CH ₂ -, -CX ^and 2-, -S- (CH ₂ ) _m - and -N (R ⁷ ) (CH ₂₎ ) _m - wherein m = 1 to 3, X 'is halogen and R ⁷ is hydrogen or a carbon-based moiety having up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted halogen except perhalogen. A compound according to claim 16, wherein 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 ) _n -O-, - (CH ₂ ) _m -S-, - (CH ₂ ) _m -N (R ⁷ ) -, -O (CH ₂ ) _m -CHX ^and -, -CX ^and 2-, -S- (CH 2) m - and -N (R ⁷ ) (CH 2) _m - wherein m = 1 to 3, X 'is halogen and R ⁷ is hydrogen or a carbon-based moiety having up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen except for perhalogen. The compound of 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 (O) -, -CH (OH) -, - (C, H ₂ ) _m -O-, - (CH ₂ ) _in -S-, - (CH ₂ ) _m -N (R ⁷ ) -, -O (CH ₂ ) _m -CHX ^and -, -CX ^and 2-, -S- (CH 2) m - and -N (R ⁷ ) (CH 2) _m -, wherein the index m = 1 to 3, X ^a is halogen and R ⁷ is a hydrogen atom or a carbon-based moiety having up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen except for perhalogen. r r 106 The compound of claim 1, wherein L ¹ is additionally substituted one to three times with one or more substituents selected from the group consisting of C 1 -C 10 alkyl, up to perhalogen substituted C 1 -C 10 alkyl, -CN, -OH, halogen, C 1 -C 10 alkoxy, and up to perhalogen substituted C 1 -C 10 alkoxy groups. The compound of claim 13, wherein L ¹ is additionally substituted one to three times with one or more substituents selected from the group consisting of C 1 -C 10 alkyl, up to perhalo substituted C 1 -C 10 alkyl, -CN, -OH, halogen, C 1 -C 10 alkoxy and up to perhalogen substituted C 1 -C 10 alkoxy groups. 24. The compound of Claim 18, wherein L ¹ is additionally substituted one to three times by one or more substituents selected from the group consisting of C-C _O alkyl, up to per halo substituted CiCioalkylu, -CN, -OH, halogen, Ci-Cioalkoxy group and to perhalogen substituted C 1 -C 10 alkoxy groups. The compound of claim 19, wherein L ¹ is additionally substituted one to three times with one or more substituents selected from the group consisting of C 1 -C 10 alkyl, up to perhalogen substituted C 1 -C 10 alkyl, -CN, -OH, halogen, C 1 -C 10 alkoxy and up to perhalogen substituted C 1 -C 10 alkoxy groups. The compound of claim 20, wherein L ¹ is additionally substituted one to three times with one or more substituents selected from the group consisting of C 1 -C 10 alkyl, up to perhalogen substituted C 1 -C 10 alkyl, -CN, -OH, halogen, C 1 -C 10 alkoxy and up to perhalogen substituted C 1 -C 10 alkoxy groups. r r 107 The compound of claim 21, wherein L ¹ is additionally substituted one to three times with one or more substituents selected from the group consisting of C 1 -C 10 alkyl, up to perhalo substituted C 1 -C 10 alkyl, -CN, -OH, halogen, C 1 -C 10 alkoxy and up to perhalogen substituted C 1 -C 10 alkoxy groups. 28th The compound of claim 1, wherein L ¹ is substituted with -C (O) R _X. 29th The compound of claim 1, wherein L ¹ is substituted with -SC 1 R x. 30th A compound according to claim wherein L 1 is substituted only with -C (O) R _X. 31st The compound of claim 1, wherein L ¹ is substituted only with -SO 2 R V The compound of claim 1, wherein L ¹ is substituted with -C (O) R _X or -SC 2 R _X , wherein R _x is NR _and R _b . The compound of claim 13, wherein L ¹ is substituted with -C (O) R _X or -SChR _x , wherein R _x is NR _and R _b and the substituents R _a and R _b are (a) independently hydrogen, 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 with halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms optionally containing 108 heteroatoms selected from the group consisting of N, S and O and are optionally substituted with halogen, or -OSi (Rf) ₃ , wherein Rf is a hydrogen atom 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 with halogen, hydroxy and carbon-based substituents of up to 24 carbon atoms; 24 carbon atoms optionally containing heteroatoms 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- to 7-membered heterocyclic structure having 1 to 3 heteroatoms selected from the group consisting of N, S and O, or a substituted 5- to 7-membered heterocyclic structure having 1 to 3 heteroatoms selected from the group consisting of from N, S and O, substituted with halogen, hydroxy or carbon-based substituents having 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 1 -C 8 divalent alkylene group or a substituted C 1 -C 8 divalent alkylene group bonded to the L moiety to form a cyclic structure with at least 5 members wherein the substituted C 1 -C 8 divalent substituents the alkylene group is selected from the group consisting of halogen, hydroxy and carbon-based substituents having up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen. The compound of claim 18, wherein L ¹ is substituted with -C (O) R 1 or -SO ₂ R _X , wherein R _x is NR _and R b and R _a and R b are independently hydrogen or a carbon-based moiety having up to 30 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen, hydroxy The group consisting of carbon atoms and substituents having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen. The compound of claim 19, wherein L ¹ is substituted with -C (O) R x, wherein R _x is NR _and R b and R _a and R b are independently hydrogen or 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 with halogen, hydroxy and carbon-based substituents having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen. The compound of claim 20 wherein L ¹ is substituted with -C (O) R x or -SChR _x wherein R _x is NR _and R b and R _a and R b are independently hydrogen or a carbon-based moiety of up to 30 atoms carbon optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen, hydroxy and carbon-based substituents having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted halo. The compound of claim 21 wherein L ¹ is substituted with -C (O) R x or -SChR _x wherein R _x is NR _and R b and R _a and R b are independently hydrogen or a carbon-based moiety of up to 30 atoms carbon optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted with halogen, hydroxy and carbon-based substituents having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and O and optionally substituted halo. 110 (0 «* f f f · · · · 38. A compound of formula I: A-D-B (I) or a pharmaceutically acceptable salt thereof, wherein D is -NH-C (O) -NH-, A is a substituted moiety having up to 40 carbon atoms in the formula: -L-CM-Ljq, wherein L is a 6-membered aryl moiety or a 6-membered hetaryl moiety bonded directly to D, L ¹ contains a substituted cyclic moiety having at least 5 members, is a bridging group having at least one atom, q is an integer ranging from 1 to 3; and each cyclic structure of L and L ¹ contains 0 to 4 members of the group consisting of nitrogen, oxygen and sulfur; and B is a substituted or unsubstituted to tricyclic aryl or heteroaryl moiety having up to 30 carbon atoms with at least one 6-membered cyclic structure bonded directly to D containing 0 to 4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L ¹ is substituted with 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 consisting of a nitrogen, oxygen and sulfur atom and optionally substituted with halogen up to perhalogen, R ₂ is a hydrogen atom or a carbon-based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur 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 nitrogen, oxygen and sulfur atoms and are optionally substituted with halogen; * r r c e · r • e r f P r '' 'r 'r r - * * r 111 R R _x is R _z or NR _a R b, wherein R _a and R b are (a) independently hydrogen, a carbon-based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur 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 nitrogen, oxygen and sulfur atoms and are optionally substituted with halogen, or -OSi (Rf) 3, wherein Rf is hydrogen or a carbon-based moiety having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen, hydroxy and carbon-based substituents up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen; or b) R _a and R b together form a 5- to 7-membered heterocyclic structure containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or a 5- to 7-membered heterocyclic structure having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur substituted by halogen, hydroxy and carbon-based substituents having up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted by halogen; or c) one of R _a or R b is -C (O) - and a C 1 -C 5 divalent alkylene group or a substituted C 1 -C 5 divalent alkylene group bonded to the L moiety to form a cyclic structure with at least 5 members wherein the substituents of the substituted Ct-Cs divalent The 112 alkylene groups are selected from the group consisting of halogen, hydroxy and carbon-based substituents having up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and optionally substituted with halogen; wherein B is substituted, L is substituted or L ¹ is additionally substituted and the substituents are selected from the group consisting of halogen, up to total halogen substitution being possible, and Wn, wherein n is 0 to 3; wherein each W is independently 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 , -NR ⁷ R ⁷ , NO 2, -NR ⁷ C (O) R ⁷ , -NR ⁷ C (O) OR ⁷ , -Q-Ar and carbon-based moieties having up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with one or more substituents independently 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 , -NR ⁷ R ⁷ , NO ₂ , -NR ⁷ C (O) R ⁷ , -NR ⁷ C (O) OR ⁷ and halogen, up to total halogen substitution being possible; wherein each R ⁷ is independently selected from hydrogen or a carbon-based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen, wherein Q is -O-, -S -, -N (R ⁷⁾ -, - (CH2) m-, -C (0) -, -CH (OH) -, - (CH 2) m0-, - (CH 2) m S-, - (CH 2) m N (R ⁷ ) -, -O (CH 2) _m -, -CHX ^a , -CX ^and 2-, -S- (CH 2) m - and -N (R ⁷ ) (CH 2) _m -, where m = 1 to 3 and X ^a is halogen; and Ar is a 5- or 6-membered aromatic structure containing 0 to 2 members of the group consisting of nitrogen, oxygen and sulfur which is optionally substituted by halogen except for total halogen substitution and optionally substituted by _Zn i, wherein the index n 1 is 0-3 and each Z is independently selected from the group consisting of -CN, -CO ₂ R ⁷ , -C (O) NR ⁷ R ⁷ , -NO ₂ , -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) OR ⁷ , -C (O) R ⁷ , -NR ⁷ C (O) R ⁷ and moieties on 113 a carbon base having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with one or more substituents independently 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 , -NR ⁷ R ⁷ , NO ₂ , -NR ⁷ C (O) R ^7, and -NR ⁷ C (O) OR ⁷ , wherein the substituent 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) -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 ^and 2-, -S- ( CH 2) m - and -N (R ⁷ ) (CH 2) _m - wherein m = 1 to 3 and X ^a is halogen. 39. A compound of formula I: A-D-B (I) or a pharmaceutically acceptable salt thereof, wherein D is -NH-C (O) -NH-, A is a substituted moiety having up to 40 carbon atoms in the formula: -L- (M-L) _q , wherein L is a substituted or unsubstituted phenyl or pyridinyl group bonded directly to D, L * contains a substituted phenyl, pyridinyl or pyrimidyl group, M is a bridging group having at least one atom, q is an integer ranging from 1 to 3; and B is a substituted or unsubstituted phenyl or pyridine group bonded directly to D, wherein L ¹ is substituted with 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 a hydrogen atom or a carbon-based moiety having up to 24 carbon atoms optionally containing heteroatoms selected from the group 114 consisting of a nitrogen, oxygen and sulfur atom and optionally substituted with halogen up to perhalogen, and R ₂ is a hydrogen atom or a carbon-based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur 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 nitrogen, oxygen and sulfur atoms and are optionally substituted with halogen; R _x is R _z or NR _and R b, wherein R _a and R b are (a) independently hydrogen, a carbon-based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur 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 nitrogen, oxygen and sulfur atoms and are optionally substituted with halogen, or -OSi (Rf) 3, wherein Rf is hydrogen or a carbon-based moiety having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen, hydroxy and carbon-based substituents up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen; or b) R _a and R b together form a 5- to 7-membered heterocyclic structure containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or a 5- to 7-membered heterocyclic structure having 1 to 3 heteroatoms selected from er 115 a group consisting of nitrogen, oxygen and sulfur substituted with halogen, hydroxy and carbon-based substituents having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen; or c) one of the substituents R _a or R b is -C (O) - and a C 1 -C 4 divalent alkylene group or a substituted C 1 -C 4 divalent alkylene group bonded to the L moiety to form a cyclic structure, with at least 5 members wherein the substituents substituted by C 1 -C 5 the divalent alkylene group is selected from the group consisting of halogen, hydroxy and carbon-based substituents having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen; wherein B is substituted, L is substituted or L ¹ is additionally substituted and the substituents are selected from the group consisting of halogen, up to total halogen substitution being possible, and Wn, wherein n is 0 to 3; wherein each W is independently 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 , -NR ⁷ R ⁷ , NO 2 , -NR ⁷ C (O) R ⁷ , -NR ⁷ C (O) OR ⁷ , -Q-Ar, and carbon-based moieties having up to 24 carbon atoms, optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with one or more substituents independently 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 , -NR ⁷ R ⁷ , NO 2, -NR ⁷ C (O) R ⁷ , -NR ⁷ C (O) OR ⁷ and halogen, up to total halogen substitution being possible; wherein each R ⁷ is independently selected from hydrogen or a carbon-based moiety having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen, 116 wherein Q is -O-, -S-, -N (R ⁷ ) -, - (CH ₂ ) - _m , -C (O) -, -CH (OH) -, - (CH ₂ ) _n , O -. - (CH ₂ ) _m S-, - (CH ₂ ) _m N (R ⁷ ) -, -O (CH ₂ ) n 1 -, -CHX ^a , -CX ^a 2-, -S- (CH ₂ ) _m - a -N (R ⁷ ) (CH ₂ ) _m -, wherein the index m = 1-3 and X ^a is halogen; and Ar is a 5- or 6-membered aromatic structure containing 0 to 2 members of the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen except for total halogen substitution and optionally substituted by Z 1, where n 1 is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO ₂ R ⁷ , -C (O) NR ⁷ R ⁷ , -NO 2, -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O OR ⁷ , -C (O) R ⁷ , -NR ⁷ C (O) R ^7, and carbon-based moieties of up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms and optionally substituted with one or more substituents independently 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 , -NR ⁷ R ⁷ , NO ₂ , -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) -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 ^and 2-, -S- ( CH 2) m - and -N (R ⁷ ) (CH 2) _m - wherein m = 1 to 3 and X ^a is halogen. The compound of claim 38, wherein the cyclic structures B and L bonded directly to D are not substituted at the ortho position by -OH. The compound of claim 38, wherein the cyclic structures B and L bonded directly to D are not substituted at the ortho position with an ionizable hydrogen moiety and a pK a of 10 or less. e f 117 The compound of claim 39, wherein the cyclic structures B and L bonded directly to D are not substituted at the ortho position by -OH. The compound of claim 39, wherein the cyclic structures B and L bonded directly to D are not substituted in the ortho position with an ionizable hydrogen moiety and a pK a of 10 or less. The compound of claim 38, wherein the B and L substituents and the other L ¹ substituents are selected from the group consisting of C 1 -C 10 alkyl to perhalo substituted C 1 -C 10 alkyl, CN, OH, halogen, C 1 -C ₁₀ alkoxy and up to perhalogen substituted C 1 -C 10 alkoxy groups. The compound of claim 39, wherein the B and L substituents and the other L ¹ substituents are selected from the group consisting of C 1 -C 10 alkyl to perhalo substituted C 1 -C 10 alkyl, CN, OH, halogen, C 1 -C 10 alkoxy and up to perhalo substituted C 1 -C 10 alkyl. Cioalkoxy groups. The compound of claim 38, wherein L * is substituted with C (O) R _X or SO ₂ R _X. The compound of claim 39, wherein L 1 is substituted with C (O) R _X or SO ₂ R _X. The compound of claim 46, wherein R _x is NR _and Rb 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 with halogen, hydroxy The group may be optionally substituted with a halogen atom and a hetero-atom selected from the group consisting of N, S and O and optionally substituted with halogen. The compound of claim 47, wherein R _x is NR _and Rb 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 with halogen, hydroxy and carbon-based substituents having 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 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 inorganic acids selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, trifluorosulfonic, benzenesulfonic, p -toluenesulfonic acid (tosylate salt), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, tartaric, citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic and mandelic acids; and (b) acidic salts of organic and inorganic bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cation, ammonium-substituted aliphatic moieties and ammonium-substituted aromatic moieties. A compound according to claim 2 which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of r 9 119 (a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, trifluorosulfonic, benzenesulfonic, p-toluenesulfonic (tosylate salt), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic, tartaric, citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic and mandelic acids; and (b) acidic salts of organic and inorganic bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cation, ammonium-substituted aliphatic moieties and ammonium-substituted aromatic moieties. A compound according to claim 33, which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of (a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, trifluorosulfonic, benzenesulfonic, t-toluenesulfonic (tosylate salt), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic, tartaric, citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic and mandelic acids; and (b) acidic salts of organic and inorganic bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cation, ammonium-substituted aliphatic moieties and ammonium-substituted aromatic moieties. 120 53rd 54th The compound of 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 acids and inorganic acids selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, trifluorosulfonic, benzenesulfonic, t-toluenesulfonic (tosylate), 1-naphthalenesulfonic, 2-naphthalenesulfonic, , tartaric, citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic and mandelic acids; and (b) acidic salts of organic and inorganic bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cation, ammonium-substituted aliphatic moieties and ammonium-substituted aromatic moieties. 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 acids and inorganic acids selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, trifluorosulfonic, benzenesulfonic, p-toluenesulfonic (tosylate salt), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic, tartaric, citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic and mandelic acids; and (b) acidic salts of organic and inorganic bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cation, ammonium-substituted aliphatic moieties and ammonium-substituted aromatic moieties. r t 121 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 comprising a compound of claim 2 according to Formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. 57. A pharmaceutical composition comprising a compound of claim 33 according to Formula I, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. 58. A pharmaceutical composition comprising a compound of claim 38 according to Formula I, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. 59. A pharmaceutical composition comprising a compound of claim 39 according to Formula I, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. 60. A compound selected from the group consisting of 3-tert-butylphenylureas from Table 1 above; 5- (tert -butyl-2-methoxyphenylureas) from Table 2 above; 5- (trifluoromethyl) -2-phenylureas from Table 3 above; 3- (trifluoromethyl) -4-chlorophenyl ureas of Table 4 above; 3- (trifluoromethyl) -4-bromophenylureas from Table 5 above; r · 122 5- (trifluoromethyl) -4-chloro-2-methoxyphenylureas from Table 6 above; and ureas 10 to 103 listed in Table 7 above. 61. A compound selected from the group consisting of 3-tert-butyl phenyl urea n: N - (3-tert-butylphenyl) -77- (4- (3- (N-methylcarbamoyl) phenoxy) phenyl urea) and N- (3-tert-butylphenyl) -N '- (4- (4-acetylphenoxy) phenyl urea; 5 / CRC-butyl-2-methoxyphenyl ureas: N- (5-tert-butyl-2-methoxyphenyl) -77- (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea ;//-( 5-tert-butyl- 2-methoxyphenyl) -77- (4- (1-oxoisoindolin-5-yloxy) phenyl) urea; 77- (5- tert -butyl-2-methoxyphenyl) -N '- (4- (4-methoxy-3- (N-ethylcarbamoyl) phenoxy) phenyl) urea and N - (5-tert- butyl-2-methoxyphenyl) -77- (4- (3- (7-methylcarbamoyl) phenoxy) phenyl) urea; 2-methoxy-5-trifluoro methyl) phenyl urinary N: ^N - (2-methoxy-5- (trifluoromethyl) phenyl) -N ^&apos' - (3- (2-carbamoyl-4pyridyloxy) phenyl) urea, N - (2-methoxy-5- (trifluoromethyl) phenyl) -77- (3- (2- (N-methylcarbamoyl) -4pyridyloxy) phenyl) urea, N - (2-methoxy-5- (trifluoromethyl) phenyl) -77- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N - (2-methoxy-5- (trifluoromethyl) phenyl) -7 / '- (4- (2- (7 / methylcarbamoyl) -4pyridyloxy) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) N 7- (4- (2- (N-methylcarbamoyl) -4pyridyltio) phenyl) urea, P P 123 N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (Armethylcarbamoyl) (4-pyridyloxy)) phenyl) urea and γ- (2-methoxy-5- (trifluoromethyl) phenyl) -7V - (3-chloro-4- (2- (2Vmetylkarbamoyl) (4-pyridyloxy)) phenyl) urea; 4-chloro-3- (trifluoromethyl) phenyl urea n: N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N'. - (3- (2 - (/ V-methylcarbamoyl) -4pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea and N- (4-chloro-3- (trifluoromethyl) phenyl) -N ^l - (4- (2- ^{(N-methylcarbamoyl)} -4pyridyloxy) phenyl) urea; 4-Bromo-3- (trifluoromethyl) phenyl urea: N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl) -4pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) - / ^V, - (4- (2- (AÁmetylkarbamoyl) -4pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (3- (2- (7V-methylcarbamoyl) -4pyridyltio) phenyl) urea, ^N - (4-bromo-3- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (AÍmetylkarbamoyl) (4-pyridyloxy)) phenyl) urea and N - (4-bromo- 3- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (Aŕmetylkarbamoyl) (4-pyridyloxy)) phenyl) urea; and 2-Methoxy-4-chloro-5- (trifluoromethyl) phenyl urea: N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (3- (2- (N-methylcarbamoyl)) - 4-pyridyloxy) phenyl 1) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N, 4-methylcarbamoyl) -4-pyridyloxy) phenyl) ) urea, 124 N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (2-chloro-4- (2- (p-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea and 7 / - (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (Ymetylkarbamoyl) (4-pyridyloxy)) phenyl) urea. 62. A method of treating carcinogenic cell growth mediated by rafkinase, comprising administering a compound of formula I according to claim 1. 63. A method of treating carcinogenic cell growth mediated by raffinase, comprising administering a compound of Formula 1 according to claim 33. 64. A method of treating carcinogenic cell growth mediated by rafkinase, comprising administering a compound of formula I according to claim 38. 65. A method of treating carcinogenic cell growth mediated by rafkinase, comprising administering a compound of formula I according to claim 39. 66. A method of treating carcinogenic cell growth mediated by raffinase, comprising administering a compound selected from the group consisting of: The 3-tert-butylphenyl ureas of Table 1 above; 5- tert -butyl-2-methoxyphenylureas from Table 2 above; 5- (trifluoromethyl) -2-phenylureas from Table 3 above; 3- (trifluoromethyl) -4-chlorophenyl ureas of Table 4 above; r r 125 3- (trifluoromethyl) -4-bromophenylureas from Table 5 above; 5- (trifluoromethyl) -4-chloro-2-methoxyphenylureas from Table 6 above; and ureas 10 to 103 listed in Table 7 above. 67. A method of treating carcinogenic cell growth mediated by rafkinase, comprising administering a compound selected from the group consisting of: 3 / erc'-butylfenylmočovín: N- (3- tert -butylphenyl) -N '- (4- (3- (2H-methylcarbamoyl) phenoxy) phenyl urea), and N- (3-tert-butylphenyl) -N '- (4- (4-acetylphenoxy) phenyl urea; 5-tert-butyl-2-methoxyphenyl urea n: N- (5-tert-butyl-2-methoxyphenyl) -7H-4- (1,3-dioxoisoindolin-5-yloxy) phenyl urea, ^L - (5 / tert-butyl-2-methoxyphenyl) -N '- (4- (l-oxoisoindolin-5-yloxy) phenyl) urea, N 7- (5 / t? / T-butyl-2-methoxy-phenyl) -7V ^- (4- (4-methoxy-3- (7Vmetylkarbamoyl) phenoxy) phenyl) urea and N- (5 / tear-strip-butyl-2-methoxyphenyl) -N '- (4- (3- (ymetylkarbamoyl) phenoxy) phenyl) urea; 2-Methoxy-5-trifluoromethyl) phenyl urea: 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) -4pyridyloxy) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -7V ^- (4- (2-carbamoyl-4pyridyloxy) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -7V ^- (4- (2- (7V-methylcarbamoyl) -4py R pyridyloxy) phenyl) urea, 126 N- (2-methoxy-5- (trifluoromethyl) phenyl) -2 '- (4- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -7 / - (2-chloro-4- (2- (S ^/ 'methylcarbamoyl) (4-pyridyloxy)) phenyl) urea and ^N - (2-methoxy-5- (trifluoromethyl) phenyl) - N - (3-chloro-4- (2- (N -methylcarbamoyl) (4-pyridyloxy)) phenyl) urea; 4-chloro-3- (trifluoromethyl) phenyl urea; N - (4-chloro-3- (trifluoromethyl) phenyl) -N '- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N - (4-chloro-3- (trifluoromethyl) phenyl) -? '- (3- (2- (7V-methylcarbamoyl) -4pyridyloxy) phenyl) urea, N - (4-chloro-3- (trifluoromethyl) phenyl) -7V ^- (4- (2-carbamoyl-4pyridyloxy) phenyl) urea and N- (4-chloro-3- (trifluoromethyl) phenyl) -7V ^- (4- (2- (methylcarbamoyl-2 V) -4pyridyloxy) phenyl) urea; 4-bromo-3- (trifluoromethyl) phenyl urea: N- (4-bromo-3- (trifluoromethyl) phenyl) -N ^, N- (3- (2- (N-methylcarbamoyl) -4pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl) phenyl) ) - / ^V, - (3- (2- (N-methylcarbamoyl) -4pyridyltio) phenyl) urea, 7V '- (4-bromo-3- (trifluoromethyl) phenyl) -7V ^- (2-chloro-4- (2- ^{(N-methylcarbamoyl)} (4-pyridyloxy)) phenyl) urea and N- (4-bromo-3- (trifluoromethyl) phenyl) -7V - (3-chloro-4- (2- (7Vmetylkarbamoyl) (4-pyridyloxy)) phenyl) urea; and 2-Methoxy-4-chloro-5- (trifluoromethyl) phenyl urea n: 7V- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N- ^f - (3- (2- (ethyl-m and ^L 1 carb amo yl) -4-pyridin pyridyloxy) phenyl) urea, 127 7V- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N / ^- (4- (2- (E / methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -7V ^- (2-chloro-4- (2 - (/ Vmetylkarbamoyl) (4-pyridyloxy)) phenyl) urea and 7V- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N- (3-chloro-4- (2- (7Vmetylkarbamoyl) (4-pyridyloxy)) phenyl) urea.