CZ20012489A3 - Omega -carboxyaryl substituted diphenyl ureas as raf kinase inhibitors - Google Patents

Description

Diphenyl ureas substituted with ω-carboxvaryl group as rafkinase inhibitors

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). Biochemically, ras is a guanine nucleotide binding protein, and cyclization between the GTP-linked activated form and the GDP-linked quiescent form is precisely regulated by the activity of endogenous ras GTPase and other regulatory proteins. In cancer cell mutants, endogenous GTPase activity is low, and therefore the protein transmits constitutive growth signals to downstream effectors, such as the raffinase enzyme, resulting in cancerous growth of cells that carry these mutants (Magnuson et al., Semin. Cancer Biol. 1994 5, 247-53). It has been found that 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 substrate of rafkinase, results in reverse transformed cells to 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 a similar way, inhibition of raffinase (antisense oligodeoxynucleotides) was correlated in vitro and in vivo with inhibition of growth of various human tumor types (Monia et al., Nat. Med., 1996, 2). , 668-75).

· · ΦΦΦΦ φ φ

Φ Φ · · · · · · ·

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 racinase pathway is indicated, e.g. in the treatment of tumors and / or cancer cell growth associated with raffinase. The compounds are particularly effective in the treatment of human or animal cancers, e.g., mouse cancers, since the progression of these cancers is dependent on the cascade of signal transduction of the ras protein and is therefore prone to cascade disruption treatment, i.e., inhibition of raffinase. Thus, the compounds of the invention are effective in the treatment of solid tumors, e.g., carcinomas (e.g., lung, pancreatic, 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 analogues 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-CM-L ¹ , wherein L is a 5- or 6-membered cyclic structure bonded directly to D, L ¹ comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, index 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, up 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 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 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 or sulfur and optionally substituted by halogen up to per halogen,

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 or sulfur and optionally substituted by halogen, hydroxy and carbon based substituents having up to 24 carbon atoms optionally contain heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur and 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 having up to 30 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur and optionally substituted by halogen, hydroxy and carbon-based substituents having up to 24 carbon atoms, which optionally contain heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur 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 or 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 or sulfur and which is 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 substituted with a 5-7 membered heterocyclic structure having 1-3 heteroatoms selected from the group consisting of with 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 a nitrogen, oxygen or sulfur atom and optionally substituted by 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 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 or 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, -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 or sulfur and optionally substituted with one <1 or more substituents independently selected from the group consisting of -CN, -CO ₂ R, 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 possible; wherein each R 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 or sulfur and optionally substituted with halogen, wherein Q is -O-, -S- , -N (R ⁷⁾ -, - (CH2) m-, -C (O) -, -CH (OH) -, - (CH2) m O-, - (CH2) S-, - (CH2) mN ( R ⁷ ) -, -O (CH 2) _m -CHX ^and -, -CX ^and 2-, -S- (CH 2) m - and -N (R ⁷ ) (CH 2) _m -, where m = 1-3 and X ^a is halogen; and

Ar is a 5- or 6-membered aromatic structure containing 0-2 members of a group consisting of nitrogen, oxygen and sulfur, optionally substituted with halogen up to To total halogen substitution and optionally substituted Zni, wherein the index n1 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 a carbon based moiety having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -CO 2 R ^7, -C ( O) ^R7, -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 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 eg 1-4 atoms The carbon atoms in one or more rings may be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. For example, B may be 2- or 3-furyl, 2- or 3-thienyl, 2 or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3 -, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4 or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazole-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; 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; -, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 3-, 4-, 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or benzenzothiazolyl, 2-, 4-, 5 -, 6- or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 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-pyrryl, 3pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For example, B may be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, 1-methyl-3-pyrryl, 1-methyl-3-pyrazolyl, 5-methyl2 -thiazolyl or 5-methyl-1,2,4-thiadiazol-2-yl.

· · E e e e e e e e e e e e e e e e e e e e e e e e ···

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

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

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

The invention relates to compounds of formula I per se.

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

The present invention also provides 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, for example, hydrochloric, hydrobromic, sulfuric, orthophosphoric, methanesulfonic, trifluoromethanesulfonic, benzenesulfonic, p-toluenesulfonic. -naphthalenesulfonic, 2-naphthalenesulfonic, acetic, trifluoroacetic, malic, tartaric, citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic and phenylglycolic acids. In addition, pharmaceutically acceptable salts include acidic 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 acidic salts of organic bases including ammonia-substituted aliphatic and aromatic group and quaternary ammonium cations, e.g. resulting from the protonation or peralkylation of triethylamine, N-diethylamine, N-dicyclohexylamine, lysine, pyridine, N, Ndimethylamine (N, Ndimethylamine) DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) α1,8-diazabicyclo [5.4.0] undek-7-ene (DBU).

Many compounds of formula (I) have asymmetric carbon atoms and may therefore exist in racemic and optically active forms. Methods for separating enantiomeric and diastereomeric mixtures are well conventional techniques. 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

The compounds of formula I may be prepared by known chemical reactions and procedures, some of the starting materials being commercially available. However, the following general methods of preparation are set forth below and are intended to serve as guidance to those skilled in the art of synthesizing these compounds. Methods of preparation are provided with more detailed examples described in the experimental section.

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 reduction of nitroaryls with catalysts (metals), e.g., Ni, Pd or Pt and H ₂ , or hydride transfer agents, such as formate, cyclohexadiene or borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK) 1985)). Nitroaryls can also be directly reduced by a strong hydride source such as LiAlH4 (Seyden-Penne. Reductions by Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)) or zero-charge metals such as Fe, Sn, or Ca, usually in an 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 //( eg Ni, Pd, Pt)

ffl ------ ArNH ₂ \ M (0) (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 NO ₂ ⁺ source. The nitroaryls may be further processed prior to reduction. Thus substituted nitroaryls

HNO ₃

Ar-H —---------- ► AtNO _{2 with a} strong leaving group (eg F, Cl, Br, etc.) may undergo substitution reactions in the reaction of a snucleophile, eg thiolate (shown in the examples in Scheme II) ) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme Π).

base

CuO / base

ArSH

Selected nucleophilic aromatic substitution by nitroaryls

Nitroaryls may also undergo metal-mediated cross-coupling reactions in the transit state. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo palladium-mediated cross-coupling reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reaction shown below), arylcins (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 arensulfonyl chlorides (7) by reaction with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source such as KF provides the sulfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source such as tris (dimethylamino) sulfonium difluorotrimethylsiliconate (TASF) affords the corresponding trifluoromethylsulfone (9). Alternatively, the sulfonyl chloride 7 can be reduced to arenthiol (10) by, for example, zinc amalgam. Reaction 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).

[Ol

AND

Scheme III Selected methods for the synthesis of fluorinated arylsulfones

According to Scheme IV, 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, eg, trichloromethylchloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene) or 7V, N'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, e.g.

· 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 ··· 9 9 ··· 9

9 999 99 99 99 of an ester, from an acid halide or from 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.

Ar ¹ —NHj 13 | COCI ₂ . HjN-Ar ²

Ar-NCO ------>

Ark

17

Scheme IV Selected methods of 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 "injections" includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as the use of infusion techniques. One or more compounds may be together with 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 formulations may

contain one or more agents selected from the group consisting of diluents, sweeteners, flavoring agents, coloring agents and preservatives to provide readily digestible preparations. 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, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and tablet disintegrating agents such as corn starch or alginic acid; and binders such as 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 such as glyceryl monostearate or glyceryl distearate may be used. These compounds may also be prepared in a solid, rapidly releasing form.

Formulations for oral use may be solid gelatin capsules wherein the active ingredient is admixed with an inert solid diluent such as 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, 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 such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; dispersants or detergents may be natural phosphatides, e.g., lecithin or condensation products or fatty acid alkenoxide, e.g., polyoxyethylene stearate, or ethylene oxide condensation products with long-chain aliphatic alcohols, e.g. and hexitol such as polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, e.g., ethyl or n-propyl (p-hydroxybenzoate), one or more preservatives.

0 0 0 • · ♦ 0 00 0 0 0 * · · *** 0 0 0 0 00 00 000 0 ··· * 000 * 0 • 0 000 0 * ·· * 0 0 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 dispersing or detergent and suspending agents are illustrated in the above examples. Other excipients, such as sweetening, flavoring and coloring agents, may also be present.

The compounds may also be in the form of anhydrous liquid preparations, e.g., oily suspensions, which may be prepared by suspending the active ingredients in a vegetable oil, e.g. arachis oil, olive oil, sesame oil or arachis oil, or in a mineral oil, e.g. paraffin oil. The oily suspensions may contain thickeners, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide readily digestible oral preparations. These compositions may be protected by the addition of an antioxidant, such as 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, such as olive oil or arachis oil, or a mineral oil, such as paraffin oil or mixtures thereof. Suitable emulsifiers may be natural gums such as gum arabic or tragacanth, natural phosphatides such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate and condensation products of said partial esters with ethylene oxide , such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, such as 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 preparations can be prepared by mixing the drug with a suitable non-irritating agent. 9 9 9 9 999

9 9 9 9 99 99 Ι · 999 excipient which is solid at normal temperature but liquid at rectal temperature and therefore dissolves in the rectum or vagina to release the drug. Such materials include cocoa oil and polyethylene glycols.

For all treatment regimens used herein, the daily oral dosage will preferably be from 0.01 to 200 mg / kg of total body weight. 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 dose for topical administration will preferably be from 0.1 to 200 mg to 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. all that are commonly considered when therapeutic agents are applied. Obviously, the specific dose 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, the time of administration, route of administration and excretion rate. combination and severity of the ongoing therapy. Nevertheless, it will be further clear to the professional public that the optimal course of treatment, i.e.. the method of treatment and the daily number of doses of the compounds 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, dietary guidelines, time and mode of administration, excretion rate, drug combination and other conditions during therapy.

All data of all applications, patents and publications cited above and below are incorporated herein by reference, including Provisional Application No. 50 / 115,877, filed January 13, 1999, and Non-Provisional Application No. 09 / 257,266, filed February 25, 1999.

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 • 0 ··· 0 · Φ0 0 »000

The compounds of Figure I can be prepared from known compounds (or starting materials that can be prepared from known compounds), for example, using the general preparation methods outlined above. The activity of the provided compound to inhibit the racinase can be routinely determined, e.g., by the procedures set forth 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 a positive pressure of dry argon or dry nitrogen. Stirring was performed magnetically unless otherwise indicated. The appropriate liquids and solutions were operated via syringe or cannula and introduced into reaction vessels via a rubber septum. Unless otherwise stated, the term "reduced pressure concentration" refers to the use of a Buchi rotary evaporator at about 15 mmHg. Unless otherwise stated, the term "high vacuum" refers to a vacuum of 0.4 - 1.0 mmHg.

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) kiarbodiimide was purchased from CalbiochemNovabiochem Corp. and purchased 3-fluoro-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 used without further purification. Synthesis of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem. 3, 1995, 129), 4- (3-carbamoylphenoxy) - 1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3- tert -butylphenyl isocyanate (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) has been described above.

• 99 * · • · 9 • · ♦

Thin layer chromatography (TLC) was performed on a glass plate coated with Whatman® silica gel, silica gel 60A F-254 250 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 tray in a 10% solution of molybdophosphoric acid in ethanol and subsequent heating; followed by heating and / or (e) immersion of the tray in an acidic ethanolic solution of 2,4-dinitrophenylhydrazine and subsequent heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science® silica gel.

Melting points were determined using a Thomas-Hoover instrument or a Mettler FP 66 automated melting point apparatus, and these melting points are not corrected. Fourier transform infrared spectroscopy spectra were obtained from a Mattson 4020 Galaxy Series spectrophotometer. 1 H NMR spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (d 0.00) or residual protonated solvent (CHCl 3 δ 7.26; MeOH δ 3.30; DMSO δ 2.49) standard. . ¹³ C NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCl 3 δ 77.0; MeOD-d3; δ 49.0; DMSO-d6 δ 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra 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 sensor for sample introduction. The ion source was maintained at 250 ° C. Electron ionization impacts were performed with an electron energy of 70 eV and a flow collector of 300 μΑ. Liquid Cesium secondary ion mass spectra (FAB-MS), 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 as the gaseous reagent (1 χ 10 ^-4 tor to 2.5 x 10 ^-4 tor). Direct insertion desorption chemical ionization (DCI) sensor (Vaccumetrics, Inc.) Was ramped 0-1.5 amps in 10 sec and held at 10 amps until all traces of specimens had disappeared (~ 1-2 min). Spectra were taken from 50-800 amu at 2 sec per image. HPLC 16

electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC instrument 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 recorded from 120-800 amu using variable ion time according to the number of ions in the source. Gas Chromatography - Ion-Selective Mass Spectrum (GC-MS) was 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 mass-selective detector (ionization) energy 70 eV). Elemental analysis was performed at 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 anhydrous atm atmosphere BOC tert-butoxycarbonyl CDI 1,1'-carbonyldiimidazole conc concentrated d day Dec degradation DMAC N, N-dimethylacetamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone DMF N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDCI 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide EtOAc ethyl acetate EtOH ethanol (100%) Et ₂ O diethyl ether

• · · · p

Et ₃ N triethylamine h hour HOBT 1-Hydroxybenzotriazole w-CPBA 3-chloroperoxybenzoic acid MeOH methanol five. ether petroleum ether (boiling range 30-60 ° C) THF tetrahydrofuran TFA trifluoroacetic acid Tf trifluoromethanesulfonyl

DETAILED DESCRIPTION OF THE INVENTION

A. General methods for the synthesis of substituted anilines

Al. General process for preparing arylamine including ether formation, ester saponification,

Curtius rearrangement and deprotection of carbamate.

Synthesis of 2-amino-3-methoxynaphthalene

Krokl. 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-d 6) δ 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t,> 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 ΕΐβΝ (2.59 mL, 18.6 mmol) in anhydrous toluene (70 mL) was stirred at room temperature for 15 min, 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 cooling the mixture to room temperature, benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was then heated to 80 ° C 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 silica gel column chromatography using 14% EtOAc and 86% hexanes to give 2- (N - (carbobenzyloxy) amino-3 methoxynaphthalene as a pale yellow oil (5.1 g, 100%); 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).

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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 The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a light pink powder (2.40 g, 85%): 1 H NMR (DMSO-d ₆₎ δ 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, J = 8.0 Hz 1H, 7.56 (d, J = 8.0 Hz, 1H); EI-MS m / z 173 (M ^& lt ^{; +} & gt ^; ).

A2. Synthesis of ω-carbamylanilines involving preparation of carbamylpyridine and nucleophilic coupling with arylamine.

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

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% VH 2 O, 17 mL) followed by FeSO 4 .7H 2 O (0.56 g) to generate 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 completion of the bubble formation, the reaction was 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 are washed separately with a saturated solution

NaCl (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;

Δ 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,> 5.1 Hz, 1H); CI-MS m / z 171 ((M + H) &lt; + & gt ^; ).

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 performed 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). %).

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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. The solution was stirred in this temperature range for 10 min, then picolinic acid (100 g, 812 mmol) was added 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 performed twice more. The resulting almost dry

the 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 put 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 Et ₂ O (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; 1 H NMR (DMSO-d ₆ ) δ 3.88 (s, 3H); 7.82 (dd, J = 5.5, 2.2 Hz, 1H); 8.08 (d, J = 2.2Hz, 1H); 8.68 (d, J = 5.5Hz, 1H); 10.68 (br s, 1H); HPLC ES-MS m / z 172 ((M + H) &lt; + & gt ^; ).

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NHMe

Step 3a, Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from methyl 4-chloropyridine-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-pyridine carboxamide as pale yellow crystals (71.2 g, 97%): Mp 41-43 ° 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, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.85 (br d, 1H); CI-MS m / z 171 ((M + H) &lt; + & gt ^; ).

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-A-methyl-2-pyridinecarboxamide as a yellow crystalline solid (4.95 g, 88% Melting point: 37-40 ° C.

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NHMe

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-N-methyl-2-pyridine carboxamide (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- (77-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 (ΑΑ'ΒΒ 'quartet,

J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J 2.5 Hz, IH), 8.44 (d J = 5.5 Hz (1H), 8.73 (br d, 1H); HPLC ES-MS m / z 244 ((M + H) &lt; + & gt ^; ).

A3. General method of 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

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 adjusted to pH 10 with 1 N 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, Δ (m, 2H), 7.56 (d, J = 9.3 Hz, 1H).

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

To a stirred slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 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 warmed 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) R f = 0.28; 1 H NMR (DMSO-d ₆ ) δ 7.32 (d, J = 12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 9Hz, 2H), 11.43 (brs, 1H); CI-MS m / z 285 ((M + H) &lt; + & gt ^; , 100%).

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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 was added slowly and iron powder (0.59 g, 55.9 mmol) was added slowly. The mixture was stirred at room temperature for 72 hours, then diluted with water (25 mL) and extracted with EtOAc (3 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) R f = 0.27; 1 H NMR (DMSO-d ₆ ) δ 5.14 (br s, 2H), 6.62 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H) ), 7.03 (d, J = 2.1 Hz, 1 H), 7.23 (dd, 1H), 7.75 (d, J = 8.4 Hz, 1 Η), 11.02 (s, 1 H); HPLC ES-MS m / z 255 ((M + H) &lt; + & gt ^; , 100%).

A4. General method of pyrrolylaniline synthesis.

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

Ar

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 was 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 sequentially with 1N HCl solution (15 mL) and 1 N NaOH solution (15 mL) and saturated NaCl solution (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 6% EtOAc / 94% hexane to 25% EtOAc / 75% hexane),

9 · 9 * 99 9 · 9 9 · 999 · · ···· <1 • · 99 909 · 9 • 99 9999 9 ·· φ 9 999 «· ·· · ♦♦♦ · gives 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) &lt; + & gt ^; , 50%).

Step 2. Synthesis of 5- tert -butyl-2- (2,5-dimethylpyrrolyl) 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-dimethylpyrrolyl) aniline as a yellowish solid (0.30 g, 99%); TLC (10% EtOAc / 90% hexane) R f = 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 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 was stirred at room temperature until the temperature in the flask reached 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 residual black oil was treated with Et ₂ O (50 mL) and sonicated. The solution was then treated with HCl (1 M in Et ₂ O; 100 mL) and stirred at room temperature for 5 minutes. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration from the solution and stored at 0 ° C before use in the absence of air: 1 H NMR (DMSO-d ₆ ) δ 2.41 (s, 3H), 2.78 (d,> 4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd,> 8.5, 2.6 Hz, 1H), 7.23 (dd, > 5.5, 2.6 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.55 (d, > 2.6 Hz, 1H), 7.64 (d, > 8.8 Hz, 1, H), 8.55 (d, > 5.9 Hz, 1H), 8.99 (q, > 4.8 Hz, 1H).

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 off from the solution and the residue is concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To this yellow solution was added saturated NaHCO 3 (50 mL). The solid which precipitates out of solution is removed. The filtrate was slowly quenched with sodium bicarbonate solution until the product was visibly separated from the solution (small flask work was selected 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.

φ · v v φ v v φ v v v v v v v v v v v

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-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). The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by silica gel column chromatography with a gradient of 20% EtOAc / petroleum ether to 40% EtOAc / petroleum ether to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl (2,2,2) (trifluoro) acetamide as a yellow solid (8.59 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 which solidified on standing (2.86 g, 10.30 mmol): 1 H NMR (DMSO-d 6) δ 2.77 (d, J = 4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd,> 8.5) 2.6 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 7.07 (dd, J = 5) Δ, 2.6, Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.75 (q , J = 4.8.1H).

·· • · • 9 • • · • 9 9 9 ♦ ♦ 9 • • 9 9 · 9 9 • · • · 9 9 9 9 • · • · 9 9 * 99 ·· 9

A7. General method for deprotecting from acylated aniline.

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

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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 and solidified somewhat. 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-) day) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

A8. General method for the synthesis of ω-alkoxy-ω-carboxyphenylanilines.

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

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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

Mp 115-118 ° C.

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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 was acidified with 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to give 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (1.04 g).

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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 treated portionwise with a solution of methylamine (2.0 M in 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%).

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

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9 · 9 9 9 9 99

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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 d, then was filtered through celite®. The resulting solution was concentrated under reduced pressure to give 4- (3- (N-methylcarbamoyl) -4-methoxyphenoxy) aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et ₂ N) (99.9% EtOAc) R f = 0.36.

A9. General process for the preparation of ω-alkylphthalimide anilines.

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

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

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) Stir at room temperature for 1 hour, then react 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 pale yellow solid (0.87 g, 83%): TLC (35% EtOAc / 65% hexane) Rf = 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-methylisoindoline-1,3-dione as a yellow solid compound (0.67 g, 86%): TLC (40% EtOAc / 60% hexane) R f = 0.27.

A10. General method of 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- (N - (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, 2, 2, 2, 2, 55 mL, 19.4 mmol) and the resulting solution was heated at reflux for 20 h, cooled to room temperature and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (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) R f = 0.50.

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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 t-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-ylethyl) carbamoyl) pyridine (1.22 g, 4.52 mmol) and K 2 CO 3 (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 ° C overnight, cooled to room temperature and partitioned between a layer of EtOAc (25 mL) and saturated NaCl solution (25 mL). The aqueous layer was re-extracted with EtOAc (25 mL). The combined organic layers were washed with saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure. The 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-yl-ethyl) carbamoyl) pyridyloxy) aniline (1.0 g, 65%): TLC (10% MeOH / 90% EtOAc) R f = 0.32.

All. General method for reducing nitroarenes to arylamines.

Synthesis of 4- (3-carboxyphenoxy) aniline.

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 Cl 2) R f = 0.44 (broad dot).

A12. General method for the synthesis of anilines containing isoindolinone.

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, filter hot and concentrate 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) R f = 0.17; HPLC ES-MS m / z 150 ((M + H) ⁺ ) &lt; + &^gt;

· · · · · · · · · · · · · · · · · · · · ·

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- (1-isoindolinon-5-yloxy) -1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) R f = 0.35 .

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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- (1-oxoisoindolin-5-yloxy) aniline as a dark yellow solid: TLC (100% EtOAc) R f = 0.15.

A13. General method of synthesis of ω-carbamoylanilines via amide prepared by EDCI and nitroarene reduction. Synthesis of 4- (3-7 N-methylcarbamoylphenoxy) aniline.

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 overnight. Cool to room temperature and react 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).

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 LiOH.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 = 2 with 1M HCl solution. The resulting pale 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).

NHMe

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. H ₂ (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 of 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-fluorometrobenzene (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). ml), followed by water (50 ml). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 30% EtOAc and 70% hexane to give 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.60 g).

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. H2 (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%): ^lH NMR (CDCfi) 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).

Al 5. Synthesis of aniline by electrophilic nitration and reduction.

Synthesis of 4- (3-methylsulfamoylphenoxy) aniline.

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

To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0 ° C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was warmed to room temperature and stirred at room temperature overnight. The resulting mixture was partitioned between EtOAc (25 mL) and 1M HCl solution (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%).

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 mL). (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 aqueous phase.

Φ • 9 Φ 9 ♦ · · · · · · · · · · 3 3 3 3 3 3 3 3 3 · · · · · NaCl solution (50 mL), dried (MgSO 4) and concentrated under reduced pressure. The residual oil was purified by silica gel column chromatography using 30% EtOAc and 70% hexane to yield

4- (3- (N-methylsulfamoyl) phenyloxy) benzene (0.30 g).

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 g) portionwise over 5 minutes. , 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

A slurry of 4- (3- (N-methylsulfamoyl) phenyloxy) -1-nitrobenzene (0.30 g) and 10% Pd / C (0.030 g) in EtOAc (20 mL) was stirred under atm. 1¾ (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 using 30% EtOAc and 70% hexane to give 4- (3- (N-methylsulfamoyl) phenyloxy) aniline (0.070 g).

A16. Modification of ω-ketones. Synthesis of hydrochloride

4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline)

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. O-methylhydroxylamine 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- (Vmethoxy) 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 - (ω-silyloxyalkyl) amides. Synthesis

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

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

To a solution of 4-chloro- N - (2-hydroxyethyl) pyridine-2-carboxamide (prepared 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) were added. 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- (77- (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide as an orange oil (2.32 g, 88%). This material was used in the next step without further purification.

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

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. An additional 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 slowly added to an ice bath. water (approximately 1 ml) was 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- (V (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.

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 give 4- (5- (2-methyl) pyridyloxy) -nitrobenzene. as a brown solid (12.3 g).

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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).

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

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 H 2 (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 is 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:

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

Bl. General method for the synthesis of isocyanates from anilines by CDI. Synthesis of 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 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 4-bromo-3- (trifluoromethyl) phenyl isocyanate obtained is a brown solid (35.1 g, 86%): GC-MS m / z 265 (M ^& lt ^{; +} & gt ^; ).

C. Methods of preparation of ureas

Cla. General method of urea synthesis by reaction of isocyanate with aniline. Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (N-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) -N '- ( 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea as an off-white solid (28.5 g, 93%); Mp 207209 ° 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 = 2.5Hz, 1H), 8.49 (d, J = 5.5Hz, 1H), 8.77 (br d, 1H) 1.99 (s, 1H); 9.21 (s, 1H); HPLC ES-MS m / z 465 ((M + H) &lt; + & gt ^; ).

Clb. General method of urea synthesis by reaction of isocyanate with aniline. Synthesis of N - (4-bromo-)

- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea

A solution of 4-bromo-3- (trifluoromethyl) phenyl isocyanate (Method B1, Step 2; 8.0 g, 30.1 mmol) in CH 2 Cl 2 (80 mL) was added dropwise to a solution of 4- (2- (N-methylcarbamoyl)). -4-pyridyloxy) aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH 2 Cl 2 (40 mL) at 0 ° C. 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 N - (4-bromo-3- (trifluoromethyl) phenyl) N - (4- (2- (V-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 > 2.5 Hz, 1H) 7.58 (m, 3H), 7.77 (d, > 8.8 Hz, 1H), 8.11 (d, > 2.5 Hz, 1H), 8 -19 (d, > 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) &lt; + & gt ^; ).

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

NHMe

A solution of 2-methyl-4- (2- (N-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 N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (2-methyl-4- (2- (7-methylcarbamoyl)) ( 4-pyridyloxy) phenyl) urea as a brown oil (0.11 g, 0.22 mmol): 1H

NMR (DMSO-d 6) δ 2.27 (s, 3H), 2.77 (d, J = 4.8 Hz, 3H), 7.03 (dd, J = 8.5, 2.6 Hz, 1H 7.11 (d, J = 2.9 Hz, 1H), 7.15 (dd, J = 5.5, 2.6, Hz, 1H), 7.38 (d, J = 2.6) Hz, 1H), 7.62 (app d, J = 2.6 Hz, 2H), 7.84 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1 H); 8.50 (d, J = 5.5Hz, 1H); 8.78 (q,

J = 5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m / z 479 ((M + H) &lt; + & gt ^; ).

Cld. General method of urea synthesis by reaction of isocyanate with aniline. Synthesis of N - (4-chloro-3- (trifluoromethyl) phenyl) -7 N - (4-aminophenyl) urea

Cl

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) all at once. 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) Rf = 0.72.

Cle. General method of urea synthesis by reaction of isocyanate with aniline. Synthesis of V- (4-chloro-3- (trifluoromethyl) phenyl) - (4-ethoxycarbonylphenyl) urea

Cl

OEt

To a solution of ethyl 4-isocyanate benzoate (3.14 g, 16.4 mmol) in CH 2 Cl 2 (30 mL) was added 4-chloro-3- (trifluoromethyl) aniline (3.21 g, 16.4 mmol) and Stir at room temperature overnight. The resulting slurry was diluted with CH2Cl2 (50 mL) and filtered to give N- (4-chloro-3- (trifluoromethyl) phenyl) -V ^'- (4-ethoxycarbonyl-phenyl) -urea as a white solid (5.93 g, 97%); TLC (40% EtOAc / 60% hexane) R f = 0.44.

Clf. General method of urea synthesis by reaction of isocyanate with aniline. Synthesis; V- (4-chloro-3- (trifluoromethyl) phenyl) - (3-carboxyphenyl) urea

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (1.2 µg, 5.46 mmol) in CH 2 Cl 2 (8 mL) was added 4- (3-carboxyphenoxy) aniline (Method All; 0.81 g, 5, 76 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 (1.21). g, 76%).

C2a. General method for the synthesis of urea by reacting aniline with Ν ', N'-carbonyldiimidazole and adding a second aniline. Synthesis of V- (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 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- (V-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 in · in · · in · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Extract 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 residual 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) -77 '- (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, 1H), 8.75 (d, J = 4.8 Hz, 1H), 9.55 (s, 1H); FAB-MS m / z 461 (M + H) &lt; + &^gt;

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 in preparation

N, N ' -carbonyldiimidazole. pyridyloxy) phenyl) urea Synthesis bis (4- (2- (N, N-methylcarbamoyl) -4- O O MeHN il? Íí ^^ ° Ύ ^ ι ^ΝΗΜθ 1 JI 11 Η H

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- (N-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)} -4pyridyloxy) phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) R f = 0 , 50; 1 H NMR (DMSO-d ₆ ) δ 2.76 (d, J = 5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J = 5.4) Hz, 1H), 8.75 (d, J = 4.8 Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m / z 513 ((M + H) &lt; + & gt ^; ).

• ·

C2c. General method of urea synthesis by reaction of isocyanate with aniline. Synthesis of V- (2-methoxy-5- (trifluoromethyl) phenyl-V '- (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea

To a stirred solution of 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.47 mmol) in CH 2 Cl 2 (1.5 mL) was added 5- (4-aminophenoxy) isoindoline-1,3-dione ( method A3, 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-V '). - (4- (1,3-dioxoisoindolin-5yloxy) 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,> 9.3 Hz, 2H), 7.80 (d, J = 8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS 472.0 ((M + H) ⁺ , 100%).

C2d. 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) -4-pyridyloxy) phenyl) urea

NHMe

To a stirred solution of CDI (0.2 µg, 1.30 mmol) in CH ₂ Cl ₂ (2 mL) was added 5 - (tert -butyl) -2- (2,5-dimethylpyrrolyl) aniline (Method A4, Step 1) simultaneously. 2; 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, 0.267 mmol) was added in one portion. The resulting mixture is ····

Heat at 36 ° C overnight, cool to room temperature and dilute 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-dimethylpyrrolyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea j as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc / 60) % hexane) Rp = 0.24; 1 H NMR (acetone-de) 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 = 5.4 Hz, 1H) 8.57 (d, J = 2.1 Hz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M + H) &lt; + & gt ^; , 100%).

C3. Combination method of diphenylurea synthesis using triphosgene

One of the anilines to be coupled 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 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 N- (2-methoxy-5- (trifluoromethyl) phenyl) -V '- (4- (2- (7V-methylcarbamoyl) -4pyridyloxy) phenyl) urea _CF3 \ O

NHMe

To a stirred solution of phosgene (1.9 M in toluene; 2.07 mL 0.2 lg, 1.30 mmol) in

CH 2 Cl 2 (20 mL) at 0 ° C add 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% EtOAc, then concentrated under reduced pressure at 45 ° C to obtain a hot concentrated EtOAc solution, which was washed with hexane (10 mL) to slowly form crystals of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2- (N-methylcarbamoyl)) (4-pyridyloxy) phenyl) urea (0.44 g): TLC (1% Et 3 N / 99% EtOAc) R f = 0.40.

D. Interconversion of ureas

Dia. Conversion of ω-aminophenylureas to ro- (aroylamino) phenylureas. Synthesis of N- (4-chloro-3 - ((trifluoromethyl) phenyl) - R '- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea

Cl

About me

To a solution of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4-aminophenyl) urea (Method Cld; 0.050 g, 1.52 mmol), m-methylisophthalate (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). The mixture was stirred at room temperature overnight, diluted with EtOAc (25 mL), washed sequentially with water (25 mL) and saturated NaHCO 3 solution (25 mL), and the organic layer was dried (Na 2 SO ₄ ) and concentrated to a residue. The resulting solid was triturated with EtOAc (80% EtOAc / 20% hexane) to give a solid. · 9 9 99

9 ·· 99 ·· ·· ♦ ··

N - (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea (0.27 g, 43%): mp 121122 ° C; TLC (80% EtOAc / 20% hexane) Rf = 0.75.

Dlb. Conversion of ω-carboxyphenylureas to ω- (arylcarbamoyl) phenylureas. Synthesis

N- (4-chloro-3 - ((trifluoromethyl) phenyl) -V ^'- (4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea

To a solution of ^N - (4-chloro-3 - ((trifluoromethyl) phenyl) -7V ^- (4- (3methylkarbamoylfenyl) 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 -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 allowed to warm to room temperature and stirred overnight, treated with water (10 mL), extracted with EtOAc (25 mL), and the organic phase was concentrated under reduced pressure. 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 V- (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) R f = 0, 23.

According to. Combination method for the conversion of ω-carboxyphenylureas to ω- (arylcarbamoyl) phenylureas. Synthesis of V- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (N - (3- (N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea • · · ·

A mixture of N- (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (3-carboxyphenyl) urea (Method C1f; 0.030 g, 0.067 mmol) and N-cyclohexyl-N' - (methylpolystyrene) carbodiimide (55). mg) in 1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CH 2 Cl 2 (1 M; 0.074 mL, 0.074 mmol) (if insoluble or cloudy, a small amount of DMSO was added). at 36 ° C overnight The cloudy reaction mixture was then treated with THF (1 mL) and heating was continued for 18 hours. The resulting mixture was treated with poly (4- (isocyanatomethyl) styrene) (0.040 g). The 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 N - (4-chloro-3- ((trifluoromethyl) phenyl) -N '- (4- (N - (3- (77- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea (0.024 g, 59%): TLC (70% EtOAc / 30%) hexane) Rf = 0.1 2.

D2. Conversion of ω-carboalkoxyarylureas ω-carbamoylarylureas. Synthesis of N - (4-chloro-3 - ((trifluoromethyl) phenyl) -7 - N - (4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea

NHMe

To a sample of N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N - (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) -N '- (4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea as a white solid: mp 247 DEG C. TLC (100% EtOAc) Rf = 0.35.

·

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

Do mushy

((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 mL). mmol). The resulting mixture was heated at reflux for 12 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water (50 mL), treated with 1 N HCl and the pH was adjusted to 2-3. 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 of N- (4-chloro-3 ((trifluoromethyl) phenyl) -N '- ((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea

Step 1. Synthesis

N- (4-chloro-3- (tri-fluoromethyl) phenyl) -N '- ((4- (3- (5-carboxypyridyl) oxyphenyl) urea)

N- (4-Chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea) is prepared from 4-chloro-3- (trifluoromethyl) phenyl isocyanate and 4- (3- ( 5-methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) analogously to Method Cla.A suspension of N- (4-chloro-3- (trifluoromethyl) phenyl) N '- ((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea) (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and stirred at room temperature for 1 hour. The resulting mixture was adjusted to pH 5 with 1 N HCl solution.

* * W W ·· w 9 9 9 9 99 99

9 9 9 9 9 99

999 99 99 ** 9

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. This procedure was repeated twice to give N - (4-chloro-3- (trifluoromethyl) phenyl) -N '- ((4- (3- (5-carboxypyridyl) oxyphenyl) urea) (0.18 g, 71%).

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

A mixture of N- (4-chloro-3- (trifluoromethyl) phenyl) -N- ((4- (3- (5-carboxypyridyl) oxyphenyl) urea (0.050 g, 0.011 mmol)), N-dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N-methylmorpholine (0.035 g, 0.28 mmol) and EDCI.HCl (0.032 g, 0.17 mmol) in DMF (2.5 mL) After stirring at room temperature overnight, the resulting solution was partitioned between EtOAc (50 mL) and water (50 mL), the organic phase was washed with water (35 mL), dried (MgSO 4) and concentrated under reduced pressure. minimal CH 2 Cl 2 (about 2 mL) The resulting solution was treated dropwise with Et ₂ O to give N - (4-chloro-3- (trifluoromethyl) phenyl) - N - ((4- (3- (5 - (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea as a white precipitate (0.48 g, 84%: 1 H NMR (DMSO-d ₆ ) δ 2.10 s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s; 1H), 8.43 (s, 1H), 8.58 (t H, 8.69 (s, 1H), 8.90 (s, 1H), 9.14 (s, 1H), HPLC ES-MS m / z 522 ((M + H) ⁺ ) ^. ).

D5. General method for deprotection of N - (n-silyloxyalkyl) amides. Synthesis

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

Cl

.0.

·· ·· • • • · • · • $ * • · • » • and • • Φ • · ·· ··· · « · « * · ··

To a solution of N - (4-chloro-3 - ((trifluoromethyl) phenyl) - N - (4- (4- (2 - (N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea (prepared in an analogous manner 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 N - (4-chloro-3 - ((trifluoromethyl) phenyl) -N '- (4- (4- (2- (N - (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea) was obtained 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- (3-7 N-methylcarbamoylphenoxy) aniline was prepared according to Method A13. And according to Method C3, 3-ZerZ-butylaniline is reacted with bis (trichloromethyl) carbonate, followed by 4- (3-7 N-methylcarbamoylphenoxy) aniline to give urea.

Example 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to give 4- (4-acetylphenoxy) -1-nitrobenzene. 4- (4-Acetylphenoxy) -1-nitrobenzene is reduced according to Method A13, 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- (3-7 / methylcarbamoyl) -4-methoxyphenoxy) aniline, which was prepared according to Method A8 to give the urea.

• · · ·

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

Example 5: According to Method C2d, 5-Zez-butyl-2-methoxyaniline was reacted with CDI, followed by 4- (3-7-N-methylcarbamoyl) -4-methoxyphenoxy) aniline, which was prepared according to Method A8 to give the 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- (looisoindolin-5-yloxy) aniline to give urea.

Example 8: 4- (3-7-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- (3-7-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, with 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 the urea.

Example 10: 4-Fluoro-1-nitrobenzene and? -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 obtain urea.

Example 11: 4-Chloro- N -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- (N-methylcarbamoyl) -4-pyridyloxy) aniline. And according to Method C4, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene followed by 3- (2- (N-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 3-aminophenol according to Method A2, Step 4 using DMAC instead of DMF to give 3- (2-carbamoyl-4-pyridyloxy) aniline. And according to method C2a, 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 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. And according to method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI, followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give 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 is 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- (3-7-methylcarbamoyl) -4-methoxyphenoxy) aniline, which was prepared according to Method A8 to afford the 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- (7-methylcarbamoyl) -4-pyridyloxy) -2-methylaniline according to method Cle 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 C a to give urea.

Example 18: 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) -4-methylaniline. 5- (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline according to method C a to give 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-pyridyloxyaniline. 5- (Trifluoromethyl) -2- methoxyaniline is converted to 5- (trifluoromethyl) 2-methoxyphenyl isocyanate according to Method B1 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate is reacted with 4- (2- (7-ethylcarbamoyl) -4-pyridyloxy) aniline according to Method C1a, to obtain urea.

Example 20: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 4- (2- ( N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 5- (Trifluoromethyl) -2-methoxyaniline is converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to the method

······· · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

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5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (7-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline according to method C a 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. Nitrobenzene is reduced according to Method A19, Step 2 to give 4- (4-methylsulfonylphenoxy) -1-aniline. According to method C a, 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-methoxyphenylisocyanate is reacted with 4- (3-carbamoylphenoxy) ) aniline to obtain urea.

Example 23: 5- (4-Aminophenoxy) isoindoline-1,3-dione was prepared according to Method A3. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione according to method 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 was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-dimethylcarbamoyl) -4-pyridyloxy) aniline. 5- (Trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method B1. 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline according to method C a to give 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- (1-oxoisoindolin-5yloxy) aniline according to Method C2d to give the urea.

Example 26: 4-Hydroxyacetophenone is reacted with 4-fluorometrobenzene 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-methoxyphenylisocyanate according to method B1, 5- (Trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (4- (1- (N-methoxy) iminoethyl) phenoxyaniline hydrochloride) according to method Cla to give urea.

Example 27: 4-Chloro-N-methylpyridine carboxamide 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- (77-methylcarbamoyl) phenylthio) aniline according to Method Cla to give urea).

Example 28: 5- (4-Aminophenoxy) -2-methylisoindoline-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 the method of Cla to give urea.

Example 29: 4-Chloro-N-methylpyridine carboxamide 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- (77-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 3- (4- (2- (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- (7760). · 0 ·· · · · · «· ·

9 9 Isopropylcarbamoyl-4-pyridyloxy) 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- (2- (iso-isopropylcarbamoyl) -4-pyridyloxy) aniline according to method Cla to give 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 is saponified 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 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 methylamine according to Method D4, step 2 to obtain 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 N, N-dimethylethylenediamine according to Method D4, Step 2 to obtain the amide.

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Example 34: 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-Carboxyphenoxyjaniline) is reacted with 5- (trifluoromethyl) -2-methoxyphenylisocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) urea which is treated according to the method It is coupled with 3aminopyridine.

Example 35: 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 was treated according to the method It is coupled with A (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 is 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 D1.

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-methoxyphenylisocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl) -N- (3-carboxyphenyl) urea. wine which is coupled with 4 (dimethylamino) aniline according to Method D1.

Example 38: 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-).

•

O • 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · methoxyphenyl) -N '- (3-carboxyphenyl) urea which is coupled with 5-amino-2-methoxypyridine according to Method D1.

Example 39: 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-methoxyphenylisocyanate according to Method C1f to give N - (5- (trifluoromethyl) -2-methoxyphenyl) -N '- (3-carboxyphenyl) urea which is coupled with 4-morpholinoaniline according to method D1.

Example 40: 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 is 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 N- (2-pyridyl) piperazine according to Method D1.

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

Example 42: 4- (2- N -Methylcarbamyl-4-pyridyloxy) aniline was prepared according to Method A2. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- N, N -methylcarbamyl-4-pyridyloxy) aniline according to method C a 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.

9 9 999 9

99 9 9 9 9 99

9 9 99 99

9 9 9 9 9 99

9 99 9 9

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 3-aminophenol 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-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 (7 N '-) methylcarbamoyl) -4-pyridyloxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is 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 is reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to give urea.

Example 47: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was prepared according to Method A5. And according to method Cle, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to give urea.

Example 48: 4- (3-7-Methylsulfamoyl) phenyloxy) aniline was prepared according to Method A15. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-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 C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to give urea.

Example 50: 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) -4-methylaniline. And according to the method of Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 3- (2). - (N-methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to give the urea.

Example 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro- N -ethyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-ethylcarbamoyl) -4-pyridyloxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is 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-methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to give urea.

Example 53: 4- (4-Methylthiophenoxy) -1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. 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 is reacted with 4- (4-methylsulfonylphenoxy) -1-aniline to give urea.

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 was 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) -1-nitrobenzene is reduced to 4- (4- (methylsulfamoyl) phenyloxy) aniline according to Method A15, step 4. And according to Method C a 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-methylsulfamoyl) phenyloxy) aniline to obtain 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. 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 the method of Cla to give the urea.

Example 56: 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. 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 the method of Cla to give N - (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (methoxycarbonyl) -) - 5-pyridyloxy) phenyl) urea. The methyl ester is reacted with methylamine according to Method D2 to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (4- (2- (methylcarbamoyl) -5-pyridyloxy) phenyl) urea.

Example 57: 7V- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4-aminophenyl) urea was prepared according to method Cld. 7V- (4-Chloro-3- (trifluoromethyl) ^phenyl-N' - (4-Aminophenyl) urea is coupled with worao-methyl isophthalate according to method Dia to give urea.

Example 58: N- (4-Chloro-3- (trifluoromethyl) phenyl-N '- (4-aminophenyl) urea was prepared according to Method C. N - (4-Chloro-3- (trifluoromethyl) phenyl-N' - ( The 4-aminophenyl) urea is coupled with the obtained isomethylisophthalate according to Method Dia to give N - (4-chloro-3- (trifluoromethyl) phenyl-N- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea. A according to Method D2 are 7V- (4-chloro-3- (trifluoromethyl) ^phenyl-N '- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea was reacted with methylamine to afford the corresponding methyl amide.

* · * * * * * * * * * * * * * * * * * * * * * * * * * ··· «· ··· · · · * ·

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

Example 60: 4-Hydroxyacetophenone was reacted with 4-fluorometrobenzene 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- (N-methoxy) iminoethyl) phenoxyaniline hydrochloride according to Method A16). Duty was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate 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- (N - (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene. And according to method A13 step 4, 4- (3- (N - (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (N- (2-morpholinylethyl) carbamoyl) phenoxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (3/2-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 is coupled with 1- (2-aminoethyl) piperidine according to Method A13, Step 3 to give 4- (3- (N - (2-piperidylethyl) carbamoyl) phenoxy) - lnitrobenzene. And according to method A13, step 4, 4- (3- (N - (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (N - (2-piperidylethyl) carbamoyl) phenoxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (3 - (2-piperidylethyl) carbamoyl) phenoxy) aniline to give urea.

• Φ · φ · · φ · φ ΦΦ φ φ φ · · φ φ φ φ • • φ φ φ φ φ φ φ φ φ

Example 63: 4- (3-Carboxyphenoxy) -1-nitrobenzene was prepared according to Method A13, Step 2. 4- (3-Carboxyphenoxy) -1-nitrobenzene was coupled with tetrahydrofurfiirylamine according to Method A13, Step 3 to give 4- (3- (77- (tetrahydrofurylmethyl) carbamoyl) phenoxy) -nitrobenzene. And according to Method A13 step 4, 4- (3- (77 (tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (N (tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (77 (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 to give 4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene. And according to method A13 step 4, 4- (3- (N - ('(1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene is reduced to 4- (3- (77 - ((1-methylpyrrolidinyl) methyl) (carbamoyl) phenoxy) aniline. According to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (N - ((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) aniline to give urea.

Example 65: 4-Chloro-N-methylpyridine carboxamide 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. According to Method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is left. with 4- (4- (2- (77-methylcarbamoyl) phenylthio) aniline) to afford the urea.

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 was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (77-isopropylcarbamoyl) -4-pyridyloxy) aniline. And according to method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-isopropylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 67: N- (4-Chloro-3- (trifluoromethyl) phenyl-77 ^' - (4-ethoxycarbonylphenyl) urea was prepared according to Method Cle. 77- (4-Chloro-3- (trifluoromethyl) phenyl-7' - ( 4-

Ethoxycarbonylphenyl) urea is saponified according to Method D3 to give N- (4-chloro-3- (trifluoromethyl) phenyl-N- (4-carboxyphenyl) urea).

N - (4-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-methylcarbamoylphenyl) carbamoylphenyl) 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 is reacted with 5- (4-aminophenoxy) -2-methylisoindoline-1,3-dione to give urea.

Example 69: 4-Chloro-N-methylpyridine carboxamide 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 C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is left. react 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 is 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-methoxyphenylisocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method Customs yielding 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. 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 with methylamine according to Method D4, Step 2 to give 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) -N ⁾ - (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with N-dimethylethylenediamine according to Method D4, step 2 to obtain 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-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide. 4-Chloro- N - (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide is reacted with triisopropylsilyl chloride followed by 4-aminophenol according to Method A17 to give 4- (4- (2 (N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline). according to Method C a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline) to give N - (4-chloro-3 ((trifluoromethyl)) phenyl) -N '- (4- (4- (2- (N - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea).

Example 75: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A11. 4-Chloro-3 (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1f to give urea which is coupled with 3-aminopyridine according to Method D1.

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 urea which is coupled with N - (4-acetylphenyl) piperazine according to Method D1.

····

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

According to.

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 D1.

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 D1.

Example 80: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A11. 4-Chloro-3 (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to Method C1f to give urea which is coupled with 2-methoxyethylamine according to Method D1.

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 urea which is coupled with 5-amino-2-methoxypyridine according to Method D1.

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 D1.

Example 83: 4- (3-Carboxyphenoxy) aniline was prepared according to Method A11. 4-Chloro-3 (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline according to * 00 → 0 • 0 • 9 • 0 0

90 · · ·

99 0 0 0 0 0 0

Of process C1f to give urea which is coupled with N - (2-pyridyl) piperazine according to method D1.

Example 84: 4-Chloropyridine-2-carbonyl chloride hydrochloride was reacted with 2-hydroxyethylamine according to Method A2, Step 3b, to give 4-chloro-N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide. 4-Chloro- N - (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride followed by 4-aminophenol according to Method A17 to give 4- (4- (2 (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline)). according to Method C a, 4-chloro-3- (trifluoromethylphenylisocyanate) is reacted with 4- (4- (2- (2 - (2 - triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline) to give N - (4-chloro-3 ((trifluoromethyl) phenyl) - N - (4- (4- (2- (2 - (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea) The urea was deprotected according to Method D5 to give N - (4-chloro-3- ( (trifluoromethyl) phenyl) -2 '- (4- (4- (2- (2 - (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 C a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (2 H -methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 86: 4- (2- (N-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. A method according to Cla, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ^{(N-methylcarbamoyl)} -4-pyridyloxy) -

2-chloroaniline to give urea.

Example 87: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-2-methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 4- (2- (N-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 the method of Cla, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is left to form a 4-bromo-3- (trifluoromethyl) phenyl isocyanate. React with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to give 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 is 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 C a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-ethylcarbamoyl) -4-pyridyloxyjaniline) 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 (N-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 the method of Cla, 4bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 3 - (- 2- (N-methylcarbamoyl) -4pyridyloxy) aniline to give urea.

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

Example 92: 4-Chloro-N-methylpyridine carboxamide 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-3- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (4- (2- (7-methylcarbamoyl) phenylthio) aniline) to give urea.

Example 93: 4-Chloro-N-methylpyridine carboxamide 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- (77-methylcarbamoyl) phenylthio) aniline) to give urea.

Example 94: 4- (2- (77- [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 C a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N - (2-morpholin-4-ethyl-ethyl) carbamoyl) pyridyloxy) aniline to give urea.

Example 95: 4- (2- (77-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 C a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 96: 4- (2- (77-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 9 9 9 9 9 9 (trifluoromethyl) phenyl isocyanate according to Method B1. According to method C a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (77-methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to give urea.

Example 97: According to Method A2, Step 4, 4-amino-2-chlorophenol is reacted with 4-chloro-7-methyl-2-pyridinecarboxamide prepared according to Method A2, Step 3b to give 4- (2- ( 77-methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. 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 the method of Cla, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (77-methylcarbamoyl) -4-pyridyloxy) -

3-chloroaniline to give urea.

Example 98: 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. 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 C a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 3 - (- 2- (77-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-77-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (77-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- (77-ethylcarbamoyl) -4-pyridyloxyjaniline) to give urea.

Example 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-7H, 77-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (7H, 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 B1. And according to method C a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- (N, N-dimethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Example 101: 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 (N-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- (N-methylcarbamoyl) -4-pyridyloxy) aniline to form urea.

Example 102: 4- (2- (N-Methylcarbamoyl) -4-pyridyloxy) aniline was prepared according to Method A2.

5-tert-Butyl-2- (2,5-dimethylpyrrolyl) aniline was prepared according to Method A4. 5- tert -Butyl-2- (2,5-dimethylpyrrolyl) aniline was reacted with CDI followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline according to Method C2d to give the urea.

Example 103: 4-Chloro-A ^/ -methyl-2-pyridinecarboxamide was prepared according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4, using DMAC instead of DMF to give 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline. And according to method C2b, reaction of 3-amino-2-methoxyquinoline with CDI, followed by 4- (2- (N-methylcarbamoyl) -4-pyridyloxy) aniline affords bis (4- (2- (N-methylcarbamoyl) -4-pyridlyoxy) phenyl) ) urea.

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

Tables

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

Example R Melting point TQ HPLC (min) TLC ^R r TLC System MS [ionization] Synthesis method 1 0 NH ^Μθ 0.22 50% EtOAc / 50% hexane 418 (M + H) &lt; + &gt; (HPLC ES-MS) A13 C3 2 0.58 50% EtOAc / 50% hexane 403 (M + H) &lt; + &gt; (HPLC ES-MS) A13 C3 3 0 / —NH - ^ ~~ y ~ O — OMe 133- 135 0.68 100% EtOAc 448 (M + H) &lt; + &gt; (FAB) A8 C2d

Table 2

5-tert-butyl-2-methoxyphenyl urea

Example R Melting point (° C) HPLC (min) TLC ^R r TLC System MS flonizace] Synthesis method 4 / - NH ^Me 5.93 448 (M + H) &lt; + &gt; (HPLC ES-MS) A13 B1 Cla 5 O / -NH 120- 122 0.67 100% EtOAc 478 (M + H) &lt; + &gt; (FAB) A8 C2d 6 0 0.40 50% EtOAc / 50% hexane 460 (M-H) &lt; + &gt; (HPLC ES-MS) A3 C2d

Table 3

5- (trifluoromethyl) -2-methoxyphenyl urea

Example R Melting point (fC) HPLC (min) TLC ^R r TLC System MS (ionization) Synthesis method 8 fc, Ϋ-ΝΗ 250 (Dec) 460 (M + H) + (FAB) A13 C2a 9 206208 0.54 10% MeOH / 90% CH 2 Cl 2 446 (M + H) &lt; + &gt; (HPLC ES-MS) A3 step 2, A8 step 4, B1, Cla 10 0.33 50% EtOAc / 50% pet ether 445 (M + H) &lt; + &gt; (HPLC ES-MS) A13 C3 11 —Y V — NH / = (Me ° -w 0.20 2% Et 3 N / 98% EtOAc 461 (M + H) &lt; + &gt; (HPLC ES-MS) A2 C4 12 —_> - nh ₂ ^oh C / 0.27 1% Et 3 N / 99% EtOAc 447 (M + H) &lt; + &gt; (HPLC ES-MS) A2 C4 13 0 V-NH ^Me 0.62 100% EtOAc 461 (M + H) &lt; + &gt; (FAB) A2 C2a 14 O, ^n- 2 -O- ° C 0 ^N 114- 117 0.40 1% Et 3 N / 99% EtOAc 447 (M + H) &lt; + &gt; (FAB) A2 C4

· · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 ·····························

15 Dec 0.1 H-NH- ^Me 232- 235 0.54 100% EtOAc 490 (M + H) &lt; + &gt; (FAB) A8 C2d 16 0 Me (—NH) = < ^Me — y y ° -4 /> 210- 213 0.29 5% MeOH / 45% EtOAc / 50% pet ether 475 (M + H) &lt; + &gt; (HPLC ES-MS) A5 Bl Cle 17 ° Cl / -NH) 'V / = < ^Μθ - \ / ⁰ 4 / 187- 188 0.17 50% EtOAc / 50% pet ether 495 (M + H) &lt; + &gt; (HPLC ES-MS) A6 Bl Cla 18 C / -Me _Y-NH2 o <f ~? N 0.48 100% EtOAc 475 (M + H) &lt; + &gt; (HPLC ES-MS) A2 step 4, Bl Cla 19 Dec O _x Vnh -O- ° -O *. ^Et 194- 196 0.31 5% MeOH / 45% EtOAc / 50% pet ether 475 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Bl Cla 20 May 0 CI / NH / - </ = ^ ^'Me - \ / 4 ° ~ // ^N 214- 216 0.25 5% MeOH / 45% EtOAc / 50% pet ether 495 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 21 208- 210 0.30 50% EtOAc / 50% hexane 481 (M + H) &lt; + &gt; (HPLC ES-MS) A19C2a 22nd O y-NHa 188- 190 0.30 70% EtOAc / 50% hexane 447 (M + H) &lt; + &gt; (HPLC ES-MS) A15. Step 4 Cla 23 0 0.50 70% EtOAc / 30% hexane 472 (M + H) &lt; + &gt; (FAB) A3 Bl Cla 24 0 Me 203- 205 0.13 100% EtOAc 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Bl Cla

• «· ·

I «·

25 —O- ° AA ° 0.09 75% EtOAc / 25% hexane 458 (M + H) &lt; + &gt; (HPLC ES-MS) A12 C2d 26 MeQ 169171 0.67 50% EtOAc / 50% pet ether 474 (M + H) &lt; + &gt; (HPLC ES-MS) A13 steppes, A13 step 4, A16, Bl Cla 27 Mar: o _in Ϋ-ΝΗ ^ -O ^Me 218219 0.40 50% EtOAc / 50% pet ether 477 (M + H) &lt; + &gt; (HPLC ES-MS) A2 step 3b, A2 step 4, Bl, Cla 28 -Oo-Q ' ⁰ 0 212- 214 0.30 40% EtOAc 60% hexane A9 Bl Cla 29 -ΛΛ Vnh ' ⁼ \ / = \ Me ^with -w 0.33 50% EtOAc / 50% pet ether 474 (M + H) &lt; + &gt; (HPLC ES-MS) A2 step 3b, A2 step 4, B1, Cla 30 Vnh ^Pr 210211 A2 Bl Cla 31 o _at ~ 0 ~ ^ο Α / Αλ \ -o ' 210- 204 0.43 10% MeOH / CH2Cl 2 A14 Bl D4 32 0 Vnh * 247249 0.57 10% MeOH / CH2Cl2 A14 Bl D4 33 0 y- nh - N-Me \ = i / \ —N Me 217219 0.07 10% MeOH / CH2Cl 2 A14 Bl D4

• · · ·

34 0 Vnh 0.11 70% EtOAc 30% hexane All B1 Clf Dle 35 O N -ο «· <Γ 0.38 70% EtOAc / 30% hexane All B1 Clf Dle 36 ^f ~ CHo-£ yo-O 0.77 70% EtOAc / 30% hexane All B1 Clf Dle 37 ^M \ _ from _NH Me ^ == / ^ = 0 - <X) 0.58 70% EtOAc / 30% hexane All B1 Clf Dle 38 MeO— <7 γ ~~ NH \ = / \ = Q 0.58 70% EtOAc 30% hexane All B1 Clf Dle 39 O ⁷ N- (-N-NH) - / - = q - O ^- O 0.17 70% EtOAc / 30% hexane All B1 Clf Dle 40 {2H2> -C >> ₀ 4> »- d 0.21 70% EtOAc / 30% hexane All B1 Clf Dle

Table 4.

3- (Trifluoromethyl) -4-chlorophenyl urea

Η H

Cl •

Example R Melting point (fC) HPLC (min) TLC ^R r TLC System MS [ionization] Synthesis method 41 Vnh -0-0 163- 165 0.08 50% EtOAc / 50% pct ether 464 (M + H) &lt; + &gt; (HPLC ES-MS) A13 C3 42 Knh -0-0 ^Me 215 0.06 50% EtOAc / 50% pet ether 465 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 43 0 -O “ ^0- O 0.10 50% EtOAc / 50% pet ether 451 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 44 - ^ ~ ^NH 2 ⁰ W 0.25 30% EtOAc / 70% pet ether 451 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 45 - / Λ Vnh / = (Me ° ° O) 0.31 30% EtOAc / 70% pet ether 465 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 46 O 176- 179 0.23 40% EtOAc / 60% hexane 476 (M + H) &lt; + &gt; (FAB) A3 Cla 47 0 Me (-NH) = < ^Me \ / ° ~ 4 / 0.29 5% MeOH / 45% EtOAc / 50% pet ether 478 (M + H) &lt; + &gt; (HPLC ES-MS) A5 Cle 48 o./P 'S-NH -ο * ύ 206- 209 A15 Cla 49 0 Cl> -NH / = <Me / / ⁰ Y / ^N 147- 151 0.22 50% EtOAc / 50% pet ether 499 (M + H) &lt; + &gt; (HPLC ES-MS) A6 Cla 50 - / Λ-Μθ NH \ = (/ = (Me ° ~ w 0.54 100% EtOAc 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla

>

51 0> -NH ^E * 187- 189 0.33 5% MeOH / 45% EtOAc / 50% pet ether 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 52 0 Cl / NH-e 7-0-4 // ^N 219 0.18 5% MeOH / 45% EtOAc / 50% pet ether 499 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 53 - € Y ~ O-Y 246248 0.30 50% EtOAc / 50% hexane 485 (M + H) &lt; + &gt; (HPLC ES-MS) A19, Cla 54 Me 196- 200 0.30 70% EtOAc / 30% hexane) 502 (M + H) &lt; + &gt; (HPLC ES-MS) A15 Cla 55 0 _in Vq ^ θ-Ο ^Μβ 228- 230 0.30 30% EtOAc / 70% CH 2 Cl 2 466 (M + H) &lt; + &gt; (HPLC ES-MS) 56 -o <H Me 238245 57 oY " 221- 222 0.75 80% EtOAc / 20% hexane 492 (M + H) &lt; + &gt; (FAB) Cld Dia 58 0 7 — NH ^Me . 247 0.35 100% EtOAc Cd Dia D2 59 About me 198- 200 0.09 100% EtOAc 479 (M + H) &lt; + &gt; (HPLC ES-MS) A2 Cla 60 MeO 158160 0.64 50% EtOAc / 50% pet ether .61 5-nh 195- 197 0.39 10% MeOH / CH 2 Cl 2 A13 Cla

• · · ·

62 0. Vnh 170- 172 0.52 10% MeOH / CH 2 Cl 2 A13 Cla 63 168- 171 0.39 10% MeOH / CH 2 Cl 2 A13 Cla 64 <In ^Et 'V — NH 176- 177 0.35 10% MeOH / CH 2 Cl 2 A13 Cla 65 About _K V-NH ^Me 130133 487 (M + H) &lt; + &gt; (HPLC ES-MS) A2 B1 Cla 66 γ-NH ^PN 155 A2 Cla 67 0 V-NH-cyya-M ^Me 225- 229 0.23 100% EtOAc Cle D3 Dlb 68 V-NMe 0 234- 236 0.29 40% EtOAc / 60% hexane A9 Cla 69 —E 2 y ~ nh \ == (/ = (Me ^S -W 0.48 50% EtOAc / 50% pet ether 481 (M + H) &lt; + &gt; (HPLC ES-MS) 70 o _at Ύ-ΝΗ -0- ° -0 ^ 0 0.46 5% MeOH / 95% CH 2 Cl 2 564 (M + H) &lt; + &gt; (HPLC ES-MS) A10 Cla

71 0 y-NH 'Cy- ° ~ Q 199- 201 0.50 10% MeOH / CH 2 Cl 2 2 A14 Cla D4 72 0 _K ' -NH 235- 237 0.55 10% MeOH / CH 2 Cl 2 2 A14 Cla D4 73 0 y- nh N-Me \ = / V-N Me 200201 0.21 50% MeOH / CH 2 Cl 2 2 A14 Customs D4 74 O _{/ O} N NH C = ^ ~ ^0_ C / ^ (OSI-i Pr) 3 145- 148 75 -O-o-O 0.12 70% EtOAc / 30% hexane 527 (M + H) &lt; + &gt; (HPLC ES-MS) All Clf According to 76 0 Me — Y Q 0 ^ - ~ 3 0.18 70% EtOAc / 30% hexane All Clf By 77 F-NH -o ° ~ o 0.74 70% EtOAc / 30% hexane All Clf By 78 Me ^ = / γ = Ο 0.58 70% EtOAc / 30% hexane All Clf By

• φ · · · · φ φ φ • • • • φ φ φ φ

79 0, Vnh d 0.47 70% EtOAc / 30% hexane 569 (M + H) &lt; + &gt; (HPLC ES-MS) All Clf By 80 Q. V- ^NH —— ^ —O ~~ OMe 0.18 70% EtOAc / 30% hexane 508 (M + H) &lt; + &gt; (HPLC ES-MS) All Clf By 81 MeO - ^ Y - NH ^Λ = ο = ° 0.58 70% EtOAc / 30% hexane 557 (M + H) &lt; + &gt; (HPLC ES-MS) All Clf By 82 0 N - <V ^NH 's — f \ = j ý = o 0.37 70% EtOAc / 30% hexane 611 (M + H) &lt; + &gt; (HPLC ES-MS) AU Clf According to 83 / = \ Q O N 0.19 70% EtOAc / 30% hexane All Clf By 84 ^N -NH-yy-G ^N 179- 183 A2 A17 Cla D5

Table 5.

3- (Trifluoromethyl) -4-bromophenylurea

9 φ 9 φ

• φ φ φ * * φ φ · · φ φ φ φ φ φ φ φ φ φ

Example R Melting point (fC) HPLC (min) TLC ^R r TLC System MS [ionization] Synthesis method 85 ό 186- 0.13 50% 509 A2 > -ΝΗ 187 EtOAc / (M + H) &lt; + &gt;. Bl Ζ — χ Γ -— \ Μβ 50% pet (HPLC ES- Cla ~ 0 ~ ⁰ O ether MS) 86 0 150- 0.31 50% 545 A6 Cl F-NH 152 EtOAc / (M + H) &lt; + &gt;. Bl / = (Me 50% pet (HPLC ES- Cla \ Z ⁰ "E / ether MS) 87 O 217- 0.16 50% 545 A2 Cl-NH 219 EtOAc / (M + H) &lt; + &gt;. Bl z— / / == (Me 50% pet (HPLC ES- Cla \ / ⁰ V // ^N ether MS) 88 0 183- 0.31 50% 525 A2 y- nh 184 EtOAc / (M + H) &lt; + &gt;. Bl z ^- —x / = (Et 50% pet (HPLC ES- Cla ether MS) 89 z — x Q. 0.21 50% 511 A2 - ('y y-nh EtOAc / (M + H) &lt; + &gt;. Bl \ f (\ f 50% pet (HPLC ES- Cla ° I ⁿ ether MS) 90 z-x o 0.28 50% 525 A2 —3 γ — Me y — NH EtOAc / (M + H) &lt; + &gt;. Bl == (/ = (Me 50% pet (HPLC ES- Cla ° ~ v / ether MS) 91 O _in Me 214- 0.28 50% 522 A2 Vn 216 EtOAc / (M + H) &lt; + &gt;. Bl z — x / = (Me 50% pet (HPLC ES- Cla -O ° O ether MS) 92 O 0.47 50% 527 A2 step y — nh EtOAc / (M + H) &lt; + &gt;. 3b. z — x / = \ Me 50% pet (HPLC ES- A2 step - <X / ether MS) 4, Bl, Cla 93 z-x 0 0.46 50% 527 A2 step —3 y y — nh EtOAc / (M + H) &lt; + &gt;. 3b. \ = (/ = (Me 50% pet (HPLC ES- A2 step ^S “W ether MS) 4. Bl. Cla

• ·

Table 6.

5- (Trifluoromethyl) -4-chloro-2-methoxyphenyl ureas

Example R Melting point (fC) HPLC (min) TLC ^R r TLC System MS [lonizacel Synthesis method 95 Oy-NH-OoO ^Me 140- 144 0.29. 5% MeOH / 45% EtOAc / 50% pet ether 495 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 B1 Cla 96 Cl y-NH ^{Me -} C ( ^O ) ^- , ^N 244- 245 0.39 5% MeOH / 45% EtOAc / 50% pet ether 529 (M + H) &lt; + &gt; (HPLC ES-MS) A6 A7 B1 Cla 97 0 CI y NH rk ^Me - \ / ⁰ / ^N 220- 221 0.25 5% MeOH / 45% EtOAc / 50% pet ether 529 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 B1 Cla 98 \ θ \ —C)> y-NH \ = (/ = (Me ^Ó Á_ /) 0.27 5% MeOH / 45% EtOAc / 50% pet ether 495 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 B1 Cla • 99 0 γ-NH-0 ° hQ ^B 180- 181 0.52 5% MeOH / 45% EtOAc / 50% pet ether 509 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A7 B1 Cla 100 ALIGN! 0 γ-NH 162- 165 A2 A7 B1 Cla

Table 7.

9999 • · »· 99 9 9 9 99 9 9 9 • 9 9 9 9 9 9 9 9 99 • 9 9 9 • 9 9 • 9 9 · 99 9 9 9 99 • · 99 99

More ureas

Example R Melting point (° C) HPLC (min) TLC ^R r TLC System MS {ionization] Synthesis method 101 to ^HH 162- 165 Al A2 C3 102 0 A ⁰ ^ ^ζ ° ν ^{/ 5% ΝΗ} Me i HH 0.10 50% EtOAc / 50% hexane 442 (M + H) &lt; + &gt; (HPLC ES-MS) A2 A4 C2d 103 ά jQr * ÍJY o 125- 130 0.24 40% EtOAc / 60% hexane 512 (M + H) &lt; + &gt; (FAB) A2 C2b

The synthesis of the compound of the above examples can be repeated with similar success by replacing the generically or specifically described reactants and / or reaction conditions of the present invention in the above-described examples.

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

Claims (39)

1. A compound of formula I: A-D-B (I) 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: -IXM-11jq, wherein L is a 5- or 6-membered cyclic structure bonded directly to D, L ¹ comprises a substituted cyclic moiety having at least 5 members, M is a moiety forming a bridge having at least one atom, index 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 nitrogen, oxygen and sulfur; and B is a substituted or unsubstituted, up 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 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 having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms and optionally substituted with halogen to per halogen, 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 atoms 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 optionally substituted with halogen; R _x is R _z or NR _and R b, wherein R _a and R b are a) independently hydrogen, 99 99 9 9 9 9 9 9 9 9 9 99 99 999 99 99 · 9999 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 optionally substituted with halogen; -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 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 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 a 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 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 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 0-3; 9 9 9 9 9 99 99 99 9 9 9 9 9 9 9 9 9 ♦ 9 9 9 9 99 99 999 999 99 99 99999 where 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 contain 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; 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, wherein Q is -O-, -S -, -N (R ⁷⁾ -, - (CH2) m-, -C (0) -, -CH (OH) -, - (CH2) m O-, - (CH2) S-, - (CH2) mN ^(R7) -, -O (CH2) _m ^and CHX, ^and -CX 2-, -S- (CH2) m- and -N ^(R7) (CH2) _m -, wherein m = 3 and X ^a is halogen; and Ar is a 5- or 6-membered aromatic structure containing 0-2 members of a group consisting of nitrogen, oxygen and sulfur, which is optionally substituted with halogen except for total halogen substitution and optionally substituted with _Zn i, where nl is O 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 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 R ⁷ is as defined above. The compound of claim 1, wherein: R _y is hydrogen, C walkyl, Cioalkoxy group, _C3 .iocykloalkyl having 0-3 heteroatoms, _C2 .ioalkenyl, Ci.ioalkenoyl C ₆ .i ₂ aryl, C ₃ -i2hetaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, C7. ₂ 4aralkyl, Cy. ₂ 4alkaryl substituted CMOalkyl substituted Cpioalkoxy group, a substituted C ₃ .i ₀ cycloalkyl having 0-3 heteroatoms selected from the group consisting of N, S and O, substituted with CO-Cuaryl, ·· * · Φ · ·· ► * 9 9 99 99 9 9 9 9 9 9 9 9 99 99 999 99 99 99999 substituted C3-12hetaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted C7-24 alkaryl or substituted C7-C24 aralkyl, when R _y is a substituted group, it is halogen substituted except for perhalogen , R _z is hydrogen, C 1-10 alkyl, C 10 alkoxy, C 3-10 cycloalkyl having 0-3 heteroatoms, C 2-10 alkenyl, C 1-10 alkenoyl, C 6-12 aryl, C 3-12 heteroaryl having 1-3 heteroatoms selected from the group consisting of , S, N and O, C 7-24 alkaryl, C 7-24 aralkyl, substituted C 1-10 alkyl, substituted C 1-10 alkoxy, substituted C 6 -C 14 aryl, substituted C 3 -C 10 cycloalkyl having 0-3 heteroatoms selected from the group consisting of S, N and O, substituted C 3 -i2hetaryl having 1-3 heteroatoms selected from the group consisting of S, N and O, substituted C7 -C24 alkaryl or substituted C7-C24aralkyl, wherein when R is _a substituted group, it is substituted by halogen, up to perhalo allogen, hydroxy, C 1-10 alkyl, C 3 -C 12 cycloalkyl having 0-3 heteroatoms selected from the group consisting of O, S and N, C 3 -C 12 hetaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, C 1-10 alkoxy, C 6 -C 6 aryl, C 1 -C 6 halo substituted alkyl up to perhaloalkyl, C 6 -C 6 halo substituted aryl up to perhalogenaryl, C 3 -C 6 halo substituted cycloalkyl up to perhalo-cycloalkyl having 0-3 heteroatoms selected from the group consisting of with N, S and O, halogen substituted C3-C12hetaryl up to perhalohetaryl having 1-3 heteroatoms selected from the group consisting of O, N and S, halogen substituted C7C24aralkyl up to perhalogenaralkyl, halogen substituted C7-C24alkaryl up to perhalogenalkaryl, and -C (O) R _g, R _a and R b are a) independently hydrogen, a 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 10-10 alkenyl, C 6-10 aryl, C 3-12 heteroaryl having 1-3 heteroatoms selected from the group consisting of O, N and S, C 3-12 cycloalkyl having O 3 heteroatoms selected from the group consisting of N, S and O, C 7-24 aralkyl, C 2 -C 24 alkaryl, substituted C 1-10 alkyl, substituted C 1-10 alkoxy, substituted C 3-8 iocykloalkylu having 0-3 heteroatoms selected from the group consisting of N, S and O, substituted C3-i2arylu substituted C3.i2hetarylu having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted C ₇ .24aralkylu , • · · · • • • ·· • * fc fc · • fc • • • fc • • • · • • fc 9 • 9 fc • 9 • · • fc 9 · • fc · • fc ·· ·· substituted C 7-24 alkaryl, wherein when R _a and R b are a substituted group, it is substituted with halogen up to perhalogen, hydroxy, C 1-10 alkyl, C 3. ncycloalkyl having 0-3 heteroatoms selected from the group consisting of O, S and N, C3. 12-heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, C 1-10 alkoxy, C 6-10 aryl, C 6-10 substituted alkyl up to perhaloalkyl, C 6 -C 10 halogen substituted aryl up to perhalogenaryl, C 3-6 halo substituted cycloalkyl having 0-3 heteroatoms selected from the group consisting of N, S and O, except perhalo-cycloalkyl, halogen-substituted C3-C12hetaryl up to perhalo-heteroaryl, halogen-substituted C7-C24 aralkyl up to perhalogenaralkyl, halogen-substituted C7-C24alkaryl up to perhaloalkaryl and ) R _g; or -OSi (Rf) 3, wherein Rf is hydrogen, C1-10alkyl, C1-10alkoxy, C3Ciocycloalkyl having 0-3 heteroatoms selected from the group consisting of O, S and N, C6C12aryl, C3-C12hetaryl having 1-3 heteroatoms selected from the group consisting of O, S and N, C 7-24 aralkyl, substituted C 1-10 alkyl, substituted C 1 -C 10 alkoxy, substituted C 3 -C 12 cycloalkyl having 0-3 heteroatoms selected from the group consisting of O, S and N, substituted C 3 -C 12 hetaryl having 1-3 heteroatoms selected from the group consisting of O, S, and N, substituted C 6-12 aryl, and substituted C 7-24 alkaryl, wherein when R f is a substituted group, it is substituted with halogen up to perhalogen, hydroxy, C 1-10 alkyl, C 3-12 cycloalkyl having 0-3 heteroatoms selected from the group consisting of O, S and N, C 3-12 heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, C 1-10 alkoxy, C 6-14 aryl, C7-C24 alkaryl, C7-C24 aralkyl , Ci. 6-halo-substituted alkyl up to perhaloalkyl, C 6 -C 6 halo-substituted aryl up to perhaloaryl, C 3 -C 12 halo-substituted cycloalkyl having 0-3 heteroatoms selected from the group consisting of N, S and O, except perhalo-cycloalkyl, halo-substituted C 3 -C 12 heteroaryl on perhalogenheteraryl, halosubstituted C ₇ -C24aralkylem until perhalogenaralkyl, halo substituted C7 -C24 alkaryl up to perhalogenalkaryl and -C (O) R _g, or b) R _a and R b together form a 5-7 membered heterocyclic structure having 1-3 heteroatoms selected from the group consisting of N, S and O or substituted ···· • <·· ·· • ·· • • • • • • ·· • • • ·· * • · • • • 9 • • • · » · «· ·· ♦ ♦ A 5-7 membered heterocyclic structure having 1-3 heteroatoms selected from the group consisting of N, S and O, substituents selected from the group consisting of halogen through perhalogen, hydroxy, C 1-10 alkyl, C 3-12 cycloalkyl having 0-3 heteroatoms selected from the group consisting of O, S and N, C 3-12 heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, C 1-10 alkoxy, C 6-12 aryl, C 7 C 24 alkaryl, C 2 -C 24 aralkyl, halogen substituted C 1 6alkyl up to perhaloalkyl, halogen substituted C 6 -C 6 aryl to perhalogenaryl, halogen substituted C 3 -C 12 cycloalkyl having 0-3 heteroatoms selected from the group consisting of N, S and O, up to perhaloencycloalkyl, halogen substituted C 3 -C 4 hetaryl to perhaloheteraryl, substituted C 2 -C 24 aralkyl to perhaloaralkyl, halogen substituted C 7 -C 24 alkaryl to perhaloalkaryl and C (O) R _g , 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 attached to the L moiety to form a cyclic structure with at least 5 members, wherein the substituents substituted by C 1 -C 5 divalent alkylene groups are selected from the group consisting of halogen, hydroxy, C 1-10 alkyl, C 3-12 cycloalkyl having 0-3 heteroatoms selected from the group consisting of O, S and N, C 3-12 heteroetaryl having 1-3 heteroatoms selected from the group consisting of with from N, S and O, C 1-10 alkoxy, C 6-14 aryl, C 7 -C 24 alkaryl, C 7 -C 24 aralkyl, C 1-6 halo substituted alkyl to perhaloalkyl, C 6 -C 6 halo substituted aryl to perhaloaryl, C 3 -C 6 halo substituted cycloalkyl having 0 -3 heteroatoms selected from the group consisting of N, S and O, up to perhalo-cycloalkyl, halo-substituted C 3 -C 4 hetaryl to perhalo-heteroaryl, halo-substituted C 7 -C 24 aralkyl, and perhalogenaralkylu, a halo substituted C7 -C24 alkaryl and perhalogenalkarylu and -C (O) R _g, wherein R _g is CMOalkyl; -CN, -CO ₂ Rd, -OR a, -SR d, -NO 2, -C (O) R e, -NR d R e, -, NR d C (O) OR e and -NR d C (O) R e, and R a and R b are independently selected selected from the group consisting of hydrogen, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl having 0-3 heteroatoms selected from the group consisting of O, N and S, C 6-12 aryl, C 3-10 hetaryl with 1-3 heteroatoms selected from the group consisting of O, N and S and C7c 4aralkylu _2, C ₂ -C ₇ 4alkarylu, halosubstituted Cl-Clo alkyl, up to φ φ φ · halosubstituted C3 Ciocykloalkylu having 0-3 heteroatoms selected from the group consisting of O, N and S, up to perhalogen substituted C 6 -C 14 aryl, up to perhalogen substituted C 3 -C 12 heteroaryl having 1-3 heteroatoms selected from the group consisting of O, N, and S, halogen substituted C 7 -C 24 alkaryl to perhaloalkaryl, and up to perhalogen substituted C7-C24aralkyl, 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-Clo alkyl, _Ci-Cioalkoxy group -Cioalkenylu C _2, C Cioalkenoylu, _C3 -Ciocykloalkylu having 0-3 heteroatoms selected from the group consisting of O, S and N, CN-Cuarylu, C7 -C24 alkaryl, C7C24aralkylu, C ₃ -C ^ heteroaryl having 1-3 heteroatoms selected from the group consisting of O, N and S, C2-C4 alkheteroaryl having ₃ 1-3 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 ₆ cycloalkyl having 0-3 heteroatoms selected from the group consisting with O, N and S, substituted C 6 -C 4 aryl, substituted C ₃ -C ₁₂ heteroaryl having 1-3 heteroatoms selected from the group consisting of O, N and S, substituted C 7 -C _2-4 aralkyl, s substituted C 7 -C 24 alkaryl, substituted C 4 -C ₂ alkheteroaryl having 1-3 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 0-3 heteroatoms selected from the group consisting of O, S and N, C 6 - C | ₄ aryl, _C3 -Ci3hetarylu having 1-3 heteroatoms selected from the group consisting of O, N and S, C7 Ci4alkarylu, C7C24aralkylu, C4 -C23 alkheteroaryl having 1-3 heteroatoms selected from the group consisting of O, N and S, up to perhalogen substituted C ₃ -C ₁₀ alkyl, up to perhalogen substituted C ₃ -C ₁₀ cycloalkyl having 0-3 heteroatoms selected from the group consisting of O, N and S, up to perhalogen substituted C 6 -C 10 aryl, up to perhalogen substituted C 3 -C 13 heteroaryl having 1-3 heteroatoms selected from the group consisting of O, N and S, up to perhalogen substituted C 2 -C 24 aralkyl, up to perhalogen substituted C 7 -C 24 alkaryl, and up to perhalogen substituted C 4 -C 23 alkheteroaryl; • φ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ 96 each Z is independently selected from the group consisting of -CN, -CO ² R 67, -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 Oalkyl, C 1 -C 10 alkoxy, C 2 -C 10 alkenyl, C 1 -C 10 alkenoyl, C 3 -C 10 cycloalkyl having 0-3 heteroatoms selected from the group consisting of O, N and S, CeCuaryl, C 3 -C 1-3 heteroaryl having 1-3 heteroatoms selected from the group consisting of O, N and S, C 7 -C 24 alkaryl, C 2 -C 24 aralkyl, C 4 -C 23 alkheteroaryl having 1-3 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 0-3 heteroatoms selected from the group consisting of O, N and S, substituted C 6 -C 12 aryl, substituted C 7 - C 24 alkaryl, substituted C 2 -C 24 aralkyl and substituted C 4 -C 23 alkheteroaryl having 1-3 heteroatoms selected from the group consisting of O, N and S, and when Z is a substituted group, one or more substituents are selected from the group consisting of -CN , -CO2R 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 . The compound of 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 = 1-3, 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 ortho by the -OH group. The compound of claim 1, wherein the cyclic structures B and L bonded directly to D are not substituted at the ortho position of the moieties having ionizable hydrogen and pK _and 10 or less. The compound of claim 1, wherein B of formula I is substituted or unsubstituted A 6-membered aryl moiety or a 6-membered hetaryl moiety, wherein said hetaryl moiety having 1-4 members selected from the group of hetaryl atoms consisting of nitrogen, oxygen and sulfur atoms has a hetaryl moiety 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, substituted pyrimidinyl groups 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 pyrridyl 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 halogen-substituted phenyl 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 1-4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur atoms have 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. * ♦ * * 9 • Λ 9 Λ «« « 9 9 The compound of claim 1, wherein said substituted L ¹ cyclic moiety comprises a 5-6 membered aryl moiety or a hetaryl moiety, wherein said hetaryl moiety comprises 1-4 members selected from the group of heteroatoms consisting of a nitrogen, oxygen, and open. 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 ¹ 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 a phenyl, pyridinyl or pyrimidinyl group. 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) -, - (CH ₂ ) _m -, -C (0) -, -CH (OH) -, - (CH _{2) m} -O-, - (CH _{2) m} -S-, - (CH _{2) m} -N ^(R7) -, -O (CH 2 ) m-CHX ^and -, -CX ^and 2-, -S (CH ₂ ) _m - and -N (R ⁷ ) (CH ₂ ) _m -, where m = 1-3, X ^a is halogen and R is 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 up to perhalogen. The compound of claim 15, wherein M is one or more bridging groups selected from the group consisting of -O-, -S-, -N (R) -, - (CH ₂ ) _m -, -C (0) -, -, -, -, -, -, - 9 9 ·· 9 · In »· · ··· -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 -, where m = 1-3, 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 perhalogen. The compound of claim 16, wherein M is one or more bridging groups selected from the group consisting of -O-, -S-, -N (R) -, - (CH ₂ ) _m -, -C (0) -, -CH (OH) -, - (CH _{2) m} -O-, - (CH _{2) m} -S-, - (CH _{2) m} -N ^(R7) -, -O (CH 2 ) m-CHX ^and -, -CX ^and 2-, -S (CH ₂ ) _m - and -N (R ⁷ ) (CH ₂ ) or a carbon-based moiety having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of from N, S and O and optionally substituted with halogen up to perhalogen. The compound of claim 17, wherein M is one or more bridging groups selected from the group consisting of -O-, -S-, -N (R) -, - (CH ₂ ) _m -, -C (0) -, -CH (OH) -, - (CH _{2) m} -O-, - (CH _{2) m} -S-, - _{(CH2) ffl} -N ^(R7) -, -0 (CH2 ) m-CHX ^and -, -CX ^and 2-, -S (CH ₂ ) _m - and -N (R ⁷ ) (CH ₂ ) _m -, where m = 1-3, X ^a is halogen and R is 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 up to perhalogen. 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, to perhalogen substituted C 1 -C 10 alkyl, -CN, -OH, halogen, C 1 -C 10 alkoxy, and to perhalo-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. The compound of claim 18, wherein L ¹ is additionally substituted one to three times with one or more substituents selected from the group consisting of C 1-4. 100 • 4 ♦ ·· 4 * · ·· 4 4 4 4 44 • 4 4 44 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 perhalo 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 perhalo substituted C 1 -C 10 alkyl, -CN, -OH, halogen, C 1 -C 10 alkoxy and up to perhalo substituted C 1. -C 10 alkoxy groups. 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 perhalo substituted C 1 -C 10 alkoxy groups. The compound of claim 1, wherein L ¹ is substituted with -C (O) R _X. The compound of claim 1, wherein L ¹ is substituted with -SO ² R X. The compound of claim 1, wherein L ¹ is substituted only with -C (O) R _X. The compound of claim 1, wherein L ¹ is substituted only with -SO 2 R _X. The compound of claim 1, wherein L ¹ is substituted with -C (O) R _X or SO 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 -SC 2 R _x , wherein R _x is NR _and R b and the substituents R _a and R _b are a) independently hydrogen, 101 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 and carbon-based substituents having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of and z are N, S and O 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 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; or b) R _a and R b together form a 5-7 membered heterocyclic structure having 1-3 heteroatoms selected from the group consisting of N, S and O, or a substituted 5-7 membered heterocyclic structure having 1-3 heteroatoms selected from the group consisting of of N, S and O substituted by 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 by 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 attached to the L moiety to form a cyclic structure with at least 5 members, wherein the substituted C 1 -C 8 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 N, S and O and optionally substituted with halogen. The compound of claim 18, wherein L * is substituted with -C (O) R x 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 and carbon-based substituents having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of N, S and O; are optionally substituted with halogen. • 1 » 102 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 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 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 having 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 being optionally substituted with halogen. 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 having 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 being optionally substituted with halogen. 8. The compound of formula: 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- (ML ¹⁾ _q, where L is a 6 membered aryl moiety or a 6 membered hetaryl moiety bound directly to D, L comprises a substituted cyclic moiety having at least 5 of members, M is a bridge forming group having at least one atom, index q is an integer taking • 103 values 1-3; and each cyclic structure of L and L ¹ contains 0-4 members of a group consisting of nitrogen, oxygen and sulfur; and B is a substituted or unsubstituted, up 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 with at least one substituent selected from the group consisting of -SChRx, -C (O) R _X and -C (NR _y ) R _z , R _y 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 atoms and optionally substituted with halogen up to 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 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 with halogen; R _x is R _z or NR _and R b, where R _a and R b are (a) independently of hydrogen, 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 n-carbon 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 -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: 104 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 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 5-7 membered heterocyclic structure having 1-3 heteroatoms selected from the 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 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, thereby forming a cyclic structure with at least 5 members, wherein the substituents substituted with C 1 - C 5 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 a carbon-based moiety having up to 24 carbon atoms optionally containing heteroatoms selected from the group consisting of a nitrogen atom, 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 possible; wherein each R ⁷ is independently selected from hydrogen; or 105 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 Q is -O-, -S-, -N (R ⁷ ) -, - (CH ₂ ) - _m , -C (O) -, -CH (OH) -, - (CH ₂ ) _m O-, - (CH ₂ ) _m S 5 - (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 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 Z _n j, where the index n1 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 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 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 = 1-3 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- (ML ^] ) q, wherein L is a substituted or unsubstituted phenyl or peritoneal moiety bonded directly to D, L ¹ contains a substituted phenyl, peritoneal, or pyrimidyl moiety; 106 Λ · · ♦ Μ is a bridging group having at least one atom, index q being an integer of 1-3; 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 consisting of nitrogen, oxygen and sulfur and optionally substituted with halogen up to 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 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 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 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 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 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 107 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 5-7 membered heterocyclic structure having 1-3 heteroatoms selected from the 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 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 substituted by C 1 -C 5 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; or 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 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 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) ^OR7 and halogen, it being possible to total halogen substitution; 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, X> X 108 wherein Q is -Ο-, -S-, -N (R ⁷ ) -, - (CH ₂ ) - _m , -C (O) -, -CH (OH) -, - (CH ₂ ) _m O- , - (CH _{2) m} S9 - (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 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 a 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 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 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 9 - (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 the index m = 1-3 and X ^a is halogen. The compound of claim 38, wherein the cyclic structures B and L bonded directly to D are not substituted to 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 of moieties having ionizable hydrogen and a pKa of 10 or less. The compound of claim 39, wherein the cyclic structures B and L bonded directly to D are not substituted to the ortho position by -OH. • · 109 The compound of claim 39, wherein the cyclic structures B and L bonded directly to D are not substituted at the ortho position of moieties having ionizable hydrogen and a pKa 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 groups 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 groups and up to perhalo substituted C 1 -C 10 alkoxy groups. The compound of claim 38, wherein L ¹ 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 R b and R _a and R b are independently hydrogen and 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 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 47, wherein R _x is NR _and R b and R _a and R b are independently hydrogen and a carbon-based moiety having up to 30 carbon atoms, optionally containing heteroatoms selected from the group consisting of N, S and O and And i 110 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 (tosylate salt), 1-naphthalenesulfonic, 2-naphthalenesulfonic, acetic, trifluoroacetic, 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 cations, 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 (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, 2-naphthalenesulfonic, acetic, trifluoroacetic, malic, 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 cations, 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 111 (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, acetic, trifluoroacetic, malic, 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 cations, ammonium-substituted aliphatic moieties and ammonium-substituted aromatic moieties. 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, p-toluenesulfonic (tosylate salt), 1-naphthalenesulfonic, 2-naphthalenesulfonic, acetic, trifluoroacetic, , 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 cations, 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, t-toluenesulfonic (tosylate), 1-naphthalenesulfonic, 2-naphthalenesulfonic, acetic, trifluoroacetic, malic, tartaric, citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic and mandelic acids; and 112 b) acidic salts of organic and inorganic bases containing cations selected from the group consisting of alkali cations, alkaline earth cations, ammonium cations, ammonium-substituted aliphatic moieties and ammonium-substituted aromatic moieties. 55. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt of a compound of the formulas and a physiologically acceptable carrier. 56. A pharmaceutical composition comprising a compound according to claim 2 in accordance with Formula I, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. 57. A pharmaceutical composition comprising a compound according to claim 33 identical 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 according to 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-methoxyphenyl ureas 5- (trifluoromethyl) -2-phenylurea 3- (trifluoromethyl) -4-chlorophenyl urea 3- (trifluoromethyl) -4-bromophenylurea from above listed tables from above listed tables from above listed tables from above listed tables 2; 3; 4; 5; AND Xj i 113 5- (trifluoromethyl) -4-chloro-2-methoxyphenylureas from Table 6 above; and ureas 101-103 listed in Table 7 above. 61. A compound selected from the group consisting of 3- N -butylphenyl ureas: N - (3-tert-butylphenyl) - N - (4- (3- (N -methylcarbamoyl) phenoxy) phenyl urea and N - (3-tert-butylphenyl) -N- (4- (4 acetylphenoxy) phenyl urea; 5- (tert-Butyl-2-methoxyphenylureas): N - (5- tert -butyl-2-methoxyphenyl) - N - (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea, N - (5-tert-butyl-2-methoxyphenyl) - N - ( 4- (1-oxoisoindolin-5-yloxy) phenyl) urea, N- (5- tert -butyl-2-methoxyphenyl) -N- (4- (4-methoxy-3- (7-methylcarbamoyl) phenoxy) phenyl) urea and N- (5-tert-butyl-2-methoxyphenyl) -N '- (4- (3- (methylcarbamoyl) 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) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -N- (4- (2-carbamoyl-4pyridyloxy) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -N- (4) - (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -N- (4- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, ^N - (2-methoxy-5- (trifluoromethyl) phenyl) -7V- (2-chloro-4- (2- (7V-methylcarbamoyl) (4pyridyloxy)) phenyl) urea and ^N - (2-methoxy-5- (trifluoromethyl) phenyl) -7V- (3-chloro-4- (2- (7V-methylcarbamoyl) (4pyridyloxy)) phenyl) urea; 4-chloro-3- (trifluoromethyl) phenyl urea: N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (3- (2-carbamoyl-4pyridyloxy) phenyl) urea; · ··· ♦ 9 ₉ 9 ₉ 9 ₉ 9 ₉ 9 ₉ 9 114 N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (3- (2- (N-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- (4- (2- (N-methylcarbamoyl) -4pyridyloxy) phenyl) urea; 4-bromo-3- (trifluoromethyl) phenyl lmočovin N- (4-bromo-3- (trifluoromethyl) phenyl) -N- (3- (2- ^{(7-methylcarbamoyl)} -4pyridyloxy) phenyl) urea,? / - (4-bromo-3- (trifluoromethyl) phenyl) -N- (4- (2- (N-methylcarbamoyl) -4pyridyloxy) phenyl) urea, N - (4-bromo-3- (trifluoromethyl) phenyl) - N - (3- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, AA (4-bromo-3- (trifluoromethyl) phenyl) -N- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea and N- (4-bromo-3- (trifluoromethyl) phenyl) -N- (3-chloro-4- (2- (N-methylcarbamoyl) (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) -4pyridyloxy) (phenyl) urea N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N- (4- (2- (N-methylcarbamoyl) -4pyridyloxy) phenyl) urea, N - (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -7 '- (2-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea; and N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea. 62. A method of treating carcinogenic cell growth mediated by raffinase, comprising administering a compound of formula I according to claim 1. 115 63. A method of treating carcinogenic cell growth mediated by raffinase, comprising administering a compound of formula I according to claim 33. 64. A method of treating carcinogenic cell growth mediated by raffinase, 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 rafkinase comprising administering a compound selected from the group consisting of: 3-tert-Butylphenyl ureas of Table 1 above; 5- tert -Butyl-2-methoxyphenyl ureas 5- (trifluoromethyl) -2-phenylurea 3- (trifluoromethyl) -4-chlorophenyl urea 3- (trifluoromethyl) -4-bromophenylurea from above listed tables from above listed tables from above listed tables from above listed tables 5- (trifluoromethyl) -4-chloro-2-methoxyphenylmethyl of Table 6 above; and ureas 101-103 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- tert -butylphenylureas: N- (3- tert -butylphenyl) -N- (4- (3- (N-methylcarbamoyl) phenoxy) phenyl urea) and 77- (3- tert -butylphenyl) -TV- (4- ( 4-acetylphenoxy) phenyl urea; 5-Ze / 7-butyl-2-methoxyphenyl ureas: N - (5- tert -Butyl-2-methoxyphenyl) - N - (4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea, N - (5- (N-Butyl-2-methoxyphenyl) -N '- (4- (1-oxoisoindolin-5-yloxy) phenyl) urea; • 9 • 9 • 9 • 9 • 9 • 9 9 9 9 · N- (5- tert -butyl-2-methoxyphenyl) -N- (4- (4-methoxy-3- (N-methylcarbamoyl) phenoxy) phenyl) urea; and N - (5- tert -butyl-2-methoxyphenyl) - N - (4- (3- (N-methylcarbamoyl) 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) -7- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N - (2-methoxy-5- (trifluoromethyl) phenyl) - N - (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea, ^N - (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (4- (2- (7V-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -N- (4- (2- (N-methylcarbamoyl) -4-pyridylthio) phenyl) urea, N- (2-methoxy-5- (trifluoromethyl) phenyl) -7V- (2-chloro-4- (2- ^{(N-methylcarbamoyl)} (4pyridyloxy)) phenyl) urea and ^N - (2-methoxy-5- (trifluoromethyl) phenyl) -N '- (3-chloro-4- (2- (7V-methylcarbamoyl) (4pyridyloxy)) phenyl) urea; 4-chloro-3- (trifluoromethyl) phenyl urea: N- (4-chloro-3- (trifluoromethyl) phenyl) -7- (3- (2-carbamoyl-4-pyridyloxy) phenyl) urea, N - (4-chloro-3- (trifluoromethyl) phenyl) -7- (3- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (4- (2-carbamoyl-4-pyridyloxy) phenyl) urea and N- (4-chloro-3- (trifluoromethyl) phenyl) -N- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea; 4-bromo-3- (trifluoromethyl) phenyl urea: N - (4-bromo-3- (trifluoromethyl) phenyl) - N - (3- (2- (N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea, .. «Ζ .. .. .. .. .. .. .. .. .. .. .. 117 N- (4-bromo-3- (trifluoromethyl) phenyl) -N- (4- (2- (N-methylcarbamoyl) -4-pyridyloxy) phenyl) urea, N- (4-bromo-3- (trifluoromethyl)) phenyl) - N - (3- (2- (N -methylcarbamoyl) -4-pyridylthio) phenyl) urea, N - (4-bromo-3- (trifluoromethyl) phenyl) -N- (2-chloro-4- (2 - (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea a N - (4-bromo-3- (trifluoromethyl) phenyl) - N - (3-chloro-4- (2- (N -methylcarbamoyl) (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) -4pyridyloxy)) phenyl) urea 7V- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -7V- (4- (2- ^{(N-methylcarbamoyl)} -4pyridyloxy) phenyl) urea, N - (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) - N - (2-chloro-4- (2- (N -methylcarbamoyl) (4-pyridyloxy)) phenyl) urea; and N- (2-methoxy-4-chloro-5- (trifluoromethyl) phenyl) -N- (3-chloro-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea.