MXPA01004180A - 4-arylamino, 4-aryloxy, and 4-arylthio diarylamines and derivatives thereof as selective mek inhibitors - Google Patents

Abstract

The invention provides compounds of formula (II), wherein Ar, R3, R4, R5, R6, R7, R8 and W have the meanings given in the description. They are selective MEK inhibitors.

Description

4-AR1LAMINO.4-ARILOXI AND 4-ARILTIO DIARILAMINAS AND DERIVATIVES OF THEM AS INHIBITORS SELECTIVES OF MEK This invention relates to 4-arylamino, 4-aryloxy, and 4-arylthio diarylamines and derivatives thereof.

BACKGROUND MEK enzymes are specifically double kinases involved in, for example, immunomodulation, inflammation and proliferative diseases such as cancer and restenosis. Proliferative diseases are caused by a defect in the intracellular signaling system, or the mechanism of signal transduction of certain proteins. The defects include a change in either the intrinsic activity or the cellular concentration of one or more signaling proteins in the signaling cascade. The cell can produce a growth factor that binds to its receptors, resulting in an autocrine loop, which continuously stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to false mitogenic signals within the cell. Some of the most common mutations occur in genes that encode the protein known as Ras, a G protein that is activated when it binds to GPT, and inactivated when it binds to GDP. The aforementioned growth factor receptors, and many other mitogenic receptors, when activated, lead to Ras being converted from the GDP binding state to the GTP binding state. This signal is an absolute prerequisite for proliferation in more cell types. Defects in this signaling system, especially in the deactivation of the Ras-GTP complex, are commonly in cancers, and lead to the signaling cascade under Ras being chronically activated. Activated Ras leads in turn to the activation of a cascade of serine / threonine kinases. One of the known kinase groups requires an active Ras-GTP for its own activation is the Raf family. This in turn activates MEK (eg ME ^ and MEK2) which then activates the MAP kinase, ERK (ERKi and ERK2) Activation of the MAP kinase by mitogens appears to be essential for proliferation; The constitutive activation of this kinase is sufficient to induce cellular transformation. The blocking of Ras downstream signaling, for example by the use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, if it is induced from cell surface receptors or oncogenic Ras mutants. Although Ras is not a protein kinase by itself, it is involved in the activation of Raf and other kinases, most likely through a phosphorylation mechanism. Once activated, Raf and other MEK phosphorylated kinases in two intimately adjacent serine residues, S218 and S222 in the case of MEK-1, which are the prerequisite for the activation of MEK as a kinase. MEK in turn phosphorylates the MAP kinase on a tyrosine, Y185, and a threonine residue, T183, separated by a single amino acid. This double phosphorylation activates the MAP kinase at least 100 times. The activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including various transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activated by the target protein, such as a kinase, a transcription factor, or other cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK by itself appears to be a signal integrating kinase. The current understanding is that MEK is highly specific for phosphorylation of the MAP kinase. In fact, no substrate for MEK other than the MAP kinase, ERK, has been shown to date and MEK are not phosphorylated peptides based on the phosphorylation sequence of the MAP kinase, or even phosphorylate the denatured MAP kinase. MEK also appears to strongly associate with MAP kinase before to phosphorylate it, suggesting that phosphorylation of the MAP or MEK kinase may require a strong anterior interaction between the two proteins. This requirement and the unusual specificity of MEK are suggested that they may have sufficient difference in their mechanism of action to other protein kinases that selective inhibitors of MEK, possibly operating through allosteric mechanisms rather than through the unusual blocking of the ATP binding site , it can be established.

PREVIOUS ART The invention features compounds of the following formula (II), such as the formula (I): (II) (i) In formulas (I) and (II), W is ORi, NR2OR ?, NRARB, NR2NRARB, OR NR2 (CH2) 2-4 NRARB, RI is H, C1-8 alkyl, C3-8 alkenyl , C3-8 alkynyl, C3-8 cycloalkyl, phenyl, (phenyl) C? - alkyl, (C3-4 phenyl) alkenyl, C3-4 (phenyl) alkynyl, (C3-8 cycloalkyl) - C1-6alkyl, (C3-8 cycloalkyl) C3-4l alkenyl (C3-8 cycloalkyl) C3- alkynyl, C3-8 heterocyclic radical, (C3-8 heterocyclic radical) C alkylene? 4l (C3-8 heterocyclic radical) C3- alkenyl, (C3-8 heterocyclic radical) C3- alkynyl, or (CH2) 2.4NRARB- R2 is H, phenyl, C? -4 alkyl, alkenyl C3-4, C3-8 alkynyl, C3-8 cycloalkyl, or C3- (C3-8 cycloalkyl) alkyl of C? -, RA is H, C1-6 alkyl, C3-8 alkenyl, alkynyl C3-8, cycloalkyl of 03.3, phenyl, (C-8 cycloalkyl) C? -4 alkyl, (C3-8 cycloalkyl) C3- alkenyl, (C3-8 cycloalkyl) C3- alkynyl, heterocyclic radical of C3-8) (C heterocyclic radical) 3-8) C 1-4 alkyl, (aminosulfonyl) phenyl, [(aminosulfonyl) phenyl] C 1-4 alkyl (aminosulfonyl) C 1-6 alkyl, (aminosulfonyl) C 3-6 cycloalkyl, or [(aminosulfonyl) cycloalkyl of C3-6_alkyl of C? -4. RB is H, C? -8 alkyl, C3-8 alkenyl, C3-8 C3-8 alkynyl C3-8 cycloalkyl, or C6-? R3 aryl is halo, NO2, SO2NR, (CH2) 2-4NRERF, SO2NR | R or (CO) T. T is C? -8 alkyl, C3-8 cycloalkyl, (NRERF) C1-4 alkyl, ORF, NRI (CH2) 2-4NRERF, OR NRERF- R4 is H or F; R5 is H, methyl, halo, or NO2; and R6 is H, methyl, halo, or NO2. In the formula (II), Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. Each of R7 and R8 is independently selected from H, halo, C1-4alkyl, SO2NRJ (CH2) 2-4NRGRH, (CO) (CH2) 2-4NRGRH, (CO) NRJ (CH2) 2-4NRGRH , (CO) O (CH2) 2- NRGRH, SO2NRGRH and (CO) NRGRH- However, when Ar is a pyridyl, each of R and R8 is H. Each of Rc, RD, RE, RF, RG and RH is independently selected from H, C ?4 alkyl, C3.4 alkenyl, C3-4 alkynyl, C3-6 cycloalkyl, and phenyl. Each of NRCRD, NRERF, and NRGRH may also independently be morpholinyl, piperazinyl, pyrrolidinyl, or piperadinyl. Each of R * and Rj is independently H, methyl or ethyl. R? is C 1-4 alkyl, C 3-4 alkenyl, C 3-4 alkynyl, C 3-6 cycloalkyl, or phenyl. X is O, S or NH. Finally, each hydrocarbon radical or heterocyclic radical above is optionally substituted with 1 to 3 substituents independently selected from halo, C? -4 alquiloalkyl, C3.6 cycloalkyl, C-4-4 al alkenyl, d-4-phenyl alkynyl , hydroxyl, amino, (amino) sulfonyl, and NO2, wherein each alkyl, cycloalkyl, alkenyl, alkynyl or phenyl substituent is in turn optionally substituted between 1 and 3 substituents independently selected from halo, C? , hydroxyl, amino and NO2. In addition to the above compounds, the invention also provides a pharmaceutically acceptable salt or C 1-7 ester thereof.

The invention also relates to a pharmaceutical composition that includes (a) a diarylamine (for example, of the formula I) and (b) a pharmaceutically acceptable carrier. The invention further relates to a method for treating proliferative diseases, such as cancer, restenosis, psoriasis, autoimmune disease, and atherosclerosis. Other aspects of the invention include methods for treating MEK-related cancer, breast, lung, colorectal, pancreatic, prostate, brain, kidney, or ovarian tumors, and other solid or hematopoietic cancers. Additional aspects of the invention include methods to treat or reduce the symptoms of xenograft (organ, cells, limb, skin or bone marrow transplant), rejection, osteoarthritis, rheumatoid arthritis, cystic fibrosis, hepatomegaly, cardiomegaly, complications of diabetes (including nephropathy diabetic and diabetic retinopathy), shock, heart failure, septic shock, asthma and Alzheimer's disease. The compounds of the invention are also useful as antiviral agents to treat viral infections such as HIV, hepatitis B virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). ). The methods include administering to a patient in need of such treatment, or suffering from such a disease or condition, a pharmaceutically effective amount of a described compound or pharmaceutical composition thereof.

The invention also features methods of combination therapy, such as a method of treating cancer wherein the method further includes providing radiation therapy or chemotherapy, for example, with mitotic inhibitors such as a taxane or an alkaloid vinca. Examples of mitotic inhibitors include paclitaxel, docetaxel, vincristine, binblastine, vinorelbine, and vinflunine. Other therapeutic combinations include a MEK inhibitor of the invention and an anti-cancer agent such as cisplatin, 5-fluorouracil or 5-fluoro-2-4 (1 H, 3H) -pyrimidinedione (5FU), flutamide, and gemcitabine. Chemotherapy or radiation therapy may be administered before, at present, or after the administration of a compound described according to the needs of the patient. The invention also characterizes synthetic intermediates and methods described herein. Other aspects of the invention are provided in the description, the examples, and the following claims.

DETAILED DESCRIPTION The invention features diarylamine compounds of the formula (I), pharmaceutical compositions thereof, and methods of using such compounds and compositions. According to one aspect of the invention, the compounds are MEK inhibitors, MEK inhibition assays include the cascade assay for MAP kinase pathway inhibitors described in column 6, line 36, column 7, line 4 of the Patent North American Number 5,525,625, and the MEK in vitro assay in column 7, lines 4-27 of the same patent, the full disclosure of which is incorporated for reference (see also Examples 2-5 below).

A. Terms Certain terms are defined later and for use everywhere on this description. Alkyl groups include aliphatics (i.e., the subset of hydrocaror hydrocarbon radical structures containing hydrogen and carbon atoms, but do not contain heteroatoms in the backbone, or unsaturated carbon-carbon bonds) with a free valence. The alkyl groups are understood to include straight and branched chain structures. Examples include methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, 2,3-dimethylhexyl, 1,1-dimethylpentyl, heptyl and octyl. . Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. Alkyl groups may be substituted with 1, 2, 3 or more substituents which are independently selected from halo (fluoro, chloro, bromo or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical) oxy. Specific examples include fluoromethyl, hydroxyethyl, 2,3-dihydroxyethyl, (2- or 3-furanyl) methyl, cyclopropylmethyl, benzyloxyethyl, (3-pyridinyl) methyl, (2- or 3-furanyl) methyl, (2-thienyl) ethyl , hydroxypropyl, aminocyclohexyl, 2-dimethylaminobutyl, methoxymethyl,? -p? rid ini leti lo, diethylaminoethyl, and cyclobutylmethyl. Alkenyl groups are analogs in the alkyl groups, but have at least one double bond (two adjacent sp2 carbon atoms). Depending on the use of a double bond and the substituents, if any, the geometry of the double bond can be entgegen (E), zusammen (Z), cis, or trans. Similarly, the alkynyl groups have at least one triple bond (two adjacent sp carbon atoms). The unsaturated alkenyl or alkynyl groups may have one or more double or triple bonds, respectively, or a mixture thereof; as alkyl groups, they may be straight or branched chain, and may be substituted as described above and as exemplified throughout the description. Examples of alkenyls, alkynyls, and substituted forms include cis-2-butenyl, trans-2-butenyl, 3-butynyl, 3-phenyl-2-propynyl, 3- (2'-fluorophen-yl) -2-propynyl, -methyl (5-phenyl) -4-pentynyl, 2-hydroxy-2-propynyl, 2-methyl-2-propynyl, 2-propenyl, 4-hydroxy-3-butynyl, 3- (3-fluorophenyl) -2-propynyl, and 2-methyl-2-propenyl. In the formulas (I) and (II) the alkenyls can be C2-4 or C2-8, and are preferably C3-4 or C3-8. The more general forms of substituted hydrocarbon radicals include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl and corresponding forms for the amino-, halo- (eg, fluoro-, chloro- or bromo-), nitro-, alkyl-, phenyl prefixes. -, cycloalkyl- and etc., or combinations of substituents. According to formula (I), therefore, substituted alkyls include hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkylalkyalkyl (branched alkyls, such as methylpentyl), (cycloalkyl) alkyl, phenylalkyl, alkoxy, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryloxyalkyl , arylalkyloxyalkyl, (heterocyclic radical) alkyl, and (heterocyclic radical) oxyalkyl. Ri thus includes hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl) alkyl, (haloaryl) alkyl, (hydroxyaryl) alkynyl, and so forth. Similarly, RA includes hydroxyalkyl and aminoaryl, and RB includes hydroxyalkyl, aminoalkyl, and hydroxyalkyl (heterocyclic radyl) alkyl. Heterocyclic radicals, including but not limited to heteroaryls, include: furyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, 1,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl pyridazinyl, indolyl and their non-aromatic counterparts . Additional examples of heterocyclic radicals include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl and octahydobenzofuranyl. Selective MEK 1 or MEK 2 inhibitors are those compounds that inhibit the MEK 1 or MEK 2 enzymes, respectively, without substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A, phosphorylase kinase, EGF, and PDGF receptor kinases, and C -src. In general, a selective MEK 1 or MEK 2 inhibitor has an IC 5o for MEK 1 or MEK 2 which is at least one fiftieth (1/50) of its IC 50 for one of the other enzymes mentioned above. Preferably, a selective inhibitor has an IC50 that is at least 1/100, more preferably, 1/500, and even more preferably 1/1000, 1/5000, or less than that of its IC50 or one or more of the enzymes mentioned above.

B. Compounds One aspect of the invention features disclosed compounds shown in formulas (I) and (II) in the Summary section. The embodiments of the invention include compounds of the formula (I) wherein: (a) R3 is NO2; (b) R4 is fluoro; (c) each of R3 and R4 is independently selected from H and fluoro; (d) R5 is methyl, fluoro, or chloro; (e) R6 is methyl, chloro, fluoro, nitro, or hydrogen; (f) Re is H; (g) R6 is fluoro; (h) Rk is methyl or ethyl; (i) Ri is H, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, phenyl, phenethyl, allyl, C3-5 alkenyl, C3-6 cycloalkyl, (C3-5 cycloalkyl) C1-2 alkyl, (C3-5 heterocyclic radical) C? -2 alkyl, or (CH2) 2-4 NRCRD; (j) Ri is H or (C3-5 cycloalkyl) C? -2 alkyl, (k) R2 is H or methyl; (I) RA has at least one hydroxyl substituent; (m) RA is H, methyl, ethyl, isobutyl, hydroxyethyl, phenyl, 2-piperidin-1-yl-etio, 2,3-dihydroxy-propyl, 3- [4- (2-hydroxyethyl) -piperazin-1- il] -propyl, 2-pyrrolidin-1-yl-ethyl, or 2-diethylamino-ethyl; and RB is H; or where RB is methyl and RA is phenyl; (n) W is NRARB or NR2NRARB; (o) W is NR2 (CH2) 2-4 NRARB U O (CH2) 2-3 NRARB; (p) W is NROR!; (q) W is ORB; (r) R7 is in the para position relative to X; (s) R7 is iodine; (t) Rs is in the ortho position relative to X; (u) or combinations thereof. In further embodiments, if R6 is H, then R5 is nitro; or R6 is methyl, halo, or nitro; or R3 is SO2NR? (CH2) 2-4NRERF, SO NR | R? O (CO) T. In some embodiments, Ar is phenyl (e.g., formula (I)), and in other embodiments, Ar is 2-pyridyl, 3-pyridyl or 4-pyridyl. Preferably, where one of R1 (R2, RA, RB, Rc and RD is an alkenyl or alkynyl group, the double or triple bond, respectively, is not adjacent to the point of attachment, eg, where W is NR2OR !, R2 is preferably prop-2-ynyl, or but-2 or 3-enyl, and less preferably prop-1-inyl or but-1-enyl.Some embodiments include the formula of 2,4-bis (2-chloro-4) acid iodo-phenylamino) -3-fluoro-5-nitro-benzoic acid, the compounds in the following list, and 2-methyl analogs (instead of 2-chloro) thereof: 1. 2- (2-Chloro-4-acid iodo-phenylamino) -3-fluoro-5-nitro -4 - (4-sul-famoyl-phenylamino) -benzoic acid 2. 2- (2-Chloro-4-iodo-phenylamino) -3-fluoro-5-nitro- 4-phen i lam i non-benzoic 3. 2- (2-Chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-4-f-enoxyl-benzoic acid 4. 2- (2-Chloro) acid -4-iodo-phenylamino) -3-fluoro-5-nitro-4-phenylsulfanyl-benzoic acid 5. 2- (2-Chloro-4-iodo-phenylamino) -3-fluoro-4- (methyl-phenyl-amino) acid ) -5-nitro-benzoic acid 6. 2 - [(2-Chloro-4-iodophenyl) amino] -3-fluoro-4 - [[4- [[(2-hydroxyethyl) amino] -carbonyl] faith nyl] amino] -5-nitro-benzoic acid; 7. 2 - [(2-Chloro-4-iodophenyl) amino] -4 - [[4 - [(dimethylamino) ca rbonyl-1-yfen-1-amino] -3-fluoro-5-n-tro-benzoic acid; 8. 2- (2-Chloro-4-iodo-phenylamino) -3,5-difluoro-4-phenylamino-benzoic acid 9. 2- (2-Chloro-4-iodo-phenylamino) -3-fluoro-5 acid -nitro-4- (3-sulfamoyl-phenylamino) -benzoic acid; 10. 2- (2-Chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-4- (2-sulfamoyl-phenylamino) -benzoic acid; 11. 2- (2-Chloro-4-iodo-phenylamino) -3-fluoro-N-hydroxy-5-nitro-4- (4-sufamoyl-phenylamino) -benzamide acid; 12. 2- (2-Chloro-4-iodo-nylamino) -3-fluoro-N-hydroxy-5-nitro-4-phenylamino-benzamide; 13. 2- (2-Clo ro-4-iodo-nylamino) -3-fluoro-N-hydroxy-5-nitro-4-f-enoxyl-benzamide; 14. 2- (2-Chloro-4-iodo-phenylamino) -3-fluoro-N-hydroxy-5-niro-4-phenylsulfanyl-benzamide; 15. 2- (2-Chloro-4-iodo-phenylamino) -3-fluoro-N-hydroxy-4- (methyl-phenylamino) -5-nitro-benzamide; 16. 2 - [(2-Chloro-4-iodophenyl) amino] -3-fluoro-N-hydroxy-4 - [[4 - [[(2-hydroxyethyl) amino] carbonyl] pheny] amino] -5 -nitro-benzamide; 17. 2 - [(2-Chloro-4-iodophenyl) amino] 4 - [[4 - [(dimethylamino) carbonyl] -phenyl] amino] -3-fluoro-N-hydroxy-5-nitro-benzamide; 18. 2- (2-Chloro-4-iodo-phenylamino) -3,5-difluoro-N-hydroxy-4-phenylamino-benzamide; 19. 2- (2-Chloro-4-iodo-phenylamino) -3-fluoro-N-hydroxy-5-nitro-4- (3-sulfamoyl-phenylamino) -benzamide; 20. 2- (2-chloro-4-iodo-p-n-amino) -3-fluoro-N-hydroxy-5-nitro-4- (2-sulfamoyl-phenylamino) -benzamide; 21. 2- (2-Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3-fluoro-5-nitro-4- (4-sulfamoyl-phenylamino) -benzamide; 22. 2- (2-Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3-fluoro-5-nitro-4-phenylamino-benza mide; 23. 2- (2-Chloro-4-iodo-nylamino) -N-cyclop ro -pyrmetoxy-3-fluoro-5-nitro-4-phenoxy-benzamide; 24. 2- (2-Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3-fluoro-5-nitro-4-phenylsulfanyl-benzamide; 25. 2- (2-Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3-fluoro-4- (methyl-phenyl-amino) -5-nitro-benzamide; 26. 2 - [(2-Chloro-4-iodophenyl) amino] -3-fluoro-N-cyclopropylmethoxy-4 - [[4 - [[(2-hydroxyethyl) amino] -carbonyl] phenyl] amino] -5- nitro-benzamide; 27. 2 - [(2-Chloro-4-iodophenyl) amino] -4 - [[4- [(dimethylamino) carbonyl] phenyl] amino] -3-fluoro-N-cyclopropylmethoxy-5-nitro-benzamide; 28. 2- (2-Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,5-difluoro-4-phenylamino-benzamide; 29. 2- (2-Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3-fluoro-5-nitro-4- (3-sulfamoyl-phenylamino) benzamide; and 30. 2- (2-chloro-4-iodo-nylamino) -N-cyclopropyl-3-fluoro-5-nitro-4- (2-sulfamoyl-phenylamino) -benzamide. In the following scheme, W may also be any of the values described herein for formula (I) or (II) in the section describing the preferred values for W. The numbers of the compound provided in the scheme correspond to the numbers provided in the previous list; These compounds are illustrative, not limiting, of the invention.

C. Synthesis The described compounds can be synthesized according to the following two Schemes, or variants thereof (see also Example 1). With respect to the first step of Synthetic Scheme 1, the reaction of the aniline and the benzoic acid derivative is generally achieved by mixing the benzoic acid with an equimolar amount or excess of the aniline in a non-reactive organic solvent such as tetrahydrofuran, or toluene , in the presence of a base such as lithium diisopropylamide, lithium hexamethyldisilazide, n-butyl lithium, sodium hydride, or sodium amide. The reaction is generally carried out at a temperature from about -78 ° C to about 25 ° C, and is normally completed within 2 hours to about 4 days. The product can be isolated by removing the solvent, for example, by evaporation under reduced pressure and further purified, if desired, by standard methods such as chromatography, crystallization or distillation. Returning to the second step, the 2-phenylaminobenzoic acid derivative is then reacted with an equimolar or excess amount of a nucleophile such as an aniline, a phenol or a thiophenol by mixing in a non-reactive organic solvent such as tetrahydrofuran, or toluene, in the presence of a base such as lithium diisopropylamide, lithium hexamethyldisilazide, n-butyl lithium, sodium hydride or sodium amide. The reaction is generally carried out at a temperature of about -78 ° C to boiling and is usually completed within 2 hours to about 4 days. The product can be isolated by removing the solvent, for example, by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization or distillation. Finally, with respect to step 3, the 4-arylheteroatom-2-phenylamino benzoic acid derivative is next reacted with a nucleophile such as ammonia, an amine, an alcohol, hydrazine, a hydrazine derivative, or a hydroxylamine derivative in the presence of a peptide coupling reagent. The amines that can be employed include monomethylamine and aniline. Alcohols that can be employed include cyclobutylmethanol and phenol. The hydrazine derivatives that may be employed include N, N-dimethylhydrazine and 1-aminopiperidine. The hydroxylamine derivatives that may be employed include methoxylamine, N-ethyl-isopropoxyamine and tetrahydrooxazine. Typical coupling reagents include 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 1,3-dicyclohexylcarbodiimide (DCC), bromo-tris- (pyrrolidino) -phosphonium hexafluorophosphate (PyBrOP) and hexafluorophosphate ( benzotriazolyloxy) tripyrrolidino phosphonium (PyBOP). The 4-arylheteroatom-2-phenylaminobenzoic acid derivative and the nucleophile are usually mixed in approximately equimolar amounts in a non-reactive solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar amount of the coupling reagent is added. A base such as triethylamine or diisopropylethylamine can be added to act as a cleaning acid if desired. The coupling reaction is generally completed after about 10 minutes to 2 hours, and the product is easily isolated by removing the reaction solvent, for example by evaporation under reduced pressure and by purifying the product by standard methods such as chromatography or solvent crystallizations. as acetone diethyl ether or ethanol. Referring to Synthetic Scheme 2, an alternative method for carrying out the compounds of the invention involves first coupling the benzoic acid derivative with the arylheteroatom nucleophile, and then reacting this benzoic 4-arylhetero-atom acid derivative with an aniline. The final step involves coupling the 4-arylheteroatom-2-phenylaminobenzoic acid derivative with ammonia amine, alcohol, hydrazine, hydrazine derivative, or hydroxylamine derivative with a peptide coupling reagent. The general reaction conditions for all of the steps in Scheme 2 are similar to those described above for Synthetic Scheme 1.

D. Uses The compositions described are useful as prophylactic and therapeutic treatments for diseases or conditions as provided in the Summary section, as well as diseases or conditions modulated by the MEK cascade. Examples include shock, heart failure, osteoarthritis, rheumatoid arthritis, rejection of organ transplantation, and a variety of tumors such as ovary, lung, pancreatic, and colon. 1. Dosage Those skilled in the art will be able to determine, according to known methods, the appropriate dose for a patient, taking into account factors such as age, general health, the type of treatment that requires pain, and the presence of other medications. In general, an effective amount will be between 0.1 and 1000 mg / kg per day, preferably between 1 and 300 mg / kg of body weight, and daily doses will be between 10 and 5000 mg for an adult subject of normal weight. Commercially available capsules or other formulations (such as liquids and film-coated tablets), of 100 mg, 200 mg, 300 mg, or 400 mg can be administered according to the methods described. 2. Formulations Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted by subdivision into individual doses. Dosage unit forms can also be adapted by various methods of administration, including controlled release formulations, such as subcutaneous implants. Methods of administration include oral, parenteral rectal (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intravesical, intraperitoneal, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal sprinkler). Parenteral formulations include pharmaceutically acceptable aqueous or non-acidic solutions, dispersions, suspensions, emulsions, and sterile powders for the preparation thereof. Examples of carriers include water, ethanol, polyols, (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate. The fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or by maintaining the appropriate particle size. Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption accelerators, (g) adsorbents, (h) lubricants, (i) damping agents, and (j) propellants.

The compositions may also contain adjuvants such as preservatives, wetting, emulsification and dispersion; antimicrobial agents such as parabens, chlorobutanol, phenol and sorbic acid; isotonic agents such as a sugar or sodium chloride; agents that prolong absorption such as aluminum monostearate and gelatin; and agents that improve absorption. 3. Related compounds The invention provides the described and closely related compounds, pharmaceutically acceptable forms of the described compounds, such as salts, esters, amides, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms. Pharmaceutically acceptable salts, esters and amides include carboxylate salts (e.g.

C? -8, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic), amino acid addition salts, esters, amides that are at a reasonable benefit / risk ratio, pharmacologically effective, and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, lauryl sulphonate. These may include alkali metal and alkaline earth metal cations such as sodium, potassium, calcium and magnesium, as well as toxic ammonium, quaternary ammonium, and amine cations such as tetramethylammonium, methylamine, trimethylamine, and ethylamine. See, for example, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66: 1-19 which is incorporated herein for reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, C1-primary alkylamines and secondary C6 -6-di (alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring portions containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are ammonia derivatives, primary amines of C 1-3 alkyl, and d i (C 1 -2 a) alkanol amines. Representative pharmaceutically acceptable esters of the invention include C?-7 alkyl, C 5-7 cycloalkyl, phenyl and phenylalkyl of C -?-6 esters. Preferred esters include methyl esters. The invention also includes disclosed compounds having one or more functional groups (eg, hydroxyl, amino or carboxyl) masked by a protecting group. Some of these masked and protected compounds are pharmaceutically acceptable; others will be useful as intermediaries. The synthetic intermediates and processes described herein, and minor modifications thereof are also within the scope of the invention.

HYDROXYL PROTECTION GROUPS Hydroxyl protection groups include: ethers, esters, and protection for 1,2- and 1,3-diols. Ether protection groups include: methyl, substituted methyl ethers, substituted ethylethers, substituted benzylethers, silylethers and conversion of silylethers to other functional groups. Substituted Methylethers Substituted methyl ethers include: methoxymethyl, methylthiomethyl, 1-phenylethyloxymethyl, benzyloxymethyl, p-ethoxybenzyloxymethyl, (4-methoxyphenoxy), methyl, guaiacolmethyl, 1-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl , 2,2,2-trichlorotoxymethyl, bis (2-chloro-ethoxy) methyl, 2- (trimethylsilyl) toxymethyl, tetrahydropyranyl, 3-bromotetrahydro-pyranyl, tetrahydrothiopyranyl, 1-methoxy-cyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetra- hydrothiopyranyl, S, S-4-methoxytetrahydrothiopyranyl dioxide, 1 - [(- chloro-4-methyl) phenyl] -4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, tetrhahydrofuranyl, tetrahydrothiofuranyl, and , 3, 3a, 4, 5, 6,7, 7a-octahydro-7,8,8-trimethyl-4,7-ethanobenzofuran-2-yl.

Substituted Ethylethers Substituted ethylethers include: 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-1-methoxy-ethyl, 1-methyl-1-benzyloxy-ethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylenyl) ethyl, f-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl and benzyl. Substituted benzyl ethers Substituted benzyl ethers include: p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p, p'-dinitrobenzhydryl, 5-dibenzosuberyl, tri-phenylmethyl, a-naphthyldiphenyl ethyl, p-ethoxy phenyl phenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri- (p -methoxyphenyl) methyl, 4- (4'-bromophenacyloxy) phenyldiphenylmethyl, 4,4'-4"-tris (4,5-dichlorophthalimide-f-enyl) methyl, 4,4'-4" -tris (levulinoyloxyphenyl) methyl , 4,4'-4"tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-ylmethyl) bis (4 ', 4" -dimethoxyphenyl) -methyl, 1,1-bis (4-methoxy fe nil) -1' -pi re nilm ethyl, 9-anthryl, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl and S, S-benzisothiazolyl dioxide.

Silyl ethers Silyl ethers include: tri-methylsulfonyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyl-isysilyl, f-butyldimethylsilyl, -butyldiphenylsilyl, tribenylilyl, tri-p-xylsilyl, triphenyl-lysyl, d-ifeny I meti Isi I ilo and f-butylmethoxyphenylsilyl.

ESTERS Esters protecting groups include: esters, carbonates, assisted division, diverse and suifonted esters.

Esters Examples of protective esters include: format, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, pP-phenylacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylendithio) pentanoate pivaloate, adamanthoate, crotonate, 4-methoxyrotonate, benzoate, p-phenylbenzoate and 2,4,6-trimethylbenzoate (mesitoate). Carbonates Carbonates include: methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, 2- (triphenylphosphonium) ethyl, isobutyl, vinyl, allyl, p- nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl and methyl dithiocarbonate.

Assisted Division Examples of power-assisted protection groups include: 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzene sulfonate, 2- (methylthiomethoxy carbonate) ) ethyl, 4- (methylthiomethoxymethyl) benzoate and 2- (methylthio methoxy methyl) benzoate. Miscellaneous Esters In addition to the previous classes, the various esters include: 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1, 1, 3, 3 -tetra met i Ib u ti l) f enoxyacetate, 2,4-bis (1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E) -2-methyl-2-butenoate (tigloate), o- (methoxycarbonyl) benzoate, pP-bezoate, a-naphthoate, nitrate, alkyl? /,? /,? / '/ V'-tetramethylphosphorodiamidate,? / - phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-dinitrofenyl sulfenate. Sulfonates Protective sulfonates include: sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate.

PROTECTION FOR 1.2- AND 1.3- DIOLES Protection for the 1,2 and 1,3-diols groups include: cyclic acetals and ketals, cyclic orthoesters and silyl derivatives.

Cyclic and Cetal Acétals Cyclic acetals and ketals include: methylene, ethylidene, 1-γ-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene , benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene and 2-nitrobenzylidene. Cyclic orthoesters Cyclic orthoesters include: methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxycytidene, 1-ethoxyethylidene, 1,2-dimethoxyethylidene, a-methoxybenzylidene, 1 - (N,? / - dimethylamino) ethylidene derivative, derivative of - (N , N-dimethylamino) benzylidene and 2-oxacyclopentylidene.

PROTECTION FOR THE CARBOXYL ESTERS GROUP The ester protection groups include: esters, substituted methyl esters, 2-substituted ethylesters, substituted benzyl esters, silylesters, activated esters, various derivatives, and stanilsters. Substituted Methyl Esters Substituted methyl esters include: 9-fluoenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxy-methyl, benzyloxymethyl, phenacyl, p-bromophenacyl, α-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and? / -ftalmidmidlo. 2-Substituted Ethyl Esters The 2-substituted ethylesters include: 2,2,2-trichloroethyl, 2-haloethyl, 1-chloroalkyl, 2- (trimethylsilyl) ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2 (p-Nitrophenylsulfenyl) -ethyl, 2- (p-toluenesulfonyl) ethyl, 2- (2'-pyridyl) ethyl, 2- (diphenylphosphino) ethyl, 1-methyl-1-phenylethyl, f-butyl, cyclopentyl, cyclohexyl , allyl, 3-buten-1-yl, 4- (trimethylsilyl) -2-buten-1-yl, cinnamyl, α-methylcinyl, phenyl, p- (methylmercapto) -phenyl, and benzyl Substituted benzyl esters Substituted benzyl esters include: triphenylmethyl, diphenylmethyl, bis (o-nitrophenyl) methyl, 9-anthrylmethyl, 2- (9,10-dioxo) anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl, 2- (trifluoromethyl) -6-chloromethyl, 2,4,6 -trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4- (methylsulfinyl) benzyl, 4-sulfobenzyl, piperonyl and 4-P-benzyl. Silyl esters Silyl esters include: tri-methyl isi, triethylsilyl, t-butyldimethylsilyl, / -propyl imeti Isi lyl, phenyldimethylsilyl and di-f-butylmethylsilyl. Miscellaneous Derivatives Various derivatives include: oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, orthoesters, group phenyl, and penta amino cobalt complex (III). Stanolsters Examples of stanilsters include: triethylstannyl and tri-p-butylstannyl. AMIDES AND HYDRAZIDES Amides include:? /,? / - dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenyilantridinyl, o-nitroanilides,? / - 7-nitroindolyl,? / - 8-nitro-1, 2,3,4 -tetrahydroquinolyl, and pP-benzenesulfonamides. The hydrazides include:? / - phenyl, N, N'-diisopropyl and other dialkylhydrazines.

PROTECTION FOR THE AMINO CARBAMATES GROUP Carbamates include: carbamates, substituted ethyl, assisted divisions, photolytic division, urea derivatives and various carbamates. Carbamates The carbamates include: methyl and ethyl, 9-fluorenylmethyl, 9- (2-sulfo) fluorenyl-methyl, 9- (2,7-dibyl) f luo re nilm ethyl, 2,7-di-f-buti l- [9- (10,10-dioxo-10, 10, 10,10-tetrahydro-thioxanthyl)] methyl and 4-methoxyphenacyl. Substituted Ethyl The protecting groups of substituted ethyl include: 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1- (1-adamantyl) -1-methylethyl, 1,1-dimethyl-2-haloethyl, 1 , 1 dimethyl il-2, 2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1- (3,5-d if-butylphen ) - 1-methylethyl, 2- (2'- and 4'-pi rid i I) eti lo, 2 - (? /, / V-icylohexylcarboxamido) -ethyl, f-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylalyl, conamyl, 4-nitrocinnamyl, quinolyl,? / - hydroxypiperidinyl, alkyldithium, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl, Assisted Division The protection through of the assisted division includes: 2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1,3-dithianyl)] methyl, 4-methylthiophenyl, 2,4-dimethyl-thiophenyl, 2- phosphoniumethyl, 2-t rife nilphosphonioisopro pyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p- (dihydroxyboronyl) benzyl, 5-benzisoxazolyl-methyl and 2- (trifloromethyl) -6-chloromonylmethyl. Photolytic Division Photolytic splitting methods use groups such as: m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl and phenyl (o-nitrophenyl) methyl. Urea-Type Derivatives Examples of urea-type derivatives include: phenothiazinyl- (10) -carbonyl derivatives,? / '- p -toluenesulfonylaminocarbonyl and? /' - phenylaminothiocarbonyl.

Miscellaneous Carbamates In addition to the foregoing, various carbamates include: f-amyl, S-benzylthiocarbamate p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, or- (N , N-dimethyl-carboxamido) -benzyl, 1,1-dimethyl-3 (? /,? / - dimethylcarboxa-mido) propyl, 1,1-dimethyl-propinyl, di (2-pyridyl) methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p (p'-metoxifennylazo) benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropyl ethyl, 1-methyl- (3,5-dimethoxyphenyl) ethyl , 1-methyl-1- (p-henilazophenyl) -ethyl, 1-methyl-1-phenylethyl, 1-methyl-1- (4-pyridyl) I, phenyl, p (phenylazo) benzyl, , 4,6-tri-f-butylphenyl, 4- (trimethylammonium) benzyl and 2,4,6-trimethylbenzyl.

AMIDAS Amides Amides include:? / - formyl,? / - acetyl, N-chloroacetyl, N-trichloroacetyl,? / - trifluoroacetyl,? / - phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, / V-3-pyridylcarboxamide,? / -benzoylphenollanedyl,? / - benzoyl, and? / - p-phenylbenzoyl derivative. Assisted Division Assisted division groups include: Nitrophenylacetyl,? / - o-nitrophenoxyacetyl,? / - acetoacetyl, (? / '- dithiobenzyloxycarbonylamino) acetyl N- 3- (p-hydroxy nyl) propionyl,? / -3- (o-nitrophenyl) propionyl,? / - 2-methyl-2- (o-nitrophenoxy) propionyl, / V-2-methyl-2- (o-phenylazophenoxy) propionyl,? / - 4-chlorob uti ryl,? / - 3-methyl-3-nitrobutyryl, Non-nitrocinnamoyl, N-acetylmethionine derivative,? / - o -nitrobenzoyl, No- (benzoyloxymethyl) benzoyl, and 4,5-diphenyl-3-oxazolin-2- none Cyclic Imide Derivatives Cyclic imide derivatives include:? / - phthalimide,? / - dithiasuccinoyl,? / - 2,3-diphenyl-maleoyl, N-2, 5-dimethyl pyrrolyl, adduct of? / - 1, 1, 4,4-tetramethyldisilylazacicopentane, 1,3-dimethyl-1, 3,5-triazacyclohexan-2-one 5-substituted, 1,3-dibenzyl-1, 3,5-triazacyclohexan-2-one 5- substituted and substituted 1-substituted 3,5-dinitro-4-pyridonyl.

SPECIAL NH PROTECTIVE GROUPS Protective groups for -NH include:? / - alkyl and ? - allylamines, imine derivatives, enamine derivatives, and? / - heteroatom derivatives (such as? / - metal, N-N, N-P, N-Si and N-S), N-sulfenyl and? / - sulfonyl. ? / - Alkyl and? / - Arylanes? The? / - alkyl and? / - arylamines include: / V-methyl, N-allyl,? / - [2- (trimethylsilyl) ethoxy] -methyl, N-3 -acetoxypropyl? / - (1-isopropyl-4-nitro-2-oxo-3-pyrroin-3-yl), quaternary ammonium salts,? / - benzyl,? / - di (4-methoxyphenyl) methyl,? / -5-dibenzosuberil,? / - triphenylmethyl,? / - (4-methoxyfe nyl) di phenylmethyl,? / - 9-phenylfluorenyl,? / - 2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and? / -2-picolylamine N'-oxide. Imine Derivatives Imine derivatives include:? - 1,1-dimethylthiomethylene,? / -benzylidene,? / - p-methoxybenzylidene, N-diphenylmethylene,? / - [(- pyridyl) mesityl] methylene, N (N ', N' -dimethylaminomethylene), N, N'-isopropylidene,? / - p-nitrobenzylidene, N-salicylidene, / V-5-chlorosalicilidene,? / - (5-chloro-2-hydroxyphenyl) phenylmethylene and / V-cyclohexylidene. Enamina Derivative An example of an enamine derivative is? / - (5,5-dimethyl-3-oxo-1-cyclohexenyl). Derivatives of? / - Heteroatom Derivatives of? / - metal include: N-borane derivatives,? / - diphenylborinic acid derivative, N- [phenyl (pentacarbonylchromium- or -tungsten)] carbenyl, and? / - copper, or chelate of? / - zinc. Examples of N-N derivatives include:? / - nitro, ? / - nitrous, and? / - oxide. Examples of N-P derivatives include: N-diphenylphosphinyl,? / - dimethylthiophosphinyl,? / - diphenylthiophosphonyl, N-dialkylphosphoryl, / V-dibenzylphosphoryl and? / - diphenylphosphoryl. Examples of? / -sulfenyl derivatives include:? / - benzenesulfenyl, N-o-nitrobenzenesulfenyl,? / - 2,4-dinitrobenzenesulfenyl, N-penta cyclohexenulfe nsulfe nyl,? / - 2-nitro-4-methoxy-benzenesulfenyl, ? -triphenylmethylsulfenyl, and? / - 3-nitropyridinesulfenyl. The? / -sulfonyl derivatives include: / Vp-toluenesulfonyl,? / - benzenesulfonyl, N-2,3,6-trimethyl-4-methoxybenzenesulfonyl, N -2,4,6-trimethoxybenzenesphonyl,? / - 2,6-dimethyl -4-methoxy-benzenesphonyl, / V-pentamethylbenzenesulfonyl,? / - 2, 3, 5, 6 -tetra meth i 1-4-methoxybenzenesulfonyl, / V-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl, / / 2,6-dimethoxy -4-methylbenzenesulfonyl,? / -, 2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesul fonyl, N-ß-trimethylsilyletanesulfonyl,? / - 9-anthracensulfonyl,? / - 4- (4'-8'-dimethoxynaphthylmethyl) -benzenesulfonyl,? / - benzylsulfonyl, N-trifluoromethylsulfonyl and? / - phecylsulfonyl. The disclosed compounds that are masked or protected may be pro-drugs, the compounds metabolized or otherwise transformed in vivo to produce a described compound, for example, transiently during metabolism. This transformation can be a hydrolysis or oxidation that results from contact with a body fluid such as blood, or the action of acids, or liver, gastrointestinal or other enzymes. Characteristics of the invention are further described in the following examples.

E. Examples EXAMPLE 1 Preparation of 2,4-bis (2-chloro-4-vodo-phenylamino) -3-fluoro-5-nitrobenzoic acid Step a: Preparation of 5-nitro-2,3,4-tr acid Fluorobenzoic A gently concentrated stirring of sulfuric acid (50 ml) was added to steaming nitric acid (3.4 ml, 0.076 moles). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring for 45 minutes, the reaction mixture had become a homogeneous orange solution which was then emptied into ice water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3 x 200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a slightly opaque yellow solid. Recrystallization from chloroform (50 ml) yielded 9.54 g of the pale yellow microcrystalline product; 78% yield; p.f .; 1H-NRM (400 MHz; DMSO) d 14.29 (dd, JC-F = 270.1, 10.7 Hz), 148.35 (dd, JC-F = 267.0, 9.2 Hz), 141.23 (dt, JC-F = 253.4 Hz) 133.95 , 123.30 (d, JC-F = 2.2 Hz), 116.92 (dd, JC-F = 18.2, 3.8 Hz); 19F-NMR (376 MHz, DMSO) 5120.50 to 120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).

Step b: Preparation of the acid 2,4-bis- (2-chloro-4-iodo-nylamino) -3-f-5-benzoic acid to a stirred solution comprising 2-chloro-4- Iodoaniline (Lancaster, 98%, 12.33 g, 0.04864 moles) in tetrahydrofuran (20 ml) at -78 ° C under nitrogen was added a solution of 2.0 M lithium diisopropylamide in tetrahydrofuran-heptane-ethylbenzene (Aldrich, 35 ml, 0.070 moles) with a syringe. The addition formed a thick suspension. After five minutes of stirring, a solution comprising 5-nitro-2,3,4-trifluorobenzoic acid (5.00 g, 0.0226 moles) in tetrahydrofuran (30 ml) was added with a syringe to give a dark reaction mixture. The cold bath was removed and the reaction mixture was stirred for 20 minutes. The cold reaction mixture is emptied into ether (600 ml) containing an excess of acid chloride. The red solution instantaneously turned to a yellow suspension as a formed precipitate. This precipitate was removed by vacuum filtration. The filtrate was concentrated in vacuo to a red powder (10.5 g). The red powder was titrated with boiling chloroform (800 ml). The titrated solids were collected by vacuum filtration to give an orange powder (2.42 g). The mother liquor from the titration was concentrated in vacuo to give a red-orange solid (approximately 10 g without drying). This solid was loaded onto a flash silica column. Elution with dichloromethane removed some impurities. Elution was continued with 1% methanol in dichloromethane yielding approximately 4 g of a red solid. This red solid was dissolved in hot absolute ethanol (100 ml). This solution was boiled to 50 ml and rediluted to 300 ml with hexanes. This solution was boiled to 150 ml and rediluted to 300 ml with hexanes to produce light turbidity. The mixture was cooled in the refrigerator for three days, producing a yellow precipitate. The precipitate was collected by vacuum filtration and dried with suction to yield 0.15 g of a yellow solid; 1% yield; 1H-NRM (400 MHz; DMSO) 6 8.94 (s, 1H), 8.55 (s, 1H), 7.79 (d, 2H, J = 2.0 Hz) 7.61-7.57 7.57 (m, 2H), 6.90 (dd, 1H , J = 8.5, 3.9 Hz), 6.84 (dd, 1H, J = 8.3, 6.6 Hz); 19 F-NMR (376 MHz, DMSO) d -122.62 (s); MS (APCI +) 692 (6), 691 (8), 690 (31) 689 (10) 688 (55), 171 (47), 130 (100); (APCI-) 691 (4), 690 (12), 689 (14), 688 (70), 687 (32), 686 (100), 506 (50), 453 (97); IR (KBr) 1523 crn "1; Anal.calculated / found by Ci9H10CI2FI2N3O4 C, 33.17 / 33.32; H, 1.47 / 1.33; N, 6.11 / 5.73; Cl, 10.31 / 10.04; F, 2.76 / 3.70; I, 36.89 / 34.32 The IC50 APK for 2,4-bis- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitrobenzoic acid is 29.6 nM.

EXAMPLE 2 Test Cascade for MAP Kinase Pathway Inhibitors Incorporation of 32P into the myelin basic protein (MBP) is assayed in the presence of a glutathione S-transferase fusion protein containing p44MAP kinase (GST-MAPK) and glutathione S-transferase fusion protein containing p45MEK (GST-MEK). The test solution contains 20 mM HEPES, pH 7.4, 10mM of 1 mM MgC12 of MnC12, 1 mM of EGTA, 50, μM [? -32P] ATP, 10 μg of GST-MEK, 0.5 μg of GST-MAPK and 40 μg of MBP in a final volume of 100 μL. The reactions were stopped after 20 minutes by the addition of trichloroacetic acid and filtered through GF / C filter material. The 32P retained in the filter material was determined using a Beta 120S plate. The compounds were evaluated at 10 μM for the ability to inhibit 32 P incorporation. To make sure if the compounds are inhibiting GST-MEK or GST MAPK, two additional protocols are employed. In the first protocol, the compounds are added to tubes containing GST-MEK, followed by the addition of GST-MAPK, MBP and [? -32P] ATP. In the second protocol, the compounds were added to tubes containing GST-MEK and GST-MAPK, followed by MBP and [? -32P] ATP. Compounds showing activity in both protocols are classified as MAPK inhibitors, while compounds showing activity in only the first protocol are classified as MEK inhibitors.

EXAMPLE 3 MAP In Vitro Kinase Assay Inhibitory activity can be confirmed in direct assays. For the MAP kinase, 1 μg of GST-MAPK was incubated with 40 μg of MBP for 15 minutes at 30 ° C in a final volume of 50 μl containing 50 mM Tris (pH 7.5), 10 μM MgC12, 2 μM EGTA , and 10 μM [? -32P] ATP. The reaction was stopped by the addition of the Laemmli SDS sample buffer and phosphorylated MBP resolved by electrophoresis in a 10% polycrylamide gel. The readioactivity incorporated in MBP was determined by autoradiography and balloon band count imposed.

EXAMPLE 4 MEK assay In vitro For the evaluation of direct MEK activity, 10 μg of GST-MEKi was incubated with 5 μg of a glutathione S-transferase fusion protein containing p44MAP kinase with a lysine to mutation of alanine at position 71 ( GST-MAPK-KA). This mutation eliminates the kinase activity of MAPK, thus only the kinase activity attributed to the remains of MEK aggregates. Incubations are 15 minutes at 30 ° C in a final volume of 50 μl containing 50 mM Tris (pH 7.5), 10 μM MgC12, 2, μM EGTA, and 10 μM [α-32 P] ATP. The reaction was stopped by the addition of the Laemrnli SDS sample buffer. The phosphorylated GST-MAPK-KA was resolved by electophoresis in a 10% polyacrylamide gel. The radioactivity incorporated in GST-MAPK-KA was determined by autoradiography, and subsequent scintillation of imposed bands. Additionally, an artificially activated MEK containing serine to glutamate mutations at positions 218 and 222 (GST-MEK-2E) is used. When these two sites are phosphorylated, the MEK activity increases. Phosphorylation of these sites can be mimicked by mutation of these residues from serine to glutamate. For this assay, 5 μg of GST-MEK-2E was incubated with 5 μg of GST-MAPK-KA for 15 minutes at 30 ° C in the same reaction buffer as described above. The reactions were finished and analyzed as in the previous.

EXAMPLE 5 Complete cellular MAP kinase assay To determine whether the MAP kinase activation block compounds in whole cells, the following protocol is used. The cells were plated on multi-well plates and grown to confluence. The cells were depressed overnight in serum. The cells were exposed to the desired concentrations of the compound or vehicle (DMSO) for 30 minutes, followed by the addition of a growth factor, for example, PDGF (100 ng / ml). After a 5 minute treatment with the growth factor, the cells were washed with PBS, and used in a buffer consisting of 70 mM 10 mM NaCl HEPES (pH 7.4), 50 mM glycerol phosphate, and 1 % of Triton X-100. The lysates were clarified by centrifugation at 13,000 x g for 10 minutes. Five micrograms of the resulting supernatants were incubated with 10 μg of microtubule-associated protein 2 (Map2) for 15 minutes at 30 ° C in a final volume of 25 μL containing 50 mM Tris (pH 7.4), 10 mM MgCl 2, 2 mM of EGTA and 30 μM of [? -32P] ATP. The reactions were terminated by the addition of Laermmli sample buffer. The phosphorylated Map2 was resolved in 7.5% of acrylamide gels and the incorporated radioactivity was determined by scintillation counting of imposed bands.

EXAMPLE 6 Monolayer Growth The cells were plated in multi-well plates at 10 to 20,000 cells / ml. Forty-eight hours after seeding, the test compounds were added to the cell growth medium and the incubation was continued for 2 additional days. The cells were then removed from the wells by incubation with trypsin and enumerated with a Coulter counter.

EXAMPLE 7 Soft aqar growth Cells were seeded on 35 mm to 5 mm discs ,000 cells / discs using growth medium containing 0.3% agar. After cooling to solidify the agar, the cells were transferred to a 37 ° C incubator. After the growth of 7 to 10 days. The visible colonies were enumerated manually with the help of a scanning microscope.

EXAMPLE 8 Arthritis Induced by Collagen in Mice Arthritis induced by Type II Collagen (CIA) in mice is an experimental model of arthritis that has a number of pathological, immunological and genetic characteristics in common with rheumatoid arthritis. The disease is induced by immunization of DBA / 1 in mice with 100 μg of type II collagen, which is a major component of binding cartilage, delivered intradermally in complete Feund adjuvant. The disease is susceptibly regulated by the class of MHC class II gene site, which is analogous to the association of rheumatoid arthritis with HLA-Dr4. A progressive and inflammatory arthritis development in the majority of immunized mice, characterized by paw width is increased up to 100%. A test compound was administered to the mouse in a range of amounts, such as 20, 60, 100, and 200 mg / kg body weight / day. The duration of the test can be several weeks to a few months, such as 40, 60, or 80 days. A clinical classification index is used to help disease progression from erythema and edema (stage 1), joint distortion (stage 2), to joint ankylosis (stage 3). The disease is variable in that it can affect one or more legs in an animal, resulting in a possible total classification of 12 for each mouse. The histopathology of an arthritic joint reveals synovitis, pannus formation, and cartilage and bone erosions. All mouse strains that are susceptible to CIA are elevated antibody responses to type II collagen, and is a marked cellular response to Cll.

EXAMPLE 9 SCW-induced monoarticular arthritis Arthritis is induced as described by Schwab, et al., Infection and Immunity 59: 4436-4442 (1991)) with minor modifications. Rats received 6 μg sonicated SCW [in 10 μl Dulbecco's PBS (DPBS)] by an intraarticular injection in the right tibiotalar joint on day 0. On day 21, DTH is initiated with 100 μg of SCW (250 μl) administered iv For oral compound studies, the compounds were suspended in vehicle (0.5% hydroxypropyl methylcellulose / 0.2% Tween 80), sonicated, and administered twice daily (10 ml / kg volume) beginning 1 hour before reactivation with SCW The compounds were administered in amounts between 10 and 500 mg / kg of body weight / day, such as 20, 30, 60, 100, 200 300 mg / kg / day. Edema measurements were obtained by determining the linear base volumes of the hind paw before the reactivation on day 21, and comparing with the volumes at subsequent time points such as days 22, 23, 24 and 25. The volume of The paw is determined by mercury plethysmography.

EXAMPLE 10 Mouse Ear-Heart Transplant Model Fey, T.A. et al., describes methods for transplanting neonatal heart crack grafts into the ear of mice and rats (J. Pharm. and Toxic, Meth. 39: 9-17 (1998)). The compounds were dissolved in solutions containing combinations of absolute ethanol, 0.2% hydroxypropyl methylcellulose in water, propylene glycol, cremophor and dextrose, and another solvent or suspension vehicle. Mice were dosed orally or intraperitoneally once, twice or three times daily from the day of transplantation (day 0) until day 13 or until the grafts have been rejected. The rats were dosed once, twice, or three times daily from day 0 to day 13. Each animal is anesthetized and an incision is made at the base of the ear of the recipient, cutting only the dorsal epidermis and dermis. The incision is extended open and low to the cartilage parallel to the head, and wide enough to accommodate the tunnel for a rat or insertion tool for a mouse. A neonatal mouse or rat puppy less than 60 hours old was anesthetized and dislocated cerivally. The heart is removed from the chest, rinsed with saline, bisected longitudinally with a scalpel, and rinsed with sterile saline. The donor heart fragment is placed in the preformed tunnel with the insertion tool and air or residual fluid is gently expressed from the tunnel with light pressure. No saturation, adhesive bond, bandage, or antibiotic treatment is required. The implants are examined at a magnification of 10-20 times with a stereoscopic dissection microscope without anesthesia. Containers whose grafts are not visibly shaken can be anesthetized and evaluated for the presence of electrical activity using subdermal Grass E-2 Platinum pin microelectrodes placed either on the pineapple or directly on the graft and a tachograph. Implants can be examined 1-4 times a day for 10, 20, 30 or more days. The ability of a test compound to improved symptoms or transplant rejection can be compared to a control compound such as cyclosporin, tacrolimus, or orally administered lefluonomide.

EXAMPLE 11 Murine ovalbumin-induced eosinophilia C57BL / 6 female mice were obtained from Jackson Laboratory (Bar Harbor, ME). All the animals were given food and water ad libitum. Mice were synthesized with a unique intraperitoneal injection of OVA (grade V, Sigma Chemical Company, St. Louis, MO) adsorbed to alum, (10 μg OVa + 9 mg alum in 200 μ saline) or control vehicle (9 mg alum in 200 μl saline) on day 0. On day 14, the mice were disabled with a 12 minute inhalation of an aerosol consisting of 1.5% OVA (weight / volume) in saline produced by a nebulizer (generator). small particle, model SPAG-2; ICN Pharmaceuticals, Costa Mesa, CA). Groups of eight mice were dosed with oral vehicle (0.5% hydroxypropylmethylcellulose / 0.25% TWEEN-80), or a test compound, at 10, 30 or 100 mg / kg in oral vehicle, 200 μl per p.o. of mouse. Dosing was performed once per day started on day 7 or day, and extended through day 16. For the determination of pulmonary eosinophilia, three days after the first OVA aerosol stimulus (day 17), the mice were anesthetized with an ip injection of anesthetic (Ketamine / Acepromazine / Xylazine) and the trachea is exposed and cannulated. The lungs and upper ducts are washed twice with 0.5 ml of cold PBS. A portion (200 μl) of the bronoalveolar lavage fluid (BAL) is enumerated using a Coulter counter Model ZB1 (Colter, Electronics, Hialeah, FL). The remaining BAL fluid is then centrifuged at 300 x g for five minutes, and the cells are suspended in 1 ml of HBS (Gibco BRL) containing 0.5% fetal bovine serum (HyClone) and 10 mM HEPES (Gibco BRL). The cell suspension was centrifuged in a cytospin (Shandon Southern Instruments, Sewickley, PA) and stained by Diff Quick (American Scientific Products, McGraw Park, IL) to differentiate BAL leukocytes into subsets of neutrophils, eosinophils, monocytes or lymphocytes. The number of eosinophils in the BAL fluid is determined by multiplying the percentage of eosinophils by the total cell count.

F. Other Modes From the above description and examples, and from the following claims, the essential features of the invention are readily apparent. The scope of the invention also encompasses various modifications and adaptations within the knowledge of a person of ordinary experience. Examples include a described compound modified by the addition or removal of a protecting group, or an ester, pharmaceutical salt, hydrate, acid or amide of a described compound. The publications cited herein are incorporated herein by reference in their entirety.

Claims (45)

1. CLAIMS 1. A compound having the formula (II): W is OR1f NR2OR ?, NRARB, NR2NRARB OR NR2 (CH2) 2-4 NRARB; RA, is H, C? -8 alkyl, C3-8 alkenyl, alkynyl C3-8, C3-8 cycloalkyl, phenyl, (phenyl) C? -4 alkyl, C3-4 (phenyl) alkenyl, C3-4 (phenyl) alkynyl, (C -8 cycloalkyl) C3 alkyl ? -, (C3-8 cycloalkyl) C3-4 alkenyl, (C3-8 cycloalkyl) C3-4 alkynyl, C3-8 heterocyclic radical, (C3-8 heterocyclic radical) C1- alkyl, ( C3-8 heterocyclic radical) C3-4 alkenyl, (C3-8 heterocyclic radical) C3-4 alkynyl or (CH2) 2-4NRARB; R 2 is H, phenyl, C 1-4 alkyl, C 3-4 alkenyl, C 3-8 alkynyl C 3-8 cycloalkyl or (C 3-8 cycloalkyl) C 1-4 alkyl; RA is H, C-? -6 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, phenyl, (C3-8 cycloalkyl) C? -4 alkyl (Cs- cycloalkyl) C3-4 sjalkenyl, (C3-8 cycloalkyl) alkynyl of 03.4, C3-8 heterocyclic radical, (C3-8 heterocyclic radical) C? -? (aminosulfonyl) phenyl, [(aminosulfonyl) phenyl] alkyl of C -? - 4, (aminosulfonyl) C 1-6 alkyl, (aminosulfonyl) cycloalkyl of C3_6, or [(aminosulfonyl) C 3-6 cycloalkyl] C 4 alkyl; RB is H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, or Cß-β aryl; R3 is halo, NO2, SO2NR, (CH2) 2-4NRERF, SO2NR, Rk or (CO) T; T is C -? - 8 alkyl, C 3-8 cycloalkyl, (NRERF) C 1-4 alkyl, ORF, NR | (CH 2) 2 NRERF or NRERF; R4 is H or F; R5 is H, methyl, halo or NO2; R6 is H, methyl, halo or NO2; Ar is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl; each of R7 and R8 is independently selected from H, halo, C? -4 alkyl, SO2NRJ (CH2) 2-4NRGRH, (CO) (CH2) 2-4NRGRH, (CO) NRj (CH2) 2- 4NRGRh, (CO) O (CH2) 2-4NRGRH, SO2NRGRH, and (CO) NRGR; with the proviso that when Ar is a pyridyl, each of R7 and R8 is H; each of Rc, RD, RE, RF, RG and H is independently selected from H, C-? -4 alkyl, C3.4 alkenyl of C3-6 C3-cycloalkyl, and phenyl; each of NRCRD, NRERF, and NRGRH may also independently be morpholinyl, piperazinyl, pyrrolidinyl or piperadynyl; each of R- and Rj is independently H, methyl or ethyl; R? is C 1-4 alkyl, C 3-4 alkenyl, alkynyl C3.4, C3-6 cycloalkium or phenyl; X is O, S or NH; and wherein each hydrocarbon radical or heterocyclic radical above is optionally substituted with from 1 to 3 substituents independently selected from halo, C? -4 alquiloalkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl , phenyl, hydroxyl, amino, (amino) sulfonyl, and NO, wherein each substituted alkyl, cycloalkyl, alkenyl, alkynyl, or phenyl is in turn optionally substituted between 1 and 2 substituents independently selected from halo, C1-2alkyl , hydroxyl, amino and NO2; or a pharmaceutically acceptable salt or C? -7 ester thereof.
2. 2. The compound according to claim 1, characterized in that it has the following formula (I): (wherein W is ENT NR2ORI, NRARB, NR2NRARB OR NR2 (CH2) 2-4 NRARB; RI is H, C -? - 8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl , phenyl, (phenyl) alkyl of C? -4, (phenyl) alkenyl of C3-4, (phenyl) alkyl of C3-4, (cycloalkyl of C3-8) alkyl of C1-4, (cycloalkyl of C3-8) C3- alkenyl, (C3-8 cycloalkyl) C3-4 alkynyl, C3.8 heterocyclic radical, (C3-8 heterocyclic radical) C3-4 alkyl, (C3- heterocyclic radical) 8) C3-4 alkenyl, (C3-8 heterocyclic radical) C3-4 alkynyl or (CH2) 2-4NRARB, R2 is H, phenyl, C1-4 alkyl, C3-4 alkenyl, C3 alkynyl -8 C3-8 cycloalkyl or (C3-8 cycloalkyl) C1- alkyloxy; RA is H, C6-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3- cycloalkyl 8, phenyl, (C3-8 cycloalkyl) C1-4 alkyI (C3-8 cycloalkyl) C3-4 alkenyl, (C3-8 cycloalkyl) C3- alkynyl, C3-8 heterocyclic radical, (radical C3-8 heterocyclic) C1.4 alkyl, (am inosulfonyl) phenyl, [(aminosulfonyl) phenyl] C 1-4 alkyl, (aminosulfonyl) C 1-6 alkyl, (aminosulfonyl) C 3-6 cycloalkyl, or [(aminosulfonyl) C3-6 cycloalkyl] C? - alkyl; RB is H, C-i-β alkyl, C3-8 alkenyl, C3-8 alkynyl, C3_8 cycloalkyl, or Ce-8 aryl; R3 is halo, NO2, SO2NR, (CH2) 2-4NRERF, SO2NR | Rk or (CO) T; T is C? -8 alkyl, C3-8 cycloalkyl, (NRERF) C1-4 alkyl, ORF, NR | (CH2) 2-4 NRERF or NRERF; R is H or F; R5 is H, methyl, halo or NO2; R6 is H, methyl, halo or NO2; each of R7 and R8 is independently selected from H, halo, C1-4alkyl, S02NRJ (CH2) 2-4NRGRH, (CO) (CH2) 2-4NRGRH, (CO) NRJ (CH2) 2-4NRGRh , (CO) O (CH2) 2-4NRGRH, SO2NRGRH, and (CO) NRGRH; each of Rc, RD, RE, RF, RG and RH is independently selected from H, C? -4 alkyl, C3-4 alkenyl of C3-4 C3-6 cycloalkyl, and phenyl; each of NRCRD, NRERF, and NRGRH may also independently be morpholinyl, piperazinyl, pyrrolidinyl or piperadynyl; each of R- and Rj is independently H, methyl or ethyl; RK is C? -4 alkyl, C 3-4 alkenyl, alkynyl C3-4, C3-6 cycloalkyl or phenyl; X is O, S or NH; and wherein each hydrocarbon radical or the above heterocyclic radical is optionally substituted with from 1 to 3 substituents independently selected from halo, C-? 4 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2- alkynyl 4, phenyl, hydroxyl, amino, (amino) sulfonyl, and N02, wherein each substituted alkyl, cycloalkyl, alkenyl, alkynyl, or phenyl is in turn optionally substituted between 1 and 2 substituents independently selected from halo, C? -2, hydroxyl, amino and N02; or a pharmaceutically acceptable salt or C? - ester thereof.
3. 3. The compound according to claim 1, characterized in that R3 is NO2.
4. 4. The compound according to claim 1, characterized in that R is fluoro.
5. 5. The compound according to claim 1, characterized in that each of R3 and R is independently selected from H and fluoro.
6. 6. The compound according to claim 1, characterized in that R5 is methyl, fluoro, or chloro. The compound according to claim 1, characterized in that R & it is methyl, chlorine, fluoro, nitro or hydrogen. 8. The compound according to claim 7, characterized in that Rβ is H. 9. The compound according to claim 7, characterized in that Rβ is fluoro. 10. The compound according to claim 1, characterized in that RK is methyl or ethyl. 11. The compound in accordance with the claim I, characterized in that Ri is H, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, phenyl, phenethyl, allyl, alkenyl, C2-5, C3-6 cycloalkyl, (C3-5 cycloalkyl) C? -2 alkyl, (C3-5 heterocyclic radical) C? -2 alkyl or (CH2) 2-4 NRCRD-12. compound in accordance with the claim II, characterized in that Ri is H or (C3-4 cycloalkium) C1-2 alkyl. 13. The compound according to claim 1, characterized in that R2 is H or methyl. The compound according to claim 1, characterized in that RA has at least one hydroxyl substituent. 15. The compound according to claim 1, characterized in that RA is H, methyl, ethyl, isobutyl, hydroxyethyl, phenyl, 2-piperidin-1-ethyl-ethyl, 2,3-dihydroxy-propyl, 3- [4 - (2-hydroxyethyl) -piperazin-1-yl] -propyl, 2-pyrrolidin-1-ethyl-ethyl, or 2-diethylamino-ethyl; and RB is H; or where RB is methyl and RA is phenyl. 16. The compound according to claim 1, characterized in that W is NRARB OR NR2NRARB- 17. The compound according to claim 1, characterized in that W is NR2 (CH2) 2-4 NRARB OO (CH2) 2-3 NRARB 18. The compound according to claim 1, characterized in that W is NR2OR ?. 19. The compound according to claim 1, characterized in that W is ORB. The compound according to claim 1, characterized in that R is in the para position relative to X. 21. The compound according to claim 20, characterized in that R is iodine. 22. The compound according to claim 1, characterized in that R8 is in the ortho position relative to X. 23. The compound according to claim 1, characterized in that it has the formula of 2,4-bis- (2-) acid. chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-benzoic acid. 24. The compound according to claim 1, characterized in that it is selected from: 2- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-4- (4-sulfamoyl-phenylamino) acid )-benzoic; 2- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-4-phenylamino-benzoic acid; 2- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-4-phenoxy-benzoic acid; 2- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-4-phenylsulfanyl-benzoic acid; 2- (2-chloro-4-iodo-phenylamino) -3-fluoro-4- (methyl-phenyl-amino) -5-nitro-benzoic acid; benzamide, 2 - [(- chloro-4-iodo) nyl) amin or] -3-f I uoro-N-hydroxy -4 - [[4 - [[(2-hydroxyethyl) amino] carbonyl] phenyl] amino] - 5-nitro; benzamide, 2 - [(2-chloro-4-iodophenyl) amino] -4 - [[4 - [(dimethylamino) carbonyl] phenyl] -amino] -3-fluoro-N-hydroxy-5-nitro; 2- (2-chloro-4-iodo-phenylamino) -3,5-difluoro-4-phenylaminobenzoic acid; 2- (2-Chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-4- (3-sulfamoyl-phenylamino) -benzoic acid; and 2- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-4 - (- 2-sulfamoyl-phenylamino) -benzoic acid; and the corresponding hydroxamic acids and cyclopropylmethyl hydroxamates. 25. The pharmaceutical composition characterized in that it comprises a compound according to claim 1 and a pharmaceutically acceptable carrier. 26. A method for treating a proliferative disease, such method comprises administering to a patient in need of such treatment a pharmaceutically effective amount of a composition characterized in that it comprises a compound according to claim 1. 27. The method according to claim 26, characterized in that the proliferative disease is selected from psoriasis, restenosis, autoimmune disease, and atherosclerosis. 28. A method for treating cancer, the method comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a composition comprising a compound according to claim 1. 29. The method according to claim 28, characterized because cancer is relative to MEK. 30. The method of compliance with the claim 28, characterized in that the cancer is breast, lung, ovarian, pancreatic, renal or colorectal cancer. 31. A method for treating, or improving the continuation of a shock, such method comprises administering to a patient in need of such treatment a pharmaceutically effective amount of a composition comprising a compound according to claim 1. 32. A method for to treat, or improve the continuation of heart failure, such method comprises administering to a patient in need of such treatment a pharmaceutically effective amount of a composition comprising a compound according to claim 1. 33. A method for treating or reducing symptoms for rejection of xenograft, such method comprises administering to a patient an organ transplant, limb transplant, skin transplantation, cell transplantation (s), or bone marrow transplantation a pharmaceutically effective amount of a composition comprising a compound of with claim 1. 34. A method for treating osteoarthritis, such method comprises administering to a patient in need of such treatment a pharmaceutically effective amount comprising a compound according to claim 1. 35. A method for treating rheumatoid arthritis, such method comprises administering to a patient with Such a treatment requires a pharmaceutically effective amount comprising a compound according to claim 1. 36. A method for treating asthma, said method comprises administering to a patient in need of such treatment a pharmaceutically effective amount comprising a compound in accordance with claim 1. 37. A method for treating cystic fibrosis, such method comprises administering to a patient in need of such treatment a pharmaceutically effective amount comprising a compound according to claim 1. 38. A method for treating hepatomegaly, such method comprises administering to a patient in need of such treatment an amount pharmaceutically effective comprising a compound according to claim 1. 39. A method for treating cardiomegaly, such method comprises administering to a patient in need of such treatment a pharmaceutically effective amount comprising a compound according to claim 1. 40. A method for treating Alzheimer's, such method comprises administering to a patient in need. of said treatment a pharmaceutically effective amount comprising a compound according to claim 1. 41. A method for treating a diabetes complication, said method comprises administering to a patient in need of such treatment a pharmaceutically effective amount comprising a compound of according to claim 1. 42. A method for treating septic shock, such method comprises administering to a patient in need of such treatment a pharmaceutically effective amount comprising a compound according to claim 1. 43. A method for treating cancer, such a method comprises (a) administering to a patient in need of such treatment a pharmaceutically effective amount comprising a compound according to claim 1; and (b) administering a therapy selected from radiation therapy and chemotherapy. 44. The method according to claim 43, characterized in that the chemotherapy comprises a mitotic inhibitor. 45. The method according to claim 39, characterized in that the mitotic inhibitor is selected from paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinflunine.