AU5785900A - Method for treating chronic pain using mek inhibitors - Google Patents

Description

WO 01/05391 PCT/USOO/18346 METHOD FOR TREATING CHRONIC PAIN USING MEK INHIBITORS 5 BACKGROUND The invention features a method for treating chronic pain using MEK inhibitors. Chronic pain includes neuropathic pain, and chronic inflammatory pain. 10 Abnormality anywhere in a nerve pathway disrupts nerve signals, which in turn are abnormally interpreted in the brain, causing neuropathic pain. Neuropathic pain may be, for example, a deep ache, a burning sensation, or hypersensitivity to touch. Diseases or conditions associated with neuropathic 15 pain include, without limitation, diabetic neuropathy, causalgia, plexus avulsion, neuroma, vasculitis, crush injury, viral infections (e.g., herpes virus infection or HIV), constriction injury, tissue injury, nerve injury from the periphery to the central nervous system, limb amputation, hypothyroidism, uremia, chronic alcoholism, post-operative pain, arthritis, back pain, and 20 vitamin deficiencies. Infections such as herpes zoster (shingles) can cause nerve inflammation and produce postherpetic neuralgia, a chronic burning localized to the area of viral infection. Hyperalgesia is when an already noxious stimulus becomes more painful, and allodynia, when a previously non-noxious 25 stimulus becomes painful (such as contact of clothing or a breeze). Reflex sympathetic dystrophy is accompanied by swelling and sweating or changes in local blood flow, tissue atrophy, or osteoporosis. Causalgia, including severe burning pain and swelling, sweating, and changes in blood flow, may follow an injury or disease of a major nerve such as the sciatic nerve. Some 30' types of chronic low back pain can have a neuropathic component (e.g., sciatica, postpoliomyelitis and CPRM). Neuropathic pain may also be induced by cancer or chemotherapy. 1 WO 01/05391 PCT/USOO/18346 Neuropathic pain is currently treated with anticonvulsants such as carbamazepine and antidepressants such as amitryptaline. NSAIDS and opioids generally have little effect (Fields et al 1994 Textbook of Pain p 991 996 (pub: Churchill Livingstone), James & Page 1994 5 J.Am.Pediatr.Med.Assoc, 8: 439-44 7, Galer, 1995 Neurology 45 SI 7-S25. Neuropathic conditions that have been treated with gabapentin include: postherpetic neuralgia, postpoliomyelitis, CPRM, HIV-related neuropathy, trigeminal neuralgia, and reflex sympathetic dystrophy (RSD). The generally weak efficacy of antiinflammatory agents suggests that the 10 mechanism for chronic pain is separate from hyperalgesia. SUMMARY OF THE INVENTION The invention features a method for treating chronic pain, which 15 method includes the step of administering a composition including a MEK inhibitor to a patient in need of such treatment. Chronic pain includes neuropathic pain, idiopathic pain, and pain associated with vitamin deficiencies, uremia, hypothyroidism post-operative pain, arthritis, back pain, and chronic alcoholism. The invention also features compositions as 20 disclosed, formulated for the treatment of chronic pain. Such a composition may include one or more MEK inhibitor compounds having a structure disclosed in patent application PCT/US99/30416, international filing date December 21, 1999. Examples of MEK inhibitors include a compound having the formula (1) 25 below: W R4 R1 3 R2 2 WO 01/05391 PCT/USOO/18346 W is one of the following formulae (i) - (xiii): X2 H 0, N X 2

R

5

N-NR

5 O-N O O-S, N X

N

Y X 2 N\X 0 N- H N NR 5 (i) (ii) (iii) (iV) (v) (vi) (vii)

X

2

X

2

N-NR

5 N-\/X Nr=N

N-NR

5 Xj- -N N, R I N 0 N 5 2 X2 I IX7 (viii) (ix) (x) (xi) (xii) (xiii) 5 HO 0 0 0-0 N-N X2 X X 1 N X N NN 'xx N (xiv) (xv) (xvi) (xvii) 10 X1 is 0, S, or NRF. X 2 is OH, SH, or NHRE. Each of RE and RF is H or C 1-4 alkyl; each of R 1 and R 2 is independently selected from H, F, NO 2 , Br and Cl; R 1 can also be SO2NRGRH, or R 1 and R 2 together with the benzene ring to which they are attached constitute an indole, isoindole, benzofuran, 15 benzothiophene, indazole, benzimidazole, or benzthioazole. R 3 is selected from H and F; each of RG, RH, and R 4 is independently selected from H, Cl and CH 3 . R 5 is H or C 1-4 alkyl. Each hydrocarbon radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, hydroxyl, amino, (amino)sulfonyl, and NO 2 . Each heterocyclic radical 3 WO 01/05391 PCT/USOO/18346 above is optionally substituted with between 1 and 3 substituents independently selected from halo, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-4 alkenyl, C 3 4 alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO 2 , wherein each substituent alky1, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally 5 substituted with between 1 and 2 substituents independently selected from halo, C 1-2 alkyl, hydroxyl, amino, and NO 2 . The invention also features a pharmaceutically acceptable salt or C 1-8 ester of a disclosed compound. For example, the disclosed alcohol compounds may form esters having the structure obtained by replacing the H of a hydroxyl group with a -C(=O)C 1-7 10 acyl group. Preferred embodiments of the invention include methods of using one or more of the following compounds: (a) said MEK inhibitor has a structure selected from: 2,4-bis-(2-chloro-4-iodo phenylamino)-3-fluoro-5-nitro-benzoic acid; 5-[3,4difluoro-2-(4-iodo-2-methyl 15 phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; (2,3-difluoro-6 [1,3,4]oxadiazol-2-yl-phenyl)(-(4-iodo-2-methyl-phenyl)-amine; 5-[3,4-difluoro 2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5 [3,4difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3 20 ylamine; and 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H [1,2,4]triazole-3-thiol; and (b) said MEK inhibitor has the structure selected from: 2,4-bis-(2-chloro-4 iodo-phenylamino)-3-fluoro-5-nitro-benzoic acid. Other aspects of the invention are provided in the description, 25 examples and claims below. BRIEF DESCRIPTION OF THE FIGURES 30 FIG. 1 is a bar graph representing the paw withdrawal threshold (PWT) in grams as a function of time in days. The empty, cross-hatched, and single 4 WO 01/05391 PCT/USOO/18346 hatched bars are vehicle, PD 198306, and pregabalin, respectively. The arrows indicate time of drug administration (30 mg/kg, p.o.). FIG 2. is a bar graph representing the force required in grams to elicit 5 paw withdrawal using von Frey hair filaments as a function of time in days. Baseline (BL) measurements were taken before treatment. Animals received a single p.o. administration of PD 198306 (3-30mg/kg), or pregabalin (30mg/kg) and withdrawal thresholds were re-assessed 1 h after treatment. Treatments were repeated twice a day for two days. Results are expressed 10 median ± 1 st and 3 rd quartiles. *P<0.05, **P<0.01, ***P<0.001 significantly different from vehicle treated animals (Mann-Whitney t test; n=7-8). FIG. 3. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days. 15 Baseline (BL) measurements were taken before treatment. Animals received a single p.o. administration of PD 198306 (3-30mg/kg), or pregabalin (30mg/kg) and withdrawal thresholds were re-assessed 1 h after treatment. Treatments were repeated twice a day for two days. Results are expressed median ± 1 st and 3 rd quartiles. **P<0.01 significantly different from vehicle 20 treated animals (Mann-Whitney t test; n=6). FIG. 4. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days. Baseline (BL) measurements were taken before treatment. Animals received 25 a single i.t. administration of PD 198306 (1-30ptg/10Ipl), or pregabalin (1 00ptg/I O1l) and withdrawal thresholds were re-assessed at 30min, 1 h and 2h after treatment. Results are expressed median ± 1 st and 3 rd quartiles. *P<0.05, ***P<0.001 significantly different from vehicle treated animals (Mann Whitney t test; n=7-9). 30 FIG. 5. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days. 5 WO 01/05391 PCT/USOO/18346 Baseline (BL) measurements were taken before treatment. Animals received a single i.t. administration of PD 198306 (1-30tg/10pl), or pregabalin (100ig/lOptl) and withdrawal thresholds were re-assessed at 30min, 1h and 2h after treatment. Results are expressed median ± 1 st and 3 rd quartiles. 5 *P<0.05, **P<0.01, ***P<0.001 significantly different from vehicle treated animals (Mann-Whitney t test; n=6-8). FIG. 6 is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days . 10 Animals received a single intraplantar (i.pl.) administration of PD 198306 (3mg/1 00pl), or an intrathecal injection of PD 198306 (30pg/l Op) and withdrawal thresholds were re-assessed 1 h after treatment. Results are expressed median ± 1 st and 3 rd quartiles. **P<0.01 significantly different from vehicle treated animals (Mann-Whitney t test; n=6-9). 15 FIG. 7. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days. Animals received a single intraplantar (i.pl.) administration of PD 198306 (3mg/1 00ptl), or an intrathecal injection of PD 198306 (30pg/10pld) and 20 withdrawal thresholds were re-assessed 1 h after treatment. Results are expressed median ± 1 st and 3 rd quartiles. **P<0.01 significantly different from vehicle treated animals (Mann-Whitney t test; n=6). FIG. 8 is a bar graph representing the force required in grams to elicit 25 paw withdrawal using von Frey hair filaments. Baseline (BL) measurements were taken before treatment. Animals received a single i.t. administration of PD219622, PD297447, PD 184352, or PD 254552 (30ptg/10pl), or pregabalin (100pg/10ld) and withdrawal thresholds were re-assessed at 30min, 1h and 2h after treatment. Results are expressed median ± 1 st and 3 rd quartiles. 30 *P<0.05, **P<0.01, ***P<0.001 significantly different from vehicle treated animals (Mann-Whitney t test; n=7-8). 6 WO 01/05391 PCT/USOO/18346 DETAILED DESCRIPTION The compounds disclosed herein are pharmaceutically active, for example, they inhibit MEK. MEK enzymes are dual specificity kinases 5 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 signal transduction mechanism of certain proteins. Defects include a change either in the intrinsic activity or in the cellular 10 concentration of one or more signaling proteins in the signaling cascade .The cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell. Some of the most common mutations occur 15 in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to GDP. The above mentioned growth factor receptors, and many other mitogenic receptors, when activated, lead to Ras being converted from the GDP-bound state to the GTP bound state. This signal is an absolute prerequisite for proliferation in most 20 cell types. Defects in this signaling system, especially in the deactivation of the Ras-GTP complex, are common in cancers, and lead to the signaling cascade below Ras being chronically activated. Activated Ras leads in turn to the activation of a cascade of serine/threonine kinases. One of the groups of kinases known to require an 25 active Ras-GTP for its own activation is the Raf family. These in turn activate MEK (e.g., MEK 1 and MEK 2 ) which then activates MAP kinase, ERK (ERK, and ERK 2 ). Activation of MAP kinase by mitogens appears to be essential for proliferation; constitutive activation of this kinase is sufficient to induce cellular transformation. Blockade of downstream Ras signaling, for example by use of 30 a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants. Although Ras is not itself a protein kinase, it participates in the activation of 7 WO 01/05391 PCT/USOO/18346 Raf and other kinases, most likely through a phosphorylation mechanism. Once activated, Raf and other kinases phosphorylate MEK on two closely adjacent serine residues, S 2 18 and S222 in the case of MEK-1, which are the prerequisite for activation of MEK as a kinase. MEK in turn phosphorylates 5 MAP kinase on both a tyrosine, Y 18 5 , and a threonine residue, T 18 3 , separated by a single amino acid. This double phosphorylation activates MAP kinase at least 100-fold. Activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including several transcription factors and other kinases. 10 Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK itself appears to be a signal integrating kinase. Current understanding is that MEK is highly specific for the phosphorylation of MAP kinase. In fact, 15 no substrate for MEK other than the MAP kinase , ERK, has been demonstrated to date and MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase. MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK 20 may require a prior strong interaction between the two proteins. Both this requirement and the unusual specificity of MEK are suggestive that it may have enough difference in its mechanism of action to other protein kinases that selective inhibitors of MEK, possibly operating through allosteric mechanisms rather than through the usual blockade of the ATP binding site, 25 may be found. The effect of the MEK inhibitor PD 198306 has been investigated in two animal models of neuropathic pain by assessing static allodynia with von Frey hairs. Oral administration of PD 198306 (3-30mg/kg) had no effect in the model 30 of chronic constriction injury of the sciatic nerve (CCI). However, after repeated administration (3 doses over two days) it had a transient effect in the diabetic neuropathy model (streptozocin). This may be due to disorders of the blood 8 WO 01/05391 PCT/USOO/18346 brain barrier induced by the diabetic condition in these animals, thus allowing central action of the compound. Intrathecal administration of PD 198306 (1 30ptg) dose-dependently blocked static allodynia in both the streptozocin and the CCI models of neuropathic pain, with minimum effective doses (MED) of 3 and 5 10ptg respectively. The highest dose used (30ptg) totally blocked the maintenance of static allodynia, for up to 1h. Intraplantar administration of PD 198306 (3mg/100pl) at a dose 100-fold higher than the dose shown to be effective intrathecally (30pg/1 0Il) had no effect on static allodynia in either of the neuropathic pain models. This finding confirms the lack of effect seen after 10 systemic administration and suggests a central site of action for the compound. From this study we can suggest the use of MEK inhibitors as potential new therapeutic tools for chronic pain. The study of potential side-effects, especially related to memory, of future brain-penetrant MEK inhibitors will indicate the therapeutic window for this novel class of compounds in the 15 treatment of pain. 9 WO 01/05391 PCT/USOO/18346 A. Terms Certain terms are defined below and by their usage throughout this disclosure. Alkyl groups include aliphatic (i.e., hydrocarbyl or hydrocarbon radical 5 structures containing hydrogen and carbon atoms) with a free valence. Alkyl groups are understood to include straight chain and branched 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, 10 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Alkyl groups can 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 15 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, N-pyridinylethyl, diethylaminoethyl, and cyclobutylmethyl. Alkenyl groups are analogous to alkyl groups, but have at least one 20 double bond (two adjacent sp 2 carbon atoms). Depending on the placement of a double bond and substituents, if any, the geometry of the double bond may be entgegen (E), or zusammen (Z), cis, or trans. Similarly, alkynyl groups have at least one triple bond (two adjacent sp carbon atoms). Unsaturated alkenyl or alkynyl groups may have one or more double or triple 25 bonds, respectively, or a mixture thereof; like alkyl groups, unsaturated groups may be straight chain or branched, and they may be substituted as described both above for alkyl groups and throughout the disclosure by example. Examples of alkenyls, alkynyls, and substituted forms include cis-2-butenyl, trans-2-butenyl, 3-butynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 30 3-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 10 WO 01/05391 PCT/USOO/18346 propenyl. In formula (1), alkenyls and alkynyls can be C 2-4 or C 2-8, for example, and are preferably C 3-4 or C 3-8. More general forms of substituted hydrocarbon radicals include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, 5 and corresponding forms for the prefixes amino-, halo- (e.g., fluoro-, chloro-, or bromo-), nitro-, alkyl-, phenyl-, cycloalkyl- and so on, or combinations of substituents. According to formula (1), therefore, substituted alkyls include hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyls, such as methylpentyl), (cycloalkyl)alkyl, phenylalkyl, alkoxy, alkylaminoalkyl, 10 dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, (heterocyclic radical)alkyl, and (heterocyclic radical)oxyalkyl. R 1 thus includes hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl)alkyl, (haloaryl)alkyl, (hydroxyaryl)alkynyl, and so forth. 15 Similarly, RA includes hydroxyalkyl and aminoaryl, and RB includes hydroxyalkyl, aminoalkyl, and hydroxyalkyl(heterocyclic radical)alkyl. Heterocyclic radicals, which include but are not limited to heteroaryls, include: furyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, 1,3,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, and their 20 nonaromatic counterparts. Further examples of heterocyclic radicals include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahyd ropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl, and octahydrobenzofuranyl. Selective MEK 1 or MEK 2 inhibitors are those compounds which 25 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 50 for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its IC 50 for one of the above-named other enzymes. Preferably, 30 a selective inhibitor has an IC 50 that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less than that of its IC 50 or one or more of the above-named enzymes. 11 WO 01/05391 PCT/USOO/18346 B. Compounds One aspect of the invention features the disclosed compounds shown in formula (1) in the Summary section. Embodiments of the invention include compounds wherein: (a) R, is 5 bromo or chloro; (b) R 2 is fluoro; (c) R 3 is H; (d) each of R 2 and R 3 is H; (e) each of R 2 and R 3 is fluoro; (f) R 1 is bromo; (g) each of R 1 , R 2 and R 3 is fluoro; (h) R 2 is nitro; (i) R 3 is H; (j) R 4 is chloro; (k) R 4 is methyl; (1) R 5 is H; (m) R 5 is CH 3 ; (n) X 1 is 0 or S; (o) X 1 is NH or NCH 3 ; (p) X 2 is OH, SH, or

NH

2 ; (q) X 2 is OH; (r) X 2 is NHRE; (s) R 4 is H; (t) R 4 is chloro or methyl; or 10 combinations thereof. Preferably, where one of the substituents on a heterocyclic radical is an alkenyl or alkynyl group, the double or triple bond, respectively, is not adjacent the point of attachment when it is a heteroatom. For example, in such a situation, the substituent is preferably prop-2-ynyl, or but-2 or 3-enyl, and less 15 preferably prop-1-ynyl or but-1-enyl. Examples of compounds include: [5-fluoro-2-(1 H-tetrazol-5-yl) phenyl]-(4-iodo-2-methyl-phenyl)-amine; [2,3-difluoro-6-(1H-tetrazol-5-yl) phenyl]-(4-iodo-2-methyl-phenyl)- amine; (4-iodo-2-methyl-phenyl)-[2,3,4 trifluoro-6-(1H-tetrazol-5-yl)-phenyl]-amine; [4-bromo-2,3-difluoro-6-(1H 20 tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [5-fluoro-4-nitro-2-(1H tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [2-(4,4-dimethyl-4,5 dihydro-oxazol-2-yl)-5-fluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [6-(4,4 d imethyl-4,5-d ihydro-oxazol-2-yl)-2,3-difluoro-phenyl]-(4-iodo-2-methyl phenyl)-amine; [6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2,3,4-trifluoro 25 phenyl]-(4-iodo-2-methyl-phenyl)-amine; [4-bromo-6-(4,4-dimethyl-4,5 dihydro-oxazol-2-yl)-2,3-difluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [2 (4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-fluoro-4-nitro-phenyl]-(4-iodo-2 methyl-phenyl)-amine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] [1,3,4]thiadiazol-2-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-pheny] 30 [1,3,4]thiadiazol-2-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-[1,3,4]thiadiazol-2-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[4-fluoro-2-(4-iodo-2-methyl 12 WO 01/05391 PCT/USOO/18346 phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl-[1,3,4]oxadiazol-2-ol; 5-[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[3,4,5-trifluoro-2-(4-iodo 2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[5-bromo-3,4-difluoro 5 2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[4-fluoro-2 (4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[4 fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ol; 5-[3,4 difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ol; 5 [3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ol; 10 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H [1,2,4]triazol-3-ol; and 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro phenyl]-4H-[1,2,4]triazol-3-ol. Further examples include: 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[3,4-Difluoro-2-(4-iodo-2-methyl 15 phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[3,4,5-Trifluoro-2-(4-iodo 2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[5-bromo-3,4 difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazol 2-ylamine; 5-[4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] 20 [1,3,4]oxadiazol-2-ylamine; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[5-bromo-3,4-difluoro-2 (4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-yIamine; 5-[4-fluoro 2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]oxadiazol-2-ylamine; 25 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3 ylamine; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H [1,2,4]triazol-3-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[4-fluoro-2-(4 30 iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[4 fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5 [3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2 13 WO 01/05391 PCT/USOO/18346 thiol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] [1,3,4]thiadiazole-2-thiol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2 5 methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[3,4-difluoro-2-(4 iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[3,4,5 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5 [5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-pheny] [1,3,4]oxadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro 10 phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[3,4,5-trifluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[5-bromo-3,4 difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 15 and 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4H [1,2,4]triazole-3-thiol. Additional examples are: 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-isothiazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-isothiazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino) 20 phenyl]-isothiazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isothiazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-5-nitro-phenyl]-isothiazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isoxazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isoxazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl 25 phenylamino)-phenyl]-isoxazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-isoxazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-5-nitro-phenyl]-isoxazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-1H-pyrazol-3-ol; 5-[3,4-d ifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-1H-pyrazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl 30 phenylamino)-phenyl]-1 H-pyrazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-1H-pyrazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-5-nitro-phenyl]-1 H-pyrazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl 14 WO 01/05391 PCT/USOO/18346 phenylamino)-phenyl]-isothiazol-3-ol; 4-[3,4-d ifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isothiazol-3-ol; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isothiazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2 methyl-phenylam ino)-phenyl]-isothiazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl 5 phenylamino)-5-nitro-phenyl]-isothiazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-phenyl-isoxazol-3-ol; 4-[3,4-d ifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isoxazol-3-ol; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isoxazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-isoxazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl 10 phenylamino)-5-nitro-phenyl]-isoxazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-1-methyl-1H-pyrazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-1-methyl-1H-pyrazol-3-ol; 1-methyl-4-[3,4,5 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1 H-pyrazol-3-ol; 4-[5 bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-methyl-1 H 15 pyrazol-3-ol; and 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl] 1-methyl-1 H-pyrazol-3-ol. The invention also features compounds such as: 5-[2-(2-amino-4-iodo phenylamino)-4-fluoro-phenyl]-i -methyl-1 H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4 iodo-phenylamino)-3,4-difluoro-phenyl]-1 -methyl-1 H-[1,2,3]triazol-4-ol; 5-[2-(2 20 amino-4-iodo-phenylamino)-3,4,5-trifluoro-phenyl]-1 -methyl-1 H-[1,2,3]triazol 4-ol; 5-[2-(2-amino-4-iodo-phenylamino)-5-bromo-3,4-difluoro-phenyl]-1 methyl-1H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4-iodo-phenylamino)-4-fluoro-5 nitro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-ol; 5-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 5-[3,4-difluoro-2-(4-iodo 25 2-methyl-phenylamino)-phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 3-methyl-5 [3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3H-[1,2,3]triazol-4-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3-methyl 3H-[1,2,3]triazol-4-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 4-[4-fluoro-2-(4-iodo-2-methyl 30 phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-ol; 2-methyl-4-[3,4,5 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H-pyrazol-3-ol; 4-[5 15 WO 01/05391 PCT/USOO/18346 bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2-methyl-2H pyrazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-2 methyl-2H-pyrazol-3-ol; 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] 4-methyl-1,4-dihydro-tetrazol-5-one; 1-[3,4-difluoro-2-(4-iodo-2-methyl 5 phenylamino)-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1-methyl-4-[3,4,5 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1,4-dihydro-tetrazol-5-one; 1-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl 1,4-dihydro-tetrazol-5-one; 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5 n itro-phenyl]-4-methyl- 1,4-d ihydro-tetrazol-5-one; 1-[4-fluoro-2-(4-iodo-2 10 methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; 1-[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; 1-[3,4,5-trifluoro-2-(4-iodo 2-methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; 1-[5-bromo-3,4-difluoro 2-(4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-ol; and 1-[4 fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-1 H-[1,2,3]triazol-4-ol. 15 Further examples of the invention include 3-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[3,4,5-trifluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[5-bromo-3,4-difluoro-2 (4-iodo-2-methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3-[4-fluoro-2-(4 20 iodo-2-methyl-phenylamino)-5-nitro-phenyl]-2H-isoxazol-5-one; [5-fluoro-2-(2 oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl phenyl)-amine; [2,3-difluoro-6-(2-oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol 4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; (4-lodo-2-methyl-phenyl)-[2,3,4 trifluoro-6-(2-oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-amine; 25 [4-bromo-2,3-difluoro-6-(2-oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol-4-yl) phenyl]-(4-iodo-2-methyl-phenyl)-amine; [5-fluoro-4-nitro-2-(2-oxo-2,3-dihydro 21>4_-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; 4 [4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[3,4 difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[3,4,5 30 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[5 bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5 16 WO 01/05391 PCT/USOO/18346 one; and 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4H isoxazol-5-one. Further compounds, where R 1 can also be SO 2 NRGRH, or R 1 and R 2 together with the benzene ring to which they are attached constitute an indole, 5 isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzthioazole, include the following groups: Group 1 10 (1) 2-Fluoro-5-(5-hydroxy-1,3,4-oxadiazol-2-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-1,3,4-oxadiazol-2 yl)-N-methyl-benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-1,3,4-oxadiazol-2-yl)-4-(4-iodo-2-methyl 15 phenylamino)-N,N-dimethyl-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-1,3,4 oxad iazol-2-yl)-N-methyl-N-(3-morpholin-4-yl-propyl) benzenesulfonamide (5) 2-Fluoro-5-(5-hydroxy-1,3,4-oxadiazol-2-yl)-4-(4-iodo-phenylamino)-N-[2 20 (2-methoxy-ethoxy)-ethyl]-benzenesulfonamide (6) N-(2-Dimethylamino-ethyl)-2-fluoro-5-(5-hydroxy-1,3,4-oxadiazol-2-yl)-4 (4-iodo-phenylamino)-N-methyl-benzenesulfonamide 25 Group 2 (1) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2 fluoro- benzenesulfonamide 30 (3) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2,3-difluoro-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide 17 WO 01/05391 PCT/USOO/18346 (4) 5-(5-Amino-1,3,4-oxadiazol-2-yI)-4-(2-chloro-4-iodo-phenylamino)-2,3 difluoro-benzenesulfonamide (5) 5-(5-Amino-1,3,4-oxadiazol-2-yI)-2-fluoro-4-(4-iodo-phenylamino) benzenesulfonamide 5 (6) 4-(5-Amino-1,3,4-oxadiazol-2-yI)-2-fluoro-5-(4-iodo-phenylamino) benzenesulfonamide Group 2b 10 (1) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 5-(5-Amino-1,3,4-oxadiazol-2-yI)-2-fluoro-4-(4-iodo-phenylamino)-N methyl-N-(3-morpholin-4-yl-propyl)-benzenesulfonamide (3) 5-(5-Am ino- 1,3,4-oxadiazol-2-yl)-2,3-d ifluoro-4-(4-iodo-2-methyl 15 phenylamino)-benzenesulfonamide (4) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-2-fluoro-4-(4-iodo-phenylamino) benzenesulfonamide (5) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3 difluoro-N-[3-(4-methyl-piperazin-1 -yl)-propyl]-benzenesulfonamide 20 (6) 5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2 fluoro-N-(3-piperidin-1 -yi-propyl)-benzenesulfonamide Group 3 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-mercapto-1,3,4-oxadiazol 25 2-yl)-benzenesulfonamide (2) 2-Fluoro-5-(4-iodo-phenylamino)-4-(5-mercapto-1,3,4-oxadiazol-2-yl) benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-mercapto-1,3,4 oxadiazol-2-yl)-benzenesulfonamide 30 (4) 2-Fluoro-4-(4-iodo-phenylamino)-5-(5-mercapto-1,3,4-oxadiazol-2-yl) benzenesulfonamide 18 WO 01/05391 PCT/USOO/18346 (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-mercapto-1,3,4 oxadiazol-2-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-mercapto-1,3,4-oxadiazol 2-yl)-benzenesulfonamide 5 Group 4 (1) 2-Fluoro-5-(5-hydroxy-1,3,4-thiadiazol-2-yI)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 2-Fluoro-4-(5-hydroxy-1,3,4-thiadiazol-2-yl)-5-(4-iodo-phenylamino) 10 benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-1,3,4-thiadiazol-2-yI)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (4) 2-Fluoro-5-(5-hydroxy-1,3,4-thiadiazol-2-yI)-4-(4-iodo-phenylamino) benzenesulfonamide 15 (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-1,3,4 thiadiazol-2-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-1,3,4-thiadiazol-2 yl)-benzenesulfonamide 20 Group 5 (1) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-2-fluoro-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 4-(5-Amino-1,3,4-thiadiazol-2-yl)-5-(4-iodo-phenylamino)-2-mercapto benzenesulfonamide 25 (3) 5-(5-Amino-1,3,4-thiad iazol-2-yl)-2,3-d ifluoro-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (4) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-2-fluoro-4-(4-iodo-phenylamino) benzenesulfonamide (5) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3 30 difluoro-benzenesulfonamide (6) 5-(5-Amino-1,3,4-thiadiazol-2-yl)-4-(2-chloro-4-iodo-phenylamino)-2 fluoro-benzenesulfonamide 19 WO 01/05391 PCT/USOO/18346 Group 6 (1) 2-Fluoro-5-(5-hydroxy-4H-1,2,4-triazol-3-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide 5 (2) 2-Fluoro-4-(5-hydroxy-4H-1,2,4-triazol-3-yl)-5-(4-iodo-phenylamino) benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-4H-1,2,4-triazol-3-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (4) 5-[4-(2-Dimethylamino-ethyl)-5-hydroxy-4H-1,2,4-triazol-3-yl]-2-fluoro-4 10 (4-iodo-phenylamino)-benzenesulfonamide (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-4H-1,2,4 triazol-3-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-4-methyl-4H-1,2,4 triazol-3-yI)-benzenesulfonamide 15 Group 7 (1) 5-(5-Amino-4H-1,2,4-triazol-3-yl)-2-fluoro-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 4-(5-Amino-4H-1,2,4-triazol-3-yl)-2-fluoro-5-(4-iodo-phenylamino) 20 benzenesulfonamide (3) 5-(5-Amino-4-methyl-4H-1 ,2 ,4-triazol-3-yl)-2,3-d ifluoro-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (4) 5-[5-Amino-4-(3-dimethylamino-propyl)-4H-1,2,4-triazol-3-yl]-2-fluoro-4-(4 iodo-phenylamino)-benzenesulfonamide 25 (5) 5-(5-Amino-4H-1,2,4-triazol-3-yI)-4-(2-chloro-4-iodo-phenylamino)-2,3 difluoro-benzenesulfonamide (6) 5-(5-Amino-4-methyl-4H-1,2,4-triazol-3-yI)-4-(2-chloro-4-iodo phenylamino)-2-fluoro-benzenesulfonamide 30 Group 8 (1) 2-Fluoro-5-(3-hydroxy-isoxazol-5-yI)-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide 20 WO 01/05391 PCT/USOO/18346 (2) 2-Fluoro-4-(3-hyd roxy-isoxazol-5-yI)-5-(4-iodo-phenylamino) benzenesulfonamide (3) 2 ,3-Difluoro-5-(3-hydroxy-isoxazol-5-yI)-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide 5 (4) 2-Fluoro-5-(3-hydroxy-isoxazol-5-yI)-4-(4-iodo-phenylamino) benzenesu Ifonam ide (5) 4-(2-Chloro-4-iodo-phenylamino)-2, 3-d ifluoro-5-(3-hyd roxy-isoxazol-5-yI) benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylam ino)-2-fluoro-5-(3-hydroxy-isoxazol-5-yI) 10 benzenesulfonamide Group 9 (1) 5-(3-Am ino-isoxazol-5-yI)-2-fluoro-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide 15 (2) 4-(3-Am ino-isoxazol-5-yI)-2-bromo-5-(4-iodo-phenylamino) benzenesulfonamide (3) 5-(3-Am ino-isoxazol-5-yi)-2,3-d ifluoro-4-(4-iodo-2-methyl-phenylamino) benzenesu Ifonam ide (4) 5-(3-Am ino-isoxazol-5-yI)-2-fluoro-4-(4-iodo-phenylamino) 20 benzenesulfonamide (5) 5-(3-Amino-isoxazol-5-yI)-4-(2-chloro-4-iodo-phenylamino)-2, 3-difluoro benzenesulfonamide (6) 5-(3-Amino-isoxazol-5-yI)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro benzenesulfonamide 25 Group 10 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(3-mercapto-isoxazol-5-yI) benzenesulfonamide (2) 4-(2-Ch Ioro-4-iodo-phenylamino)-2-fluoro-5-(3-mercapto-isoxazo-5-yi) 30 benzenesulfonamide (3) 2, 3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(3-mercapto-isoxazoI-5 yI)-benzenesulfonam ide 21 WO 01/05391 PCT/USOO/18346 (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(3-mercapto-isoxazol-5 yi)-benzenesulfonamide (5) 2-Fluoro-4-(4-iodo-phenylamino)-5-(3-mercapto-isoxazol-5-yl) benzenesulfonamide 5 (6) 2-Bromo-5-(4-iodo-phenylamino)-4-(3-mercapto-isoxazol-5-y) benzenesulfonamide Group 11 (1) 2-Fluoro-5-(3-hydroxy-isoxazol-4-yl)-4-(4-iodo-2-methyl-phenylamino) 10 benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(3-hydroxy-isoxazol-4-yl) benzenesulfonamide (3) 2,3-Difluoro-5-(3-hydroxy-isoxazol-4-yl)-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide 15 (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(3-hydroxy-isoxazol-4-yl) benzenesulfonamide (5) 2-Fluoro-5-(3-hydroxy-isoxazol-4-yI)-4-(4-iodo-phenylamino) benzenesulfonamide (6) 2-Bromo-4-(3-hydroxy-isoxazol-4-yl)-5-(4-iodo-phenylamino) 20 benzenesulfonamide Group 12 (1) 5-(3-Amino-isoxazol-4-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide 25 (2) 5-(3-Amino-isoxazol-4-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro benzenesulfonamide (3) 5-(3-Amino-isoxazol-4-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide (4) 5-(3-Amino-isoxazol-4-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro 30 benzenesulfonamide (5) 5-(3-Amino-isoxazol-4-yl)-2-fluoro-4-(4-iodo-phenylamino) benzenesulfonamide 22 WO 01/05391 PCT/USOO/18346 (6) 4-(3-Amino-isoxazol-4-yl)-2-chloro-5-(4-iodo-phenylamino) benzenesulfonamide Group 13 5 (1) 5-(3-Amino-isoxazol-4-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide (2) 5-(3-Amino-isoxazol-4-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro benzenesulfonamide (3) 5-(3-Amino-isoxazol-4-yl)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino) 10 benzenesulfonamide (4) 5-(3-Amino-isoxazol-4-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro benzenesulfonamide" (5) 5-(3-Amino-isoxazol-4-yI)-2-fluoro-4-(4-iodo-phenylamino) benzenesulfonamide 15 (6) 4-(3-Amino-isoxazol-4-yI)-2-chloro-5-(4-iodo-phenylamino) benzenesulfonamide Group 14 (1) 5-(2-Amino-5H-pyrrol-3-yl)-2-fluoro-4-(4-iodo-2-methyl-phenylamino) 20 benzenesulfonamide (2) 5-(2-Amino-5H-pyrrol-3-yl)-4-(2-chloro-4-iodo-phenylamino)-2-fluoro benzenesulfonamide (3) 5-(2-Amino-5H-pyrrol-3-yI)-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino) benzenesulfonamide 25 (4) 5-(2-Amino-5H-pyrrol-3-yl)-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro benzenesulfonamide (5) 5-(2-Amino-5H-pyrrol-3-yI)-2-fluoro-4-(4-iodo-phenylamino) benzenesulfonamide (6) 4-(2-Amino-5H-pyrrol-3-yl)-2-chloro-5-(4-iodo-phenylamino) 30 benzenesulfonamide 23 WO 01/05391 PCT/USOO/18346 Group 15 (1) 2-Fluoro-5-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-1 H-pyrazol-4-yl) 5 benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-1H-pyrazol-4-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-1 H-pyrazol-4 yl)-benzenesulfonamide 10 (5) 2-Fluoro-5-{5-hydroxy-1-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrazol-4 yl}-4-(4-iodo-phenylamino)-benzenesulfonamide (6) 2-Fluoro-4-(5-hydroxy-1H-pyrazol-4-yl)-5-(4-iodo-phenylamino) benzenesulfonamide 15 Group 16 (1) 2-Fluoro-5-(5-hyd roxy-3-methyl-3H- 1,2,3-triazol-4-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4 yi)-benzenesulfonamide 20 (3) 2,3-Difluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yI)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-3H-1,2,3 triazol-4-yl)-benzenesulfonamide (5) 2-Fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-4-(4-iodo-phenylamino) 25 benzenesulfonamide (6) 2-Fluoro-5-{5-hydroxy-3-[2-(2-methoxy-ethoxy)-ethyl]-3H-1,2,3-triazol-4 yl}-4-(4-iodo-phenylamino)-benzenesulfonamide Group 17 30 (1) 2-Fluoro-5-(5-hydroxy-3-methyl-3H-1,2,3-triazol-4-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide 24 WO 01/05391 PCT/USOO/18346 (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4 yl)- benzenesulfonamide (3) 2,3-Difluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-4-(4-iodo-2-methyl phenylamino)-benzenesulfonamide 5 (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-hydroxy-3H-1,2,3 triazol-4-yl)-benzenesulfonamide (5) 2-Fluoro-5-(5-hydroxy-3H-1,2,3-triazol-4-yl)-4-(4-iodo-phenylamino) benzenesulfonamide (6) 2-Fluoro-5-{5-hydroxy-3-[2-(2-methoxy-ethoxy)-ethyl]-3H-1,2,3-triazol-4 10 yl}-4-(4-iodo-phenylamino)-benzenesulfonamide Group 18 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-4,5-dihydro-tetrazol-1 yl)-benzenesulfonamide e15 (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-oxo-4,5-dihydro-tetrazol-1 yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-4,5-dihydro tetrazol-1 -yl)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-oxo-4,5-dihydro 20 tetrazol-1 -yl)-benzenesulfonamide (5) 2-Fluoro-4-(4-iodo-phenylamino)-5-(5-oxo-4,5-dihydro-tetrazol-1-yI) benzenesulfonamide (6) 2,6-Difluoro-3-(4-iodo-phenylamino)-4-(5-oxo-4,5-dihydro-tetrazol-1-yI) benzenesulfonamide 25 Group 19 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(4-methyl-5-oxo-4,5-dihydro tetrazol-1 -yl)- benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro 30 tetrazol-1 -yl)- benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-4,5-dihydro tetrazol-1 -yl)-benzenesulfonamide 25 WO 01/05391 PCT/USOO/18346 (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-oxo-4,5-dihydro tetrazol-1 -yi)-benzenesulfonamide (5) 5-[4-(2-Dimethylamino-ethyl)-5-oxo-4,5-dihydro-tetrazol-1-yl]-2-fluoro-4-(4 iodo-phenylamino)-benzenesulfonamide 5 (6) 2-Fluoro-5-(4-iodo-phenylamino)-4-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1 yi)-benzenesulfonamide Group 20 10 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(2-oxo-2,3-dihydro-1,2,3,5 oxathiadiazol-4-yl)-benzenesulfonamide (2) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(2-oxo-2,3-dihydro-1,2,3,5 oxathiadiazol-4-yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(2-oxo-2,3-dihydro 15 1,2,3,5-oxathiadiazol-4-yI)-benzenesulfonamide (4) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(2-oxo-2,3-dihydro 1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (5) 2-Fluoro-4-(4-iodo-phenylamino)-5-(2-oxo-2,3-dihydro-1,2,3,5 oxathiadiazol-4-yl)-benzenesulfonamide 20 (6) 2-Fluoro-5-(4-iodo-phenylamino)-4-(2-oxo-2,3-dihydro-1,2,3,5 oxathiadiazol-4-yl)-benzenesulfonamide Group 21 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(3-methyl-2-oxo-2,3-dihydro 25 1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (2) 2,6-Difluoro-3-(4-iodo-phenylamino)-4-(3-methyl-2-oxo-2,3-dihydro 1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(3-methyl-2-oxo-2,3 dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide 30 (4) 2-Fluoro-4-(4-iodo-phenylamino)-5-(3-methyl-2-oxo-2,3-dihydro-1,2,3,5 oxathiadiazol-4-yl)-benzenesulfonamide 26 WO 01/05391 PCT/USOO/18346 (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(3-methyl-2-oxo-2,3 dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-N-methyl-5-(3-methyl-2-oxo-2,3 dihydro-1,2,3,5-oxathiadiazol-4-yl)-benzenesulfonamide 5 Group 22 (1) 2-Fluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-2,5-dihydro-isoxazol 3-yl)-benzenesulfonamide (2) 2,6-Difluoro-3-(4-iodo-phenylamino)-4-(5-oxo-2,5-dihydro-isoxazol-3-yl) 10 benzenesulfonamide (3) 2,3-Difluoro-4-(4-iodo-2-methyl-phenylamino)-5-(5-oxo-2,5-dihydro isoxazol-3-yl)-benzenesulfonamide (4) 2-Fluoro-4-(4-iodo-phenylamino)-5-(5-oxo-2,5-dihydro-isoxazol-3-yI) benzenesulfonamide 15 (5) 4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-(5-oxo-2,5-dihydro isoxazol-3-yl)-benzenesulfonamide (6) 4-(2-Chloro-4-iodo-phenylamino)-2-fluoro-5-(5-oxo-2,5-dihydro-isoxazol-3 yl)-benzenesulfonamide 20 Group 23 (1) 5-[6-(4-lodo-2-methyl-phenylamino)-1H-benzimidazol-5-yl]-1,3,4 oxadiazol-2-ol (2) 5-[6-(4-lodo-phenylamino)-benzofuran-5-yl]-1,3,4-oxadiazol-2-oI (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoxazol-5-y]-1,3,4 25 oxadiazol-2-ol (4) 5-[5-(4-lodo-phenylamino)-benzofuran-6-yl]-1,3,4-oxadiazol-2-oI (5) 5-[6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-1,3-dihydro-isobenzofuran-5 yl]-1,3,4-oxadiazol-2-ol (6) 5-[6-(2-Chloro-4-iodo-phenylamino)-1-methyl-1H-benzimidazol-5-yl]-1,3,4 30 oxadiazol-2-ol 27 WO 01/05391 PCT/USOO/18346 Group 24 (1) 5-[2-Amino-6-(4-iodo-2-methyl-phenylamino)-1H-benzimidazol-5-yl]-1,3,4 oxadiazol-2-ol (2) 5-[6-(4-lodo-phenylamino)-benzo[b]thiophen-5-yl]-1,3,4-oxadiazol-2-oI 5 (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzothiazol-5-yl]-1,3,4 oxadiazol-2-ol (4) 5-[5-(4-lodo-phenylamino)-benzo[b]thiophen-6-yl]-1,3,4-oxadiazol-2-oI (5) 5-[6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-1,3-dihydro benzo[c]thiophen-5-yl]- 1, 3,4-oxad iazol-2-ol 10 (6) 5-[6-(2-Chloro-4-iodo-phenylamino)-2-oxo-2,3-dihydro-1H-2$1>4_-2,1,3 benzothiadiazol-5-yl]-1,3,4-oxadiazol-2-oI Group 25 (1) 5-[2-Amino-6-(4-iodo-2-methyl-phenylamino)-benzothiazol-5-yl]-1,3,4 15 oxadiazol-2-ol (2) 5-[6-(4-lodo-phenylamino)-1H-indol-5-yl]-1,3,4-oxadiazol-2-oI (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzothiazol-5-yl]-1,3,4 oxadiazol-2-ol (4) 5-[5-(4-lodo-phenylamino)-1H-indol-6-yl]-1,3,4-oxadiazol-2-oI 20 (5) 5-[6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-2,3-dihydro-1H-isoindol-5-yl] 1,3,4-oxadiazol-2-ol (6) 5-[5-(2-Chloro-4-iodo-phenylamino)-1H-indazol-6-y]-1,3,4-oxadiazol-2-oI Group 26 25 (1) 5-[2-Amino-6-(4-iodo-2-methyl-phenylamino)-benzothiazol-5-yI]-1,3,4 oxadiazol-2-ol (2) 5-[6-(4-lodo-phenylamino)-1H-indol-5-yI]-1,3,4-oxadiazol-2-oI (3) 5-[7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoxazol-5-yl]-1,3,4 oxadiazol-2-ol 30 (4) 5-[5-(4-lodo-phenylamino)-benzoxazol-6-yl]-1,3,4-oxadiazol-2-oI (5) 5-[6-(2-Chloro-4-iodo-phenylamino)-7-fluoro-2,3-dihydro-1H-isoindol-5-yI] 1,3,4-oxadiazol-2-ol 28 WO 01/05391 PCT/USOO/18346 (6) 5-[5-(2-Chloro-4-iodo-phenylamino)-1H-indazol-6-yl]-1,3,4-oxadiazol-2-oI 29 WO 01/05391 PCT/USOO/18346 C. Synthesis The disclosed compounds can be synthesized according to Schemes 1-25 or analogous variants thereof. These synthetic strategies are further 5 exemplified in Examples 1-8 below. The solvent between compounds 4 and 5 in Scheme 1 is toluene (PhMe). 30 WO 01/05391 PCT/USOO/18346 Scheme 1 OH O

H

2 NN,, HHkj H H H N N NCI Cki N N DMF N RR I RRR, R2 , R2 5 R R 3 I hCI3

R

2

R

2 7 N CH 3 9HO Nx 0 N\ 0 OHOH N N Ph H & H RR 2 R2R 2 H -NNH 2 Ph/A N N NH 2 N\ 0 H N _H N N N N 31 R 7 4 Ph? 0 OH aNA( H H H H' N N conc.HCIN I I EtOH ,R R2 R 2 8 9 5 31 WO 01/05391 PCT/USOO/18346 Scheme 2 OH Ph-O NH H N\ NH H )l NH 2 H

H

2 N N N R, R I Pyridine R, R R2 R2 10 11 OH N - OH C I N R4 N NH R4 N K-N=S=0 N R R3 I Et3N/Ph RI R3 R2 R2 12 13 Ph O HO N -- N H R4 NH R4 N H 2 NNH2 N I I I EtOH R, R3 i tHRi R3 R2 R2 14 15 HO 0 N O NN 0 H R 4

OCH

3 SOC12 OCH 3 LDA N R, R 3

H

2 N OH R 1

R

3 H2 R 4

R

1 R3 R2 R2R2 16 17 I 18 32 WO 01/05391 PCT/USOO/18346 Scheme 3 OEt 0H'flNN N\N NH 0 OH O, ,N' H 1. AcONa/Br 2 F FI /AcOH - 1 2. KSCN F R R3 R R 3 2. KOH, EtOH R, R 3 3. EtOH R, R 3 R2 R 2

R

2 4. NH 2

NH

2

R

2 19 20 / 21 , 22 0 HCl

H

2 N N NH2 H 0 OH ' OH O I''R4'N HO o A ,N 0 N\ NH H2N N\ NH HN H 2 NH R F F NaOH F N R R 3 R, RH R, R3 LDA R R3

R

2

R

2 R2 2 22 23 24 25 1. HCI/ H 2 0

NH

2

NH

2 2. NaOH/H 2 0 PyBOP H

H

2 N F HOCN Ri R,+

NH

3 R2 26 33 WO 01/05391 PCT/USOO/18346 Scheme 4 OH OH HR HN-N O N HNk4N F N F N - I R, R, R R3 LDA R R 3 R2 R2 R2 26 24 25 S Cl iJCl pC1 5 /POCl 3 1. PCl 5 /POCl 3 SH Cl N 0N 2. HO NH 2 F F R, R3 Rl R3 R2 R2 27 28 1. CH3 2. KMnO 4 0 N " N O0H N O HO -. NH 2 NN H R F A N R, R3 R, R3I R2 R2 29 30 34 WO 01/05391 PCT/USOO/18346 Scheme 5 OH N=(OH

CH

3 N S H 2 N\ S F Ph N OEt F N R R3 Lawesson's reagent , R LDA R, R3I R2 R2 R2 31 32 33 0 0 HS S O O S S 0 Ph, N N'N S F HO Br F Ph, NH2 H H N), BO , F NN'N F H H H R, R2 R 3 piperidine/acetone R, R3 R R3 34 35 36 OH OH R4 N S H 2 N N N\ S H conc. HCI FN EtOH R R3 LDA R R3 1

R

2 R2 37 9 35 WO 01/05391 PCT/USOO/18346 Scheme 6 R4 COOH H2N COOH R4 RI R3 LHMDS RI R3 I R2 R2 N O R4 (1)(COCR) 2 (2) H OH 2 RI R3 1 (3) SOCI 2 R2 36 WO 01/05391 PCT/USOO/18346 Scheme 7 R4 COOH H 2 N COOH R4 RI R3 LHMDS RI R3 I R2 R2 0 H2N O R4 2H AO R4

NH

2

NH

2 ,PY-BOPH 2 N R4 CICO 2

C

2 H, 5 RI R3 i RI R3 R2 R2 OH N POcla N 0 R4 RI R3 I R2 37 WO 01/05391 PCT/USOO/18346 Scheme 8 R4 COOH H2N COOH R4 F RI R3 LHMDS RI R3 I R2 R2 0 O

C

2

H

6 0 R4

NH

2

NH

2 ,PY-BOP H2N

CCO

2

C

2 H RI R3 I RI R3 R2 R2 Lawesson s Reagent Lawesson's Reagent Xylene ~Tol uene SH OH N N N S R4 N S R1 R3 I RI R3 R2 R2 38 WO 01/05391 PCT/USOO/18346 Scheme 9 R4 COOH 2 COOH R4 F I I RI R3 LHMDS RI R361 R2 R2

NH

2 S N H2N - O4 [H+] N 111S R4 (1)(COCI) 2 R4 (2) NH 2

NHC(S)NH

2 RI R3 RI R3 R2 R2 NaOCH 3

/CH

3 OH Reflux SH N NN NH R4 RI R3 I R2 39 WO 01/05391 PCT/USOO/18346 Scheme 10 R4 COOH FHN6COOH M R4 RI R3 LHMDS RI R3I R2 R2

NH

2

NH

2

NH

2 H2 4BrCNINaHCO 3 (aq.) N 110R4 PY-BO ' Dioxane, r.t. RIR3 I RI R3 R2 R2 S1)CS 2 , KOH 2)HCI SH N N~O R4 RI R3 I R2 40 WO 01/05391 PCT/USOO/18346 Scheme 11 R4 COOH COOH R4 HF H 2 NN RI R3 LHMDS R1 R3 I R2 R2

NH

2 I

COOCH

3 R4 N NH H aminoguanidine nitrate R4

CH

3 0HIH 2

SO

4 N ________H NaOCH 3

/CH

3 0H N RI R3 I RI R3 R2 S MeNH

NH

2 N MeNCS N N R4 RI R3 I R2 41 WO 01/05391 PCT/USOO/18346 Scheme 12 0 C0 2 C 2 HS F (1)PPh 3 ,CBr 4 F (2)n-BuLi, I RI R3 then CICO 2

C

2 HsRI R3 R2 R2 COACH5 HO R4 LHMDS

NH

2

NHCH

3

NHCH

3 R4

H

2 N R4 RI R3 IN' R2 RI ""R3 R2 42 WO 01/05391 PCT/USOO/18346 Scheme 13 R4 COOH

H

2 N R COOH R4 1 -RI R3 : RI R3 LHMDS R3 R2 CH OH R4

CH

2 Br R4

CH

2 CN R4 N R3 Bromination Rl R3 . RIj R3 RI R3)~ 1 RI j R3 N-S NC CS 2 Na R4 HO SO 3 Na M ' 'N excess H 2 0 2 HCONMe 2 RI R3 I RI R3 R2 R2 N-S [H+] HO R4 RI R3 I R2 43 WO 01/05391 PCT/USOO/18346 Scheme 14 COOH R4 COOH 0 CO F HM1 jR4 R R2 RI4 R3 I R2 R2 COWS2 H 5. 00 R4 BF, H SC HR4 -~ ~ etherate M25 R3 RI 4 R3 R ~JIJ N-N NHN2R4 Alkalation " OH R4 RI R31tI RI R3 R2 R2 44 WO 01/05391 PCT/USOO/18346 Scheme 15 R4 COOH F 2, COOH M R4 RI R3 LHMDS RI R3 R2 R2 OH

N

C

2 H0 0 R4 N

NH

2

NH

2 ,EtOH R4 RI R3 I RI R3 R2 I R2

NH

2

NHCH

3 ,EtOH OH N N R4 RI R3 I R2 45 WO 01/05391 PCT/USOO/18346 Scheme 16 R4 COOH H 2 N COOH H R4 F N R1 R3 LHMDS R R3 I R2 R2 EtOOC Br CH2COOEt R4 R4 N I)LDA I 2)Br2 -~ ii R3 RI R3 1 R2 R2 INH 2 EtOOC N 3 EtOOC N=N R4 NaN 3 /DMF H 2 RI R3 RI R3 R2 R2 R --N N-N 0 N alkylation HO N O___R4 aMH R4 RI R3 I RI R3 R2 R2 alkylation N N HO N-R R4 RI R3 I R2 46 WO 01/05391 PCT/USOO/18346 Scheme 17 R4 CN H 2 N CN R4 F 1 R1 R3 LHMDS R1 R3 I R2 R2 0 OH S-O

NH

2 OH.HCI H 2 N N HN N aCCaCaHH R4 sc/tNR4 NaOCH 3

/CH

3 OH H SOCIJEt 3 N RI R3 I RI R3 R2 R2 0 S-O / \

R

5 'N 7 N alkylation R4 RI R3 I R2 47 WO 01/05391 PCT/USOO/18346 Scheme 18 R4 COOH H2N COOH R4 F II RI R3 LHMDS R1 R3 R2 R2 OH N O Ns NH

NH

2

NH

2 ,PY-BOP

H

2 N R4 Urea/KOH/EtOH R4 RI R3 RI R3 I R2 R2 RsNCO/NaOHIH 2 0 OH N NK N'RS R4 H N RI R3 I R2 48 WO 01/05391 PCT/USOO/18346 Scheme 19 R4 CN H 2 N CN R4 F RI R3 LHMDS RI R3 R2 R2 0 OH H2N ZNNN

NH

2 OH.HCI 2 R4 CICOOC 2 H6 N , N R4 NaOCH 3

/CH

3 OH pyridine RI R3 RI R3 R2 R2 49 WO 01/05391 PCT/USOO/18346 Scheme 20 O C0 2 CHS C0 2

CH

5 F (I)PPh 3 ,CBr, F LHMDS R RI R3 (2)n-BuLi, il-HN R then CICO 2

C

2

H

5 RI R3 2 R~ RI- R3 R2 R2 R2 HO MeO

NH

2 OH.HCI ""~ R4 CH 2

N

2

ICH

3 OH ""0 R4 RI R31t I RI R31t R2 R2 MeO MeO I)n-BuLiITHF -NI)DPPAIEt 3 N 2)C0 2 2)TMS(CH 2

)

2 0H 2)H 3 C HOC2 0 3)n-Bu4NFITHF 0 N ~ R 3)HO- OOCR4 ______R4_ RI R3 1 RI R31: R2 R2 HO NN RI R3I R2 50 WO 01/05391 PCT/USOO/18346 Scheme 21 R4 COOH F 2,CCOOH M R4 RI R3 LHMDS RI R3 EtO C 0~ R4 N2HEtH HNHNOC 0O R4 (I )(COCI) 2 NN ,EONN (2)CNCH 2

CO

2

C

2

H

5 Et 3 NITHF RI R3 RI R3 R2 R2 HO N RI R3 I R2 51 WO 01/05391 PCT/USOO/18346 Scheme 22 R4

NO

2

H

2 N NO 2 R4 NH 2 R4 RI R3 LHMDS R1 R3 I RI R3 R2 R2 R2 0 H N R4 -N N R3 IICH 2 =CHO R N R4 RRI R3 R2 R2 N, N OH R4 N OH R4 IMil RR3RI R3 R2 R2 Alternate synthesis: OH(TMS) N /N N R4 OH(TMS) N OH(TMS) N R 3H C O(MS R4 N R4 RI R3 I RI R3 IR1 R3 2 R2 R2 52 WO 01/05391 PCT/USOO/18346 Scheme 23 R4

NO

2 FH 2 N,6 1 NO 2 R4 NH 2 R4 'N.'~ [H] 30 R1 R3 LHMDS RI R3 I I R3 R2 R2 R2 N-N N R4 N R4 HC(OEt) 3 , NaN 3 N RI R3 I RI R3 i R2 R2 N-N 12, H NR ArOHK 2

CO

3 N N OAr R4 2KMnO 4

,H

2 S0 4 'N R4 W R1 R3 I R1 R3 R2 R2 R5 N-N NaH 2 PO2Pd-C NN>,O R4 Alkylation N O R4 R1 R3 RI R3 R2 R2 53 WO 01/05391 PCT/USOO/18346 Scheme 24 R4 CHO H 2 N CHO R4 F R1 R3 LHMDS R1 R3 I R2 NH R2 ON HO N R4

KCN/(NH

4

)

2

CO

3

/NH

4 CI EtOH/H 2 0 RI R3 I R2 Alternate Sythesis:

NH

2 CHO HO N F KCN/(NH 4

)

2

CO

3

/NH

4 CI EtOH/H 2 O F RI R3 R2 RI R3 R2

NH

2 H2N HO N R4 LHMDS R1 R3 R2 54 WO 01/05391 PCT/USOO/18346 Scheme 25 R4 COOH H 2 N COOH R4 F N RI R3 LHMDS RI R3 I R2 R2 COOH 0 NH N O R4

H

2 N COOH R4 DMF/SOCl 2 RI R3 I R1 R3 R2 R2 55 WO 01/05391 PCT/USOO/18346 D. Uses The disclosed compositions are useful as both prophylactic and therapeutic treatments for diseases or conditions relating to chronic pain, 5 including neuropathic pain, as provided in the Summary section, as well as diseases or conditions modulated by the MEK cascade. For example, in one embodiment, the disclosed method relates to postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, 10 vasculitis, crush injury, constriction injury, tissue injury, post-surgical pain, arthritis pain, or limb amputation For example, local injuries can be treated with local or topical administration. Chronic pain affecting the entire body, such as diabetic neuropathy can be treated with systemic administration (injection or orally) of 15 a disclosed composition. Treatment for chronic pain (e.g., post-operative pain) confined to the lower body can be administered centrally, e.g., epidurally. Formulations and methods of administration can include the use of more than one MEK inhibitor, or a combination of a MEK inhibitor and another pharmaceutical agent, such as an anti-inflammatory, analgesic, muscle 20 relaxing, or anti-infective agent. Preferred routes of administration are oral, intrathecal or epidural, subcutaneous, intravenous, intramuscular, and, for non-human mammals, intraplantar, and are preferably epidural. 1. Dosages 25 Those skilled in the art will be able to determine, according to known methods, the appropriate dosage for a patient, taking into account factors such as age, weight, general health, the type of pain requiring treatment, 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 30 body weight, and daily dosages will be between 10 and 5000 mg for an adult subject of normal weight. Commercially available capsules or other 56 WO 01/05391 PCT/USOO/18346 formulations (such as liquids and film-coated tablets) of 100 mg, 200 mg, 300 mg, or 400 mg can be administered according to the disclosed methods. 2. Formulations 5 Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses. Dosage unit forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants. 10 Administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal spray). Parenteral formulations include pharmaceutically acceptable aqueous 15 or nonaqueous solutions, dispersion, 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. Fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or maintaining appropriate 20 particle size. Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption acccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and (j) propellants. Compositions may also contain adjuvants such as preserving, wetting, 25 emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption-enhancing agents. 57 WO 01/05391 PCT/USOO/18346 3. Related compounds The invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; masked or protected 5 forms; and racemic mixtures, or enantiomerically or optically pure forms. Pharmaceutically acceptable salts, esters, and amides include carboxylate salts (e.g., C 1-8 alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic), amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective, and suitable for 10 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, 15 lactiobionate, and laurylsulfonate. These may include alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine. See, for example, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 20 66:1-19 which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C 1-6 alkyl amines and secondary di (C 1-6 alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and 25 optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C 1-3 alkyl primary amines, and di (C 1-2 alkyl)amines. Representative pharmaceutically acceptable esters of the invention include C 1-7 alkyl, C 5.7 cycloalkyl, phenyl, and phenyl(C 1 .)alkyl esters. Preferred esters include methyl esters. 30 The invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. Some of these masked or protected compounds are pharmaceutically 58 WO 01/05391 PCT/USOO/18346 acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention. 5 HYDROXYL PROTECTING GROUPS Hydroxyl protecting groups include: ethers, esters, and protection for 1,2- and 1,3-diols. The ether protecting groups include: methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and conversion of silyl ethers to other functional groups. 10 Substituted Methyl Ethers Substituted methyl ethers include: methoxymethyl, methylthiomethyl, t utylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, t butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 15 2,2,2-trich loroethoxymethyl, bis(2-chloro- ethoxy)methyl, 2 (trimethylsilyl)ethoxymethyl, tetrahyd ropyranyl, 3-bromotetrahydro-pyranyl, tetrahyd rothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4 methoxytetrahydrothio-pyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxido, 1 -[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, 20 tetrahydrofuranyl, tetrahydrothiofuranyl, and 2,3,3a,4,5,6,7,7a-octahydro 7,8,8-trimethyl-4,7-ethanobenzofuran-2-yl. Substituted Ethyl Ethers Substituted ethyl ethers include: 1-ethoxyethyl, 1-(2,chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1 -benzyloxy-2 25 fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilyethyl, 2-(phenylselenyl)ethyl, t 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, 30 p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenyl methyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, 59 WO 01/05391 PCT/USOO/18346 tri-(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)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 5 methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl) xanthenyl, 9-(9 phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl SS dioxido. Silyl Ethers Silyl ethers include: trimethylsilyl, triethylsilyl, triisopropylsilyl, 10 dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenysilyl. ESTERS 15 Esters protecting groups include: esters, carbonates, assisted cleavage, miscellaneous esters, and sulfonates. Esters Examples of protective esters include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, 20 methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4 oxopentanoate (levulinate), 4,4-(ethylenedithio) pentanoate, pivaloate, adamantoate, crotonate,4-methoxycrotonate, benzoate, p-phenylbenzoate, and 2,4,6-trimethylbenzoate (mesitoate). 25 Carbonates Carbonates include: methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl) ethyl, 2-(phenylsulfonyl) ethyl, 2-(triphenylphosphonio) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4 dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4 30 ethoxy-1-naphthyl, and methyl dithiocarbonate. 60 WO 01/05391 PCT/USOO/18346 Assisted Cleavage Examples of assisted cleavage protecting groups include: 2-iodobenzoate, 4 azido-butyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl) benzoate, 2 formylbenzene-sulfonate, 2-(methylthiomethoxy) ethyl carbonate, 4 5 (methylthiomethoxymethyl) benzoate, and 2-(methylthiomethoxymethyl) benzoate. Miscellaneous Esters In addition to the above classes, miscellaneous esters include: 2,6-dichloro-4 methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl) 10 phenoxyacetate, 2,4-bis(1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate (tigloate), o (methoxycarbonyl) benzoate, p-P-benzoate, c-naphthoate, nitrate, alkyl NN,N SN '-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, 15 dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate. Sulfonates Protective sulfates includes: sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate. 20 PROTECTION FOR 1,2- AND 1,3-DIOLS The protection for 1,2 and 1,3-diols group includes: cyclic acetals and ketals, cyclic ortho esters, and silyl derivatives. Cyclic Acetals and Ketals Cyclic acetals and ketals include: methylene, ethylidene, 1-t-butylethylidene, 25 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 Ortho Esters 30 Cyclic ortho esters include: methoxymethylene, ethoxymethylene, dimethoxy methylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1,2 dimethoxyethylidene, 61 WO 01/05391 PCT/USOO/18346 a-methoxybenzylidene, 1-(NN-dimethylamino)ethylidene derivative, a-(NN dimethylamino) benzylidene derivative, and 2-oxacyclopentylidene. 5 PROTECTION FOR THE CARBOXYL GROUP ESTERS Ester protecting groups include: esters, substituted methyl esters, 2 substituted ethyl esters, substituted benzyl esters, silyl esters, activated esters, miscellaneous derivatives, and stannyl esters. 10 Substituted Methyl Esters Substituted methyl esters include: 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahyd ropyranyl, tetrahyd rofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxy-methyl, benzyloxymethyl, phenacyl, p-bromophenacyl, a-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N 15 phthalimidomethyl. 2-Substituted Ethyl Esters 2-Substituted ethyl esters include: 2,2,2-trichloroethyl, 2-haloethyl, | chloroalkyl, 2-(trimethylsily)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2(p-nitrophenylsulfenyl)-ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2'-pyridyl)ethyl, 2 20 (diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsily)-2-buten-1-yl, cinnamyl, a methylcinnamyl, phenyl, p-(methylmercapto)-phenyl, and benzyl. Substituted Benzyl Esters Substituted benzyl esters include: triphenylmethyl, diphenylmethyl, 25 bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5 d ibenzo-suberyl, 1 -pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 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. 30 Silyl Esters Silyl esters include: trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, i propyldimethylsilyl, phenyldimethylsilyl, and di- t-butylmethylsilyl. 62 WO 01/05391 PCT/USOO/18346 Miscellaneous Derivatives Miscellaneous derivatives includes: oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl 5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group, and pentaaminocobalt(Ill) complex. 5 Stannyl Esters Examples of stannyl esters include: triethylstannyl and tri-n-butylstannyl. AMIDES AND HYDRAZIDES Amides include: N,N -dimethyl, pyrrolidinyl, piperidinyl, 5,6 10 dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-nitro-1,2,3,4 tetrahydroquinolyl, and p-P-benzenesulfonamides. Hydrazides include: N phenyl, N,N'-diisopropyl and other dialkyl hydrazides. PROTECTION FOR THE AMINO GROUP 15 CARBAMATES Carbamates include: carbamates, substituted ethyl, assisted cleavage, photolytic cleavage, urea-type derivatives, and miscellaneous carbamates. Carbamates 20 Carbamates include: methyl and ethyl, 9-fluorenylmethyl, 9-(2 sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-butyl-[9-(10,10 dioxo-1 0,10,10,1 0-tetrahydro- thioxanthyl)]methyl, and 4-methoxyphenacyl. Substituted Ethyl Substituted ethyl protective groups include: 2,2,2-trichloroethyl, 2 25 trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl 2-haloethyl, 1,1dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1 methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'-and 4'-pyridyl)ethyl, 2-(N,N-icyclohexylcarboxamido)- ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, connamyl, 4-nitrocinnamyl, quinolyl, N 30 hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p bromobenzyl, p-chlorobenzyl, 2,4dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, and diphenylmethyl. 63 WO 01/05391 PCT/USOO/18346 Assisted Cleavage Protection via assisted cleavage includes: 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 5 4-methylthiophenyl, 2,4-dimethyl-thiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2cyanoethyl, m-chloro-p acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolyl-methyl, and 2-(trifluoromethyl)-6-chromonylmethyl. Photolytic Cleavage 10 Photolytic cleavage 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 of urea-type derivatives include: phenothiazinyl-(1 0)-carbonyl 15 derivative, N'-p-toluenesulfonylaminocarbonyl, and N' phenylaminothiocarbonyl. Miscellaneous Carbamates In addition to the above, miscellaneous carbamates include: t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, 20 cyclopropylmethyl, p-decyloxy-benzyl, diisopropylmethyl, 2,2 dimethoxycarbonylvinyl, o-(NN-dimethyl-carboxamido)-benzyl, 1,1-dimethyl 3(N,N-dimethylcarboxamido)propyl, 1,1-dimethyl-propynyl, d i(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p(p' methoxyphenyl- azo)benzyl, 1 -methylcyclobutyl, 1 -methylcyclohexyl, 1 25 methyl-1 -cyclopropyl- methyl, 1-methyl-(3,5-dimethoxyphenyl)ethyl, 1-methyl 1 (p-henylazophenyl)- ethyl, 1-methyl-1 -phenylethyl, 1-methyl-1 -(4 pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4 (trimethylammonium) benzyl, and 2,4,6-trimethylbenzyl. 30 64 WO 01/05391 PCT/USOO/18346 AIDES Amides Amides includes: N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3 5 pyridyl-carboxamide, N-benzoylphenylalanyl derivative, N-benzoyl, and N-p phenylbenzoyl. Assisted Cleavage Assisted cleavage groups include: N-o-nitrophenylacetyl, N-o nitrophenoxyacetyl, N-acetoacetyl, (N'-dithiobenzyloxycarbonylamino)acetyl, 10 N-3-(p-hydroxphenyl) propionyl, N-3-(o-nitrophenyl)propionyl, N-2-methyl-2 (o-nitrophenoxy)propionyl, N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4 chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N acetylmethionine derivative, N-o-nitrobenzoyl, N-o (benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-one. 15 Cyclic Imide Derivatives Cyclic imide derivatives include: N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenyl-maleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1, 3-d imethyl- 1, 3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl 20 1,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl. SPECIAL -NH PROTECTIVE GROUPS Protective groups for - NH include: N-alkyl and N-aryl amines, imine 25 derivatives, enamine derivatives, and N-hetero atom derivatives (such as N metal, N-N, N-P, N-Si, and N-S), N-sulfenyl, and N-sulfonyl. N-Alkyl and N-Aryl Amines N-alkyl and N-aryl amines include: N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxyl]-methyl, N-3-acetoxypropyl, 30 N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, 65 WO 01/05391 PCT/USOO/18346 N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and N-2-picolylamine N'-oxide. Imine Derivatives Imine derivatives include: N-1, 1 -dimethylthiomethylene, N-benzylidene, 5 N-p-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, N-(N',N'-dimethylaminomethylene), N,N'-isopropylidene, N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N-(5-chloro-2-hydroxyphenyl)phenyl-methylene, and N-cyclohexylidene. 10 Enamine Derivative An example of an enamine derivative is N-(5,5-dimethyl-3-oxo-1 -cyclohexenyl). N-Hetero Atom Derivatives N-metal derivatives include: N-borane derivatives, N-diphenylborinic acid 15 derivative, N-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, and N-copper or N-zinc chelate. Examples of N-N derivatives include: N-nitro, N-nitroso, and N-oxide. Examples of N-P derivatives include: N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, and N-diphenyl phosphoryl. 20 Examples of N-sulfenyl derivatives include: N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesufenyl, N-2-nitro-4-methoxy-benzenesulfenyl, N triphenylmethylsulfenyl, and N-3-nitropyridinesulfenyl. N-sulfonyl derivatives include: N-p-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl 25 4-methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N 2,6-dimethyl-4-methoxy-benzenesulfonyl, N-pentamethylbenzenesulfonyl, N 2,3,5,6-tetramethyl-4-methoxybenzene- sulfonyl, N 4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl, N 2,6-dimethoxy- 4-methylbenzenesulfonyl, N 30 2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl, 66 WO 01/05391 PCT/USOO/18346 N-p6-trimethylsilylethanesulfonyl, N-9-anthracenesulfonyl, N 4-(4',8'-dimethoxynaphthylmethyl)-benzenesulfonyl, N-benzylsulfonyl, N trifluoromethylsulfonyl, and N-phenacylsulfonyl. 5 Disclosed compounds which are masked or protected may be prodrugs, compounds metabolized or otherwise transformed in vivo to yield a disclosed compound, e.g., transiently during metabolism. This transformation may be a hydrolysis or oxidation which results from contact with a bodily fluid such as blood, or the action of acids, or liver, gastrointestinal, or other enzymes. 10 Features of the invention are further described in the examples below. 67 WO 01/05391 PCT/USOO/18346 E. Examples BIOLOGICAL EXAMPLES 5 Example 1 Effect of PD 198306 on streptozocin-induced static allodynia Animals Male Sprague Dawley rats (250-300g), obtained from Bantin and 10 Kingman, (Hull, U.K.) were housed in groups of 3. All animals were kept under a 12h light/dark cycle (lights on at 07h 00min) with food and water ad libitum. All experiments were carried out by an observer blind to drug treatments. Development of diabetes in the rat 15 Diabetes was induced in rats by a single i.p. injection of streptozocin (50 mg/kg) as described previously (Courteix et al., 1993). Evaluation of static allodynia Mechanical hypersensitivity was measured using Semmes-Weinstein 20 von Frey hairs (Stoelting, Illinois, U.S.A.). Animals were placed into wire mesh bottom cages allowing access to the underside of their paws. Animals were habituated to this environment prior to the start of the experiment. Mechanical hypersensitivity was tested by touching the plantar surface of the animals right hind paw with von Frey hairs in ascending order of force ( 0.7, 1.2, 1.5, 2, 3.6, 25 5.5, 8.5, 11.8, 15.1 and 29g) for up to 6 sec. Once a withdrawal response was established, the paw was re-tested, starting with the next descending von Frey hair until no response occurred. The highest force of 29 g lifted the paw as well as eliciting a response, thus represented the cut off point. The lowest amount of force required to elicit a response was recorded as the paw 30 withdrawal threshold (PWT) in grams. 68 WO 01/05391 PCT/USOO/18346 Drugs PD 198306 [N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl phenylamino)-benzamide] and CI-1008 (pregabalin) were synthesized at Parke-Davis (Ann Arbor, MI, USA). PD 198306 was suspended in 5 cremophor:ethanol:water (1:1:8) vehicle. Pregabalin was dissolved in water. Both compounds were administered orally. Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCl and administered intraperitoneally. Drug administrations were made in a volume of 1 mi/kg. 10 Statistics The static allodynia data were analysed using a Kruskall-Wallis ANOVA for non-parametric results, followed when significant by Mann-Whitney's t test. Experimental protocol 15 Static allodynia was assessed with von Frey hairs, before (baseline, BL) and Ih after oral administration of PD 198306 (30mg/kg, p.o.), vehicle (cremophor:ethanol:water, 1:1:8) or pregabalin (30mg/kg, p.o.) (test). Animals were administered again the same compounds on the following day, both in the morning and the afternoon. Static allodynia was assessed only 20 before and 1 h after the afternoon administration, in order to minimise the habituation of the animals to the testing conditions. Animals treated with pregabalin received water in the morning administration, in order to avoid the potential development of tolerance to the compound with repeated administration. 25 Day 1: Day2: a.m.: PD 198306 Water 30 Vehicle p.m.: BL p.m.: BL 69 WO 01/05391 PCT/USOO/18346 PD 198306 PD 198306 Pregabalin Pregabalin Vehicle Vehicle Test Test 5 RESULTS A single administration of pregabalin (30mg/kg, p.o.) significantly blocked streptozocin-induced static allodynia 1h after administration. In contrast, a single administration of PD 198306 (30mg/kg, p.o) had no effect on 10 streptozocin-induced static allodynia 1h after administration (see below). However, after the compound had been administered twice more on the following day, it significantly blocked streptozocin-induced static allodynia 1h after the third administration. The effects had disappeared by the following day (see FIG. 1). 15 Example 2 MATERIALS AND METHODS Animals 20 Male Sprague Dawley rats (250-300g), obtained from Charles River, Margate, U.K.) were housed in groups of 3-6. All animals were kept under a 12h light/dark cycle (lights on at 07h 00min) with food and water ad libitum. All experiments were carried out by an observer blind to drug treatments. Diabetes was induced in rats by a single i.p. injection of streptozocin 25 (50mg/kg) as described previously (Courteix et al., 1993). Development of Chronic Constriction Injury in the rat Animals were anaesthetised with 2% isoflurane 1:4 0 2

/N

2 0 mixture maintained during surgery via a nose cone. The sciatic nerve was ligated as 30 previously described by Bennett and Xie, 1988. Animals were placed on a homeothermic blanket for the duration of the procedure. After surgical preparation the common sciatic nerve was exposed at the middle of the thigh 70 WO 01/05391 PCT/USOO/18346 by blunt dissection through biceps femoris. Proximal to the sciatic trifurcation, about 7mm of nerve was freed of adhering tissue and 4 ligatures (4-0 silk) were tied loosely around it with about 1mm spacing. The incision was closed in layers and the wound treated with topical antibiotics. 5 Intrathecal injections PD 198306 and pregabalin were administered intrathecally in a volume of 10 pl using a 100 pl Hamilton syringe by exposing the spine of the rats under brief isoflurane anaesthesia. Injections were made into the intrathecal space 10 between lumbar region 5-6 with a 10 mm long 27 gauge needle. Penetrations were judged successful if there was a tail flick response. The wound was sealed with an autoclip and rats appeared fully awake within 2-3 min following injection. Evaluation of static allodynia 15 Mechanical hypersensitivity was measured using Semmes-Weinstein von Frey hairs (Stoelting, Illinois, U.S.A.). Animals were placed into wire mesh bottom cages allowing access to the underside of their paws. Animals were habituated to this environment prior to the start of the experiment. Mechanical hypersensitivity was tested by touching the plantar surface of the animals right 20 hind paw with von Frey hairs in ascending order of force ( 0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29g) for up to 6sec. Once a withdrawal response was established, the paw was re-tested, starting with the next descending von Frey hair until no response occurred. The highest force of 29g lifted the paw as well as eliciting a response, thus represented the cut off point. The lowest 25 amount of force required to elicit a response was recorded as the paw withdrawal threshold (PWT) in grams. Experimental protocol Static allodynia was assessed with von Frey hairs, before (baseline, 30 BL) and 0.5h, 1 h and 2h after intrathecal or intraplantar administration of PD 198306 (1-30pg, i.t.), vehicle (cremophor:ethanol:water, 1:1:8) or pregabalin (10pg, i.t). For oral administration experiments, static allodynia was assessed 71 WO 01/05391 PCT/USOO/18346 with von Frey hairs, before (baseline, BL) and 1 h after oral administration of PD 198306 (3-30mg/kg, p.o.), vehicle (cremophor:ethanol:water, 1:1:8) or pregabalin (30mg/kg, p.o.). Animals were administered again the same compounds on the following day, both in the morning and the afternoon. Static 5 allodynia was assessed before and 1 h after the morning administration. In the afternoon static allodynia was assessed before, 1h, 2h and 3h after administration for streptozocin treated animals. CCI animals were assessed before, 1 h and 2h after administration 10 Drugs used PD 198306 and pregabalin were synthesised at Parke-Davis (Ann Arbor, MI, USA). PD 198306 was suspended in cremophor:ethanol:water (1:1:8) vehicle. Pregabalin was dissolved in water. Both compounds were administered orally, intrathecally or intraplantar in volumes of 1ml/kg, 10ljI and 15 100pl respectively. Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCl and administered intraperitoneally in a volume of lml/kg. Statistics Data were analysed using a Kruskall-Wallis ANOVA for non-parametric 20 results, followed when significant by Mann-Whitney's t test vs vehicle group. RESULTS 1. Effects of PD 198306 on static allodynia, following systemic administration 25 1.1. Effect of PD198306 on streptozocin-induced static allodynia A single administration of pregabalin (30mg/kg, p.o.) significantly blocked streptozocin-induced static allodynia 1h after administration. In contrast, a single administration of PD 198306 (3-30mg/kg, p.o) had no effect on streptozocin-induced static allodynia 1 h after administration (FIG. 2). 30 However, after the compound had been administered twice more on the following day, PD 198306 (30mg/kg) significantly blocked streptozocin induced static allodynia for 2h after the third administration (FIG. 2). 72 WO 01/05391 PCT/USOO/18346 1.2. Effect of PD198306 on CCI-induced static allodynia A single administration of pregabalin (30mg/kg, p.o.) significantly blocked CCI induced static allodynia 1 h after administration. In contrast, neither a single or 5 multiple administration of PD 198306 (3-30mg/kg, p.o) had any effect on CCI induced static allodynia (FIG. 3). 2. Effects of PD 198306 on static allodynia, following intrathecal administration 10 Intrathecally administered PD198306 (1-30ptg) dose-dependently blocked the maintenance of static allodynia in both streptozocin (FIG. 4) and CCI animals (FIG. 5) with respective MEDs of 3 and 10 pig. This antiallodynic effect lasted for 1h. 15 3. Effects of PD 198306 on static allodynia, following intraplantar administration An intrathecal administration of PD 198306 (30pjg) significantly blocked static allodynia in both neuropathic pain models (FIGS. 6,7). In contrast, a single administration of PD 198306 at a dose 100-fold higher (3mg/1 00pl) directly 20 into the paw had no effect on streptozocin (FIG. 6) or CCI-induced static allodynia (FIG. 7). REFERENCES Bennett GJ, Xie Y-K. A peripheral mononeuropathy in rat that produces 25 disorders of pain sensation like those seen in man. Pain 1988;33:87-107. Courteix C, Eschalier A and Lavarenne J. Streptozocin -induced rats: behavioural evidence for a model of chronic pain. Pain 1993;53:81-8 73 WO 01/05391 PCT/USOO/18346 Example 3 Effect of other MEK inhibitors in a neuropathic pain model in the rat 5 SUMMARY The effect of several MEK inhibitors, with different binding affinities, has been investigated in the CCI model of neuropathic pain in the rat, by assessing static allodynia with von Frey hairs. Intrathecal administration of PD219622 or PD297447 (30ptg) had no significant effect on allodynia. This lack of effect 10 may reflect the low affinity or solubility of the compounds. However, intrathecal administration of PD 254552 or PD 184352 (30pg), which posses higher binding affinities, blocked the maintenance of static allodynia in CCI animals. The antiallodynic effect was only evident for 30min post-injection and thus, shorter than the one observed for pregabalin (100pg). The magnitude of 15 the effect was similar for 30ptg of PD 184352 and 100ptg of pregabalin. From this study it is concluded that MEK inhibitors exert an antiallodynic effect in CCI-induced neuropathic rats when administered intrathecally, and that the antiallodynic effect correlates with the affinity of the compounds. 20 The animals and methods for developing chronic constriction injury in the rat, injecting test compounds, and evaluation of static allodynia were according to Example 2 above. PD219622, PD297447, PD 184352, PD 254552 and pregabalin were administered intrathecally at doses of 30ptg for all PD compounds and 100ptg for pregabalin. Static allodynia was assessed with 25 von Frey hairs, before (baseline, BL) and 0.5h, 1h and 2h after intrathecal administration of the compounds Drugs used PD297447, PD219622, PD 254552, PD 184352 (CI-1040), and pregabalin 30 were synthesised at Parke-Davis (Ann Arbor, MI, USA). PD297447, PD219622, PD 254552 and PD 184352 were suspended in 74 WO 01/05391 PCT/USOO/18346 cremophor:ethanol:water (1:1:8) vehicle. Pregabalin was dissolved in water. All compounds were administered intrathecally in a 10ptl volume. Statistics 5 Data were analysed using a Kruskall-Wallis ANOVA for non-parametric results, followed when significant by Mann-Whitney's t test vs vehicle group. RESULTS Intrathecally administered PD297447 or PD219622 (30pg) had no 10 significant effect on allodynia. This lack of effect may reflect the low affinity of the compounds (965nM and 100nM respectively). However, intrathecal administration of PD 184352 or PD 254552 (30tg) blocked the maintenance of static allodynia in CCI animals (see FIG. 8). These compounds possess higher affinity (2 and 5 nM respectively). The antiallodynic effect was only 15 evident for 30min post-injection and thus, shorter than the one observed for pregabalin (100pg). The magnitude of the effect was similar for 30pg of PD 184352 and 100ptg of pregabalin. The results indicate that MEK inhibitors exert an antiallodynic effect in CCI-induced neuropathic rats when administered intrathecally, and that the 20 antiallodynic effect correlates with the affinity of the compounds. 75 WO 01/05391 PCT/USOO/18346 CHEMICAL EXAMPLES EXAMPLE 1 5 [4-Chloro-2-(4,4-Dimethyl-4,5-dihvdro-oxazol-2-yl)-phenvll-(4-iodo-2-methyl phenyl)-amine (18). (Scheme 2, R 1 =CI, R 2

=R

3 =H, R 4

=CH

3 ) a). A mixture of 5-chloro-2-methoxybenzoic acid 16 (14.8 g, 0.0793 mole) and SOC1 2 (28.31 g, 14.97 ml, 0.1584 mole) was refluxed for 2 hours and 10 excess SOC1 2 removed leaving a white residue. The solid was dissolved in

CH

2

CI

2 and added to a solution of 2-amino-2-methyl-1-propanol (13.98 g, 14.97 ml, 0.1584 mole) in CH 2

CI

2 cooled with ice-bath. The ice-bath was removed, and after stirring at room temperature for 3 hours a white solid precipitated. The precipitate was separated by filtration and discarded. The 15 filtrate was concentrated leaving a thick colorless oil. SOC 2 (17.4 ml) was added to the oil dropwise. An exothermic reaction took place resulting in to a freely flowing solution. After stirring for 30 minutes, the reaction mixture was poured in to Et 2 0 (200 ml). An oil separated out. The Et 2 0 layer was removed by decanting and discarded. The oily residue was dissolved in a 20 minimum amount of water, basified with aqueous 20% NaOH, and extracted with Et 2 0. The Et 2 0 layer was dried (K 2

CO

3 ) and concentrated to give 17 as tan oil. Yield 14.63 g (77%). b). LDA (5 ml of 2.0 M solution in THF) was added to a solution of 4-iodo 25 2-methylaniline (2.33 g, 0.010 mole) in THF (15 ml) at-78 *C. The mixture was stirred at -78 *C for 30 minutes. To this, a solution of 17 (1.199 g, 0.005 mole) in THF (15 ml) was added. The mixture stirred for 16 hours as it warmed up to room temperature. The reaction mixture was quenched with aqueous NH 4 CI and extracted with Et 2 O. The Et 2 0 layer was dried (MgSO 4 ) 30 and concentrated to give crude 18 as brown oil. The oil was purified on silica column chromatography. Eluting with CH 2

CI

2 gave pure 1.7 g (77%) of 18 as brown oil. Four hundred and nine milligrams of the oil were dissolved in Et 2 0 and treated with Et 2 0-HCI giving the HCI salt as a light yellow solid 76 WO 01/05391 PCT/USOO/18346 precipitate. Yield 356.4 mg (81%); mp 324-330 0C; Anal. Calcd/found for

C

18

H

18

N

2 0Cll.HCI.0.5H 2 0: C, 44.47/44.32; H, 4.15/3.94; N, 5.76/5.66. EXAMPLE 2 5 [2,3-Difluoro-6-( H-tetrazol-5-yI)-phenvll-(4-iodo-2-methyl-phenyl)-amine N=N / \ CN N, NH H N NaN 3 , (C 2

H,)

3 N.HCI N toluene/reflux F F F F F 10 [2,3-Difluoro-6-cyano-phenyl]-(4-iodo-2-methyl-phenyl)-amine (1.11 g, 3mmol) and Sodium azide(0.255g, 3.9mmol) and triethylamine hydrochloride (0.537g, 3.9mmol) were all suspended in 1Oml toluene and stirred at 100*C for 12 hours. The mixture was concentrated and the residue purified by column chromatography with ethyl acetate/methanol (10/1) to give the product 15 as a foam-like solid. The yield: -50% m.p: 83.4-88.7*C 1 H NMR(CDC1 3 , 400Hz): 8/ppm 7.69(1 H, m, Phenyl-H); 7.42(1 H, s, Phenyl-H); 7.27(1H, m, Phenyl-H); 6.91(1H, dd, J=16.2Hz, 8.3Hz, Phenyl-H); 6.40(1H, dd, Phenyl-H); 2.28(3H, s, CH 3 ) 20 77 WO 01/05391 PCT/USOO/18346 EXAMPLE 3 [6-(4,4-Dimethyl-4,5-d ihyd ro-oxazol-2-yl)-2,3-d ifluoro-phenyll-(4-iodo-2 methyl-phenyl)-amine COOH H N 0 N (1) (COCi) 2 H N (2)2-amino-2-methyl-1-propanol F I F F 1 5 F A solution of 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (1.17g, 3mmol), oxalyl chloride (0.457g, 3.6mmol) in 30ml dichloromethane was treated with 2 drops of dimethylformamide, stirred at room temperature for 3 hours then concentrated. The residue was dissolved in 25 ml 10 dichloromethane then the solution was added dropwise to a solution of 2 amino-2-methyl-1-propanol (0.623g, 7mmol) in 25 ml dichloromethane at 0*C, then stirred at room temperature for 12 hours, filtered off the precipitate, the filtration was washed with water, 5% aqueous sodium bicarbonate, 1 N HCI, brine, dried with sodium sulfate. Concentration gave the crude product, then 15 resuspended in 25 ml chloroform, then thionyl chloride was added at 0*C and stirred at room temperature for 15 hours, then concentrated and the residue was dissolved in 30 ml dichloromethane , 1 N HCI was added to adjusted the pH value to 11, the separated and extracted with chloroform, dried with sodium sulfate. Concentrated and then run column with 20 hexanes/dichloromethane (20/1) to give the compound as a white crystal. The yield: 65% m.p.: 103.7-104.4 0 C 1 H NMR(CDCl 3 , 400Hz): S/ppm 10.2(1H, s, NH), 7.48-7.58(1H, m, Phenyl-H); 7.48(1H, s, Phenyl-H); 7.38(1H, d, J=8.5Hz, Phenyl-H), 6.66-6.72(1H, m, 25 Phenyl-H); 6.58(1H, t, J=8.OHz, Phenyl-H); 4.01(2H, s, -CH 2 -); 2.31(3H, s, Phenyl-CH 3 ); 1.32(6H, s, -C(CH 3

)

2 -) 78 WO 01/05391 PCT/USOO/18346 EXAMPLE 4 5 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid methyl ester COOH O O H H N

H

2

SO

4

/CH

3 0H N reflux F I F I F F 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (5g) was dissolved 10 in 100ml methanol and 5 drops of concentrated sulfuric acid was added, reflux for 4 days. Run column with hexanes/dichloromethane to give the product as a white solid, yield: 50%. m.p.:90.1-90.4 0 C 1 H NMR(CDCl 3 , 400Hz): S/ppm 8.92(1H, s, NH), 7.75-7.78(1H, m, Phenyl-H); 15 7.49(1 H, s, Phenyl-H); 7.38(1H, dd, J=8.5Hz, 2.0Hz, Phenyl-H), 6.66-6.73(1 H, m, Phenyl-H); 6.56-6.60(1H, m, Phenyl-H); 3.88(3H, s, -OCH 3 ); 2.30(3H, s, Phenyl-CH 3 ) 79 WO 01/05391 PCT/USOO/18346 EXAMPLE 5 5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyll-4H-[1,2.41triazol-3 Vlamine 5

H

2 N \N 0 0 N NH H N aminohuanidine nitrate H NaOCH 3

/CH

3 0H 4 F F F I F F Aminoguanidine nitrate (1.65g, 12mmol) was added to a solution of sodium methoxide (0.648g, 12mmol) in methanol (12ml) at 0 0 C, then 3,4-Difluoro-2 (4-iodo-2-methyl-phenylamino)-benzoic acid methyl ester was added as a 10 solution of methanol and refulx for 20 hours, concentration and run column with hexanes/ethyl acetate to give the product as a white crystal. The yield: 60% m.p.: 191.7-192.0OC 1 H NMR(DMSO, 400Hz): 6/ppm 9.45(1H, s, -NH-); 7.79(1H, t, J=7.3Hz, 15 Phenyl-H); 7.51(1H, s, Phenyl-H); 7.35(1H, d, J=10.lHz, Phenyl-H); 7.05 7.11(1H, m, Phenyl-H); 6.44-6.48(1H, m, Phenyl-H); 6.32(2H, s, -NH 2 ), 2.32(3H, s, CH 3 ) 80 WO 01/05391 PCT/USOO/18346 EXAMPLE 6 5-f3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyll-[1,3,4loxadiazol-2 ylamine 5

H

2 N N 0 NHNH 2 O N H N BrCN/NaHCO 3 (aq) H dioxane, r.t. F I F I F F To a solution of 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (0.806g, 2mmol) in 5ml of dioxane was added cyanogen bromide (0.212g, 2mmol) followed by a solution of sodium bicarbonate (0.17g, 2mmol) 10 in 5ml of water. The resulting mixture was stirred 18 hours at room temperature the solution was concentrated and the residure was run column with hexanes/ethyl acetate (3/1) to give the product which was recrystallized from ethyl acetate / hexanes to provide a pale-yellow crystal. The yield: 58% m.p.: 183.7-184.0*C 15 1 H NMR(CDCl 3 , 400Hz): s/ppm 8.87(1H, s, -NH-); 7.52(1H, s, Phenyl-H); 7.45-7.49(1H, m, Phenyl-H); 7.40(1H, d, J=8.3Hz, Phenyl-H); 6.77-6.83(1H, m, Phenyl-H); 6.60-6.63(1H, m, Phenyl-H); 5.02(2H, s, -NH 2 ), 2.36(3H, s,

CH

3 ) 81 WO 01/05391 PCT/USOO/18346 EXAMPLE 7 2-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino) benzovllhvdrazinecarbothioamide 5 S COOH .O H H2N N N (1) (CO1) 2 H H N (2) thiosemicarbazide F I F I F F A solution of 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (3.9g, 0.01mol), oxalyl chloride (1.90g, 0.015mol) in 40ml dichloromethane was treated with 2 drops of dimethylformamide, stirred at room temperature for 3 10 hours before concentration. The residue was dissolved in 10 ml tetrahydrofuran and added to a solution of thiosemicarbazide (2.0g, 0.022mol) in 50ml tetrahydrofuran at 0*C, stirred at room temperature for 14 hours. Concentrated and run column chromatography with hexanes/ethyl acetate (1/1) to give the product as a yellow solid. 2.91g. The yield: 63% 15 m.p.: 159.5-160.0 0 C 1 H NMR(DMSO, 400Hz): 6/ppm 10.58(1H, s, -NH-); 9.28(1H, s, -NH-); 8.83(1H, s, -NH-); 7.95(1H, s, Phenyl-H); 7.12-7.75(2H, m, NH 2 ); 7.51(1H, s, Phenyl-H); 7.37(1H, dd, J=8.6Hz, 1.7Hz, Phenyl-H); 7.16(1H,dd, J=17Hz, 9.0Hz, Phenyl-H); 6.40-6.50(1 H, m, Phenyl-H); 5.02(2H, s, -NH 2 ), 2.00(3H, s, 20 CH 3 ) 82 WO 01/05391 PCT/USOO/18346 EXAMPLE 8 5-[3,4-Difuoro-2-(4-iodo-2-methyl-phenylamino)-phenyll-4H-[1,2,4]triazole-3 thiol 5 H S S N HN N 0N~ NH H2N N 2 H H H N NaOCH 3

/CH

3 0H N reflux 1 F I F I F F 2-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino) benzoyl]hydrazinecarbothioamide (1.386g, 3mmol) was dissolved in 15 ml 10 anhydrous methanol, sodium methoxide (25% wt% in methanol) 2.5ml was added at 00C in one portion. The resulting mixture was heated at reflux for 17 hours before concentration. Run column with hexanes/ethyl acetate to give the product as a needle white crystal. The yield: 40% m.p.: 196.5(dec.) 15 'H NMR(DMSO, 400Hz): 6/ppm 13.87(1H, s, -NH-); 13.80(1H, s, -NH-); 8.16(1H, s, -NH-); 7.61-7.65(1H, m, Phenyl-H); 7.48(1H, s, Phenyl-H); 7.32(1H, dd, J=8.6Hz, 2.2Hz, Phenyl-H); 7.24(1H,dd, J=16.4Hz, 9.5Hz, Phenyl-H); 6.42-6.46(1H, m, Phenyl-H); 5.02(2H, s, -NH 2 ), 2.20(3H, s, CH 3 ). 83 WO 01/05391 PCT/USOO/18346 EXAMPLE 9 (2,3-Difluoro-6-[1,3,4loxadiazol-2-yl-phenyl)-(4-iodo-2-methyl-phenyl)-amine NN N O N O N HC(OEt) 3 N pTsOH, EtOH F I F I 5 F F 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (146 mg, 0.36 mmol) was suspended in 7 mL of absolute EtOH and 2 mL of HC(OEt) 3 was added along with approximately 3 mg of pTsOH> The reaction 10 was heated to reflux for 3h, cooled and concentration on a rotary evaporator. The reaction was purified (SiO2, 4:1 Hexane/EtOAc) to afford 117 mg (79%) of (2,3-difluoro-6-[1,3,4]oxadiazol-2-yl-phenyl)-(4-iodo-2-methyl-phenyl)-amine as a yellow powder. M.p. = 144.4 - 145.5 0C. 1 H NMR (400MHz, CDCl 3 ) 8 8.89 (s, 1H), 8.44 (s, 1H), 7.66 (m, 1H), 7.52 (d, J = 1.7 Hz, 1 H), 7.38 (dd, J = 15 8.5, 1.9 Hz, 1 H), 6.83 (m, 1H), 6.14 (dd, J = 8.5, 5.9 Hz, 1 H), 2.37 (s, 3 H). EXAMPLE 10 5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyll-[1,3,4loxadiazole-2 thiol S N O N - IN N 0 N CS 2 , KOH N F i EtOHFI F IF 20 F F 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (170 mg, 0.42 mmol) was suspended in 7 mL of absolute EtOH and cooled to 84 WO 01/05391 PCT/USOO/18346 0 'C. Carbon disulfide (74 mg, 0.97 mmol) was added followed by 24 mg (0.42 mmol) of powdered KOH. The reaction was stirred for 1 h at 0 *C, 1 h at rt, and refluxed for 3 h to afford a homogeneous reaction. The reaction was cooled to rt, at which point a ppt formed. Water was added and the reaction 5 diluted with 5 mL of EtOAc. 1N HCI was added to acidify the aqueous layer (pH = 2). The aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over Na 2

SO

4 and concentrated to obtain 96 mg (51%) of 5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] [1,3,4]oxadiazole-2-thiol as a yellow powder. M.p. = 231.8 - 232.8 *C. 'H 10 NMR (400MHz, CDCl 3 ) 5 7.62 (m, 2H), 7.47 (s, 1H), 7.30 (complex m, 2H), 6.44 (dd, J = 8.0, 4.5 Hz, 1H), 2.19 (s, 3H). F. OTHER EMBODIMENTS From the above disclosure and examples, and from the claims below, the essential features of the invention are readily apparent. The scope of the 15 invention also encompasses various modifications and adaptations within the knowledge of a person of ordinary skill. Examples include a disclosed compound modified by addition or removal of a protecting group, or an ester, pharmaceutical salt, hydrate, acid, or amide of a disclosed compound. Publications cited herein are hereby incorporated by reference in their 20 entirety. What is claimed is: 85

Claims (33)

1. A method for treating chronic pain, said method comprising administering to a subject in need of such treatment a composition comprising 5 a MEK inhibitor selected from: a compound of formula (1): W R4 R1 3 R, R3 R2 10 W is one of the following formulae (i) - (xiii): NX2 RN X 2 NX 1 0 y X NH N N 5 X 2 X 2 N--( 5 5>INR -NN N 0 N R5N X2 X2 X2 I IX (viii) (ix) (x) (xi) (xii) (xiii) HO 0 0 0 0 \N /N-N X2 X X N X, N N N (xiv) (xv) (xvi) (xvii) 15 X 1 is 0, S, or NRF; 86 WO 01/05391 PCT/USOO/18346 X 2 is OH, SH, or NHRE; each of RE and RF is H or C 1-4 alkyl; 5 each of R 1 and R 2 is independently selected from H, F, NO 2 , Br and Cl; R 1 can also be SO2NRGRH, or R 1 and R 2 together with the benzene ring to which they are attached constitute an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzthioazole; 10 R 3 is H or F; each of RG, RH, and R 4 is independently selected from H, Cl and CH 3 ; 15 R 5 is H or C 34 alkyl; and wherein each hydrocarbon radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, hydroxyl, amino, (amino)sulfonyl, and NO 2 ; and 20 wherein each heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C 3-4 alkyl, C 3-6 cycloalkyl, C 34 alkenyl, C 34 alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO 2 , wherein each substituent alkyl, cycloalkyl, alkenyl, 25 alkynyl or phenyl is in turn optionally substituted with between 1 and 2 substituents independently selected from halo, C 1-2 alkyl, hydroxyl, amino, and NO 2 ; or a pharmaceutically acceptable salt or C 1-8 ester thereof. 30 87 WO 01/05391 PCT/USOO/18346

2. The method of claim 1, wherein said chronic pain is selected from neuropathic pain, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.

3. The method of claim 2, wherein said chronic pain is a type of 5 neuropathic pain.

4. The method of claim 3, wherein said neuropathic pain is associated with one of the following: inflammation, postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, 10 viral infection, crush injury, constriction injury, tissue injury, limb amputation, post-operative pain, arthritis pain, and any other nerve injury between the peripheral nervous system and the central nervous system, inclusively.

5. The method of claim 2, wherein said chronic pain is associated with 15 chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.

6. The method of claim 2, wherein said chronic pain is associated with idiopathic pain. 20

7. The method of claim 1, wherein said chronic pain is associated with inflammation.

8. The method of claim 1, wherein said chronic pain is associated with arthritis. 25

9. The method of claim 1, wherein said chronic pain is associated with post-operative pain. 30

10. The method of claim 1, wherein R 1 is bromo or chloro. 88 WO 01/05391 PCT/USOO/18346

11. A method of claim 1, wherein R 2 is fluoro.

12. A method of claim 1, wherein R 3 is H. 5

13. A method of claim 12, wherein each of R 2 and R 3 is H.

14. A method of claim 1, wherein each of R 2 and R 3 is fluoro. 10

15. A method of claim 14, wherein R 1 is bromo.

16. A method of claim 14, wherein R 1 is fluoro.

17. A method of claim 1, wherein R 2 is nitro. 15

18. A method of claim 16, wherein R 3 is H.

19. A method of claim 1, wherein R 4 is chloro.

20 20. A method of claim 1, wherein R 4 is methyl.

21. A method of claim 1, wherein R 5 is H.

22. A method of claim 1, wherein R 5 is CH 3 . 25

23. A method of claim 1, wherein X 1 is 0 or S.

24. A method of claim 1, wherein X 1 is NH or NCH 3 . 30

25. A method of claim 1, wherein X 2 is OH, SH, or NH 2 .

26. A method of claim 1, wherein X 2 is NHCH 3 or OH. 89 WO 01/05391 PCT/USOO/18346

27. A method of claim 1, wherein said MEK inhibitor has a structure selected from: [5-fluoro-2-(1H-tetrazol-5-yI)-phenyl]-(4-iodo-2-methyl-phenyl) amine; [2,3-difluoro-6-(1 H-tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl-phenyl) 5 amine; (4-iodo-2-methyl-phenyl)-[2,3,4-trifluoro-6-(1 H-tetrazol-5-yl)-phenyl] amine; [4-bromo-2,3-difluoro-6-(1H-tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl phenyl)-amine; [5-fluoro-4-nitro-2-(1 H-tetrazol-5-yl)-phenyl]-(4-iodo-2-methyl phenyl)-amine; [2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-fluoro-phenyl]-(4 iodo-2-methyl-phenyl)-amine; [6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yI)-2,3 10 difluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [6-(4,4-dimethyl-4,5-dihydro oxazol-2-yl)-2,3,4-trifluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [4-bromo 6-(4,4-dimethyl-4,5-d ihydro-oxazol-2-yl)-2,3-difluoro-phenyl]-(4-iodo-2-methyl phenyl)-amine; [2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yI)-5-fluoro-4-nitro phenyl]-(4-iodo-2-methyl-phenyl)-amine; 5-[4-fluoro-2-(4-iodo-2-methyl 15 phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[5-bromo-3,4-difluoro-2 (4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[4-fluoro-2-(4 iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazol-2-ol; 5-[4-fluoro 20 2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[3,4-difluoro 2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[3,4,5 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[5 bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol 2-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl] 25 [1,3,4]oxadiazol-2-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H [1,2,4]triazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H [1,2,4]triazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] 4H-[1,2,4]triazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ol; and 5-[4-fluoro-2-(4-iodo-2 30 methyl-phenylamino)-5-nitro-phenyl]-4H-[1,2,4]triazol-3-ol. 90 WO 01/05391 PCT/USOO/18346

28. A method of claim 1, wherein said MEK inhibitor has a structure selected from: 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] [1,3,4]thiadiazol-2-ylamine; 5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[3,4,5-Trifluoro-2-(4-iodo-2-methyl 5 phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[5-bromo-3,4-difluoro-2 (4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[4-fluoro 2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2 ylamine; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] 10 [1,3,4]oxadiazol-2-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo 2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[4-fluoro 2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[3,4 15 difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3 ylamine; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H [1,2,4]triazol-3-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl 20 phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[3,4,5-trifluoro-2-(4 iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5-[5-bromo-3,4 difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]thiadiazole-2-thiol; 5 [4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]thiadiazole-2 25 thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2 thiol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] [1,3,4]oxadiazole-2-thiol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[5-bromo-3,4-d ifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl 30 phenylamino)-5-nitro-phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[3,4-difluoro-2-(4 iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[3,4,5 91 WO 01/05391 PCT/USOO/18346 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol; 5 [5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H [1,2,4]triazole-3-thiol; and 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro phenyl]-4H-[1,2,4]triazole-3-thiol. 5

29. A method of claim 1, wherein said MEK inhibitor has a structure selected from: 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol 3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 5-[5 10 bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 5 [4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-isothiazol-3-ol; 5-[4 fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 5-[3,4-difluoro 2-(4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 5-[3,4,5-trifluoro-2-(4 iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 5-[5-bromo-3,4-difluoro-2 15 (4-iodo-2-methyl-phenylamino)-phenyl]-isoxazol-3-ol; 5-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-5-nitro-phenyl]-isoxazol-3-ol; 5-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-1H-pyrazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-1 H-pyrazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-1H-pyrazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4 20 iodo-2-methyl-phenylamino)-phenyl]-1 H-pyrazol-3-ol; 5-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-5-nitro-phenyl]-1 H-pyrazol-3-ol; 4-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[3,4,5-trifluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4 25 iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-5-nitro-phenyl]-isothiazol-3-ol; 4-[4-fluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-isoxazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isoxazol-3-ol; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-isoxazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2 30 methyl-phenylamino)-phenyl]-isoxazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-5-nitro-phenyl]-isoxazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-1 -methyl-1 H-pyrazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2 92 WO 01/05391 PCT/USOO/18346 methyl-phenylamino)-phenyl]-1-methyl-1H-pyrazol-3-ol; 1-methyl-4-[3,4,5 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1 H-pyrazol-3-ol; 4-[5 bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-methyl-1 H pyrazol-3-ol; and 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl] 5 1-methyl-1 H-pyrazol-3-ol.

30. A method of claim 1, wherein said MEK inhibitor has a structure selected from: 5-[2-(2-amino-4-iodo-phenylamino)-4-fluoro-phenyl]-l-methyl 1H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4-iodo-phenylamino)-3,4-difluoro-phenyl] 10 1-methyl-1H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4-iodo-phenylamino)-3,4,5 trifluoro-phenyl]-1 -methyl-1 H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4-iodo phenylamino)-5-bromo-3,4-difluoro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-ol; 5 [2-(2-amino-4-iodo-phenylamino)-4-fluoro-5-nitro-phenyl]-1 -methyl-1 H [1,2,3]triazol-4-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-3 15 methyl-3H-[1,2,3]triazol-4-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 3-methyl-5-[3,4,5-trifluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-3H-[1,2,3]triazol-4-ol; 5-[5-bromo-3,4-difluoro-2 (4-iodo-2-methyl-phenylamino)-phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 5-[4 fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-3-methyl-3H 20 [1,2,3]triazol-4-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2 methyl-2H-pyrazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-2-methyl-2H-pyrazol-3-ol; 2-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2 methyl-phenylamino)-phenyl]-2H-pyrazo-3-ol; 4-[5-bromo-3,4-difluoro-2-(4 iodo-2-methyl-phenylamino)-phenyl]-2-methyl-2H-pyrazol-3-ol; 4-[4-fluoro-2 25 (4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-2-methyl-2H-pyrazol-3-ol; 1-[4 fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl- 1,4-dihyd ro-tetrazol 5-one; 1-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl- 1,4 dihydro-tetrazol-5-one; 1-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-1,4-dihydro-tetrazol-5-one; 1-[5-bromo-3,4-difluoro-2 30 (4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1 [4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4-methyl-1,4 dihydro-tetrazol-5-one; 1-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] 93 WO 01/05391 PCT/USOO/18346 1H-[1,2,3]triazol-4-ol; 1 -[3,4-d ifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] 1H-[1,2,3]triazol-4-ol; 1-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-1H-[1,2,3]triazol-4-ol; 1 -[5-bromo-3,4-d ifluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-1 H-[1,2,3]triazol-4-ol; and 1-[4-fluoro-2-(4-iodo-2 5 methyl-phenylamino)-5-nitro-phenyl]-1 H-[1,2,3]triazol-4-ol.

31. The method of claim 1, wherein said MEK inhibitor has a structure selected from: 3-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H isoxazol-5-one; 3[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H 10 isoxazol-5-one; 3-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2H isoxazol-5-one; 3-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-2H-isoxazol-5-one; 3-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5 nitro-phenyl]-2H-isoxazol-5-one; [5-fluoro-2-(2-oxo-2,3-dihydro-21>4_ [1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; [2,3 15 difluoro-6-(2-oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol-4-yI)-phenyl]-(4 iodo-2-methyl-phenyl)-amine; (4-lodo-2-methyl-phenyl)-[2,3,4-trifluoro-6-(2 oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol-4-yI)-phenyl]-amine; [4-bromo 2,3-difluoro-6-(2-oxo-2,3-dihydro-21>4_-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4 iodo-2-methyl-phenyl)-amine; [5-fluoro-4-nitro-2-(2-oxo-2,3-dihydro-21>4 20 [1,2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; 4-[4 fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[3,4 difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[3,4,5 trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[5 bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5 25 one; and 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-4H isoxazol-5-one.

32. The method of claim 1, wherein said MEK inhibitor has a structure selected from: 2,4-bis-(2-chloro-4-iodo-phenylamino)-3fluoro5-nitro-benzoic 30 acid; 5-[3,4difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol 2-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl] [1,3,4]oxadiazol-2-ol; (2,3-difluoro-6-[1,3,4]oxadiazol-2-yI-phenyl)(-(4-iodo-2 94 WO 01/05391 PCT/USOO/18346 methyl-phenyl)-amine; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino) phenyl]-[1,3,4]oxadiazole-2-thiol; 5-[3,4difluoro-2-(4-iodo-2-methyl phenylamino)-phenyl]-4H-[1,2,4]triazole-3-ylamine; and 5-[3,4-difluoro-2-(4 iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazole-3-thiol. 5

33. The method of claim 1, wherein said MEK inhibitor has the structure: 2,4 bis-(2-chloro-4-iodo-phenylamino)-3-fluoro-5-nitro-benzoic acid. 95