AU2004200722A1 - Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors - Google Patents

Description

Our Ref: 12225931 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Bayer Corporation 100 Bayer Road Pittsburgh Pennsylvania 15205-9741 United States of America Address for Service: Invention Title: DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street Sydney, New South Wales, Australia, 2000 c-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors The following statement is a full description of this invention, including the best method of performing it known to me:- 5951 co-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors This application is a divisional of Australian Patent Application No. 25016/00, the entire disclosure of which is incorporated herein by reference.

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

Background of the Invention The p21' oncogene is a major contributor to the development and progression of human solid cancers 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, unmutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avruch et al. Trends Biochem. Sci. 1994, 19, 279-83).

Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTPbound activated and a GDP-bound resting form is strictly controlled by ras' endogenous GTPase activity and other regulatory proteins. In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to the cancerous growth of the cells which carry these mutants (Magnuson et al. Semin. Cancer Biol. 1994. 5, 247-53). It has been shown that inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administration of deactivating antibodies to rafkinase or by co-expression of dominant negative raf kinase or dominant negative MEK. the substrate oft WO 00/42012 PCT/USOO/00648 raf kinase, leads to the reversion of transformed cells to the 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) have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes.

Similarly, inhibition of rafkinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996, 2, 668-75).

Summary of the Invention The present invention provides compounds which are inhibitors of the enzyme raf kinase.

Since the enzyme is a downstream effector of p 2 1 ras, the inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compounds are useful in the treatment of human or animal solid cancers, murine cancer, since the progression of these cancers is dependent upon the ras protein signal transduction cascade and therefore susceptible to treatment by interruption of the cascade, by inhibiting raf kinase. Accordingly, the compounds of the invention are useful in treating cancers, including solid cancers, such as, for example, carcinomas of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders myeloid leukemia) or adenomas villous colon adenoma).

The present invention therefore provides compounds generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit the raf kinase pathway. The invention also provides a method for treating a raf mediated disease state in humans or mammals. Thus, the invention is directed to compounds which inhibit the enzyme rafkinase and also compounds, compositions and methods for the treatment of cancerous cell growth mediated by raf kinase wherein a compound of Formula I is administered or pharmaceutically acceptable salt thereof.

A-D-B (I) In formula I. D is -NH-C(O)-NH-, WO 00/42012 PCT/USOO/00648 A is a substituted moiety of up to 40 carbon atoms of the formula: )q where L is a 5 or 6 membered cyclic structure bound directly to D, L' comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L i contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L' is substituted by at least one substituent selected from the group consisting 10 of-SO 2 Rx, and -C(NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally halosubstituted, up to per halo, Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; Rx. is Rz or NRaRb where Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen, or -OSi(Rr) 3 where Rr is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or WO 00/42012 PCT/USOO/00648 b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0 substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or c) one of Ra or Rb is a C -C 5 divalent alkylene group or a substituted CI- Cs divalent alkylene group bound to the moiety L to form a cyclic structure with at least members, wherein the substituents of the substituted Ci-C 5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; where B is substituted, L is substituted or L' is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of-CN, -CO 2

R

7

-C(O)NR

7

R

7

-C(O)-R

7

-NO

2

-OR

7

-SR

7

-NR

7

R

7

-NR

7 C(0)OR 7

-NR

7

C(O)R

7 -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -C0 2

R

7

-C(O)R

7 -C(O)NR 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 per-halo; with each R 7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, wherein Q is -N(R 7

-(CH

2

-(CH

2

-(CH

2 )mS-,

-(CH

2 )mN(R 7

-O(CH

2 CHXa-, -CX3 2

-S-(CH

2 and -N(R 7

)(CH

2 where m= 1-3, and Xa is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO z -C(O)NR R NO,, -OR7. SR 7

-NR'R

7 -NR'C(0)OR 7 -NR C(O)R 7 and a carbon based moiety of up to WO 00/42012 PCTfUJSOO/00648 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents selected from the group consisting of -CN, -CO2R, COR', -C(O)NR

-NO

2

-NR

7 R -NR and -NR 7 C(O)OR With R' as defined above.

In formula I, suitable hetaryl groups include, but are not limited to, 5-12 carbon-atom aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in which one or more, 1-4 carbon atoms in one or more of the rings can be replaced by oxy .gen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. For example, B can be oio 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 2- or 3 -pyrrolyl, 4- or or 5-pyrazolyl, 4- or 5-oxazolyl, 4- or 5-isoxazolyl, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazoly], 3- or 4-pyridyl, 5- or 6 -pyrimidinyl, l, 2 ,3-triazol-l-, or yl, 1,2,4-triazol-1-, or -5-yl, 1- or 5-tetrazolyl, l, 2 ,3-oxadiazol-4. or -5-yl, 1,2,4oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4thiadiazol-2- or -5-yl, I,3,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, or 6-2H-thiopyranyl, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 6- or 7-benzofuryl, 6- or 7-benzothienyl, 6- or 7-indolyl, 1 2-, 4- or 5-benzimidazolyl, 6- or 7-benzopyrazolyl, 6- or 7-benzoxazolyl, 5- 6- or 7-benzisoxazolyl, 6- or 7 -benzothiazolyl, 6- or 7benzisothiazolyl, 6- or 7 -benz-1,3-oxadiazolyl, 7- or 8-quinolinyl, 8- isoquinolinyl, or 9-carbazolyl, 8or 9-acnidinyl, or 7- or 8-quinazolinyl, or additionally optionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, I methyl-3-pyrryl, 1 -methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-I ,2,4-thiadiazo 1-2y 1 Suitable alkyl groups and alkyl portions of groups, alkoxy, etc. throughout' include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers such as isopropyl, isobuty[, sec-butyl, terr-butyl, etc.

m ~Suitable aryl groups \.vhich do not contain heteroatomns icue o xml.pe and I- aind 2-1naphth vj.

WO 00/42012 PCT/US00/00648 The term "cycloalkyl", as used herein, refers to cyclic structures 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", as used herein also includes saturated heterocyclic groups.

Suitable halogen groups include F, Cl, Br, and/or I, from one to per-substitution (i.e.

all H atoms on a group replaced by a halogen atom) being possible where an alkyl group is substituted by halogen, mixed substitution of halogen atom types also being possible on a given moiety.

The invention also relates to compounds per se, of formula I.

The present invention is also directed to pharmaceutically acceptable salts of formula I.

Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, -methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations Li+ Na 4 or alkaline earth cations Mg 2 Ca 2 or Ba+2), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabiclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

A number of the compounds of Formula I possess asymmetric carbons and can therefor exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art. The present invention encompasses any isolated racemic or optically active form of compounds described in Formula I which possess raf inhibitory activity.

WO 00/42012 PCT/US00/00648 General Preparative Methods The compounds of Formula I may be prepared by the use of known chemical reactions and procedures, some from starting materials which are commercially available. Nevertheless, general preparative methods are provided below to aid one skilled in the art in synthesizing these compounds, with more detailed examples being provided in the Experimental section which follows.

Substituted anilines may be generated using standard methods (March. Advanced Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H 2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH 4 (Seyden-Penne.

Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many methods exist for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)).

H

2 catalyst (eg, Ni, Pd, Pt) ArNO 2 m ArNH 2

M()

(eg. Fe, Sn, Ca) Scheme I Reduction of Nitroaryls to Aryl Amines Nitroaryls are commonly formed by electrophilic.aromatic nitration using HNO-,. or an alternative NO- source. Nitroaryls may be further elaborated prior to reduction. Thus.

nitroaryls substituted with WO 00/42012 PCT/US00/00648

HNO

3 Ar-H ArNO 2 potential leaving groups F, Cl, Br, etc.) may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme II).

2N F ArSH R base 1 O 2

N

S-Ar 0R 02S Br-Ar 2 R2 CuO base 3 Scheme 1 Selected Nucleophilic Aromatic Substitution using Nitroaryls Nitroaryls may also undergo transition metal mediated cross coupling reactions. 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 reactions, exemplified below), aryltins (Stille reactions) or arylzincs (Negishi reaction) to afford the biaryl 0 2 N ArB(OR') 2 0 2

N

^X Ar R Pd(Q) RA 4 Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl chloride on treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source, such as KF then affords sulfonyl fluoride Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, such as tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the corresponding tritluoromethylsulfone Alternatively, sulfonyl chloride 7 may be reduced to the arenethiol for example with zinc amalgum. Reaction of thiol 10 with CHCIF- in the WO 00/42012 PCT/USOO/00648 presence of base gives the difluoromethyl mercaptam which may be oxidized to the sulfone (12) with any of a variety of oxidants, including CrO 3 -acetic anhydride (Sedova et al.

Zh. Org. Khim. 1970, 6, (568).

O R CISOH

R

6

KF

SO

2

F

R 8 (Me 2

N)

3 S Me 3 SiF 2 Me 3 SiCF3

SO

2

CF

3 R 9

SO

2

CI

-R 7 \Zn(Hg)

SH

CHCIF

2 base

SCHF

2 6'R

SO

2

CHF

2 R 12 Selected Methods of Fluorinated Aryl Sulfone Synthesis Scheme III As shown in Scheme IV, non-symmetrical urea formation may involve reaction of an aryl isocyanate (14) with an aryl amine The heteroaryl isocyanate may be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or i0 N.N'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement. Thus, reaction of acid derivative 16 with an azide source, followed by rearrangement affords the isocyanate. The corresponding carboxylic acid (17) may also be WO 00/42012 PCT/USOO/00648 subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent.

Ar'-NH 2 13 COCI2 H2N-Ar 2 1 Ar'-NCO Ar N.Ar 2 N N 14 H H N3 DPPA 0 0 Ar--X Ar 'OH 16 17 Scheme IV Selected Methods of Non-Symmetrical Urea Formation Finally, ureas may be further manipulated using methods familiar to those skilled in the art.

The invention also includes pharmaceutical compositions including 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 'administration by injection' includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. One or. more compounds may be present in association with one or more nontoxic pharmaceutically acceptable carriers and if desired other active ingredients.

Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable 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 WO 00/42012 PCT/USOO/00643 carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.

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

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the 3 addition of water provide the active ingredient in admixture with a dispersing or wetting agcnt, suspending agent and one or more preservatives. Suitable dispersing or wetting agents WO 00/42012 PCT/USOO/00648 and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.

The compounds may also be in the form of non-aqueous liquid formulations, oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturallyoccurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

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

1( For all regimens of use disclosed herein for compounds of Formula 1, the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daill dosage WO 00/42012 PCT/US00/00648 for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg oftotal body weight. The daily rectal dosage regime will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regime will preferably be from 0.1 to 200 mg administered between one to four times daily. The daily inhalation dosage regime will preferably be from 0.01 to 10 mg/Kg of total body weight.

It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be appreciated by one skilled in the art that the specific dose level for a given patient depends on a variety of factors, including specific activity of the compound administered, age, body weight, health, sex, diet, time and route of administration, rate of excretion, etc. It will be further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and :the severity of the condition undergoing therapy.

The entire enclosure of all applications, patents and publications cited above and below are hereby incorporated by reference, including provisional application Serial No. 60/115,877, filed January 13, 1999 and non-provisional application Serial No. 09/257,266 filed February 1999.

The compounds can be produced from known compounds (or from starting materials which, in turn, can be produced from known compounds), through the general preparative methods shown below. The activity of a given compound to inhibit raf kinase can be routinely assayed. according to procedures disclosed below. The following examples WO 00/42012 PCT/USOO/00648 are for illustrative purposes only and are not intended, nor should they be construed to limit the invention in any way.

EXAMPLES

All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mmHg. Unless otherwise stated, the term 'under high vacuum' refers to a vacuum of 0.4 1.0 mm.Hg.

All temperatures are- reported uncorrected in degrees Celsius Unless otherwise indicated, all parts and percentages are by weight.

Commercial grade reagents and solvents were used without further purification. Ncyclohexyl-N'-(methylpolystyrene)carbodiimide was purchased from Calbiochem- Novabiochem Corp. 3-tert-Butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-3- (trifluoromethyl)aniline, 4 -chloro- 3 -(trifluoromethyl)aniline (trifluoromethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4-chloro-3- (trifluoromethyl)phenyl isocyanate were purchased and used without further purification.

Syntheses of 3-amino-2-methoxyquinoline Cho et al. WO 98/00402; A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem.. 3, 1995, 129), 4 3 -carbamoylphenoxy)-l-nitrobenzene Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-tertbutylphenyl isocyanate Rohr et al. DE 2,436,108) and (trifluoromethyl)phenyl isocyanate Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491) have previously been described.

Thin-layer chromatography (TLC) was performed using Whatmanl pre-coated glass-backed silica gel 60A F-254 250 uam plates. Visualization of plates was effected by one or more of the tbllowing techniques: ultraviolet illumination, exposure to iodine vapor. (c) WO 00/42012 PCT/US00/00648 immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, immersion of the plate in a cerium sulfate solution followed by heating, and/or immersion of the plate in an acidic ethanol solution of 2 4 -dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science® silica gel.

Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer.

Proton nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me 4 Si (5 0.00) or residual protonated solvent (CHCI 3 5 7.26; MeOH 5 3.30; DMSO 5 2.49) as standard. Carbon 3

C)

NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1 3 8 77.0; MeOD-d 3 5 49.0; DMSO-d 6 6 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction.

The ion source was maintained at 250 Electron impact ionization was performed with electron energy of 70 eV and a trap current of 300 p.A. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept I-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas (1x10 4 torr to 2.5x10' 4 torr). The direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10.amps until all traces of the sample disappeared -1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-800 amu using a variable ion time accordinu to the number of ions in the source. Gas chromatography ion selective mass spectra (GC-%MS) WO 00/42012 PCT/USOO/00648 were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP- 1 methyl silicone column (0.33 mM coating; 25 rm x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eV). Elemental analyses are conducted by Robertson Microlit Labs, Madison NJ.

All compounds displayed NMR spectra, LRMS and either elemental analysis or H-RMS consistent with assigned structures.

List of Abbreviations and Acronyms: AcOH acetic acid anh anhydrous atmn atmosphere(s).

BOC tert-butoxycarbonyl CDI 1,1 '-carbonyl diimidazole conc concentrated d day(s) dec decomposition DMAC NN-dimethylacetamide DMPU 1 ,3-dimethyl-3 ,4,5 ,6-tetrahydro-2( 1H)-pyrimidinone 2o DMF NN-dimethylformamide DMSO dimethylsulfoxide DPPA diphenyiphosphoryl azide EDGI 1 -dimethylaminopropyl)-3-ethylcarbodiimide EtOAc ethyl acetate EtOH ethanol (100%) Et 2 Q diethyl ether Et 3 N triethylamine h hour(s) HOBT I -hydroxybenzotr-iazole n-CPBA 3-chloroperoxybenzoic acid NMeOH methanol pet, ether petroleum ether (boiling range 30-60 TC) WO 00/42012 PCT/USOO/00648 temp. temperature THF tetrahydrofuran TFA trifluoroAcOH Tf trifluoromethanesulfonyl A. General Methods for Synthesis of Substituted Anilines Al. General Method for Aryl Amine Formation via Ether Formation Followed by Ester Saponification, Curtius Rearrangement, and Carbamate Deprotection. Synthesis of 2-Amino-3-methoxynaphthalene.

CO

2 Me OMe Step 1. Methyl 3-methoxy-2-naphthoate A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K 2 C0 3 (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temp. for 15 min., then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temp.

overnight, then was treated with water (200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO 4 concentrated under reduced pressure (approximately 0.4 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10.30 'H- NMR (DMSO-d 6 5 2.70. 3H), 2.85 3H), 7.38 (app t, J=8.09 Hz, IH), 7.44 IH), 7.53 (app t, J=8.09 Hz, 1H), 7.84 J.=8.09 Hz, 1H), 7.90 1H), 8.21 1H).

CO

2

H

OMe 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 temp. was treated with a 1 N NaOH solution (33.4 mL, 33.4 mmol).

The mixture was heated at the reflux temp. for 3 h, cooled to room temp.. and madc acidic with a 10% citric acid solution. The resulting solution was extracted with EtOAc 2 h\ It, WO 00/42012 PCT/US00/00648 mL). The combined organic layers were washed with a saturated NaCi solution, dried (MgSO 4 and concentrated under reduced pressure. The residue was triturated with hexane then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 'H-NMR (DMSO-d 6 5 3.88 3H), 7.34-7.41 2H), 7.49-7.54 1H), 7.83 J=8.09 Hz, 1H), 7.91 J=8.09 Hz, 1H), 8.19 1H), 12.83 (br s, 1H).

NO

OMe H O Step 3. 2 -(N-(Carbobenzyloxy)amino-3-methoxynaphthalene A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et3N (2.59 mL, 18.6 mmol) in anh toluene (70 mL) was stirred at room temp. for 15 min., then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resulting mixture was heated at 80 °C for 2 h. After cooling the mixture to room temp., benzyl alcohol (2.06 mL, 20 mmol)'was added via syringe. The mixture was then warmed to 80 °C overnight. The resulting mixture was cooled to room temp., quenched with a 10% citric acid solution, and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCI solution, dried (MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc/86% hexane) to give 2-(N- (carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%): 'H-NMR (DMSO-d 6 5 3.89 3H), 5.17 2H), 7.27-7.44 8H), 7.72-7.75 2H), 8.20 1H), 8.76 1H).

I-

NH

2 OMe Step 4. 2-Amino-3-methoxynaphthalene A slurry of 2 -(N-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a H 2 atm (balloon) at room temp.

overnight. The resulting mixture was filtered through Celitel and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder (2.40 g.

WO 00/42012 PCT/USOO/0064S 'H-NMR (DMSO-d 6 5 3.86 3H), 6.86 2H), 7.04-7.16 2H), 7.43 Hz, 1H), 7.56 J=8.0 Hz, 1H); EI-MS m/z 173 (Mf).

A2. Synthesis of co-Carbamyl Anilines via Formation of a Carbamylpyridine Followed by Nucleophilic Coupling with an Aryl Amine. Synthesis of 4- (2-N-Methylcarbamyl-4-pyridyloxy)aniline 0 CI NHMe Step la. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide via the Menisci reaction Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temp. was added conc.

H

2

SO

4 (3.55 mL) to generate an exotherm. To this mixture was added H 2 0 2 (30% wt in H 2 0, 17 mL) followed by FeSO 4 *7H20 (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temp. for 1 h, then warmed slowly over 4 h to 45 °C.

When bubbling had subsided, the reaction was heated at 60 °C for 16 h. The resulting opaque brown solution was diluted with H 2 0 (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with a saturated NaCI solution (3 x 150 mL), then they were combined, dried (MgSO 4 and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, TLC (50% hexane) Rf 0.50; 'H NMR (CDC1 3 8 3.04 J=5.1 Hz, 3H), 7.43 (dd, J=5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 1H), 8.44 J=5.1 Hz, I CI-MS m/z 171 0 Cl N HCI Step lb. Synthesis of 4-chloropyridine-2-carbonyl chloride HCI salt via picolinic acid WO 00/42012 PCT/USOO/00648 Anhydrous DMF (6.0 mL) was slowly added to SOC12 (180 mL) between 400 and 50 OC.

The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g, 487 mmol) was added in portions over 30 min. The resulting solution was heated at 72 °C (vigorous SO2 evolution) for 16 h to generate a yellow solid precipitate. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and dried under high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chloride HCI salt as a yellow-orange solid (92.0 g, 89%).

0 CI O OMe N HCI Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HCI salt Anh DMF (10.0 mL) was slowly added to SOC1 2 (300 mL) at 40-48 The solution was stirred at that temp. range for 10 min., then picolinic acid (100 g, 812 mmol) was added over min. The resulting solution was heated at 72 °C (vigorous SO 2 evolution) for 16 h to generate a yellow solid. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered, and the solids were washed with toluene (50 mL) and dried under high vacuum for 4 hours to afford 4-chloropyridine-2carbonyl chloride HC1 salt as an off-white solid (27.2 g, This material was set aside.

.0 The red filtrate was added to MeOH (200 mL) at a rate which kept the internal temperature below 55 The contents were stirred at room temp. for 45 min., cooled to 5 °C and treated with Et20 (200 mL) dropwise. The resulting solids were filtered, washed with Et 2 O (200 mL) and dried under reduced pressure at .35 °C to provide methyl 4-chloropyridine-2carboxylate HCI salt as a white solid (110 g, mp 108-112 oC; 'H-NMR (DMSO-d 6 3.88 3H); 7.82 (dd, J=5.5, 2.2 Hz, 1H); 8.08 1=2.2 Hz, 1H); 8.68 J=5.5 Hz, 1H); 10.68 (br s, 1H); HPLC ES-MS m/z 172 4 WO 00/42012 PTUO/04 PCTIUSOO/00648 -NHMe Step 3 a. Synthesis of 4 -chloro-N-methyl-2-pyridinecarboxamide from methyl 4chloropyridine-2-carboxylate A suspension of methyl 4 -chloropyridine-2-carboxylate HCI salt (89.0 g,428 mrnol) in MeOfi (75 mL) at 0 'C was treated with a 2.0 M methylamine solution in THF (I L) at'a rate which kept the internal temp. below 5 The resulting mixture was stored at 3 'C for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (I L) and filtered. The filtrate was washed with a saturated NaCI solution (500 mL), dried (Na 2

SO

4 and concentrated under reduced pressure to afford 4-chloro-N-m ethyl -2 io pyridinecarboxamide as pale-yellow crystals (71.2 g, mp 4 1-43 'H-NMR (DMS0d 6 562. 81 3H), 7.74 (dd, J=5.1 2.2 Hz, I1H), 8.00 J=2.2, I1H), 8.61 J=5.1 Hz, I1H), 8.85 (br d, 1H); Cl-MS m/z 171 0 NHMe Step 3b. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4chloropyridine-2-carbonyl chloride 4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in portions to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0 'C.

The resulting mixture was stored at 3 'C for 4 h, then concentrated under reduced pressure.

The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate was washed with a saturated NaCI solution (2 x 100 mL), dried (Na 2

SO

4 and concentrated under reduced pressure to provide 4 -chloro-N-methyl-2-pyridinecarboxamide as a yellow, crystalline solid (4.95 g, mp 3 7-40 'C.

0 0 eN NHMe

H

2

N

Step 4. Synthesis of 4 2 -(N-methylcarbamoyl)-4-pyridyloxy)aniline 2i A solution of 4-aminophenol 60 g, 88.0 mmol) in anh. DMF 150 n1L) was treated with potassium tert-butoxide (10.29 g, 91.7 mrnol), and the reddish-brown mixture was stirred at WO 00/42012 PCT/USOO/00648 room temp. for 2 h. The contents were treated with 4 -chloro-N-methyl-2pyridinecarboxamide (15.0 g, 87.9 mmol) and K 2

CO

3 (6.50 g, 47.0 mmol) and then heated at °C for 8 h. The mixture was cooled to room temp. and separated between EtOAc (500 mL) and a saturated NaCI solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCI 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 h to afford 4 -(2-(N-methylcarbamoyl)-4pyridyloxy)aniline as a light-brown solid 17.9 g, 'H-NMR (DMSO-d 6 5 2.77 J=4.8 Hz, 3H), 5.17 (brs, 2H), 6.64, 6.86 (AA'BB' quartet, J=8.4 Hz, 4H), 7.06 (dd, J=5.5, 2.5 Hz, 1H), 7.33 J=2.5 Hz, 1H), 8.44 J=5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244 A3. General Method for the Synthesis of Anilines by Nucleophilic Aromatic Addition Followed by Nitroarene Reduction. Synthesis of 5-(4- Aminophenoxy)isoindoline-1,3-dione 0 HOl

NH

HOO

0 Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120 °C for 45 min., then the clear, bright yellow mixture was heated at 160 °C for 2 h. The resulting mixture was maintained at 160 °C and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a IN NaOH solution. This mixture was cooled to 0 oC and slowly acidified to pH 5 using a IN HCI solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield hydroxyisoindoline-l,3-dione as a pale yellow powder as product (3.24 g, 'H NMR (DMSO-d 6 5 7.00-7.03 2H), 7.56 J=9.3Hz, 1 H).

WO 00142012 WO 0042012PCT[US00100648 2 N- zO,-

NH

0 Step 2. Synthesis of 5-(4-n itrophenoxy)isoindoline-1 ,3-dione To a stirring slurry of NaH (1.1I g, 44.9 rnmol) in DMF (40 mL) at 0 'C was added a solution of 5 -hydroxyisoindoline-l1,3 -di one (3.2 g, 19.6 mrnol) in DIMF (40 mL) dropwise. The bright yellow-green mixture was allowed to return to room temp. and was stirred for I h, then I fluoro-4-nitrobenzefle (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated at 70 'C overnight, then cooled to room temp. and diluted slowly with water (150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (MgSO 4 and concentrated under reduced pressure to give 5-(4nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, TLC (30% hexane) P.

1 0.28; lH NMR (DMSO-d 6 5 7.32 J=12 Hz, 2H), 7.52-7.57 (in, 2H), 7.89(d, J=7.8 Hz, 11H), 8.29 1=9 Hz, 2H), 11.43 (br s, 1LH); CI-MS m/z 285 100%).

0

H

2 NJ:0

NH

0 Step 3. Synthesis of-5-(4-a min oph en oxy)isoin doline-l ,3-dion e A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g, 2.11 mmol) in conc. AcOH (12 mL) and water (0.1 mL) was stir-red under stream of argon while iron powder (0.59 g, 55.9 mmol) was added slowly. This mixture stirred at room temp. for 72 h, then was 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-(4amino phenoxy)isoindo line- 1, 3-dione as a brownish solid (0.4 g, TLC EtOAc/ 50% hexane) P.

1 0.27; 1H NMR (DMSO-d 6 5 5.14 (br s, 2H), 6.62 1=8..7 Hz, 2H), 6.84 1=8.7 Hz, 2H), 7.03 1=2.1 Hz, lH), 7.23 (dd, IH), 7.75 1=8.4 Hz, IH), 11.02 I HPLC ES-MS rn/z 255 100%).

A4. General M'%ethod for the Synthesis of Pyrrolvianilines. Synthesis of But; 1-2 WO 00/42012 WO 0042012PCTIUSOO/00648 N0 2

N

Step I. Synthesis of 1 -(4-tert-b utyl-2-nitrophenyl)-2,5-dimethylpyrrole To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in cyclohexane mL) was added ACOH (0.lmL) and acetonylacetone (0.299 g, 2.63 mniol) via syringe. The reaction mixture was heated at 120 'C for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temp., diluted with CH 2

CI

2 (10 mL) and sequentially washed with a I N HCI solution (15 mL), a I N NaOH solution (15 mL) and a saturated NaCI solution (l5mL), dried MgSO 4 and concentrated, under reduced pressure. The resulting orange-brown solids were purified via column chromatography (60 g SiO 2 gradient from 6% EtOAc/94% hexane to 25% EtOAc/75% hexane) to give l-(4-tert-butyl-2-nitrophenyl)-2,5dimethylpyrrole as an orange-yellow solid (0.34 g, TLC (15% EtOAc/85% hexane) Rf 0. 67; 'H NMR (CDCI 3 d 1.34 9H), 1.89 6H), 5.84 2H), 7.19-7.24 (in, 1H), 7.62 (dd, 111), 7.88 J=2.4 Hz, 1H); Cl-MS m/z 273

-NH

2

N

1S Step 2. Synthesis of 5-ltert-Butyl-2-(2,5.-dimethylpyrrolyl)aniline A slurry of l-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 inmol), I 0%PdIC (0.056 g) and EtOAc (50 mL) under an H 2 atmosphere (balloon) was stirred for 72 h, 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 yellowish solids (0.30 g, TLC (10% EtOAc/90% hexane) RfO0.43; 'HNMR (CDCI 3 5 1.28 9H), 1.87-1.91 (Mn. 8H), 5.85 (br s, 2H), 6.73-6.96 (mn, 3H), 7.28 (br s, I H).

24 WO 00/42012 PCT/USOO/00648 General Method for the Synthesis of Anilines from Anilines by Nucleophilic Aromatic Substitution. Synthesis of Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCI Salt 0

HN

O NHMe

H

2 N 1" N HCI Me A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the black mixture was stirred at room temp. until the flask had reached room temp. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 °C for 8 h. The mixture was cooled to room temp. and diluted with water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with a saturated NaCI solution (200 mL), dried (MgSO4) and concentrated under reduced pressure. The residual black oil was treated with EthO (50 mL) and sonicated. The solution was then treated with HCI (1 M in Et 2 0; 100 mL) and stirred at room temp. for 5 min. The resulting dark pink solid (7.04 g, 24.1 nmmol) was removed by filtration from solution and stored under anaerobic conditions at 0 °C prior to use: 'H NMR (DMSO-d 6 8 2.41 3H), 2.78 J=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J=8.5, 2.6 Hz, 1H), 7.23 (dd, J=5.5, 2.6 Hz, 1H), 7.26 J=2.6 Hz, 1H), 7.55 J=2.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 8.55 J=5.9 Hz, 1H), 8.99 J=4.8 Hz, 1H).

A6. General Method for the Synthesis of Anilines from Hydroxyanilines by N- Protection, Nucleophilic Aromatric Substitution and Deprotection.

Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline 0 O H

F

3 C N

H

C. I Step 1: Synthesis of 3-Chloro-4-(2,2,2-trifluoroacetylamino)phenol Iron (3.24 g, 58.00 mmol) was added to stirring TFA (200 mL). To this slurry was added 2chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 mL). This gray slurry was stirred at room temp. for 6 d. The iron was filtered from solution and the WO 00/42012 PCT/US00/00648 remaining material was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To the resulting yellow solution was added a saturated NaHCO3 solution (50 mL). The solid which precipitated from solution was removed. The filtrate was slowly quenched with the sodium bicarbonate solution until the product visibly separated from solution (determined-was using a mini work-up vial). The slightly cloudy yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with a saturated NaCI solution (125 mL), dried (MgSO 4 and concentrated under reduced pressure. The 'H NMR (DMSO-d 6 indicated a 1:1 ratio of the nitrophenol starting material and the intended product 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol. The crude material was taken on to the next step without further purification.

0 0 ONHMe

F

3 C NN Cl Step 2: Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 mL) was treated with potassium tert-butoxide (5.16 g, 45.98 mmol) and the brownish black mixture was stirred at room temp. until the flask had cooled to room temp. The resulting mixture was treated with 4-chloro-N-methyl-2pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 °C under argon for 4 d. The black reaction mixture was cooled to room temp. and then poured into cold water (100 mL). The mixture was. extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by column chromatography (gradient from 20% EtOAc/pet. ether to 40% EtOAc/pet.

ether) to yield 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol).

0 H2 NHMe 2

H

2 N Cr Step 3. Synthesis of 4-(2-(.N-lethylcarbamoyl)-4-pyridyloxy)-2-chloroaniline WO 00/42012 WO 0042012PCTUSOO/00648 A solution of crude 4-(2-(N-Methylcarbamoyl)-4-pyridyl0xy)-2-chlorophenyI (222tfluoro)acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a IN NaOH solution (20 mL). This brown solution was allowed to stir for 8 h. To this solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x 40 ml) and the solvent was concentrated to yield 4-(2-(N-Methylcarbarnoyl)-4-py~dyloxy)-2> chloroaniline as a green oil that solidified upon standing (2.86, g, 10.30 mmol): 'H NMR (DMSO-d 6 6 2.77 J=48 Hz, 3H), 5.51 2H), 6.60 (dd, 2.6 Hz, 11-1), 6.76 (d, 1=2.6 Hz, 1H), 7.03 J=8.5 Hz, IH), 7.07 (dd, 1=5.5, 2.6, Hz, IH), 7.27 1=2.6 Hz, 1H), 8.46 .1=5.5 Hz, IH), 8.75 J=48, 1H).

A7. General Method for the Deprotection of an Acylated Aniline. Synthesis o f 4-Chloro-2-methoxy-5-(trifluoromethyl)anilifle

CF

3 C I NH 2 OMe A suspension of 3-chloro-6-(N-acetyl)-4-(tfluoromethyl)anisole (4.00 g, 14.95 mmol) in a 6M HCI solution (24 mL) was heated at the reflux temp. for 1 h. The resulting solution was allowed to cool to room temp. during which time it solidified slightly. The resulting mixture was diluted with water (20 mL) then treated with a combination of solid NaOH and a saturated NaHCO 3 solution until the solution was basic. The organic layer was extracted with CH 2

CI

2 (3 x 50 mL). The. combined organics were dried (MgSO 4 and concentrated under reduced pressure to yield 4as a brown oil (3.20 g,14.2 mmol): 'H NMR (DMSO-d 6 6 3.84 3H), 5.30 2H), 7.01 2H).

A8. General Method for Synthesis of (o-Alkoxy-o)-carboxypbenyl Anilines.

Synthesis of 4-(3..(N-Mlethylcarbamoly)-4-methoxyphenoxy)an iline.

0 0e 0 2 N eOM Step 1. 4 -(3-NMethoxvcarbonfl-I4methoxyphefloxy)-lnitrobenzene: WO 00/42012 PCT/USOO/00648 To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-l-nitrobenzene (prepared from dihydroxybenzoic acid in a manner analogous to that described in Method A13, Step 1, 12 mmol) in acetone (50 mL) was added K 2

CO

3 (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated at the reflux temp. overnight, then cooled to room temp. and filtered through a pad of Celite®. The resulting solution was concentrated under reduced pressure, absorbed onto SiO 2 and purified by column chromatography (50% EtOAc hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene as a yellow powder (3 mp 115-118 °C.

0 O 'OH 0 2 N OMe Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-l-nitrobenzene: A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene (1.2 KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temp. overnight and then heated at the reflux temp. for 4 h. The resulting mixture was cooled to room temp. and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous mixture was made acidic with a IN 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)-l-nitrobenzene (1.04 g).

0 O a-NHMe 0 2 N OMe Step 3. 4-(3-(1N-Methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene: To a solution of 4-(3-carboxy-4-methoxyphenoxy)-l-nitrobenzene (0.50 g, 1.75 mmol) in

CH

2

C

2 l (12 mL) was added SOC12 (0.64 mL, 8.77 mmol) in portions. The resulting solution was heated at the reflux temp. for 18 h, cooled to room temp., and concentrated under reduced pressure. The resulting yellow solids were dissolved in CH 2

CI

2 (3 mL) then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02 mmol) in portions (CAUTION: gas evolution), and stirred at room temp. for 4 h. The resulting mixture was treated with a IN NaOH solution, then extracted with CH3CI (25 mL).

WO 00/42012 WO 0042012PCTIUSOO/00643 The organic layer was dried (Na 2

SO

4 and concentrated under reduced pressure to give 4-(3- (N-methy'lcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene as a yellow solid (0.50 g, 0 N NHN~e

H

2 N OMe Step 4. 4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)aniline: A slurry of 4-(3-(N-methylcarbamnoly)-4-methoxyphenoxy)-1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd/C (0.20 g) in IEtOH (55 mL) was stirred under I atm of H 2 (balloon) for d, then was filtered through a pad of Celitee. The resulting solution was concentrated under reduced pressure to afford 4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)ani line as an off-white solid (0.68 g, TLC 1% Et 3 N/99.9% EtOAc) Rf 0.36.

A9. General Method for Preparation of co-Alkylpht halimide-containing Anilines. Synthesis of 5-(4-Aminophenioxy)-2-methylisoindoline-1 ,3-dione 0 I I N-Me 0 2 NNa 0 Step 1. Synthesis of 5-(4-Nitrophenoxy)-2-methylisoindoline-1 ,3-dione: A slurry of 5-(4-nitrophenoxy)isoindo line- 1,3 -dione, (A3 Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 5.27 mmol) in DMF (15 mL) was stirred at room temp. for I h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The.-resulting mixture was stirred at room temp.

overnight, then was cooled to 'C and treated with water (10 naL. The resulting solids were collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindolline- 1,3-dione as a bright yellow solid (0.87 g, TLC (35% EtOAc/65%. hexane) Rf 0.6 1.

0 I0 0 N-Me

H

2

N

WO 00/420 12 PCT/USOO/00648 Step 2. Synthesis of 5-(4-Amnin oph en oxy)-2-mnethylisojndoline-1,3-dione: A .slurry of ni trop henoxy)-2 -methyli so indo lirne- 1 ,3 -dio ne (0.87 g, 2.78 mmol) and 10% Pd/C 10 g) in MeOH was stirred under I atm of H 2 (balloon) overnight. The resulting mixture was filtered through a pad of Celiteo and concentrated under reduced pressure. The resulting yellow Solids were dissolved in EtOAc (3 nL) and filtered through a plug of Si0 2 hexane) to afford 5 4 -aminophenoxy)-2 -methyl isoindoline- 1 ,3-di one as a yellow solid (0.67 g, TLC (40% EtOAc/60% hexane) Rf 0.27.

AlI0. General Method for Synthesis of a-Carbamoylaryl Anilines Through Reaction of co-Alkoxycarbonylaryl Precursors with Amines. Synthesis of 4-(2-(N-(2-morph olin- 4 -ylethyl)carbamoyl)pyridyboxy)aniline 0 NIf~ Step 1. Synthesis of 4 -Chloro- 2 2 -rnorpholin-4-ylethyl)carbamoy1)pyridin e To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, Step 2; 1.01 g, 4.86 mmol) in THE (20 mL) was added 4 2 -aminoet hyl)morpholine (2.55 mL, 19.4 mmol) dropwise and the resulting solution was heated at the reflux temp. for 20 h, cooled to room temp., and treated with water (50 mL). The resulting mixture was extracted with EtOAc m4L) The organic layer was dried (MgSO 4 and concentrated under reduced pressure to afford 4 -chloro- 2 2 -morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil (1.25 g, TLC (10% MeOH/90% EtOAc) RrO0.50.

0

H

2 NI~ 1:.N N,,j WO 00/42012 WO 0042012PCTIUSOO/00648 Step 2. Synthesis of 4-(2-(N-(2-Morph olin-4ylethyl)carbamoyl)pyridyIoxy)anliile.

A solution of 4-aminophenol (0.49 g, 4.52 mimol) and potassium tert-butoxide. (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temp. for 2 h, then was sequentially treated with 4choo2(-2mrhln4yehlcraolprdn (1.22 g, 4.52 =mol) and K 2 C0 3 (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 'C overnight, cooled to room temp., and separated between EtOAc (25 mL) and a saturated NaCi solution (25 mL). The aqueous layer was back extracted with EtOAc (25 ml). The combined organic layers were washed with a saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure.

The resulting brown solids were purified by column chromatography (58 g; gradient from 100% EtOAc to 25% MeOH/75% EtOAc) to afford 4-(2-(N-(2-morpholin-4ylethyl)carbamoyl)pyTidyloxy)afliline (1.0 TLC (10% MeOH/90% EtOAc) Rf 0.32.

All1. General Method for the Reduction of Nitroarenes to Arylamnines.

Synthesis of 4-(3-Carboxyphenoxy)aniline.

0

OH

A slurry of 4-(3-carboxyphenoxy)-1-r'itrobenzene (5.38 g, 20.7 mmol) and 10% PdIC (0.50 g) in MeGH (120 mL) was stirred under an H 2 atmosphere (balloon) for 2 d. The resulting mixture was filtered through a pad of Celite then concentrated under reduced pressure to afford 4-(3-carboxyphenoxy)alhline as a brown solid (2.26 g, TLC (10%

CH

2

CI

2 Rr 0.44 (streaking).

A12. General Method for the Synthesis of Isoindolinone-Containing Anilines.

Synthesis of 4-(l

NH

WO 00/42012 WO 0042012PCTUSOO/00648 Step I. Synthesis of 5-hydroxyisoindoliD-1 -one To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcQH (500 mL) was slowly added zinc dust (47.6 g, 729 inmol) in portions,. then the mixture was heated at the reflux temp. for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was repeated on the same. scale and the combined oily residue was purified by column chromatography (1.1 Kg Si0 2 gradient from 60% EtOAc/40% hexane to 25% EtOAc) to give 5-hydroxyisoindolin-1I-onle (3.77 TLC (100% EtOAc) Rf 0. 17; HPLC ES- IMS m/z 150 0 I NH 0 2 NCr 0 0 Step 2. Synthesis of 4-(1 -isoindolinon-5-yloxy)-1 -nitrobenzene To a slurry of NaHl (0.39 a, 16.1 mmol) in DMF at 0 TC was added one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp.

and was stirred for 45 min., then 4-fluoro-l1-nitrobenzene was adde d and then mixture was heated at 70 'C for 3 h. The mixture was cooled to 0 'C and treated with water dropwise until a precipitate formed. The resulting solids were collected to give 4-(1-isoindolinon-5yloxy)-1I-nitrobenzene as a dark yellow solid (3.23 g, TLC (100% EtOAc) Rf 0.35.

0 N Ja

NH

H

2 N 0 Step 3. Synthesis of 4-(1 A slurry of 4-(l-isoindolinon-5-yloxy)-1-nitrobenzene (2.12 g, 7.8 mmol) and 10% PdIC (0.20 g) in EtOHl (50 mL) was stirred under an H 2 atmosphere (balloon) for 4 h, then filtered through a pad of Celitee. The filtrate-was concentrated under reduced pressure to afford 4-(1I oxo iso indolin- 5-yloxy)ani line as a dark yellow solid: TLC (100% EtOAc) Rf 0.15.

A13. General Method for the Synthesis of (o-Carbamoyl Anilines via EDCI- Mediated Amide Formation Followed by Nitroarene Reduction.

Synthesis of 4-(3-N-Methylcarbamoylphenoxy)aniline.

WO 00/42012 PCT/USOO/00648 0 02N OOEt Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene A mixture of 4-fluoro-l-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 150 mmol) and K 2

CO

3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux temp.

overnight, cooled to room temp. and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na 2

SO

4 and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene as an oil (38 g).

0 N2 0

OH

Step 2. Synthesis of 4-(3-carboxyphenoxy)-l-nitrobenzene To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene (5.14 g, 17.9 mmol) in a 3:1 THF/water solution (75 mL):was added a solution LiOH-H 2 0 (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50 °C overnight, then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2 with a IM HCI solution. The resulting bright yellow solids were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-l-nitrobenzene (4.40 g, .0 N NHMe 0 2 N WO 00/42012 WO 0042012PCT/USOO/00648 Step 3. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)-1 -nitrobenzene A mixture of 4-(3-carboxyphenoxy)-lI-nlitrobenlzene (3.72 g, 14.4 mmoD, EDCI-HCI (3.63 g, 18.6 mmol), N-methylmorpho line (1.6 ML, 14.5 mnmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CH 2

CI

2 (45 mnL) was stirred at room temp. for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mnixture was extracted with a IM HC1 solution (50 The aqueous layer was back-.extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with a saturated NaCI solution (50 mL), dried (Na 2 SO4), and concentrated under reduced pressure to give methylcarbamoyl)phenoxy)-l-nitrobenzefle as an oil (1.89 g).

0 NHMe

H

2

N

Step 4. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)aniline A slurry of 4-(3-(N-methylcarbamoyl)pheloxy)-l-nitrobenzefle (1.89 g, 6.95 mmol) and PdIC (0.24 g) in EtOAc (20 mnL) was stirred under an H2 atm (balloon) overnight. The resulting mixture was filtered through a pad of Celitee and concentrated under reduced pressure. The residue was purified by column chromatography MeOHI95% CH 2

CI

2 The resulting oil solidified under vacuum overnight to give methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).

Al14. General Method for the Synthesis of o)-Carbamoyl Anilines via EDCI- Mediated Amide Formation Followed by Nitroarene Reduction.

Synthesis of 4-3-(5-Methylcarbamoyl)pyridyloxy)anilin e 0 0~ OMe 0 2 N

N

2 5 Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)--itrobelzefe To a slurry of NaH (0.63 g, 26.1 rnmol) in DMF (20 mL) was added a solution of methyl hydroxvnicotinate (2.0 g, 13.1 rnmol) in DNIF (10 mL). The resulting mixture was added t.o a WO 00/42012 WO 0042012PCT/USOO/00643 solution of 4-fluoronitrobenzene (1.4 m.L, 13.1 mrnol) in DMF (10 mL) and the resulting, mixture was heated at 70 -C overnight, cooled. to room temp., and treated with MeOH (5 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 column chromatography (30% EtOAc/70% hexane) to afford 4-(3 Il-nitrobenzene 60 g).

0

N

0 OMe

H

2 N'C N Step 2. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-l-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd/C in MeOHIEtOAc was stirred under an H 2 atmosphere (balloon) for 72 The resulting mixture was filtered arid the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% EtOAc/90% hexane to EtOAc/70% hexane to 50% EtOAc/50% hexane) to afford methoxycarbonyl)pyridyloxy)anilifle (0.28 g, 1 H NMR (CDCI 3 5 3.92 3H), 6.71. (d, 2H), 6.89 2H), 7.73 1H), 8.51 1H), 8.87 I).

WO 00/42012 PCT/USOO/00648 Synthesis of an Aniline via Electrophilic Nitration Followed by Reduction.

Synthesis of 4-(3-Methylsulfamoylphenoxy)aniline.

00,,P Br S'NHMe Step 1. Synthesis of N-methyl-3-bromobenzenesulfonamide To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0 OC was added methylamine (2.0 M in THF; 28 mL, 56 mmnol). The resulting solution was allowed to warm to room temp. and was stirred at room temp. overnight. The resulting mixture was separated between EtOAc (25 mL) and a 1 M HCI solution (25 mL). The aqueous phase was back-extracted with EtOAc (2 x 25 mL). The combined organic phases were sequentially washed with water (2 x 25 mL) and a saturated NaCl solution (25 mL), dried (MgSO 4 and concentrated under reduced pressure to give N-methyl-3bromobenzenesulfonamide as a white solid (2.8 g, 99%).

00 SO">SNHMe 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 Cul (4 g, 20 mmol) in DMF (25 mL) was added N-methyl-3-bromobenzenesulfonamide (2.5 g, 10mmol), and the resulting mixture was stirred at the reflux temp. overnight, cooled to room temp., and separated between EtOAc (50 mL) and a 1 N.HCI solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were sequentially washed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc/70% hexane) to give methylsulfamoyl)phenyloxy)benzene (0.30 g).

00 0 S 'NHMe 0 2 a WO 00/42012 PCT/US00/00648 Step 3. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)-l-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 NaNO 2 (0.097 g, 1.14 mmol) in portions over 5 min. The resulting solution was stirred at -10 °C for 1 h, then was allowed to warm to room temp., and was concentrated under reduced pressure. The residue was separated between EtOAc (10. mL) and water (10 mL). The organic phase was sequentially washed with water (10 mL) and a saturated NaCl solution (10 mL), dried (MgSO 4 and concentrated under reduced pressure to give 4 -(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.20 This material carried on to the next step without further purification.

00 O S" y NHMe

H

2 N Step 4. Synthesis of 4 3 -(N-methylsulfamoyl)phenyloxy)aniline A slurry of 4 3 -(N-methylsulfamoyl)phenyloxy)-l-nitrobenzene (0.30 g) and 10% Pd/C (0.030 g) in EtOAc (20 mL) was stirred under an H 2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% hexane) to give 4 -(3-(N-methylsulfamoyl)phenyloxy)aniline (0.070 g).

A16. Modification of co-ketones. Synthesis of methoxy)iminoethyl)phenoxyaniline HCI salt.

HCI

N'

0 To a slurry of 4-(4-acetylphenoxy)aniline HCI salt (prepared in a manner analogous to Method 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 HCI salt (0.65 g,.7.78 mmol, 2.0 equiv.). The resulting solution was heated at the reflux temperature for 30 min, cooled to room temperature and concentrated under reduced pressure. The resulting solids were triturated with water (10 mL) and washed with water to give 4-(4-(l-(N-methoxy)iminoethyl) phenoxyaniline HCI salt as a WO 00/42012 WO 0042012PCTUSOO/00648 yellow solid (0.85 TLC (50% EtOAc/50% pet. ether) Rf 0.78; 'H NMR (DIMSO-d 6 5 3.90 3H), 5.70 3H)- HPLC-MS m/z A17. Synthesis of N-(o-Silyloxyalkyl)amides. Synthesis of s Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.

0 Cl' N

H

Strep 1. 4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxaniide To a solution of 4-chloro-N-(2-hydroxyethyl)pyr-idine-2-carboxamnide. (prepared in a manner anialogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added trilsopropylsilyl chloride (1.59 g, 8.2 mmnol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mrol, 2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp, then was concentrated under reduced pressure. The residue was separated 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 afford 4chloro-2-(N-(2-triisopropylsilyloxy)ethyl)pyridiflecarboxamide as an orange oil (2.32 g, This material was used in the next step without further purificati Ion.

00

H

H2NJ:: Step 2. 4-(4-(2-(N-(2-Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyanilin e To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF (8 mL) was added potassium tert-butoxide (0.67 g, 6.0 minol, 1.0 equiv.) in one portion causing an exotherm.

When this mixture had cooled to room temperature, a solution of 4-chloro-2-(N-(2..

triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32'g, 6 rnmol, I equiv.) in DMF (4 mL) was added followed by K 2 C0 3 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was heated at 80 0 C overnight. An additional portion of potassium tert-butoxide (0.34 g, 3 mmol, 0.5 equiv.) was then added and the mixture was stirred at 80 'C an additional 4 The mlixture Nwas cooled to 0 'C with an ice/water bath, then water (approx. I mL) was slowly added dropwisc. The organic layer was extracted with EtOAc (3 x 10 mL). The combined WO 00/42012 PCT/USOO/00648 organic layers were washed with a saturated NaCI solution (20 mL), dried (MgSO 4 and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (SiO 2 30% EtOAc/ 70% pet ether) to afford triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown oil (0.99 g, 38%).

A18. Synthesis of 2-Pryidinecarboxylate Esters via Oxidation of 2- Methylpyridines. Synthesis of methoxycarbonyl)pyridyloxy)aniline.

0 2 N

N

Step 1. 4-(5-(2-Methyl)pyridyloxy)-l-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 the reflux temperature 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 sequentially washed with water (2 x 100 mL) and a saturated NaCI solution ((100 mL), dried (MgSO 4 and concentrated under reduced pressure to give 4- (5-(2-methyl)pyridyloxy)-l-nitrobenzene as a brown solid (12.3 g).

0 2 N N O M e 0 Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)-l-nitrobenzene.

A mixture of 4-(5-(2-methyl)pyridyloxy)-l-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the reflux temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered then concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The solution was treated with a conc HCI solution (7 mL), then heated at the reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was separated between EtOAc (50 mL) and a IN NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were sequentially WO 00/42012 PCT/USOO/00648 washed with water (2 x 50 mL) and a saturated NaCi solution (50 mL), dried WM=S0 4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 50% EtOAc/50% hexane) to afford 4 2 -methoxycarbonyl)pyridyloxy) 1nitrobenzene (0.70 g).

0 H N OMe

H

2

NN

0 Step 3. Synthesis of 4-(5-(2-Meth oxycarbonyl)pyridyloxy)aniline.

A slurry of 4-S(-ehxcroy~yrdlx)lntoezn (0.50 g) and 10% Pd/C (0.050 g) in a mixture of EtOAc (20 mL) and MeGH (5 mnL) was placed under a H 2 atmosphere (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 column chromatography (SiO 2 70% EtOAc/30% hexane) to give methoxycarbonyl)pyridyloxy)aniline (0.40 g).

A.19. Synthesis of ao-Sulfonylphenyl Anilines. Synthesis of 4-(4- Methylsulfonylphenyoxy)aniline.

0 ,Me.

Step 1. 4 4 -Methylsulfonylpbenoxy)-1- nitrobenzene: To a solution of 4-(4methylthiophenoxy)-lI-nitrobenzene (2.0 g, .7.7 mmol) in CH 2

CI

2 (75 mL) at 0 TC was slowly added m-CPBA (57-86%, 4.0 and the reaction mixture was stirred at room tem -perature for 5 h. The reaction mixture was treated with a IN NaOH solution (25 mL). The organic layer was sequentially washed with a IN NaOH solution (25 mL), water (25 mL) and a saturated NaCI solution (25 imL), dried (MgSO 4 and concentrated under reduced pressure to give 4- 4 -methylsulfonylphenoxy)- I-nitrobenzene, as a solid (2.1 g).

Step 2. .4-(4-Methylsulfonylphenoxy)-1 -aniline: 4-(4-Methylsulfonylphenoxy)- I nitrobenzene wvas reduced to the aniline in a manner analogous to that described in Method A IS. step 3.

WO 00/42012) PCTUSOO/00648 B. Synthesis of Urea Precursors Bi. General Method for the Synthesis of Isocyanates from Anilines Using CDI. Synth~esis of 4-Bromo-3-(trifluoromethy)phenyI Isocyan ate.

C F 3 Br

NH

2

*HCI

Step 1. Synthesis of 4-bromo-3-(trifluoromethy)aniine HCI salt To a solution of 4-bromo-3 -(trifluoromethyl) aniline (64 g, 267 rniol) in Et 2 O (500 mL) was added an HCI solution (1 M in Et 2 O; 300 mL) dropwise and the resulting mixture was stirred at room temp. for 16 h. The resulting pink-white precipitate was removed by filtration and.

washed with Et 2 O (50 mL) and to afford 4 -bromo-3-(trifluoromethyl)aniline HCl salt (73 g, i0 98%).

Br NC0.

Step 2. Synthesis of 4 -bromo-3-(trifluoromethyl)phenyl isocyanate A suspension of 4-bromo-3 -(tri fluoromethyl)ani line HCI salt (36.8 g, 133 mmol) in toluene (278 mL) was treated with trichloromethyl chloroformate dropwise and the resulting mixture was heated at the reflux temp. for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mnL), then concentrated under reduced pressure. The residue was treated with CH 2 Cl 2 (500 mnL), then concentrated under reduced pressure. The CH 2

CI

2 treatment' oncentration protocol was repeated and resulting amber oil was stored at -20 'C for 16 h, to afford 4 -bromo-3-(trifluoromethyl)phenyl isocyanate as a tan solid (35.1 g, GC-MS m/z 265 (M 4 C. Methods of Urea Formation Cla. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phenvl)-N'.

(4-(2-(N-methvlcarbamoyl)-4-pyridvloxy)phenvl) Urea WO 00/42012 WO 0042012PCT/USOO/00648

CF

3 0 CI 0 0 NHMe I ~I~I KN H H A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol) in CHCI 2 mL) was added dropwise to a suspension of 4-(2-(N-methylcarbarn6'yl-4pyridyloxy)ani linle (Method A2, Step 4; 16.0 g, 65.77 mmol). in CH 2 C1 2 (35 mL) at 0 The s resulting mixture was stirred at room temp. for 22 h. The resulting yellow solids were removed by filtration, then washed with CH 2

CI

2 (2 x 30 mL) and dried under reduced pressure (approximately 1 mmHg) to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2- (N-methylcarbamfoyl)-4-pyridyloxy)pheflyl) urea as an off-white solid (28.5 g, mp 207-209 'H-NMR (DMSO-d 6 5 2.77 1=4.8 Hz, 3H), 7.16 (in, 3H), 7.37 1=2.5 Hz, 1H), 7.62 (in, 4H), 8.11 J=2.5 Hz, lH), 8.49 1=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, IH), 9.21 1H); HPLC ES-MS m/z 465 Clb. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Bromo-3-(trifluoromethyl)phenyl)-N'- (4-(2-(N-methylcarbamoyl)-4-pyridyloxy)ph enyl) Urea CBr 0 Br0 NHMe N N H H; A solution of 4-bromo-3-(trifluoromethyl)phenyI isocyanate (Method B 1, Step 2; 8.0 g, 30.1 rnmol) in C14 2 0 2 (80 mL) was added dropwise to a solution of 4-(2-(N-methylcarbamoyl)-4pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 inmol) in CH 2

CI

2 (40 mL) at 0 The resulting mixture was stirred at room temp. for 16 h. The resulting yellow solids were removed by filtration, then washed with CH 2

CI

2 (2 x 50 mL) and dried under reduced pressure (approximately I mmHg) at 40 'C to afford N-(4-bromo-3-(trifluoromethyl)phenyl)- N'-(4-(2-(N-methylcarbamoy1)-4-pynldyloxy)phenyl) urea as a pale-yellow solid (13.2 IV.

mp 203-205 'H-NMR (DMSO-d 6 562.77 J=4.8. Hz, 3H), 7.16 3H), 7.37 (d.

J=2.5 Hz, I 7.58 (mn, 3H), 7.77 1=8.9 Hz, IH), 8.11 1=2.5 Hz, I 8.49 J1=5-5 Hz,, IH), 8.77 (br d, I 8.99 I 9.21 IlH); HPLC ES-MS 509 WO 00/42012 WO 0042012PCT[USO0100648 Cic. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Ch loro-3-(trifloromethyl)ph enyl)-N'- (2mty--2(-ehlabaol(-yiyoy)hnl Urea

CF

3 0 I 011:-' NHMe H_ Hq Me A solution of 2 mty--2(-ehlabmy)4prdlx) nln (Method AS; 0. 11 g, 0.45 mmnol) in CH 2

CI

2 (1 mL) was treated with Et 3 N (0.16 mL) and 4-chloro-3- (trifluoromethyl)phelyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temp. for 6 d, then was treated with water (5 The aqueous layer was back--extracted with EtOAc (3 x 5 mL). The combined organic lay ers were dried (MgSO 4 and concentrated under reduced pressure to yield N-(4-chloro-3-(trifluoromethyl)phenyl)-N'- (2mty--2(-ehlabaol(-yiyoy)hnl urea, as a brown oil (0.11 g, 0.22 mmol): 1 H NMvlR (DMSO-d 6 8 2.27 3H), 2.77 J==4.8 Hz, 3H), 7.03 (dd, fr=8.5, 2.6 Hz, 1H), 7.11 1=2.9 Hz, IH), 7.15 (dd, 1=5.5, 2.6, Hz, IH), 7.38 1=2.6 Hz, 1H), 7.62 (app d, 1=2.6 Hz, 2H), 7.84 1=8.8 H4z, 1H), 8.12 1H), 8.17 1H); 8.50 1=5.5 Hz, IH), 8.78 1=5.2, 1H), 9.52 1H); HPLC ES-MS m/z 479 Cid. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Ch loro-3-(trifluoromethyl)phenyD)-N'- (4-aminophenyl) Urea CI 0 NH 2

NN

H H To a solution of 4-chloro-3-(trifluoromethyl)phenyI isocyanate (2.27 g, 10.3 mmol) in

CH

2

CI

2 (308 mL) was added p-phenylenediamine (3.32 g, 30.7 mrnol) in one part. The resulting mixture was stirred at room temp. for I h, treated with CH 2 Cl 2 (100 mL), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc (110 mL) and MeOH (l5mL), and the clear solution was washed with a 0.05 N HCl Solution. The organic layer was concentrated under reduced pressure to afford ipr WO 00/42012 WO 0042012PCT/UJS 0/00648 jV(4-chloro-3-(tnfluoromethy)phefl)>N '-(4'-aminophenyl) urea (3.3 TLC (1 00%/ EtOAc) Rf 0.72.

Cle. General Method for the Synthesis of Ureas by Reaction of an Isocyana te ~with an Aniline. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phenyl)-;N'- (4-ethoxycarbonylpheflyl) Urea

CF

3 0 C1 1Q Et N Ne H H To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 rmol) in CH 2 C1 2 (30 mnL) was added 4-chloro-3 -(trifluoromethyl)alhlinle (3.21 g, 16.4 mmol), and the solution was stirred at room temp. overnight. The resulting slurry was diluted with CH 2

CI

2 (50 mL) and filtered to afford N-(4-chloro-3-(tri fluoromethyl)phenyl)-N -(4-ethoxycarbonylphenyl) urea as a white solid (5.93 g, TLC (40% EtOAc/60% hexane) Rf 0.44, CIL. General Method for the Synthesis of Ureas by Reaction of an Isoc yanate with an Aniline. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phenylI)-N'- (3-carboxyphenyl) Urea C1 0 0~ OH N ",N H H To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.2 1g, 5.46 mrnol) in CH 2 Cl 2 (8 mL) was added 4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76 nmol) and the resulting mixture was stirred at room temp. overnight, then treated with MeOH (8 mL), and stirred an additional 2 h. The resulting mixture was concentrated under reduced pressure.

The resulting brown solids were triturated with a 1:1 EtOAc/hexane solution to give N-(4chloro-3-(trifluoromnethyl)phenyl)-N'-(3-carboxyphenyl) urea as an off-white solid (1.21 g, 76%).

C2a. General Method for Urea Synthesis by Reaction of an Aniline with 1 Carbonyl Diimidazole Followed by Addition of a Second Aniline.

WO 00/42012 WO 0042012PCT/USOO/00648 Synthesis of iV-(2-Meth oxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(Nmethylcarbamoyl)-4-pyridyIoxy)pllenyl) Urea

CF

3 0 N N. NHMe O -eH H To a solution of 2-methoxy-5-(trifluoromethyl)aniline 15 g) in anh CH 2

CI

2 (15 rnL) at 0 'C was added CDI 13 The resulting solution was allowed to w'arm to room temp. over I h, was stirred at room temp. for 16 h, then was treated with 4-(2-(N-methylcarbamoyl)-4pyridyloxy)ani line (0.18 The resulting yellow solution was stirred at room temp. for 72 h, then was treated with H 2 0 (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCI solution (100 mL), dried (MgSO 4 and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to EtOAc/50% hexane to 100% EtOAc) to give N-(2-methoxy-5-(trifluoromethyl)phen Yl)- N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a light tan solid (0.098 g, TLC (100% EtOAc) Rf 0.62; 'H NMR (DMSO-d 6 8 2.76 J=4.8 Hz, 3H), 3.96 3H), 7.1-7.6 and 8.4-8.6 (mn, 11H), 8.75 1=4.8 Hz, lH), 9.55 I FAB-MS n/z 461 C2b. General Method for Urea Synthesis by Reaction of an Aniline with NN'- Carbonyl Diimidazole Followed by Addition of a Second Aniline.

Symmetrical Urea's as Side Products of a NN-Carbonyl Diimidazole Reaction Procedure. Synthesis of Bis(4-(2-(N-methylcarbamoyl)-4pyridyloxy)phenyl) Urea 0 0 MHN NZ 0K NHMe H H WO 00/42012 WO 0042012PCTUSOO/00648 To a stirring solution of 3 -amino-2-methoxyquino line 14 g) in anhydrous CH 2 Cl 2 (15 mL) at 0 C was added CDI (0.13 The resulting solution was allowed to warm to room temp.

over 1 h then was stirred at room temp. for 16 h. The resulting mixture was treated with 4-(2- (N-methylcarbamoyl)-4-pyfldyloxy)anliine (0.18 The resulting yellow solution stirred at room temp. for 72 h, then was treated with water (125 rnL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with a saturated NaCI solution (100 ml), dried (MgSO 4 and concentrated under reduced pressure.

The residue was triturated (90% EtOAc/1 0% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis(4-(2-(N-methylcarbamoyl)-4pyridyloxy)phenyl) urea (0.08 1 g, TLC (100% EtOAc) Rf 0.5 0; 'H NMR (DMSO0-d 6 2.76 1=5.1 Hz, 6H), 7.1-7.6 (in, 12H), 8.48 1=5.4 Hz, 1H), 8.75 1=4.8 Hz, 2H),.

8.86 2H); HPLC ES-MS m/z 513 C2c. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of

CF

3 0 *0 N N 0 OMeH NH 0 To a stirring solution of 2-methoxy-5-(trifluoromethyl)pheny I isocyanate 10 g, 0.47 rnmol) in CH 2 C1 2 (1.5 mL) was added 5 -(4-aminophenoxy)isoindo line- 1,3 -dione (Method A3, Step 2o 3;2 0.12 g, 0.47 inrol) in one portion. The resulting mixture was stirred for 12 h, then was treated with CH 2 Cl 2 (10 mL) and MeOH (5 mL). The resulting mixture was sequentially washed with a IN HCl solution (15 mL) and a saturated NaCI solution (15 mL), dried (MgSO 4 and concentrated under reduced pressure to afford (tn fl uoromethyl)phenyl-N'-(4-(,3-dioxoisoidolin-5-yloxy)phenyl) urea as a white solid (0.2 g, TLC (70% EtOAcI3O% hexane) Rf 0.50; H NMR (DMSO-d 6 8 3.95 3H), 7.31 7.10 (in, 6H), 7.57 J=9.3Hz, 2H), 7.80 J=8.7 Hz, 1H), 8.53 (br s, 9.57 I H), 11.27 (br s, I HPLC ES-MS 472.0 100%).

WO 00/42012 WO 0042012PCTIUSOO/00648 C2d. General Method for Urea Synthesis by Reaction of an Aniline with NN'- Carbonyl Diimnidazole Followed by Addition of a Second Aniline.

Synthesis of N-5(etBtl--25dmthlyrllpey)N(-2 (N-methylcarbamoyl)-4-pyridyloxy)pheuyl) Urea 0 0 NHMe N N N H

H

To a stirring solution of CDI (0.2 1g, 1.30 mmol) in CH 2 Cl 2 (2 mL) was added 2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one portion. The resulting mixture was stirred at room temp. for 4 h, then 4-(2-(N-methylcarbamoyl)- 4 pyridyloxy)aflilifle (0.065 g, 0.267mmo1) was then added in one portion. The resulting mixture was heated at 36 'C overnight, then cooled to room temp. and diluted with EtOAc mL). The resulting mixture was sequentially washed with water (15 mL) and a IN HCI solution (l5mL), dried (MgSO4), and filtered through a pad of silica gel (50 g) to afford (tert-butyl)- 2 2 ,S -dimethylpyrrolyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl)- 4 pyridyloxy)phenyl) urea as a yellowish solid. (0.033 g, TLC (40% EtOAc/60% hexane) Rf, 0.24; 1H NMR (acetone-d6) 8 1.37 911), 1.89 6H), 2.89 1=4.8Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (in, 6H1), 7.17 (dd, IH), 7.51-7.58 (mn, 3H), 8.43 1=5.4Hz, 111), 8.57 (d, 1=2.1Hz, 111), 8.80 (br s, lH); HPLC ES-MS 512 4 100%).

C3. Combinatorial Method for the Synthesis of Diphenyl Ureas Using Triphosgene One of the anilines to be coupled was dissolved in dichloroethane (0.10 This solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a bis(trichloromlethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.), followed by diisopropylethylamifle (0.35 M in dichioroethane, 0.2 mL, 1.2 equiv.). The vial was capped and heat at 80 'C for 5 h, then allowed to cool to room temp for approximately h. The second aniline was added (0.10 M in dichloroethane, 0.5 mnL, 1 .0 equiv.), followed by di sopropylethy lam ine (0.35 M in dichloroethane, 0.2 ml-, 1.2 equiv.). The resulting WO 00/42012 PCT/USOO/00648 mixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.

C4. General Method for Urea Synthesis by Reaction of an Aniline with Phosgene Followed by Addition of a Second Aniline. Synthesis of (triflu oromethyl)ph enyl)-N'-(4-(2-(N-methylcarb amoyl)-4-pyridyloxy)ph enyl) Urea

CF

3 0 f 0 0 NHMe N N OMe H

H

To a stirring solution of phosgene (1.9 M in toluene; 2.07 mL0.21g, 1.30 mmol) in CH 2

CI

2 (20 mL) at 0 °C was added anh pyridine (0.32 mL) followed by (trifluoromethyl)aniline (0.75 The yellow solution was allowed to warm to room temp during which a precipitate formed. The yellow mixture was stirred for 1 h, then concentrated under reduced pressure. The resulting solids were treated with anh toluene (20 mL) followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (prepared as described in Method A2; 0.30 g) and the resulting suspension was heated at 80 °C for 20 h, then allowed to cool to room temp. The resulting mixture was diluted with water (100 mL), then was made basic with a saturated NaHCO 3 solution (2-3 mL). The basic solution was extracted with EtOAc (2 x 250 mL). The organic layers were separately washed with a saturated NaCI solution, combined, dried (MgSO 4 and concentrated under reduced pressure. The resulting pinkbrown residue was dissolved in MeOH and absorbed onto SiO 2 (100 Column chromatography (300 g SiO 2 gradient from 1% Et 3 N/33% EtOAc/66% hexane to 1% Et 3 N/99% EtOAc to 1% Et 3 N/20% MeOH/79% EtOAc) followed by concentration under reduced pressure at 45 °C gave a warm concentrated EtOAc solution, which was treated 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 TLC Et 3 N/99% EtOAc) Rf 0.40.

WO 00/42012 WO 0042012PCT/USOO/00648 D. Interconversion of Ureas Dia. Conversion of co-AmninophenyI Ureas into co-(Aroylamino)phenyl Ureas.

Synthesis of N-(4-Chloro-3-((trifluoromfethyl)pheflyI)-N'-(4-(3methoxycarbonylpheyl)Crboxyamilophen~yl) Urea

CF

3 H CIN OMe N N. 0 0

H

To a solution of N-4clr--(rfurmty~hnl- (-iiohnl urea (Method Cld; 0.050 g, 1. 52 mmol), mono-methyl isophthalate (0.25 g, 1.38 mmnol), HOBT*H 2 0 (0.41 g, 3.03 nunol) and N-methylmorpholifle (0.33 mL, 3.03 n-uol) in DMfF (8 mL) was added EDCI -HCl (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp. overnight, io diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a saturated NaHICO 3 solution (25 mL). The organic layer was dried (Na2SO 4 and concentrated under reduced pressure. The resulting solids were triturated with an EtOAc solution hexane) to give N-(4-chloro-3-((trifluoromfethyl)phenyl)-N'-( 4 3 methoxycarbonylphenyl)carboxyamfinoPhelyl) urea (0.27 g, mp 121-122; TLC EtOAc/20% hexane) Rf 0.75.

DIb. Conversion of e)-Carboxypheflyl Ureas into (o-(AryIcarbamoy1)phenyI Ureas. Synthesis of N-(4-Chloro-3-((trifluoromethyI)phefl)-N'-( 4 3 methylcarbanloylphenyl)carbamoylphenyl) Urea

CF

3 0 CI 0 N YNHMe N Ne H 0 H H To a solution of N-(4.-chloro3((tifluoromethyl)phenyl)N -methylcarbamoylphenyl) carboxya minophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mnmol), HOBT-H 2 O (0.14 g, 1.07 mmol), and N-methylmorpholine (0.5mL, 1.07 rnmol) in DMF (3 mL) at 0 'C was added EDCI-HCI (0.10 g, 0.53 mmol). The resulting mixture was allowed to warm to room temp. and was stirred overnight. The resulti ng mixture was treated with water (I OmL), and extracted with EtOAc (25 mnL). The organic phase was concentrated WO 00/42012 WO 0042012PCTIUSOOIOO648 under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane to EtOAc) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3methylcarbamoylphenyl)carbamoylPhenyl) urea as a white solid (0.097 g, mp 225- 229; TLC (100% EtOAc) Rf 0.23.

DIc. Combinatorial Approach to the Conversion of co-Carboxyphenyl Ureas into co-(ArylcarbamoyI)phenyl Ureas. Synthesis of N-(4-Chloro-3- ((trifluoromethyl)phenyl)-N-(4-(N-(3-(N-(3pyridyl)carbamoyl)pbenyl)carbamoyl)phenyl) Urea

CF

3 0 H CI NNC

H

N IkNj:f 0 H H A mixture of N-(4-chloro-3-((trifluoromethyl)phenyl)-N '-(3-carboxyphenyl) urea (Method Cif; 0.030 g, 0.067 mniol) and N-cyclohexyl-N'-(methylpolystyrene)carbodiimide (55 mg) in 1,2-dichloroethane (I mL) Was treated with a solution of 3-arninopyridine in CH 2 Cl 2 (1 M; 0.074 mL, 0.074 rnrol). (In cases of insolubility or turbidity, a small amount of DMSO was also added.) The resulting mixture was heated at 36 'C overnight. Turbid reactions were then treated with TI{F (1 m) and heating was continued for 18 h. The resulting mixtures were treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting mixture was stirred at 36 0 C for 72 h, then cooled'to room temp. and filtered. The resulting solution was filtered through a plug of silica gel (I Concentration under reduced pressure afforded N- (4-chloro-3-((trifluoromethyl)phenyl)-N pyridyl)carbano yl)phenyl)carbamoyl)pheflyl) urea (0.024 g, TLC (70% hexane) Rf 0. 12.

D2. Conversion of c-Carboalkoxyaryl Ureas into c-Carbamoylaryl Ureas.

Syn thesis of N-(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3methylcarbamovlphenyl)carboxyaminophenvl) Urea WO 00/42012 WO 0042012PCTUSOO/00648

CF

3 H C 1 N NHMe N Ni00 H H To a sample of N-(4-chloro-3 -((trifluoromethyl)phenyl)-NV'-(4-(3 -carbomethoxyphenyl) carboxyamninophenyl) urea 17 g, 0.34 mmol) was added methylamirie (2 M in TI-F; ImL, 1.7 mmol) and the resulting mixture was stirred at room temp. overnight, then concentrated under reduced pressure to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N-(4-(3methylcarbanoylphelyl)carboxyam~inophenyl) urea as a white solid: mp 247; TLC (100% EtOAc) Rf 0.35.

D3. Conversion of co-Carboalkoxyaryl Ureas into c-Carboxyaryl Ureas.

Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4carboxyphenyl) Urea

CF

3 0 .C ~0 e OH CILN 0N H H To a slurry of N-(4-chloro-3-((trifluoromethyl)phelyl)-N-(4-ethoxycarbonylphenyl) urea (Method ClIe; 5.93 g, 15.3 mmol) in MeOH (75 mL) was a dded an aqueous KOH solution 1s (2.5 N, 10 mL, 23 inmol). The resulting mixture was heated at the reflux temp. for 12 h, cooled to room temp., and concentrated under reduced pressure. The residue was diluted with water (50 mL), then treated with a 1 N HCl solution to adjust the pH to 2 to 3. The resulting solids were collected and dried under reduced pressure to give N-(4-chloro-3- ((trifluoromethyl)phenyl)-N'-(4-carboxyphenyl) urea as a white solid (5.05 g, 92%).

D4. General Method for the Conversion of (o-Alkoxy Esters into cz)-AlkyI Amides.

Synthesis of N-(4-Ch loro-3-((trifluoromethyl)phenyl)-N-((4-(3-(5-(2d izeth yla min oeth yl)carbamoyl)pyridy)oxyphenyI) Urea

CF

3 0 C0 0 AOH N N N H H Wo 00/42012 WO 0042012PCT[USOO/00648 Step 1. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phelyl)-N'-(( 4 3 5 carboxypyridyl) oxyphenyl) Urea ,N-(4-Chloro-3 -(tri fluoromethyl)Pheflyl)-N'-((4-(3 -methoxycarbonylpyridy1)oxyphelyl) urea was synthesized from 4-chloro-3-(trifluoromethyl)phelyl isocyanate and methoxycarbonylpyridyl) oxyanline (Method A14, Step 2) in a manner analogous to Method Cla. A suspension of N-(4-chloro-3-(trifluoromethyl)pheflyl)-N methoxycarbonylpynidyl)oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH 14 g, 2.5 mmol) in water (I mL) and was stirred at room temp. for 1 h. The resulting mixtuire was adjusted to pH 5 with a I N HCl solution. The resulting io precipitate was removed by filtration and washed with water. The resulting solids were dissolved in EtCH (10 mL) and the resulting solution was concentrated under reduced pressure. The EtOH/concentratiofl procedure was repeated twice to give N-(4-chloro-3- (trifluoromethyl)phenyl)-N -carboxypyridyl) oxyphenyl) urea (0.18 g, 71%).

N1 0

NN

I

H

N N 0N H H Step 2. Synthesis of N-(4-chlora-3-(trifluoromethYl)phelY)N'(( 4 3 5 2 dimethylaminoethyl)carbamoylpyridylUoxypheIy) urea A mixture of N-(4-chloro-3-(trifluoromethyl)phenyl)-N carboxypyridyl)oxyphenyI) urea (0.050 g, 0..01 1 minol), NN-dimethylethylenediamifle (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) was stirred at room temp. overnight.

The resulting solution was separated between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (35 mL), dried (MgSO 4 and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CH 2 Cl 2 (approximately 2 mL). The resulting solution was treated with Et 2 O dropwise to give N-(4-chloro-3- (trifluorornethyl)pheflYl)-N '((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyyfloxyphenyl) urea as a white precipita te (0.48 g, 84%: 'H N-MR (DMSO-d 6 5 2.10 s, 6H), 3.26 7.03 7.52 2H), 7.60 (in, 3H), 8.05 114), 8.43 1IH), 8.58 IH), 8.69 8.90 I1-H), 9.14 IlH), HPLC ES-M/S 522 WO 00/42012 WO 0042012PCTrUSOO/00648 General Methoad for the Deprotection of N-(w-Silyloxyalkyl)a mid es.

Synthesis of N-(4-Chloro-3-((trifluoromethyl)pheflyl)-N'(4-(4-(2-(N-( 2 hydroxy)ethylearbamoyl)pyridyloxyphelyl) Urea.

CI CF 3 0 0 NI N-C N~

S

H H To a solution of N-(4-chloro-3-((trifluoromethyl)phelyl)-N triisopropylsilyloxy) ethylcarbamoyl)pyrdyloxyphenyl) urea (prepared in a manner analogous to Method Cia; 0.25 g, 0.37 mmol) in anh THF (2 mL) was tetrabutylammonium fluoride (1.0 M in THF; 2 mL). The mixture was stirred at room temperature for 5 min, then was treated with water (10 mL). The aqueous mixture was extracted with EtOAc (3 x The combined organic layers were dried (MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 gradient from 100% hexane to 40% EtOAc/60% hexane) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4- (4-(2-(N-(2-hydroxy)ethylcarbamoyl)pyfldyloxyphenyl) urea as a white solid (0.0 19 g, Listed below are compounds listed in the-Tables below which have been synthesized according to the Detailed Experimental Procedures given above: Syntheses of Exemplified Compounds (see Tables for compound characterization) Entry 1: 4-(3-N-Methylcarbarfloylphenoxy)anilline was prepared according to Method A13.

According to Method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl)carbonate followed by 4-(3-N-Methylcarbamoylphenoxy)aniline to afford the urea.

Entry 2: 4-Fluoro-1-nitrobenzefle and p-hydroxyacetophenone were reacted according to Method A13, Step I to afford the 4-(4-acetylphenoxy)-i-nitrobenzene. 4-(4-Acetylphenoxy)- 1 -nitrobenzene was reduced according to Method A13, Step 4 to afford 4acetylphenoxy)anilifle. According to Method C3, 3 -tert-butylani line was reacted w,,ith bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)anil ine to afford the urea.

WO 00/42012 WO 0042012PCTIUSOO/00648 Entry 3: According to Method C2d, 3 -tert-butylIanlilinle was treated with CDI, followed by 4- (3-N-InethylICabamoyl)4methoxyphenoxy)ni line, which had been prepared according to Method A8, to afford the urea.

Entry 4: 5-tert-Butyl-2-methoxyaflhlifle was converted to 5-tert-butyl-2-methoxypheiyl isocyanate according to Method B 1. 4-(3-N-Methylcarbamoylphenoxy)anilifle, prepared according to Method Al13, was reacted with the isocyanate according to Method Cia to afford the urea.

Entry 5: According to Method C2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI followed by 4-(3-N-Inethylcarbamnoyl)-4-methoxypheloxy)aniline, which had been prepared according to Method AS, to afford the urea.

Entry 6: 5-(4-Aminophenoxy)isoindo line- 1,3-dione was prepared according to Method A3.

According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI followed by (4-arninophenoxy)isoindohle-1I,3-dione to afford the urea.

Entry 7: 4-(l-OxoiSoindolin-5-yloxy)anIilifle was synthesized according to Method A12.

According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI followed by 4- (1l-oxoisoindolin-5-yloxy)aline to afford the urea.

Entry 8: 4-(3-N-Methylcarbamnoylphenoxy)aniline was synthesized -according to Method A13. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI followed by 4-(3-Nmethylcarbamnoylphenoxy)aniline to afford the urea.

En try 9: 4-Hydroxyacetophenofle was reacted with 2-chloro-5-nitropyridine to give 4-(4according to Method A3, Step 2. According to Method AS, Step 4, 4-(4-acetylphenoxy)-5-nitropyridifle was reduced to 4-(4-acetylphenoxy)-5aminopynidine. 2 -Methoxy-5 fluoromethyl)ani linle was converted to (trifluorornethyl)phelYt isocyanate according to Method Bi. The isocyanate was reacted with 4-(4-acetylphenoxy)-5 -amilopyridilC according to Method C Ia to afford the urea.

WO 00/42012 WO 0042012PCT/USOO/00648 Entry 10: 4-Fluoro-l1-nitrobeazene and p-hydToxyacetophenone were reacted according to' Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-l -nitrobenzene. 4-(4-Acetylphenoxy)- 1-nitrobenzene was reduced according to Method A13, Step 4 to afford* -4 acetylphenoxy)aniline. According to Method C3, 5-(trifluoromethyl)-2-methoxybutylaniline was reacted with bis(tnichloromethyl) carbonate followed by 4-(4-acetylphenoxy)an iline to afford the urea.

Entry 11: 4-Chloro-N-methyl-2-pyridinecaboxamfide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using io DMAC in place of DMF to give 3-(-2-(N-methylcarbarnoyl)-4-pyridyloxy)aniline. According to.Method C4, 2 -methoxy-5 -(tri fluoroniethyl)ai inle was reacted with phosgene followed by 3-(-2-(N-methyl carbamoyl)-4-pyridyloxy)ani line to afford the urea.

Entry 12: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxainide. 4-Chloro-2pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using D MAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aflilifle was reacted with phosgene followed by 3-(2carbamoyl-4-pyridyloxy)aniline to afford the urea.

Entry 13: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamnide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy- (tri fl uoromethyl)ani line was reacted with CDI followed by 4-(2-(N-methylcarbamoyl)-4pyridyloxy)ani line to afford the urea.

Entry 14: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxarnide. 4-Chloro-2pridiecaboxaidewas reacted with 4-aminophenol according to Method A2. Step 4 usin DMIAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Mlethod WO 00/42012 WO 0042012PCT[USOO/00648 C4, 2 -methoxy- 5-(tfluoromethyl) anilinle was reacted with phosgene followed by 4-(2carbarnoyl -4-pyridyloxy)ni linle to afford the urea.

Entry 15: According to Method C2d, 5-(triflouromethyl)-2-methoxyaniline was reacted with CDI followed by 4-(3-N-methylcarbamoyl)-4-methoxypheloxy)alhlifle, which had been prepared according to Method AS, to afford the urea.

Entry 16: 4-(2-(N-Methylcarb amoyl)-4-pyridyloxy)-2-methylaniline was .synthesized according to Method A5. 5-(Trifluorornethyl)-2-rnethoxyaniline was converted into (trifluoromethyl)-2-methoxyphenyI isocyanate according to Method B 1. The isocyanate was reacted with 4-(2-(N-methylcarbamoyl)A-pyfldyoxy)-2-methylaflilifle according to Method C I c to afford the urea.

Entry 17: 4-(2-(N-Methylcarbalnoyl)-4-pyrdyloxy)-2-chloroalifle was synthesized according to Method A6. 5 -(Trifluoromethyl)-2-rnethoxyani line was converted into (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. (Trifluoromethyl)-2-ITethoxyphenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)- 4-pynidyloxy)-2-chl oro aniline according to Method C Ia to afford the urea.

Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4chloro-N-methyl-2-pyridinecarboxamlide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridy loxy)-4-methylafliline. (Trifluoromethyl)-2 -rethoxyani linle w as conv erted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3 (-Nmtycr my)4prdlx)4mtyailn according to Method C I a to afford the urea.

Entry 19: 4-Chloropyridine-2-carboflyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl1-2-pyridinecarboxamide was reacted with 4-arninophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbanioyl)-4pyridvloxy)ani line. 5-(Tri fluoromethyI)-2 -methOXyani line was converted into (tifluorornethyl)-2-methoxypheny! isocyanate according to Method BI. WO 00/420 12 PTUO/04 PCTIUSOO/00643 2-methoxyphenyl isocyanate was reacted with 4 2 -(N-ethylcarbamoy1l)-4-py-idyloxy)ani line according to Method C Ia to afford the urea.

Entry 20: According to Method A.2, Step 4, 4 -amino-2 -chi orophenolI was reacted with 4chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4 2 -(N-methylcarbamoyl)4pyr.dyoxy)3chloroaniline. (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyI isocyanate according to Method B 1. 5-(Tifluorornethyl)-2-methoxyphenyI isocyanate was reacted with 4-(2-(N-meihylcarb amoyl)-4-pyi dyloxy)- 3 chloroani line according to Method C 1a to afford the urea.

Entry 21: 4-(4-Methyl thiophenoxy)- 1 -nitrobenzene was oxidized according to Method A 19, Step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reduced according to Method A19, Step 2 to give 4 4 -methylsulfonylphenoxy)-1 -aniline. According to Method Cla, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4methylsuifonylphenoxy)-i -aniline to afford the urea.

Entry 22: 4-(3-carbamoylphenoxy)-1I-nitrobenzene was reduced to 4-(3carbaimoylphenoxy)aniline according to Method A15, Step 4. According to Method Cia, (trilluoromethyl)-2-methoxyphenyl isocyanate was reacted with -3 carbam oylphenoxy)ani line to afford the urea.

Entry 23: 5-(4-Aminophenoxy)isoindoline-l ,3-dione was synthesized according to Method A3. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(tri fiuoromethyl rnethoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyI isocyanate was reacted with 5 -(4-aminophenoxy)i soindoline- 1 ,3 -dione according to Method Cl1 a to afford the urea.

Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N.N-dimethyl-2-pyridinecarboxarnilde was reacted with 4-aminophenol according to Method A2, Step 4 to urve dimethvlcarbarnovl)-4-pyridyloxy)anI line. 5_(Tri fluoromethyl)-2(--methoxyani Ilie U. S WO 00/42012 WO 0042012PCT/USOO/00648 converted into 5-(trifluorornethyl)-2-methoxyphenyl isocyanate according to Method B 1. (Trifluorornethyl)-2-methoxyphenyl isocyaflate was, reacted with 4-(2-(NNdimethylcarb amoy])-4-pyridyloxy)ani line according to Method CI a to afford the urea.

Entry 25: 4-(1 -Oxoisoindo lin-5 -yloxy) aniline was synthesized according to Method A12. (Tri fl uoromethyl)-2 -methoxyani line was treated with CDI, followed by 4-(1-oxoisoindolin-5yloxy)aniline according to Method C2d to afford the urea.

Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step I to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method A13, Step 4 to afford 4-( 4 -acetylphenoxy)aniline, which was converted to the 4-(4-(l1 -(N-methoxy)iminoethyl)phenoxy aniline HG] salt according to Method A 16. 5 -(Trifluoromethyl)-2-methoxyaniline was converted into 5 -(tri fluorom ethyl)- 2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyI isocyanate was reacted with 4-(4-(l1-(N-methoxy)iminoethyl)phenoxyanI line HCl salt to Method C Ia to afford the urea.

Entry 27: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chioropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio) aniline. 5-(Tri fluorom ethyl)-2methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoroinethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-(2-(N-methylcarbarnoyl)phenylthio)aniline according to Method C Ia to afford the urea.

Entry 28: 5 -(4-Aminophenoxy)-2-methylisoindo line- 1 ,3 -di one was synthesized according to Method A9. 5-(Trifluoroxnethyl)-2-methoxyaniline was converted into 5-(trifluoroniethyl)-2methoxyphenyl isocyanate according to Method B 1. S-(Trifluoromethyl)-2-methoxyphenyl.

isocyanate was reacted with aminophenoxy)-2-methyli soindo line- 1,3 -di one according to Method C Ia to afford the urea.

Entry 29: 4-Chloro-N-methylpynidinecarboxamide was synthesized as described in Method A2. Step 3b. The chioropyridine was reacted with 3-aminothiophenol according to Method WO 00/42012 WO 0042012PCT/USOO/00648 A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)pheflylthio)ani line. 5-(Tr-ifluoromethyl)-2methoxyaniline was converted into 5-(trifluoromethyl)-2-metho~xyphenyl isocyanate according to Method B 1. 5-(Trifluorornethyl)-2-methoxyphenyl isocyanate was reacted with 3-(4-(2-(N-rnethylcarbamnoyl)phenylthio)aniline according to Method Cl a to afford the urea.

Entry 3 0: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamnine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide .was reacted with 4-aininophenol according to Method A2, Step 4 to give 4-(2-(NVi sopropylcarbamoyl)-4-pyridyloxy)ani line. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. (Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with isopropylcarbamoyl)-4-pyri dyloxy)ani line according to Method C Ia to afford the urea.

Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A 14. 5 -(Trifluoromethyl)-2-methoxyaniline was converted into 5-(tri fluoroniethyl)-2methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoroinethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(.5-methoxycarbonyl)pyridyloxy)ani line according to Method Cia to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4-(2-amninoethyl)morpholine to afford the amide according to Method D4, Step 2.

Entry 32: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 5 -(Tri fluoromethyl)-2-methoxyani line was converted into 5-(trifluoromethyl)-2methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyI isocyanate was reacted with 4-(3 -methoxycarbonyl)pyridyloxy)ani line according to Method Cia to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5methoxycarbonylpyridyl)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 afford the armide.

WO 00/42012 PCTIUSOO/00648 Entry 33: 4-(3 -(5-Methoxycarbonyl)pyridyloxy)ani line was synthesized according to Method A14. 5-(Tnfluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyI isocyanate was reacted with 4-(3 -methoxycarbonyl)pyridyloxy)ani line according to Method Cia to afford the urea. N-(5-(Trifluoromethyl)- 2-methoxypheny)-N'-(4-(3-(5methoxycarbonylpyridyl)oxy)phelyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with N, N-dimethyl ethyl enedi amine according to Method D4, Step 2 to afford the amide.

Entry 34: 4-(3 -Carboxyphenoxy)ani line was synthesized according to Method All. (Trifluoromethyl)-2 -methoxyaniline was converted into 5-(trifluoromethyl)-2 -methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Cl f to afford (trifluoromethyl)-2-methoxyphenyl)-N

T

-(3-carboxyphenyl) urea, which was coupled with 3aminopyridine according to Method D Ic.

Entry 35: 4-(3-Carboxyphenoxy)ani line was synthesized according to Method All1. (TrifluoromethyD)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-rnethoxyphenyl isocyanate according to Method B 1. 4-(3 -Carboxyphenoxy)ani line was reacted with (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Cif to afford (trifluoromethy1)-2-m~ethoxyphenyl)-N'-(3-carboxypheny) urea, which was coupled with N- (47fluorophenyl)piperazine according-to Method D Ic.

Entry 36: 4-(3-Carboxyphenoxy)ani line was synthesized according to Method Al 1. (Tn fluorornethyl)-2-methoxyaniline was converted into 5-(tnfluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C if to afford (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4fluoroaniline according to Method D Ic.

so0 Entry 37: 4-(3-Carboxyphenoxy)ani line was synthesized according to Method All1. (Trifluoromet hyl)-2-methoxyani line was converted into 5-(trifluoromethyl)-2-methoxyphenyI WO 00/42012 PCTUSOOIOO643 isocyanate according to Method BI. 4 3 -Carbox yp heno xy)ani line was reacted with (trifluoromethyl)-2-methoxyphenyl isocyanate according7 to Method Cif to afford (trifluoromethyl)-2-rnethoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4- (dimethylamino)ani line according to Method Dic.

Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All1. (Tri fl uorom ethyl)-2 -methoxyani line was converted into 5-(trifluoromethyl)-2-methoxyph enyI isocyanate according to Method B 1. 4 3 -Carboxyphenoxy)aniline was reacted with (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C if to afford i0 (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with amino-2-methoxypyridine according to Method Di1c.

Entry 39: 4-(3 -Carboxyphenoxy)ani line was synthesized according to Method Al 1. (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate, according to Method BI. 4 3 -Carb oxyphenoxy)ani line was reacted with (trifluo romethyl)-2-methoxyphenyl isocyanate according to Method CIf to afford (trifluoromethy1)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4morpho linoani line according to Method Di1c.

Entry 40: 4-(3-Carboxyphenoxy)aniiine. was synthesized according to Method Al 1. (Tri fluoromethyl)-2 -methoxyani line was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method BI1. 4 -Carboxyphenoxy)ani line was reacted with (tnifluorornethyl)-2-methoxyphenyl isocyanate according to Method Cl f to afford (tri fluoromethyl)-2 -methoxyphenyl)-N '-(3.-carboxyphenyl) urea, which was coupled with N- (2-pyridyl)piperazine according to Method D Ic.

Entry 41: 4-(3-(N-Methylcarbamoyl)phenoxy)ani line was synthesized according to Method A13. According to Method C3, 4 -chloro-3 -(tri fl uoromethyl)ani line was converted to the.

isocyanate, then reacted with 4 3 -(N-Methylcarbarnoyl)phenoxy)anI line to afford the urea.

WO 00/42012 PCTUSOO/00648 Entry 42: 4 2 -N-Methylcarbamyl-4-pyridyloxy)ani line was synthesized according to Method A2. 4-Chloro-3-(trifluoron-ethyl)phenyl isocyanate was. reacted with 4-(2-Nm ethylIcarbamyl- 4 -pyri dyloxy)ani line according to Method CIa. to afford the urea.

Entry 43: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with ammonia according to Method A2, Step 3b to form 4 -chloro-2-pyridiriecarboxamide. 4-Chloro-2pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to form 4-(2 -carb amoyl -4-pyri dyloxy) aniline. According to Method Cia, 4-chloro-3- (tri fluoromnethyl)phenyl isocyanate was reacted with 4-(2 -carbarnoyl-4-pyidyloxy)ani line to afford the urea.

Entry 44: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with ammonia according to Method A2, Step 3b to form 4 -chloro-2-pyridinecarboxamide. 4-Chloro-2pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method Cia, 4-chloro-3- (trifluoromethyl)phenyl isocyanate was reacted with 3 2 -c arbamoyl-4-pyri dyloxy) aniline to afford the urea.

Entry 45: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-arninophenol according to Method A2, Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cia, 4-chioro- 3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4pyridyloxy)aniline to afford the urea.

Entry 46: 5-(4-Aminophenoxy)isoindo line-l1,3 -dione was synthesized according to Method A3. According to Method Cia, 4 -chloro-3-(trifluoromethyl)phenyl isocyanate was reacted wiih 5-(4-aminophenoxy)isoirndoline- 1,3-dione to afford the urea.

Entry 47: 4-(2 Methy Icarb amoyl)-4-pyri dyloxy)-2 -methyl aniline was synthesized according to Method A5. According to Method Cic, 4 -chloro-3-(trifluoromethy)phenyI isocyanate was reacted with 5-( 4 -aminophenoxy)isoindoline-l,3-dione to afford the urea.

WO 00/42012 WO 0042012PCTIUSOO/00648 Entry 48: 4-(3-N-Methylsulfamoyl)phenyloxy)aniline was synthesized according to Method According to Method Cia, 4-chloro-3-(trifluoromethyl)pheny isocyanate was reacted with 4-(3 -N-m ethylsul famnoyl)phenyloxy)ani line to afford the urea.

Entry 49: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroani line was synthesized according to Method A6. According to Method Cia, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-rnethylcarbamoyl)-4-pyridyloxy)-2-chlo roaniline to afford the urea.

Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3 -(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylani line. According to Method Cia, 4-chloro-3-(trifluoromethyl)phenyI isocyanate was reacted with methylcarbamoyl)-4-pyridyloxy)-4-niethylaniline to afford the urea.

Entry 51: 4-Chloropyridine-2-carbony] chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-amninopheniol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4pyridyloxy)aniline. According to Method Cia, '4-chloro-3 -(trifluoroinethyl)phenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.

Entry 52: According to Method A2, Step 4, 4-ainino-2-chlorophenol was reacted with 4chloro-N-methyl-2-pyr-idinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N-methylc arbamoyl)-4-pyridyloxy)-3 -chloroani line. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with methylc arbamoyl)-4-pyridyloxy)-3 -chioroani line to afford the urea.

Entry 53: 4-(4-Methylthiophenoxy)-lI-nitrobenzene was oxidized according to Method A 19, Step I to give 4-(4-methylsulfonylphenoxy)-lI-nitrobenzene. The nitrobenizene was reduced according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-l -aniline. According to Method Cla, 4-chloro-3-(tnifluoromethyl)phenyl isocyanate was reacted with 4-(4methylsulfonyiphenoxy)- I -aniline to afford the urea.

-WO 00/42012 W0 0042012PCT/USOO/00648 Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamirie according to Method A15, Step 1 to afford N-methyl- 4 -bromobenzenesulfonamide. N-Methyl-4bromobenzenesulfonamide. was coupled with phenol according to Method A15, Step 2 to afford 4-(4-(N-niethylsulfamnoyl)phenoxy)benzene. 4(-N Methylsulfamoyl)phenoxy)benzene was converted into 4 -(4-(N-methylsulfamoyl)phenoxy)- I -nitrobenzene according to Method Al15, Step 3. 4 -(4-(N-Methylsulfamoyl)phenoxy nit robenzene was reduced to 4 4 -N-rnethylsulfamoyl)phenyloxy)ani line according to Method A15, Step 4. .According to Method Cla, 4-chloro-3-(trifluorornethyl)phenyl isocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)ani line to afford the urea.

Entry 55: 5 -Hydroxy-2-m ethylpyri dine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4 2 -Methyl)pyridyloxy)-l-nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid, then esterified according to Method Al18, Step 2 to give 4 2 -methoxycarbonyl)pyridyloxy)-1-nitrobenzene. 'The nitrobenzene was reduced according the Method A18, Step 3 to give methoxycarbonyl)pyridyloxy)aniline The aniline was reacted with 4-chloro-3- (trifiuoromethyl)phenyl isocyanate according to Method C Ia to afford the urea.

Entry 56: S-Hydroxy-2-methylpyri dine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4 2 -Methyl)pyridyloxy)-1-nitrobenzene. 'The methylpyridine was oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2 to give 4 2 -methoxycarbonyl)pyridyloxy)-l-nitrobenizene. The nitro benzene was reduced according the Method A18, Step 3 to give methoxycarbonyl)pyridyloxy)aniline. The aniline was r eacted with 4-chloro-3- (trifluoromethyl)pheriyl isocyanate according to Method Cia to give N-(4-chloro-3- (tri fluoromethyl)phenyl)-N 4 2 -(methoxycarbonyl)-5-pyridyloxy)phenyl) urea. The methyl ester was reacted with methylamine according to Method D2 to afford N -(4-chloro-3- (trifluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamnoyl)-5-pyridyloxy)phenyl) urea.

.S0 Entry 57: N-(4-Chloro-3-( tnifluoromethyl)phenyl-N -(4-aminophenyl) urea was prepared according to M'vethod Cl d. N-(4-Chloro.-3-(trifluoromethyl)phenyl-N -(4-aminophenyl) urea was coupl ed wit~h mono-methyl isophthalate according to Method D Ia to afford the urea.

WO 00/42012 WO 0042012PCTUSOO/00648 Entry 58: N-(4-Chloro-3-(trifluoromethyl)phenyl-N '-(4-aminophenyl) urea was prepared according to Method Cl d. N-(4-Chloro-3-(tifluoromethyl)phenyl-V'-(4-aminophenyl) urea was coupled with mono-methyl isophthalate according to Method Dia to afford AV-(4-chloro- 3-(tri fluoromethyl)phenyl-N '-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea.

According to Method D2, N-(4-chloro-3-(trifluoromethyl)phenyl-N methoxycarbonylphenyl)carboxyaniinopheflyl) urea was reacted with methylamine to afford the corresponding methyl amide.

Entry 59: 4-Chloropyndiiie-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-NN-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(NNdimethylcarbamoyl)-4-pyridyloxy)alhlife. According to Method Cla, 4-chloro-3- (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(NN-dimethylcarbamoyl)-4pyridyloxy)aniline to afford the urea.

Entry 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step I to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was converted to the -(N-methoxy)iminoethyl) phenoxyaniline HCl salt according to Method A 16. According to Method C Ia, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-acetylphenoxy)aniline to afford the urea.

Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-lI-nitrobenzene was .coupled with 4-(2aminoethyl)morpho line according to Method A13, Step 3 to give morpholinylethyl)carbamoyl)pherioxy)-lI-nitrobenzene. According to Method A 13 Step 4, 4- (3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-l1-nitrobenzene was reduced to 4-(3 rnorpholinylethylcarbamoyl)phenoxy)ani line. According to Method Cl a, 4-ch Ioro-3- (tri luoromethyl)phenyl isocyanate was reacted with rnorphol inylethyl)carbamoyl)pheloxy)ani linle to afford the urea.

WO 00/42012 WO 004201PCT/USOOOO6-48 Entry 62: 4-(3-Carboxyphenoxy)- 1-nitrobenzenle was synthesized according to Method A 13, Step 2. 4-(3-Carboxyphenoxy)- I -nitrobenze ne was coupled with 1 -(2-aminoethyl)piperi dine according to Method A13, Step 3 to give 4-(3-(N-(2-piperidylethyl)carbarnoyl)phenoxy)-lnitrobenzene. According to Method A13 Step 4, pipenidylethyl)carbamoyl)PheloxY)-fl-itrobenzene was reduced to piperidylethyl)carbamoyl)phefloxY)aniline. According to Method Cia, 4-chloro-3- (trifluoromethyl)phelyl isocyanate was reacted with* 4-(3 2p iperidylethyl)carbaloyl)pheloxy) anliline to afford the urea.

Entr .y 63: 4-(3-Carboxyphenoxy)-1-nitrobeflzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobelzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4(-N (tetrahydro firylmet hyl)carbamoyl)phenoxy)- 1 -nitrobenzene. According to Method A 13 S tep 4, 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)pheloxy)-l1-nitrobenzene was reduced to 4-(3- (N-(tetrahydrofurylmethyl)carbamoyl)Phenoxy)ali line. According to Method CI a, 4-ch loro- 3-(trifluoromethyl)phenyl isocyanate was reacted with 4(-N (tetrahydrofurylmethyl)carbamfoyl) phenoxy)aniline to afford the urea.

Entry 64: 4-(3-Carboxypheloxy)-l-flitrobelzefe was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-I-litrobeflzene was coupled with 2-arninomethyl-I ethylpyrrolidine according to Method. A13, Step 3 to give methylpyrrolidilyl)methyl)carbamoyl)pheloxy> 1-nitrobenzene. According to Method A 13 Step 4, I-methylpyrro lidinyl)methyl)carbamoyl)phenoxy)-l1-nitrobenzene was reduced to 1 methylpyrrolidinyl)methyl)carbamoylphenoxy)aline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phelYl isocyanate was reacted with methylp yrro li dinyl)methyl)carbamoyl)p heioxy)alilinle to afford the urea.

Entry 65: 4-Chloro-N-methylpyn'dinecarboxarride was synthesized as described in Method A2, Step 3b. The chioropyridine was reacted with 4-atninothiophenol according to Method A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)pheflylthio)aniline. According to Method C Ia. 4-chloro-3-(trifluoromethyl)PhenyI isocyanate was reacted with 4- rnethylcarbamoyl)phenythio.)afliline to afford the urea.

WO 00/42012 WO 0042012PCTfUSOO/00648 Entry 66: 4-Chloropyridine-2-carboflyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with 4-aminiophenol according to Method A2, Step 4 to give isopropylc arbamoyl)-4-pyri dyloxy)ani line. According to Method Cia, 4-chloro-3 (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-isopropylcarbarnoyl)-4pyridyloxy)ani line to afford the urea.

Entry 67: N-(4-Chloro0-3 -(trifl.uoromethyl)phenyl-N '-(4-ethoxycarbonyiphenyl) urea was i0 synthesized according to Method Cl e. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4ethoxycarbonyiphenyl) urea was saponified according to Method D3 to give N-(4-chloro-3- (tri fluoromethyl)phenyl-N '-(4-carboxyphenyl) urea. N-(4-Chloro-3-(trifluoromethyl)phenyl- N'-(4-carboxyphenyl) urea was coupled with 3-rnethylcarbamoylaniline according to Method Dib to give N-(4-chloro-3-(trifluoromethyl)phenyl-N-(4-(3methylcarbamoylphenyl)carbamoylphenyl) urea.

Entry 68: 5-(4-Aminophenoxy)-2-rnethylisoindoline- 1,3-diane was synthesized according to Method A9. According to Method Cia, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)-2 -methylisoindo line- 1,3-dione to afford the urea.

Entry 69: 4-Chloro-N-methylpyridinecarboxainide was synthesized as described in Method A2, Step 3b. The chioropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with mnethylcarbamoyl)phenylthio)aniline to afford the urea.

Entry 70: 4-(2 -(N-(2-Morpho lin-4-ylethyl)carb amoyl)pyridyloxy)ani line was synthesized according to Method Al 0. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyI isocyanate was reacted with 4-(2-(N-(2-morpholIin-4-ylethyl)carbamoyl)pyridyloxy)ani line to afford the urea.

WO 09/42012 WO 0042012PCTIUSOO/00648 Entry 71: 4-(3 -M ethoxyc arboflyl)pyri dyloxy)ani line was synthesized according to Method A14. 4-Chloro-3-(tfluoromethyl)-2-methoxyphelyI isocyanate was reacted with methoxycarbolyl)pyridyloxy)arnline according to Method Cl a to afford the urea. N-(4- Chioro- 3-(trifluoromethyl)pheny'l)-N -methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholifle to afford the amide.

Entry 72: -Methoxycarbolyl)pyridyloxy)ani linle was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)pheflyl isocyanate was reacted with methoxycarbonyl)pyridyIoxy)anilifle according to Method Cia to afford the urea. (Tri fluorom ethyl)- 2 -m ethoxyphenyl)-N -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 afford the amide.

Entry 73: 4-(3 -Methoxycarbayl)pyridyloxy)ali linle was synthesized according to Method A14. 4-Chloro-3-(trifluoroniethyl)phenyl isocyanate was reacted with methoxycarbonyl)pyridyloxy)aflilifle according to Method Cla to afford the urea. (Trifluoromethyl)-2-methoxyphenyl)-N -(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with NN-dirnethylethylenediamine according to Method D4, Step 2 to afford the amnide.

Entry 74: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with 2hydroxyethylamnine according to Method A2, Step 3b to form 4-chloro-N-(2triisopropylsilyloxy)ethylpyridine-2-carboxamide. -4-Chloro-N-( 2triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsi lyl chloride, followed by 4-aminophenol according to Method A17 to form triisopropylsi lyloxy) ethylcarbamnoyl)pyridyloxyani line. According to Method C Ia, 4-chioro- 3-(trifluoromethylphenyl isocyanate was reacted with triisopropylsilyloxy)ethylcarbamoyl) pyri dyloxyani line to afford N-(4-ch Ioro-3 So ((trifluoromethyl)pheflyl)-N '-(4-(4-(2-(N-(2-triisopropylsilyloxy) erhylcarbamoy)pyridyIoxyphefl) urea.

WO 00/42012 WO 0042012PCTfUSOO/00648 Entry 75; 4-(3-Carboxyphenoxy)ani linle was synthesized according to Method All. 4- Chlor-o-3-(tnifluoromethylDphelyl isocyanate was reacted with methoxycarboflyl)pyfldYloxy)alhlinle according to Method Cif to afford the urea, which was coupled with 3-aminopyridine according to Method D Ic.

Entry 76: 4-(3-Carboxypheloxy')aiiiline was synthesized according to Method Al 1. 4- Chloro-3 -(trifluoromethylphenyl isocyanate was reacted with 4-(3-carboxyphenoxy)ani line accordingy to Method Cif to afford the urea, which was coupled with N-(4acetylphenyl)piperazine according to Method D Ic.

Entry 77: 4-(3 -Carboxyphenoxy)ani line was synthesized according to Method Al 1. 4- Chloro-3 -(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)ani line according to Method Cl f to afford the urea, which was coupled with 4-fluoroaniline according to Method Dic.

Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 4- Chloro-3-(trifluoroinethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)ani line according to Method Cl f to afford the urea, which was coupled with 4- (dimethyl aiino)ani line according to Method DIc.

Entry 79: 4-(3-Carboxyphenoxy)ani line was synthesized according to Method Al 11. 4- Chloro-3 -(tr-ifluoromethyl)phenyl isocyanate was reacted with, 4-(3 -carboxyphenoxy)ani line according to Method Cl f to afford the urea, which was coupled with Nphenyl ethyl enediamine according to Method Dic.

Entry 80: 4-(3 -Carboxyphenoxy) aniline was synthesized according to Method All. 4-- Chloro-3-(tri fluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Cl f to afford the urea, which was coupled with 2-methoxyethylamine according to Method Dic.

Entry 8 1: 4-(3-Carboxyphenoxy)ani line was synthesized according to Method All1. 4- Chloro-3-(trifluoromethyl)phelYI isocyanate was reacted with 4-(3-'carboxyphenoxy)aniline WO 00/42012. PCTUSOO/00648 according to Method Cif to afford the urea, which was coupled with methoxypyridine according to Method Dic6.

Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All1. 4- Chloro-3-(trifluorornethyl)phenyl isocyanate was reacted with 4 3 -carboxyphenoxy)ani line according to Method Cl f to afford the urea, which was coupled with 4 -morpholinoani line according to Method D Ic.

Entry 83: 4 -Carboxyphenoxy)ani line was synthesized according to Method Al 1. 4- Chloro-3-(tri fluorornethyl)phenyl isocyanate was reacted with 4 3 -carboxyphenoxy)aniline according to Method Cl f to afford the urea, which was coupled with N-( 2 -pyridyl)piperazine according to Method Dic.

Entry 84: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2hydroxyethylamnine according to Method A2, Step 3b to form '4-chloro-N-(2triisopropylsi lyloxy)ethylpyridine-2-carboxarnide. .4-Chloro-N-,(2 triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with trilsopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to formn triisopropylsi lyloxy)ethylcarbamoyl)pyridyloxyniline. According to Method Cl a, 4-chior o- 3-(trifluoromethyl)phenyl isocyanate was reacted. with trilsopropylsilyloxy)ethylcarbarnoyl)pyridyloxyaniline to give N-(4-chloro-3- ((ti fluoromethyl)phenyl)-N trilisopropylsilyloxy)ethylcaxbamoyl)pyridyloxyphenyl) urea. The urea was deprotected according to Method D5 to afford -N-(4-chloro-3-((tri fluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2 hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea.

Entry 85: 4 2 -(N-Methylcarbanioyl)-4-pyridyloxy)ani line was synthesized according to Method A2. 4 -Bromo-3 -(tri fluoromethyl)ani line was converted to 4-bromo-3- (trifluorornethyl)phenyl isocyanate according to Method BI. According to Method Cla, 4- 36 bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4 -(2-(N-methylcarbamoyl)-4 pyridyloxy)ani line to afford the urea.

WO 00/42012 PCT/USOO/00648 Entry 86: 4 2 -(NV-Methylcarbamoyl)- 4 -pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 4-Bromo-3 -(trifl uorom ethyl)ani line was converted into 4-bromo-3- (trifuorornethyl)phenyl isocyanate according to Method BI. According to Method Cia, 4bromo-3-(triluoromethyi)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4pyridyloxy)-2-chloroaniline to afford the urea.

Entry 87: According to Method A2, Step 4, 4 -arnino-2-chlorophenol was reacted with 4chloro-N-rnethyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N-methylcarbamoy])-4-pyridyloxy)-3-chlo roaniline. 4-Bromo-3- (trifluoromethyl)aniline was converted into 4 -brorno-3-(trifluoromethyl)phenyl isocyanate according to Method Bi. According to Method Cia, 4 -bromo-3-(trifluoromethyl)phenyI isocyanate was reacted with 4-(2-(N-methylcarbaxnoy])-4-pyridyloxy)-3 -chioroani line to afford the urea.

Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4 -chioro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbarnoyl)-4pyridyloxy)aniline. 4-Bromo-3-(trifluorornethyl)aniline was converted into 4-bromo-3- (trifluoromethyl)phenyl isocyanate according to Method B I. According to Method C I a, 4brorno-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-ethylcarbarnoyl)-4pyridyloxy)aniline to afford the urea.

Entry 89: 4-Chloro-N-methyl-2-pyridinecarboxaxnide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3 -(-2-(N-methylcarbamoyl)-4-pyri dyloxy)ani line. 4-Bromo-3-(tnifluoromethyl)ani line' was converted into 4-brorno-3-(trifluoromethyl)phenyI isocyanate according to Method B 1.

According to Method C Ia, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 2- (-2-(NV-methylcarbamoyl)-4-pyridyloxy)ani line to afford the urea.

Entry 90: According to Method A2, Step 4, S-amino-2-merhylphenol was reacted with -4chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Mlethod A2. Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyn'dyloxy)-4-rnethylani line. 4-Brorno-S- WO 00/42012 WO 0042012PCTUSOO/00648 (tri fluoromethyl)ani line was converted into 4-bromo-3 -(trifluoromethyl)phenyl isocyanate according to Method B I. According to Method C la, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3 -(NV-methylcarbaxnoyl)-4-pyridyloxy)-4-methylani line to afford the urea.

Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-NN-di methyl-2-pyridinecarboxarnide was reacted with 4-arninophenol according to Method *A2, Step 4 to give 4-(2-(NNdimethylcarbanoyl)-4-pyridyloxy)aflhline. 4-Bromo-3 -(tri fluoromethyl)ani line was converted into 4-bromo-3-(trifluorornethyl)phenyI isocyanate according to Method* B 1.

According to Method C Ia, 4-brorno-3-(trifluorornethyl)phenyl isocyanate was reacted with 4- (2-(NN-dimethylcarbamoyl)-4-pyridyloxy)ani line to afford the urea.

Entry 92: 4-Chloro-N-methylpyridinecarboxatnide was synthesized as described in Method A2, Step 3b. The chioropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(N-nmethylcarbamnoyl)phenylthio)aniline. 4-Bromo-3)- (tri fluoromethyl)an linle was converted into 4-bromo-3- (trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C la, 4-bromo-3-(trifluorornethyl)phenyl isocyanate was reacted with 4-(4-(2-(N-methylcarbainoyl)phenylthio)aniline to a fford the urea.

Entry 93: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step. 4 to give 3-(4-(2-(N-methylcarbarnoyl)phenylthio)aniline. 4-Bromo-3- (trifl uoromethyl)ani line was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method Cl1a, 4-bromo-3-(trifluorornethyl)phenyl isocyanate was reacted with 3-(4-(2-(N-rnethylcarbamoyl)phenylthio)aniline to afford the urea.

Entry 94: 4-(2-(N-(2-Morpholin-4-ylethyl)carbanoyl)p ldyloxy)anilifle was synthesized according to Method AlO. 4-Bromo-3-(trifluoromethyl)aniline Was converted into 4-bromo- 3-(tri fluoromethyl)pheny[ isocyanate according to Method B 1. According to Method C Ia, 4- WO 00/42012 PCT/USO0100648 bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-(2-Morpholin-4yl ethy l)c arb amnol)pvri dylfoxy) ani Iine to afford the urea.

Entry 95: 4 2 -(N-Methylcarbarnoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4 -Chloro-2 -me thoxy- 5-(tri fluoromethy])ani line was synthesized according to Method A7T 4-Chloro-2-rnethoxy- 5-(tri fluoromethyl) aniline was converted into 4-chloro-2isocyanate according to Method B 1. According to Method Cl a, 4-chioro-2 -rethoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4- (2 -(N-methylcarbamoy])-4-pyridyloxy)anI line to afford the urea.

Entry 96: 4-(2 ethylcarb amoyl)-4-pyridyloxy)-2 -chloro aniline was synthesized according to Method A6. 4- Chloro-2 -rethoxy- 5-(tri fluorornethyl) aniline was synthesized according to Method A7. 4-Chloro-2 -methoxy-5-(tri fluoromethyl) aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method BI.

Accordingr to Method Cia, 4-chloro-2-methoxy-5-tr-ifluoromethyl)phenyI isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline afford the urea.

Entry 97: According to Method A2, Step 4, 4-ainino-2-chlorophenol was reacted with 4chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Chloro-2was synthesized according to Method A7. 4-Chloro-2methoxy- 5 -(trifluoromethyl) aniline was converted into 4-chloro-2-methoxy-5 (trifluoromethyl)phenyl isocyanate according to Method B I. According to Method C Ia, 4chloro-2 -methoxy-5-(trifluorornethyl)phenyl isocyanate was reacted with 4-(2 m ethy lcarbamoyl)-4-pyri dyloxy)-3-chloroani line to afford the urea.

Entry 98: 4-Chloro-N-m ethyl -2 -pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to fo rm 3(+2 meth yIc arbamoyl)-4-pyri dyloxy)aniline. 4-Chloro-2 -m et hox y-5 '0 (triiluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-rnethoxy-S- (trifluoromethyl)ani line was converted into 4-chloro-2-methoxy-5-(tri fIloromcethvl )phcnvl, isocyanate according to Method BI. According to Method Cla, 4-chloro-2-rnthoxy-5> WO 00/42012 WO 0042012PCTIUSOO/00648 (trifluoromethyl)pheflyl isocyanate as was reacted with 3)-(-2-(N-methylcarbarnovl)-4pyridyloxy)aniline to afford the urea.

Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-NV-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A-9, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4pyridyloxy)ani line. 4-Chloro-2-methoxy-5 -(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2 -methoxy-5 -(trifluoromethyl) aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B 1.

io According to Method Cia, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyI isocyanate was reacted with 4-(2-(N-ethylcarbaxnoyl)-4-pyridyloxy)aniline to afford the urea.

Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-NN-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A.2, Step 4 to give 4-(2-(NNdimethylcarbamnoyl)-4-pyridyloxy) anilinle. 4-Chloro-2-methoxy-5 tri fluoromethyl)ani line was synthesized acc ording to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyI isocyanate according to Method B 1. According to Method Cia, 4-chloro-2-methoxy-5-(trifluoroniethyl)phenyI isocyanate was reacted with 4-(2-(NN-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea- Entry 101: 4-Chloro-N-methyl-2-pyridinecarboxarnide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form -(N-methylcarbamnoyl)-4-pyridyloxy)aniline. 2-Amino-3-methoxynaphthalene was synthesized as described Method Al. According to Method C3, 2-amino-3methoxynaphthalene was reacted with bis(trichloroniethyl) carbonate followed by methylcarbamoyl)-4-pyridyloxy)ani line to form the urea.

Entry 102: 4-(2-(NV-Methylcarbamoyl)-4-pyridyloxy)anI line was synthesized according to Method A2. S-terrt-Butyl-2-(2,5-dimethylpyrrolyl)aniiline was synthesized according to WO 00/42012 PCT/US00/00648 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 afford the urea.

Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b, reaction of 3-amino-2methoxyquinoline with CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline afforded bis(4-(2-(N-methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.

Listed in the Tables below are compounds which have been synthesized according to the Detailed Experimental Procedures given above: Tables The compounds listed in Tables 1-6 below were synthesized according to the general methods shown above, and the more detailed exemplary procedures are in the entry listings above and characterizations are indicated in the tables.

WO 00/42012 WO 0042012PCTIUSOO/00648 Table 1.

3-tert-Butyipbenyl Ureas 0 RN N Al H H TLC Mass mp HPLC TLC Solvent Spec. Synth.

Entry R (min.) System [Source] Method 0.22 50% 418 A 1 C3 NH EtOAc (M Me 1 50%

(HPLC

0 hexane ES-MS) 2 0 0.53 -50% 403 A13 C3 0\ EtOAc (M±H)i Me 1 50% (HPLC ___hexane ES-MS) 3 0 133- 0.68 100% 448 A8 C2d NH 135 EtOAc (M-fH)+ Me

(FAB)

'0 OMe Table 2.

5-tert-Butyl-2-methoxyphenyl Ureas 0 RN J

N

H H OMe TLC Mass mp HPLC TLC Solvent Spec. Synth.

Entry R (mini.) Syt LS-ourcel Method 4 0 5.93 448 A13 NH

BI

Me (HPLC Cla 0-6

ES-MS)

120- 0.67 100% 478 A8 NH 122 EtOAc C2d Me

(FAB)

OMe 6 0.40 50% 460 A3 0_<EtOAc C2d NH /50% (HPLC hexane ES-MS) 0 WO 00/4201 2 WO 0042012PCTIUSOOOO64S 0.79 50% 446 IA12 EtOAc (M+H)4 C2d 1 50% (HPLCV hexane ES-MS) Table 3.

5-(Trifluoromlethyl)-2-methoxypheflyI Ureas

F

F F

N

H H OMe TLC Mass mp HPLC TLC Solvent 'Spec. Synth.

Entr R Rf System, rSource1 Method 8 0 250 460 A 13 N H (dec) C2a Me

(FAB)

0 9 0 206- 0.54 10% 446 A3 step 0208 MeOH 2, N a Mie 90% (1{PLC A8 step CH2CI ES-MS) 4, 2 Bi1, 0 0.33 50% 445 A13 C3 pet ES-MS) ether 11 0 0.20 2% 461 A2 Et3N/ C4 Me 98% (HPLC o- N EtOAc ES-MS) 12 0 0.27 1 447 A2

NH

2 Et3N/ C4 -Q 99% (HPLC 0- N EtOAc ES-MS) 13 0 0.62 100% 461 A2 C2a NH EtOAc Me

(FAB)

0-

N

14 0 114- 0.40 1% 447 A2

NH

2 117 Et3N/ C4 99% (FAB) N EtOAc WO 00/42012 WO 0042012PCTUSOO/00648 0 232- 0.54 100% 490 AS C2d NH 235 EtOAc (M-iH)+ Me

(FAB)

0 /OMe 16 0 210- 0.29 475 Me NH 213 MeOH BI Cic Me /45% (HPLC 0- /N EtOAc ES-MS) pet ether______ 17 0 187- 0.17 50% 495 A6 ciNH 188 EtOAc BI Cla Me /50% (HPLC 0 N pet ES-MS) -x ether 18 0 0.48 100% 475 A2 step Me NH 2 EtOAc 4, (HPLC BI Cla 0 /N

ES-MS)

19 0 194- 0.31 5% 475 A2 NH 196 MeOH BI Cla Et 45% (HPLC 0 N EtOAc ES-MS) c 0150% pet ether______ 0 214- 0.25 5% 495 A2 Cla CI NH 216 MeOH Me 45% (HPLC 0- N EtOAc ES-MS) 150% pet ether 21 208 0.30 50% 481 A19 C2a 0 Sz 210 EtOAc -M e /50% (HPLC ___hexane ES-MS) 22 0 188- 0.30 70% 447

NH

2 190 EtOAc step 4.

(HPLC Cla 0 hexane ES-MS) 23 00.50 70% 472 A3 0 EtOAc BI Cla NH 30% (FAB) hexane 24 0 Me 203- 0.13 100% 479 A2 BI Ni 205 EtOAc Cla me

(HPLC

0 N

ES-MIS)

WO 00/42011 WO 0042012PCTUSOO/00648 0 Meq,

N

EtOAc 0.0925% hexane (M-iH)+

(HPLC

ES-MS)

4 4 -1- 169- 171 50% EtOAc 150% pet ether 474

(HPLC

ES-MS)

A13 step 1, A13 step 4, A 16,

BI

Cla 1 4 F I 27 0

N.H

S Me 50% EtOAc 1 50% pet ether 477 (M+H)i

(HPLC

ES-MS)

A2 step 3b, A2 step 4, B 1, Cla

F

28 0 212- 0.30 40% A9 214 EtOAc BI Cla NMe hexane 0 7290 0.33 50% 474 A2 step NH EtOAc 3b, Me /150% (HPLC A2 step -9 C N pet ES-MS) 4, /ether

BI,

0 210- A2 NH 211 B I Pr-i Cla 0 N 31 0 210- 0.43 10% A14 NH 204 MeOH BI Cla 0N CH2CI D4 32 0 247- 0.57 10% A14 NH 249 MeOH B1 e ICla 0CH2CI D4 0 2 N 33 0 217- 0.07 10% A14 NH 219 MeOH BI Cla 0 MN-ME CH2C1 D4 N M 2 WO 00/42012 WO 0042012PCTIUSOO/00648 Table 4.

3-(Trifluorornethyl)-4-chlorophenyl Ureas

F

F F 0

NOV

R-N J

N

H H WO 00/42012 WO 0042012PCTUSOO/00648 1TLC Mass nip HPLC TLC Solvent Spec. Synth.

EtyR (nin.) R( System Isourcel Method 41 0163- 0.08 50% 464 A 13 NH 165 EtOAc! C3 Me 50% pet (HPLC ether ES-MS) 42 0 215 0.06 50% 465 A2 NH EtOAc! Cla Me 50% pet (HPLC -0 Nether

ES-MS)

43 0 0.10 50% 451 A2

NH

2 EtOAc/ Cla 50% pet (HPLC a \N ether ES-MS) 44 0 0.25 30% 451 A2

NH

2 EtOAc! Cia 70% pet (HPLC o-CX N ether ES-MS) 0 0.31 30% 465 A2 NH EtOAc/ Cla 'me 70% pet (HPLC o C\ ether ES-MS) 46 0.23 40% .476 A3 0 179 EtOAc! Cla NH 60% (FAB) hexane 47 0 0.29 5% 478 A M e N H MeOH/A Cic Me 45% (HPLC 0 -jN-EtOAc/

ES-MS)

50% pet ______ether 48 0"0 206- eS-NH 209 Cla Me 49 0 147- 0.22 50% 499 A6 Cl NH 151 EtOAc! (M Cla Me 50% pet (HPLC a N .ether ES-MS) so/~0 0.54 100% 479 A2 ~Me -NH EtOAc Cla Me

(HPLC

0 N

ES-MS)

WO 00/42012 WO 0042012PCTIUSOO/00648 51 0 187- 0.33 5% 479 A2 NH 189 MeOI Cla Et 45%

(HPLC

0- N EtOAc/ ES-MS) 50% pet ether 52 0 219 0.18 5% 499 A2 cI NH MeOH/ Cla Me 45%

(HPLC

\-lN EtOAc! ES-MS) pet ether 53 0 246- 0.30 50-1% 485 A 19, Cla 0 0 248 EtOAc! -a l Me 50% (HPLC ___hexane 54 1 196- 0.30 70% 502 AIS 0 o 200 EtOAc! Cia NH 30% (HPLC Me ____hexane) ES-MS) 550 228- 0.30 30% 466 0 230 EtOAc! Me 70% (HPLC 0- N CH2CI2 ES-MS) 56 -N 0 238- 0 245

NH

Me 57 0 221- 0.75 80% 492 Cld 222 EtOAc! (M±H)4 Dia H 0 Me 20% (FAB) -o NI- hexane 58 0 247 0.35 100% Cid NH- EtOAc Dla H 0 Me D2 59 0 Me 198- 0.09 100% 479 A2 Ni 200 EtOAc Cia 'me

(HPLC

0e \N

ES-MS)

MeOl 158- 0.64 N 160 EtOAc/ 0 pet Me ether 61 0 195- 0.39 10% A 13 NH 197 MeOH/ Cla N 2 00 WO 00/42012 PCT[USOO100648 WO 00/42012 PCTIUSOO/00648 WO 00/42011 WO 0042012PCTIUSOO/00648 79 0 0.47 70% 569 All NH EtOAc/ Cif 11 30% (HPLC Dic "0 NH hexane ES-MS) 0 0.18 70% 508 All NH EtOAc! Cif (HPLC Dic 0- OMe hexane ES-NIS) 81 N 0.58 70% 557 All MeO NH EtOAc! (M+H)f Cif 0 30% (HPLC Dic hexane ES-MS) 82 0.37 70% 611 All O N NH EtOAc! Clf 0 30% (HPLC Dic .\hexane ES-MS) o0 83 0.19 70% All N EtOAc/ Clf Dlc N hexane

N

84 0 179- A2 N H 183 A17 0e \N OH Table 5.

3-(Trifluoromethyl)4-brolopheflyl Ureas

F

F F 0 Br R N 'kN H H WO 00/42012 WO 0042012PCTIUSOO/00648 TLC Mass mp HPLC ITLC Solvent Spec. Synth.

R (min.) R( Sse (Source] Method 850 186- 0.13 50% 509 A2 NH 187 EtOAc! BI Me 50% pet (HPLC ES- Cla O-e Nether

MS)

86 0 150- 0.31 50% 545 A6 ClNH 152 EtOAc! B I M4e 50% pet (HPLC ES- Cla Nether

MS)

87 0 217- 0.16 50% 545 A2 ci NH 219 EtOAc! BI Me 50% pet .(HPLC ES- Cia $O X N ether MS) 88 0 183- 0.31 50% 525 A2 NH 184 EtOAc! (M+H)f BI Et 50% pet (HPLC ES- Cia 0 N ether MS)

/II

890 0.21 50% 511 A2 NH EtOAc/ B I Me 50% pet (HPLC ES- Cla o elN ether MS) 0 0.28 50% 525 A2 Me NH EtOAc/ B 1 'Me 50% pet (HPLC ES- Cla 0 N ether MS) 91 0 Me 214- 0.28 50% 522 A2 r4 216. EtOAc/ B I 'Me 50% pet (H~PLC ES- Cia N ether MS) 92 0 0.47 50% 527 A2 step NH EtOAc! 3b.

Me 50% pet (HPLC ES- A2 step S N ether MS) 4, 93 0 0.46 50% 527 A2 step NH EtOAc! -1b.

'me 50% pet (HPLC ES- A2 step S -N ether MS) 4.

B81.

Cla WO 00/42012 WO 0042012PCTIUSOO/00648 0

NH

0- N 145- 150 MeOIV CH2C12

N

0 Table 6. 5-(Trifluorometliyl)-4-chloro-2-methoxyphenyl Ureas FF F 0

C

RN N '1 H H OMe TLC Mass mp HPLC TIC Solvent Spec. Synth.

FnR (OC) :R System rSourcel Method 0 140- 0.29 45%, 495 A2 NH 144 MeOHW A7 Me 45% (HPLC BI O- N EtOAc! ES-MS) Cla 50% pet ether 96 0 244- 0.39 5% 529 A6 ciNH 245 MeOI A7 Me 45% (HPLC B!I N EtOAc! ES-MS) Cla 50% pet ether 97 0 220- 0.25 5% 529 A2 Cl NH 221 MeOI A7 Me 45% (HPLC

B!I

-e N EtOAc! ES-MS) Cla 50% pet ~ether 98 0 0.27 5% 495 A2 NH MeO~i A7 Me 45% (HPLC B1I 0- N EtOAc! ES-MS) Cla 50% pet Iether '99 0 180- 0.52 5% 509 A2 N H 181 MeOWI A7 Et 45% (HPLC B!I O- lN EtOAc! ES-MS), Cla 50% pet ether_____ 100 0 162- A2 NH 165 A7 Pr-i B I X N Cla WO 00/42012 PCT/USOO/00648 Table 7.

Additional Ureas TLC Mass mp HPLC TLC Solvent Spec. Synth.

Entry__ R (min.) Rf System [Source] Method 101 0 162- Al S N 0 NH 165 A2 O jj C3 N N OMe H H 102 0 0.10 50% 442 A2 0 EtOAc/ A4 0 0 NH 50% (HPLC C2d LNflNa N Me hexane ES-MS) SH H Me Me 103 0 125- 0.24 40% 512 A2 130 EtOAc/ C2b HN NH 60% (FAB) 0 N N~ hexane 0 0 0 0 NH-Me Me-NH The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

P:\WPDOCS\Hjw\Specs 2\7619730.dc-24/02/04 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

88A

Claims (56)

1. 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 of up to 40 carbon atoms of the formula: )q where L is a 5 or 6 membered cyclic structure bound directly to D, L' comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L' contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L' is substituted by at least one substituent selected from the group consisting of-SO2Rx, -C(O)Rx and -C(NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally halosubstituted, up to per halo, Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; Rx is Rz or NRaRb where Ra and Rb. are a) independently hydrogen, a carbon based moiety of up to 30 carbon. atoms optionally containing heierouaoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen, or -OSi(Rr)3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of i0 1-3 heteroatoms selected from N, S and 0 substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or c) one of Ra or Rb is a CI-Cs divalent alkylene group or a substituted Ci- C 5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least members, wherein the substituents of the substituted Ci-C 5 divalent alkylene group are- selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; where B is substituted, L is substituted or L' is additionally substituted, the i substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of -CN, -C0 2 R 7 -C(0)NRR 7 -NO 2 -OR 7 -SR 7 -NR 7 R 7 -NR 7 C(O)OR 7 -NR 7 C(O)R 7 -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by 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'C(O)R 7 -NR 7 C(0)OR 7 and halogen up to per-halo; with each R 7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N. S and 0 and optionally substituted by halogen, wherein Q is -(CH 2 -(CH 2 -(CH 2 )mS-, -(CH 2 )mN(R -O(CH2)m- CHX a -CX 2 -S-(CH 2 and -N(R 7 )(CH 2 where m= 1-3, and X' is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 R 7 -C(O)R 7 -C(O)NR R 7 NO 2 -OR 7 SR 7 -NR 7 R 7 -NR'C(0)OR 7 -NR C(O)R 7 and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents selected from the group consisting of-CN, -C0 2 R 7 COR 7 -C(O)NR 7 -OR 7 -SR 7 -NO 2 -NR 7 R 7 -NR C(O)R 7 and -NR 7 C(O)OR 7 with R 7 as defined above.

2. A compound as in claim I wherein: Ry is hydrogen, CI-lo alkyl, Ci-lo alkoxy, C 3 1 0 o cycloalkyl having 0-3 heteroatoms, C 2 alkenyl, C 1 i-o alkenoyl, C 6 -1 2 aryl, C3- 1 2 hetaryl having 1-3 heteroatoms selected from N, S and 0, C 7 2 4 aralkyl, C7- 24 alkaryl, substituted Ci-lo alkyl, substituted CI- 1 0 alkoxy, substituted C 3 1 0 cycloalkyl having 0-3 heteroatoms selected from N, S and 0, substituted C 6 -C 14 aryl, substituted C3-1 2 hetaryl having 1-3 heteroatoms selected from N, S and 0, substituted C7-2 4 alkaryl or substituted C 7 -C 24 aralkyl, where Ry is a substituted group, it is substituted by halogen up to per halo, Rz is hydrogen, Cl-jo alkyl, Cl-o alkoxy, C3- 1 0 cycloalkyl having 0-3 heteroatom, C 2 alkenyl, Cilio alkenoyl, C 6 -1 2 aryl, C 3 -Ci 2 hetaryl having 1-3 heteroatoms selected from, S, N and O, C 7 24 alkaryl C7- 24 aralkyl, substituted C-o 10 alkyl, substituted C.lo alkoxy, substituted C 6 -C 1 4 aryl, substituted C 3 -CIo cycloalkyl having 0-3 heteroatoms selected from S, N and 0, substituted C3-1 2 hetaryl having 1-3 heteroatoms selected from S, N and 0, substituted C-._4 alkaryl or substituted C 7 -C 24 aralkyl where Rz is a substituted group, it is substituted by halogen up to per halo, hydroxy, Ci-o alkyl, C3. 1 2 cycloalkyl having 0-3 heteroatoms selected from 0. S and N, C,. 12 hetaryl having 1-3 heteroatoms selected from N, S and 0. C.i0, alkoxy, C6- 1 2 aryl, CI-6 halo substituted alkyl up to per halo alkyl, C 6 -Ci 2 halo substituted aryl up to per halo aryl, C 3 -C 2 halo substituted cycloalkyl up to per halo cycloalkyl having 0-3 heteroatoms selected from N, S and 0, halo substituted C 3 -Ci 2 hetaryl up to per halo hetaryl having 1-3 heteroatoms selected from 0, N and S, halo substituted C 7 -C 24 aralkyl up to per halo aralkyl, halo substituted C 7 -C 24 alkaryl up to per halo alkaryl, and -C(O)Rg, Ra and Rb are, a) independently hydrogen, a carbon based moiety selected from te group consisting of Cl -Cio alkyl, C, Cio alkoxy, C 3 1 0 cycloalkyl, C2-1 0 alkenyl, Ci.lo alkenoyl, C 6 -1 2 aryl, C3- 12 hetaryl having 1-3 heteroatoms selected from 0, N and S, C 3 -12 cycloalkyl having 0-3 heteroatoms selected from N, S and 0, C 7 24 aralkyl, C 7 -C 2 4 alkaryl, substituted Ci-io alkyl, substituted C.-1o alkoxy, substituted C 3 o cycloalkyl, having 0-3 heteroatoms selected from N, S and 0, substituted C 6 12 aryl, substituted C3- 1 2 hetaryl having 1-3 heteroatoms selected from N, S and 0, substituted C7- 2 4 aralkyl, substituted C7- 2 4 alkaryl, where Ra and Rb are a substituted group, they are substituted by halogen up to per halo, hydroxy, Ci-lo alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C3- 1 2 hetaryl having 1-3 heteroatoms selected from N, S and 0, Ci-io alkoxy, C 6 -1 2 aryl, C 1 6 halo substituted alkyl up to per halo alkyl, C 6 -Ci 2 halo substituted aryl up to per halo aryl, C 3 -Ci 2 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and 0, up to per halo cycloalkyl, halo substituted C 3 -C 12 hetaryl up to per halo heteraryl, halo substituted C 7 -C 24 aralkyl up to per halo aralkyl, halo substituted C 7 -C 24 alkaryl up to per halo alkaryl, and -C(0)Rg or -OSi(Rf)3 where Rr is hydrogen, Cl-o 0 alkyl, CI. 1 o alkoxy, C 3 -CIo cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C 6 1 2 aryl, C 3 -Ci 2 hetaryl having 1-3 heteroatoms selected from 0, S and N, C7- 24 aralkyl, substituted C 1-10 alkyl, substituted CI- CIo alkoxy, substituted C 3 -CI2 cycloalkyl having 0-3 heteroatoms selected from 0, S and N, substituted C 3 -C 1 2 heteraryl having 1-3 heteroatoms selected from 0, S, and N, substituted C 6 12 aryl, and substituted C 7 2 4 alkaryl, where Rf is a substituted group it is substituted halogen up to per halo, hydroxy, C 1 1 o alkyl, C 3 12 cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C.i-1 hetaryl having 1-3 heteroatoms selected from N, S and 0, Ci.io alkoxv. aryl. C 7 -C4 alkaryl, C 7 -C 2 z aralkyl, Ci-6 halo substituted alkyl up to per halo I alkyl, C 6 -C 1 2 halo substituted aryl up to per halo aryl, C 3 -Ci 2 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and 0, up to per halo cycloalkyl, halo substituted C 3 -CI 2 hetaryl up to per halo heteraryl, halo substituted C 7 -C 24 aralkyl up to per halo aralkyl, halo substituted C7-C 24 alkaryl up to per halo alkaryl, and -C(O)Rg, or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0 with substituents selected from the group consisting of halogen up to per halo, hydroxy, CI-to alkyl, C3- 1 2 cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C3- 1 2 hetaryl having 1-3 heteroatoms selected from N, S and 0, CiI-0 alkoxy, C6- 1 2 aryl, C 7 -C 24 alkaryl, C 7 -C 24 aralkyl, halo substituted CI-6 alkyl up to per halo alkyl, halo substituted C 6 -CI2 aryl up to per halo aryl, halo substituted C 3 -C 12 cycloalkyl having 0-3 heteroatoms selected from N, S and 0, up to per halo cycloalkyl, halo substituted C 3 -CI 2 hetaryl up to per halo heteraryl, halo substituted C 7 -C 24 aralkyl up to per halo aralkyl, halo substituted C 7 -C 24 alkaryl up to per halo alkaryl, and -C(O)Rg; or c) one of Ra or Rb is a CI-C 5 divalent alkylene group or a substituted Ci- Cs divalent alkylene group bound to the moiety L to form a cyclic structure with at least members, wherein the substituents of the substituted Ci-C 5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, Ci-o alkyl, C3- 1 2 cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C3- 1 2 hetaryl having 1-3 heteroatoms selected from N, S and 0, Ci. 1o alkoxy, C 6 -1 2 aryl, C 7 -C 24 alkaryl, C7 -C 24 aralkyl, CI-6 halo substituted alkyl up to per halo alkyl, C 6 -CI 2 halo substituted aryl up to per halo aryl, C 3 -Ci 2 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and 0, up to per halo cycloalkyl, halo substituted C 3 -Ci 2 hetaryl up to per halo heteraryl, halo substituted C7-C 24 aralkyl up to per halo aralkyl, halo substituted C 7 -C 2 4 alkaryl up to per halo alkaryl, and -C(O)Rg, where Rg is Ci-o 0 alkyl; -CN, -CO2Rd, -OR, -SRd, NRj C(O)ORe and -NR C(O)R 4 and Rd and R, are independently selected from the group consisting of hydrogen, C1_ 10 alkyl, C 1 0o alkoxy, C 3 10 cycloalkyl having 0-3 heteroatoms selected from 0, N and S, C 6 -1 2 any], C 3 C 1 2 hetaryl with 1-3.heteroatoms selected from 0, N and S and C 7 -C 24 aralkyl, C 7 -C 24 alkaryl, up to per halo substituted C 1 -C 10 alkyl, up to per halo substituted C 3 -CIO cycloalkyl having 0-3 heteroatoins selected from 0, N and S, up to per halo substituted C 6 -C 1 4 aryl, up to per halo substituted C 3 -C 1 2 hetaryl having 1-3 heteroatoms selected from 0, N, and S, halo substituted C 7 -C 24 alkaryl up to per halo alkaryl, and up to per halo substituted C 7 -C 24 aralkyl, W is independently selected from the group consisting of -CN, -C0 2 R 7 -C(0)NR 7 R 7 -C(O)-R 7 -NO 2 -OR 7 -SR 7 -NR 7 R 7 _NR 7 C(O)0R 7 -NR 7 C(O)R 7 C 1 -C 10 alkyl, CI-CIO alkoxy, C 2 -C 10 alkenyl, C 1 -C 10 alkenoyl, C 3 -C 10 cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C 6 -CI 4 aryl, C 7 -C 24 alkaryl, C 7 -C 24 aralkyl, C 3 -C 12 heteroaryl having 1-3 heteroatoms selected from 0, N and S, C 4 -C 23 alkheteroaryl having 1-3 heteroatoms selected from 0, N and S, substituted C 1 -C 10 alkyl, substituted C 1 -CI 0 alkoxy, substituted C 2 -CIO alkenyl, substituted CI-Cl 0 alkenoyl, substituted C 3 -C 10 cycloalkyl having 0-3 heteroatoms selected from 0, N and S, substituted C 6 -CI 2 aryl, substituted C 3 -CI 2 hetaryl haying 1-3 heteroatoms selected from 0, N and S, substituted C 7 -C 24 aralkyl, substituted C 7 -C 24 alkaryl, substituted C 4 -C 23 alkheteroaryl having 1-3 heteroatoms selected from 0, N and S, and -Q- Ar; R 7is independently selected from H, CI-CI 0 alkyl, CI-CI 0 alkoxy, C 2 -CI 0 alkenyl, C 1 CIO alkenoyl, C 3 -CIO cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C 6 -C 1 4 aryl, C 3 -C 1 3 hetaryl having 1-3 heteroatoms selected from 0, N and S, C 7 -CI 4 alkaryl, C 7 -C 24 aralkyl, C 4 -C 23 alkheteroaryl having 1-3 heteroatoms selected from 0, N and S, up to per- halosubstituted C 1 -C 10 alkyl, up to per-halosubstituted C 3 -C 10 cycloalkyl having* 0-3 heteroatoms selected from 0, N and S, up to per-halosubstituted C 6 -CI 4 aryl, up to per- halosubstituted C 3 -CI 3 hetaryl having 1-3 heteroatoms selected from 0, N and S, up to per- halosubstituted C 7 -C 24 aralkyl, up to per-halosubstituted C 7 -C 24 alkaryl, and up to per- halosubstituted C. 4 -C 23 alkheteroary]; and each Z is independently selected from the group consisting of-CN, -CO 2 R 7 -C(O)R 7 -C(O)NR 7 R, -NO 2 -OR 7 SR 7 -NR'R 7 -NR 7 C(O)OR 7 -NR 7 C(O)R 7 Cl-Co 0 alkyl, Ci-Cio alkoxy, C 2 -Clo alkenyl, Ci-Clo alkenoyl, C 3 -Clo cycloalkyl having 0-3 heteroatoms selected from 0, N and S, C 6 -Ci 4 aryl, C 3 -C 13 hetaryl having 1-3 heteroatoms selected from 0, N and S, C 7 -C 24 alkaryl, C 7 -C 2 4 aralkyl, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from 0, N and S, substituted Ci-Clo alkyl, substituted Ci-Cio alkoxy, substituted C2-Cio alkenyl, substituted Ci-Cio alkenoyl, substituted C 3 -CIo cycloalkyl having 0-3 heteroatoms selected from 0, N and S, substituted C 6 -CI2 aryl, substituted C 7 -C 24 alkaryl, substituted C 7 -C 24 aralkyl and substituted C 4 -C 23 alkheteroaryl having 1-3 heteroatoms selected from 0, N and S; wherein if Z is a substituted group, the one or more substituents are selected from the group consisting of -CN, -C0 2 R 7 -COR 7 -C(0)NR 7 R 7 -OR 7 -SR 7 -NO 2 -NR 7 -NR C(O)R and -NR 7 C(O)OR 7

3. A compound as in claim 1 wherein M is one or more bridging groups selected from the group consisting of -N(R 7 -(CH 2 -(CH 2 (CH 2 -(CH 2 )mN(R 7 -O(CH 2 CHX a -CXa2 -S-(CH 2 and -N(R 7 )(CH 2 where m= 1-3, X' is halogen and R 7 is as defined in claim 1.

4. A compound as in claim 1 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by-OH.

5. A compound as in claim I wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by a moiety having an ionizable hydrogen and a pKa of 10 or less.

6. A compound of claim 1 wherein B of Formula I is a substituted or unsubstituted six member aryl moiety or six member hetaryl moiety, said hetaryl moiety having 1 to 4 members selected from the group of hetaryl atoms consisting of nitrogen, oxygen and sulfur with the balance of the hetaryl moiety being carbon.

7. A compound of claim I wherein B of Formula I is an unsubstituted phenyl group, an unsubstituted pyridyl group, an unsubstituted pyrimidinyl, a phenyl group substituted by a substituent selected from the group consisting of halogen and Wn wherein W and n are as defined in claim 1, a pyrimidinyl group substituted by a substituent selected from the group constituting of halogen and Wn, whereas W and n are as defined in Claim 1, or a substituted pyridyl group substituted by a substituent selected from the group consisting of halogen and Wn wherein W and n are as defined in claim 1.

8. A compound of claim 6 wherein B of Formula I is a substituted phenyl group, a substituted pyrimidinyl group, or substituted pyrridyl group substituted I to 3 times by 1 or more substituents selected from the group consisting of -CN, halogen, CI-Clo alkyl, Ci-Clo alkoxy, -OH, up to per halo substituted CI-Clo alkyl, up to per halo substituted Ci-CIo alkoxy or phenyl substituted by halogen up to per halo.

9. A compound of claim 1, wherein L, the six member cyclic structure bound directly to D, is a substituted or unsubstituted 6 member aryl moiety or a substituted or unsubstituted 6 member hetaryl moiety, wherein said hetaryl moiety has 1 to 4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur with the balance of said hetaryl moiety being carbon, wherein the one or more substituents are selected from the group consisting of halogen and Wn wherein W and n are as defined in. claim 1. A compound of claim 8, wherein L, the 6 member cyclic structure bound directly to D, is a substituted phenyl, unsubstituted phenyl, substituted pyrimidinyl, unsubstituted pyrimidinyl, substituted pyridyl or unsubstituted pyridyl group.

11. A compound of claim 1, wherein said substituted cyclic moiety L' comprises a 5 to 6 membered aryl moiety or hetaryl moiety, wherein said heteraryl moiety comprises I to 4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur.

12. A compound of claim 1, wherein said substituted cyclic moiety L' is phenyl, pyridinyl or pyrimidinyl.

13. A compound of claim 3, wherein said substituted cyclic moiety L' is phenyl, pyridinyl or pyrimidinyl.

14. A compound of claim 6, wherein said substituted cyclic moiety L' is phenyl, pyridinyl or pyrimidinyl. A compound of claim 8, wherein said substituted cyclic moiety L' is phenyl. pyridinyl or pyrimidinyl.

16. A compound of claim 9, wherein said substituted cyclic moiety L' is phenyl, pyridinyl or pyrimidinyl.

17. A compound of claim 10, wherein said substituted cyclic moiety L' is phenyl, pyridinyl or pyrimidinyl.

18. A compound of claim 14, wherein M is one or more bridging groups selected from the group consisting of -N(R 7 -(CH 2 -(CH 2 (CH 2 -(CH 2 )mN(R 7 -O(CH 2 CHX a -CXa 2 -S-(CH 2 and -N(R )(CH 2 where m= 1-3, Xa is halogen and R 7 is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by 10 halogen up to per halo.

19. A compound of claim 15, wherein M is one or more bridging groups selected from the group consisting of -N(R 7 -(CH 2 -(CH 2 (CH 2 -(CH 2 )mN(R 7 -O(CH 2 CHX2-, -CXa2-, -S-(CH 2 and -N(R )(CH 2 where m= 1-3, X' is halogen and R 7 is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen up to per halo. A compound of claim 16, wherein M is one or more bridging groups selected from the group consisting of -N(R 7 -(CH 2 -(CH 2 (CH 2 -(CH 2 )mN(R 7 -O(CH 2 CHX a -CXa 2 -S-(CH 2 and -N(R 7 )(CH 2 )m where m= 1-3, Xa is halogen and R 7 is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen up to per halo.

21. A compound of claim 17, wherein M is one or more bridging groups selected from the group consisting of -(CH 2 -(CH 2 (CH 2 -(CH 2 )mN(R -O(CH 2 CHXa-, -CXa2-, -S-(CH 2 and -N(R 7 )(CH 2 where m= 1-3, Xa is halogen and R 7 is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen up to per halo.

22. A compound of claim I whereinL' is additionally substituted I to 3 times by one or more substituents selected from the group consisting of Ci-Cio alkyl, up to per halo substituted C 1 -Cio alkyl, -CN, -OH, halogen, CI-Clo alkoxy and up to per halo substituted Ci- Cio alkoxy.

23. A compound of claim 13 wherein L' is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of Ci-Cio alkyl, up to per halo substituted Ci-CIo alkyl, -CN, -OH, halogen, CI-Clo alkoxy and up to per halo substituted Cl- CIo alkoxy.

24. A compound of claim 18 wherein L- is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of Ci-CIo alkyl, up to per halo substituted Ci-C 1 o alkyl, -CN, -OH, halogen, Ci-C 1 o alkoxy and up to per halo substituted Cl- CIo alkoxy. A compound of claim 19 wherein L' is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -Clo alkyl, up to per halo substituted Ci-Cio alkyl, -CN, -OH, halogen, CI-Cio alkoxy and up to per halo substituted C l CIo alkoxy.

26. A compound of claim 20 wherein L' is additionally substituted I to 3 times by one or more substituents selected from the group consisting of Cl-CIo alkyl, up to per halo substituted Ci-Clo alkyl, -CN, -OH, halogen, Cl-Clo alkoxy and up to per halo substituted C 1 Cio alkoxy.

27. A compound of claim 21 wherein L' is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of Ci-Cio alkyl, up to per halo substituted Ci-Clo alkyl, -CN, -OH, halogen, Ci-Clo alkoxy and up to per halo substituted Ci- Cio alkoxy.

28. A compound of claim 1 wherein L' is substituted by

29. A compound of claim 1 wherein L' is substituted by -SO 2 Rx.

30. A compound of claim 1 wherein L' is substituted only by

31. A compound of claim I wherein L' is substituted only by -SO 2 R,.

32. A compound of claim 1. wherein L' is substituted by or -SOR,, wherein R, is NRaRb-

33. A compound of claim 13 wherein L' is substituted by -C(O)Rx or -SO 2 R,, wherein Rx is NRaRb, and Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen, or -OSi(Rf) 3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0 substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or c) one of Ra or Rb is a CI-Cs divalent alkylene group or a substituted Ci- C 5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least members, wherein the substituents of the substituted Ci-C 5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen.

34. A compound of claim 18 wherein L' is substituted by -C(0)Rx or -SO 2 Rx, wherein Rx is NRaRb and Ra and Rb are independently hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen. A compound of claim 19 wherein L' is substituted by wherein R, is NRaRb and Ra and Rb are independently hydrogen or a carbon based moiety of up to carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen.

36. A compound of claim 20 wherein L' is substituted by or -SO 2 Rx, wherein Rx is NRaRb and Ra and Rb are independently hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen.

37. A compound of claim 21 wherein L' is substituted by -C(O)Rx or -SO 2 Rx, wherein Rx is NRaRb and Ra and Rb are independently hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen.

38. A compound of Formula I: A-D-B (I) or a pharmaceutically acceptable salt thereof, wherein D is -NH-C(0)-NH-, A is a substituted moiety of up to 40 carbon atoms of the formula: )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 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L' contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L' is substituted by at least one substituent selected from the group consisting of-SO 2 Rx, -C(O)Rx and -C(NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally halosubstituted, up to per halo, Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; Rx is Rz or NRaRb where Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen, or -OSi(Rr) 3 where Rr is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0 substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or c) one of R, or Rb is a CI-C. divalent alkylene group or a substituted C:- Cs divalent alkylene group bound to the moiety L to form a cyclic structure with at least members, wherein the substituents of the substituted CI-C 5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; where B is substituted, L is substituted or L' is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of -CN, -C 2 R 7 -C(O)NRTR 7 -C(O)-R 7 -NO 2 -OR 7 -SR 7 -NR 7 R 7 -NR 7 C(O)OR 7 -NR 7 C(O)R 7 -Q-Ar, and 10 carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -C0 2 R 7 -C(O)R 7 -C(O)NRR 7 -OR 7 -SR 7 NR 7 R 7 -NO 2 -NR 7 C(O)R 7 -NR'C(O)OR 7 and halogen up to per-halo; with each R 7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, wherein Q is N(R 7 -(CH 2 -(CH 2 -(CH 2 )mS-, -(CH 2 )mN(R 7 -O(CH 2 CHX a -CXa 2 -S-(CH 2 and -N(R 7 )(CH 2 where m= 1-3, and Xa is halogen; Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zni, wherein nI is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 R 7 -C(O)NR'R 7 NO 2 -OR 7 SR 7 -NR 7 R 7 -NR 7 C(O)OR 7 -NR'C(O)R' and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents are selected from the group consisting of -CN, CO 2 R 7 -COR 7 -C(O)NR 7 R 7 -OR 7 -SR 7 -NO 2 -NR 7 R 7 -NR 7 C(O)R 7 and -NR 7 C(O)OR 7 with R 7 as defined above; and wherein M is one or more bridging groups selected from the group consisting of N(R 7 -(CH 2 -(CH 2 -(CH 2 -(CH 2 )mN(R 7 -0(CH 2 )m- CHX 3 -CX 3 -S-(CH 2 and -N(R )(CH 2 where m= 1-3, Xa is halogen.

39. A compound of Formula I: A-D-B (I) or a pharmaceutically acceptable salt thereof, wherein D is -NH-C(0)-NH-, A is a substituted moiety of up to 40 carbon atoms of the formula: )q, where L is a substituted or unsubstituted phenyl or peritoneal moiety bound directly to D, L 1 comprises a substituted phenyl, peritoneal or pyrimidinyl moiety, M is a bridging group having at least one atom, q is an integer of from 1-3; and B is .a substituted or unsubstituted phenyl or pyridine group bound directly to D, wherein L' is substituted by at least one substituent selected from the group consisting of-SO 2 Rx, -C(O)Rx and -C(NRy) Rz, RY is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally halosubstituted, up to per halo, and Rz is hydrogen .or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; Rx is Rz or NRaRb where Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen, or -OSi(Rr)3 where Rr- is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and 'optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0 substituted. by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or c) one of Ra or Rb is a CI-C 5 divalent alkylene group or a substituted CI- C 5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least members, wherein the substituents of the substituted Ci-C 5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; where B is substituted, L is substituted or L' is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of -CN, -CO0 2 R', -C(O)NR'R 7 -C(O)-R 7 -NO 2 -OR 7 -SR 7 -NR 7 R 7 -NR'C(O)OR', -NR 7 C(O)R 7 -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -C0 2 R 7 -C(O)R 7 -C(O)NR'R 7 -OR 7 NR 7 R 7 -NO 2 -NRC(O)R 7 -NR 7 C(O)OR 7 and halogen up to per-halo; with each R 7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, wherein Q is -N(R 7 -(CH 2 -(CH 2 -(CH 2 -(CH 2 )mN(R 7 -O(CH 2 CHX'-, -CXa 2 -S-(CH 2 and -N(R )(CH 2 )m where m= 1-3, and Xa is halogen; Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen. up to per-halo, and optionally substituted by wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 R 7 -C(O)R 7 -C(O)NR 7 R, NO 2 -OR 7 SR 7 -NR 7 R 7 -NR7C(0)OR 7 -NR 7 C(O)R 7 and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents selected from the group consisting of -CN, -CO 2 R 7 COR 7 -C(O)NR 7 R 7 -OR 7 -SR 7 -NO 2 -NR 7 R 7 -NR 7 C(O)R 7 and -NR 7 C(O)OR 7 and wherein M is one or more bridging groups selected from the group consisting of N(R 7 -(CH 2 -(CH 2 -(CH 2 -(CH 2 )mN(R 7 -O(CH 2 )m- CHXa-, -CXa2 -S-(CH 2 and -N(R 7 )(CH 2 where m= 1-3, X' is halogen. A compound as in claim 38 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by-OH.

41. A compound as in claim 38 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by a moiety having an ionizable hydrogen and a pKa of 10 or less.

42. A compound as in claim 39 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by-OH.

43. A compound as in claim 39 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by a moiety having an ionizable hydrogen and a pKa of 10 or less.

44. A compound as in claim 38 wherein substituents for B and L and additional substituents for -Li, are selected from the group consisting of Ci-Clo alkyl up to per halo substituted Ci-Clo alkyl, CN, OH, halogen, Ci-Cio alkoxy and up to per halo substituted C 1 C 10 alkoxy. A compound as in claim 39 wherein substituents for B and L and additional substituents for are selected from the group consisting of Ci-Clo alkyl up to per halo substituted Ci-Co 1 alkyl, CN, OH, halogen, Ci-CIo alkoxy and up to per halo substituted Cl- CIo alkoxy.

46. A compound of claim 38 wherein L' is substituted by C(O)Rx or SO 2 Rx.

47. A compound of claim 39 wherein L' is substituted by C(O)R, or SOR,.

48. A compound of claim 46 wherein R, is NRaRb and R, and Rb are independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen..

49. A compound of claim 47 wherein R, is NRaRb and Ra and Rb are independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen. A compound of 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 acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), l-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.

51. A compound of 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 acid, hydrobromic -acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.

52. A compound of claim 33 which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, :0 trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.

53. A 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 acid, hydrobromic acid, sulphuric acid, phosphoric acid, -o methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.

54. A compound of 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 acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt of a compound of formula I, and a physiologically acceptable carrier.

56. A pharmaceutical composition comprising a compound of claim 2 consistent with fQrmula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.

57. A pharmaceutical composition comprising a compound of claim 33 consistent with formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.

58. A pharmaceutical composition comprising a compound of claim 38 consistent with formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.

59. A pharmaceutical composition comprising a compound of claim 39 consistent with formula I or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier. A compound selected from the group consisting of 3-tert butyl phenyl ureas of Table I above; butyl-2-methoxyphenyl ureas of Table 2 above; 2 phenyl ureas of Table 3 above; 3-(trifluoromethyl) -4 chlorophenyl ureas of Table 4 above; 3-(trifluoromethy1)-4-bromophenyl ureas of Table 5 above; 5-(trifluoromethyl)-4-chloro- 2 methoxyphenyl ureas of Table 6 above; and *Sureas 10 1 -103 in Table 7 above.

61. A compound selected from the group consisting of the 3-tert butyl phenyl ureas: N-(3-tert-butylphenyl)-N '-(4-(3-(N-methylcarbaxnoyl)phenoxy)phenyl urea and N-(3-tert-butylpheflyl)-N etylphenoxy)phenyI urea; the 5-tert-butyl-2-methoxypheflyl ureas: NV-(5-tert-butyl-2-methoxypheflyl)-N 1,3-dioxoisoindolin-5 *yloxy)phenyl) urea, NV-(5-tert-butyl-2-rnethoxyPheflyl)-N'-(4-(l1-oxoisoindolin-5-yloxy)phenyl) urea, N-(5-tert-butyl-2 -met hoxypheny1)-N '-(4-(4-methoxy-3-(N- methylcarbarnoyl)phenoxy)phenyl) urea and NV-(5-tert-butyl-2-nlethoxypheflyl)-N '-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl) urea; the 2-methoxy-5-trifluoromethyl)phenyI ureas: '-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N '-(3-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl) urea, '-(4-(2-carbamoyl-4-pyridyloxy)pheny1) urea, fluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl) urea, NV-(2-methoxy-5-(trfluoromethy)phefyl)lN'(4-(2(N-lthycabamoy1)A4 pyridylthio)phenyl) urea, 2-methoxy-5 -(tri fluoromethyl)phenyl)-N '-(2-chloro-4-(2-(N-rethylcarbamoyl)(4- pyridyloxy))phenyl) urea and '-(3-chloro-4-(2 -(N-methylcarbamoyl)(4- pyridyloxy))phenyl) urea; the 4-chloro-3-(tnfluoromethyl)phenyI ureas: N-(4-chloro-3 -(trifluoromethyl)phenyl)-N -carbamoyl-4-pyridyloxy)pheny]) urea, N-(4-chloro-3-(tfluoromethyl)pheriyI)-N -(NV-methylcarbamoyl)-4-pyridyloxy)pheny I) urea, N-(4-chloro-3 )-(trifluoromethyl)phenyl)-N -carbamoyl-4-pyridyloxy)phenyl) urea and NV-(4-chloro-3 -(trifluorcrnethyl)phenyl)-N 4 -(2-(N-inethylcarbamnoyl)-4-pyridyloxy)phenyl) urea. the 4-romo-3-(trifluoromethyl)phenyl ureas: N-(4-bromo-3' -(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, N-(4-bromo-3 -(trifluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N -(2-(N-methylcarbainoyl)-4-pyridyhthio)phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N '-(2-chloro-4-(2-(N-tnethylcarbamoyl)(4- pyridyloxy))pheriyl) urea and N-(4-bromo-3-(trifluoromethyl)phenyl)-N -chloro-4-(2-(N-methylcarbamoyl)(4- pyridyloxy))phenyl) urea; and the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas: N-(2-methoxy-4-chloro-5'-(trifluoromethyl)phenyl)-N -(3-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl) urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N -(N-methylcarbaznoyl pyridyloxy)phenyl) urea, N-(2 -metho xy-4-c hlIoro-5 -(tri fl uoromnethylI)p heny I)-N -c hloro-4- (2 methylcarbamnoyl)(4-pyridyloxy))pheny!) urea and NA-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyI)-N'-(3-chloro-4-(2-(N- mnethy Icarbamnoyl)(4-pyidy loxy))pheny 1) urea.

62. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administering a compound of Formula I of claim 1.

63. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administering a compound of Formula I of claim 33.

64. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administering a compound of Formula I of claim 38. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administering a compound of Formula I of claim 39.

66. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administrating a compound selected from the group consisting of 3-tert butyl phenyl ureas of Table 1 above; butyl-2-methoxyphenyl ureas of Table 2 above; 5-(trifluoromethyl)-2 phenyl ureas of Table 3 above; 3-(trifluoromethyl) -4 chlorophenyl ureas of Table 4 above; 3-(trifluoromethyl)-4-bromophenyl ureas of Table 5 above; 5-(trifluoromethyl)-4-chloro-2 methoxyphenyl ureas of Table 6 above; and ureas 101-103 in Table 7 above.

67. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administrating a compound selected from the group consisting of the 3-tert butyl phenyl ureas: N-(3-tert-butylphenyl)-NV'-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl urea and N-(3-tert-butylphenyl)-N'-(4-(4-acetylphenoxy)phenyl urea; the 5-tert-butyl-2-methoxyphenyl ureas: .V-(5-tert-butyl-2-methoxyphenyl)-N'-(4-( 1,3-dioxoisoindolin-5-yloxy)phenyl) urea, N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-( -oxoisoindolin-5-yloxy)phenyl) urea, NV-(5-tert-butyl-2-methoxypheflyl)-NV'-(4-(4-rnethoxy-3-(N- methylcarbarnoyl)phenoxy)pheflyl) urea and ert-butyl-2-methoxyphenyl)-N'-(4-(3-(N-methylcarbamnoyl)phenoxy)pheny1) urea; the 2-methoxy-5-trifluoromethyl)phenyI ureas: carbamoyl-4-pyridyloxy)phenyl) urea, '-(3-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl) urea, -carbamoyl-4-pyridyloxy)phenyl) urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamnoyl)-4- pyridyloxy)pheriyl) urea, fluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl).4- pyridylthio)phenyl) urea, N-(2-methoxy-5-(trifluoromethyl)phenyI)-N '-(2-chloro-4-(2-(N-methylcarbamoyl)(4- pyridyloxy))phenyl) urea and -chloro-4-(2-(N-niethylcarbamoyl)(4- pyridyloxy))phenyl) urea; the 4-chloro-3 -(trifluoromethyl)phenyl ureas: N-(4-chloro-3 -(trifluoromethyl)phenyl)-N '-(3-(2-carbamoyl-4-pyridyloxy) henyl) urea, N-(4-chloro-3 -(trifluoromethyl)phenyl)-N'-( 3 2 -(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, NV-(4-chloro-3-(tri fluoromethyl)phenyl)-N -(2-carbamoyl-4-pyridyloxy)phenyl) urea and N-(4-chloro-3-(trifluoromethyiphenyl)-N 4 -(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea; the 4-rorno-3-(trifluoromethyl)phenyl ureas: NV-(4-brorno-3-(tri fluoromethyl)phenyl)-N -(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) SO urea. ,V-(4-bromo-3-(tni Aluoromethy l)p hen methyl carbamoyl)-4-pyridyioxy)phenyl) urea, N-(4-bromo-3 -(trifluoromethyl)phenyl)-N 3 2 -(N-methylcarbamoyl)-4-pyridylthio)phenyl) urea, ,V_(4-bromo-' )-(trifluoromethyl)phenyl)-N '-(2-chloro- 4 thylcarbamoyl)(4- pyridyloxy))phenyl) urea and N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4- pyridyloxy))pheriyl) urea; and the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas: iV-(2-methoxy-4-chloro-5-(trifluorornethyi)phenyl)-N'-(3 -(2-(N-methylcarbamoyl)-4- pyridyioxy)phenyl) urea, NV-(2 -methoxy-4-chloro-5 -(tri flucromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl) urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N -chloro-4-(2-(N- methylcarbamoyl)(4-pyr-idyloxy))phenyl) urea and NV-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N -chloro-4-(2-(N- methylcarbamoyl)(4-pyridyloxy))phenyl) urea. DATED this 24th day of February 2004 BAYER CORPORATION By its Patent Attorneys DAVIES COLLISON CAVE