AU6068600A - Method for treating chronic pain using mek inhibitors - Google Patents

Description

WO 01/05390 PCTIUSOO/18345 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 pain include, without limitation, diabetic neuropathy, causalgia, plexus 15 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 vitamin deficiencies. 20 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 stimulus becomes painful (such as contact of clothing or a breeze). Reflex 25 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 types of chronic low back pain can have a neuropathic component (e.g., 30 sciatica, postpoliomyelitis and CPRM). Neuropathic pain may also be induced by cancer or chemotherapy. 1 WO 01/05390 PCT/US0O/18345 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 S17-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 applications USSN 60/115,873, filed January 13, 1999, PCT/US99/30483, international filing date December 21, 1999. Examples of MEK inhibitors include a compound having the formula (1) 25 below: W Q

R

11 (I) 2 WO 01/05390 PCT/USOO/18345 In formula (1), W is OR 1 , NR 2 0R 1 , NRARB, NR 2 NRARB, O(CH 2

)

2 -4NRARB, or

NR

2

(CH

2

)

2 .4 NRARB. R 1 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 3-8 cycloalkyl, phenyl, (phenyl)C 1-4 alkyl, (phenyl)C 3-4 alkenyl, (phenyl)C 3-4 alkynyl, (C 3-8 cycloalkyl)C 1-4 alkyl, (C 3-8 cycloalkyl)C 3-4 alkenyl, (C 3-8 5 cycloalkyl)C 3.4 alkynyl, C 3-8 heterocyclic radical, (C 3-8 heterocyclic radical)C 1-4 alkyl, (C 3-8 heterocyclic radical)C 3.4 alkenyl, (C 3-8 heterocyclic radical)C 3-4 alkynyl or (CH 2

)

2

-

4 NRcRD. R 2 is H, C 1-4 alkyl, phenyl, C 3-6 cycloalkyl, C 3-6 heterocyclic radical, or (C 3-6 cycloalkyl) methyl. RA is H, C 1-6 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 3-8 cycloalkyl, phenyl, (C 3-8 cycloalkyl)C 1-4 alkyl, (C 3-8 10 cycloalkyl)C 3.4 alkenyl, (C 3-8 cycloalkyl)C 3-4 alkynyl, C 3-8 heterocyclic radical, (C 3-8 heterocyclic radical)C 1-4 alkyl, (aminosulfonyl)phenyl, [(aminosulfonyl)phenyl]C 1-4 alkyl, (aminosulfonyl)C 1-6 alkyl, (aminosulfonyl)C 3-6 cycloalkyl, [(aminosulfonyl)C 3-6 cycloalkyl]C 1-4 alkyl, or (CH 2

)

2 -4 NRcRD. RB is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 3-8 cycloalkyl, or phenyl. 15 Q is one of the following formulae (i) - (iii): R3

R

3 z 3 WO 01/05390 PCT/USOO/18345

R

3 is H or F; R 4 is halo, NO 2 , SO 2 NRo(CH 2

)

2 -4NRERF, SO 2 NRERF or (CO)T. T is C 1-8 alkyl, C 3-8 cycloalkyl, (NRERF)C 1-4 alkyl, ORF, -NRO(CH 2

)

2 -4 NRERF, or NRERF; Z is one of the following formulae (iv) - (viii): N N N X X2 N R R6R7 R7

R

5

R

6 (iv) (v) (vi) 5 N, -,N Rj N, NN X3 RG N (vii) (viii) 10 One of R 5 and R 6 is H or methyl and the other of R 5 and R 6 is H, C1-6 alkyl, C2-6 alkenyl, C 2

-

6 alkynyl, phenyl, benzyl, or -M-E-G. M is 0, CO, SO 2 , NRj, (CO)NRH, NRH (CO), NRH (SO 2 ), (S0 2 )NRH, or CH 2 . E is (CH 2 )1-4 or (CH 2 )m

O(CH

2 )p where 1 (each of m and p) 3 and 2 s (m + p) s 4; or E is absent. G is RK, OR, or NRjRK, provided that if p = 1, then G is H. R 7 is H, C 1-4 alkyl, 15 C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, (CH 2

)

1

-

2 Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl,

SO

2 NRH(CH2)2-4 NRjRK, (CO)(CH 2

)

2 .4NRRK or (CO)NRH(CH 2

)

2

-

4 NRjRK. X 1 is 0, S, NR 8 , or CHR 9 ; X 2 is 0, S, or CHR 9 ; and X 3 is 0 or S. In one embodiment, if X 1 or X 2 is CHRg, the disclosed compound may also be a 20 tautomerized indole. R 8 is H, C 1-4 alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,

(CH

2 )1- 2 Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, C 2-4 alkenyl, 4 WO 01/05390 PCT/USO0/18345 C 2-4 alkynyl, C 3-6 cycloalkyl, or (C 2-4 alkyl)NRLRM provided R 7 and R 8 together have no more than 14 carbon atoms, exclusive of RL, RM, Rj and RK. RG is C 1-4 alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C 3.4 alkenyl, C 34 alkynyl, C 3-6 cycloalkyl, (CO)ORp, (C 2-4 alkyl)NRLRM, (CO)NRN(CH 2

)

2 5 4NRLRM, (CO)NRLRM, (CO)(CH 2

)

2 4 -NRLRM, or (CH 2

)

1

-

2 Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. R 9 is C 1-4 alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, (CO)ORp, (C 2.4 alkyl)NRLRM, (CO)NRN(CH 2

)

2 -4NRLRM, (CO)NRLRM, (CO)(CH 2

)

2 -4 NRLRM, or (CH 2 )1- 2 Ar', where Ar' is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. 10 Rp is H, C 1-6 alkyl, phenyl, C 34 alkenyl, C 3-4 alkynyl, C 3-6 cycloalkyl, or

(CH

2

)

2 -4 NRLRM; R 10 is H, methyl, halo, or NO 2 ; R 1 1 is H, methyl, halo, or NO 2 . Each of Rc, RD, RE, RF, R 1 , Rj, RK, RL and RM is independently selected from H, C 1-4 alkyl, C 3-4 alkenyl, C 34 alkynyl, C 3-6 cycloalkyl, and phenyl; each of NRcRD,NRERF, NRjRK, and NRLRM can also independently be morpholinyl, 15 piperazinyl, pyrrolidinyl, or piperadinyl. Each of RH, RN, and Ro is independently H, methyl, or ethyl. Finally, each hydrocarbon radical or heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C 1-.4 alkyl, C 3-6 cycloalkyl, C 2 4 alkenyl, C 2-4 alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO 2 , 20 wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 3 substituents independently selected from halo, C 1-2 alkyl, hydroxyl, amino, and NO 2 . In addition to the above compounds, the invention also provides a pharmaceutically-acceptable salt or C 1-7 ester thereof. 25 Preferred embodiments of the invention include methods using one or more of the following compounds: (a) said MEK inhibitor has a structure selected from: 7-fluoro-6-(4-iodo-2 methyl-phenylamino)-1 H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-6,7 30 dihydro-1 H-benzoimidazole-5-carboxylic acid (hydrochloride); 7-fluoro-6-(4 iodo-2-methyl-phenylamino)-1 H-benzoimidazole-5-carboxylic acid; 7-fluoro-6 (4-iodo-2-methyl-phenylamino)-3H-benzoimidazole-5-carboxylic acid 5 WO 01/05390 PCT/US00/18345 (2-hydroxy-ethoxy)-amide; 6-(2-chloro-4-iodo-phenylamino)-7-fluoro-1H benzoimidazole-5-carboxylic acid; and 7-fluoro-6-(4-iodo-2-methyl phenylamino)-1H-benzoimidazole-5-carboxylic acid pentafluorophenyl ester; and (b) said MEK inhibitor has a structure selected from: 7-fluoro-6-(4-iodo-2 5 methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide; and 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-3H benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide. The invention also relates to a pharmaceutical composition including (a) a benzoheterocycle (e.g., of formula I) and (b) a pharmaceutically 10 acceptable carrier. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a bar graph representing the paw withdrawal threshold (PWT) 15 in grams as a function of time in days. The empty, cross-hatched, and single 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 20 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 25 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. 30 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. 6 WO 01/05390 PCTIUS0O/18345 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 treated animals (Mann-Whitney t test; n=6). 5 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 a single i.t. administration of PD 198306 (1-30p g/10il), or pregabalin (100ptg/i O1il) and withdrawal thresholds were re-assessed at 30min, 1h and 10 2h after treatment. Results are expressed median ± 1 't and 3 rd quartiles. *P<0.05, ***P<0.001 significantly different from vehicle treated animals (Mann Whitney t test; n=7-9). FIG. 5. is a bar graph representing the force required in grams to elicit 15 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 i.t. administration of PD 198306 (1-30ptg/10ptl), or pregabalin (100pjg/l0pl) and withdrawal thresholds were re-assessed at 30min, 1h and 2h after treatment. Results are expressed median ± 1 't and 3 rd quartiles. 20 *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 . 25 Animals received a single intraplantar (i.pl.) administration of PD 198306 (3mg/100pl), or an intrathecal injection of PD 198306 (30ptg/10pl) and withdrawal thresholds were re-assessed 1 h after treatment. Results are expressed median ± 1 st and 3 rd quartiles. **P40.01 significantly different from vehicle treated animals (Mann-Whitney t test; n=6-9). 30 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. 7 WO 01/05390 PCT/USO0/18345 Animals received a single intraplantar (i.pl.) administration of PD 198306 (3mg/1 00ptl), or an intrathecal injection of PD 198306 (30pLg/l0pil) and withdrawal thresholds were re-assessed I h after treatment. Results are expressed median ± 1 st and 3 rd quartiles. **P<0.01 significantly different from 5 vehicle treated animals (Mann-Whitney t test; n=6). FIG. 8 is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments. Baseline (BL) measurements were taken before treatment. Animals received a single i.t. administration of 10 PD219622, PD297447, PD 184352, or PD 254552 (30tg/10l), or pregabalin (100ptg/10tl) and withdrawal thresholds were re-assessed at 30min, 1h and 2h after treatment. Results are expressed 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). 15 DETAILED DESCRIPTION The compounds disclosed herein are pharmaceutically active, for example, they inhibit MEK. MEK enzymes are dual specificity kinases 20 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 25 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 30 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 8 WO 01/05390 PCTIUS0O/18345 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 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 5 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 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 1 10 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 a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants. 15 Although Ras is not itself a protein kinase, it participates in the activation of 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 20 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. 25 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, 30 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 9 WO 01/05390 PCT/USOO/18345 MAP kinase. MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins. Both this requirement and the unusual specificity of MEK are suggestive that it 5 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, may be found. The effect of the MEK inhibitor PD 198306 has been investigated in two 10 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 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 15 neuropathy model (streptozocin). This may be due to disorders of the blood brain barrier induced by the diabetic condition in these animals, thus allowing central action of the compound. Intrathecal administration of PD 198306 (1 30pg) dose-dependently blocked static allodynia in both the streptozocin and the CCI models of neuropathic pain, with minimum effective doses (MED) of 3 and 20 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 (30[tg/1 0pl) had no effect on static allodynia in either of the neuropathic pain models. This finding confirms the lack of effect seen after 25 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 30 treatment of pain. 10 WO 01/05390 PCT/USOO/18345 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 11 WO 01/05390 PCT/US0O/18345 propenyl. In formula (1), alkenyls and alkynyls can be C 2-4 or C 2-8, for example, and are preferably C 34 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, tetrahyd rofuryl, 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 5 0 for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its IC 5 o for one of the above-named other enzymes. Preferably, 30 a selective inhibitor has an IC50 that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less than that of its IC5o or one or more of the above-named enzymes. 12 WO 01/05390 PCT/USOO/18345 B. Compounds One aspect of the invention features the use of compounds shown in formula (1) in the Summary section. Embodiments of the invention includes compounds of formula (1) wherein: (a) Q is formula (i); (b) R 3 is H or fluoro; (c) 5 R 4 is fluoro, chloro, or bromo; (d) R 1 o is H, methyl, fluoro, or chloro; (e) R 11 is methyl, chloro, fluoro, nitro, or hydrogen; (f) R 11 is H; (g) R 11 is fluoro; (h) each of Rio and R 11 is fluoro; (i) R 1 is H, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, phenethyl, allyl, C 3.5 alkenyl, C 3-6 cycloalkyl, (C 3-s cycloalkyl)C 1-2 alkyl, (C 3.5 heterocyclic radical)C 1-2 alkyl, or (CH 2

)

24 NRcRD; (j) R 1 is H or (C 10 34 cycloalkyl)C 1-2 alkyl; (k) R 2 is H or methyl; (I) RA has at least one hydroxyl substituent; (m) RA is H, methyl, ethyl, isobutyl, hydroxyethyl, phenyl, 2 piperidin-1-yl-ethyl, 2,3-dihydroxy-propyl, 3-[4-(2-hydroxyethyl)-piperazin-1-yl] propyl, 2-pyrrolidin-1-yl-ethyl, or 2-diethylamino-ethyl; and RB is H; or where RB is methyl and RA is phenyl.; (n) W is NRARB or NR 2 NRARB; (0) W is 15 NR 2

(CH

2

)

24 NRARB or O(CH 2

)

2

-

3 NRARB; (p) W is NR 2 0R 1 ; (q) W is OR 1 ; (r) Z is formula (v); or (s) X 1 is NR 8 , and R 7 is H; or (t) combinations thereof. In formula (1), the values for Z are shown left to right, or in a counter-clockwise orientation around the phenyl ring of Q. According to one aspect of the invention, the compound of formula (1) 20 has a structure wherein: Q is formula (i) or (ii); R 3 is H or fluoro; R 4 is fluoro, chloro, or bromo; Rio is H, methyl, or chloro; R 1 1 is chloro, fluoro, or hydrogen;

R

1 is H, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, phenethyl, allyl, C 3-S alkenyl, C 3-6 cycloalkyl, (C 3-S cycloalkyl)C 1-2 alkyl, (C 3-S heterocyclic radical)C 1-2 alkyl, or (CH 2

)

2

-

4 NRcRD; R 1 is H or (C 3-4 cycloalkyl)C 1-2 alkyl; R 2 25 is H or methyl; and Z is formula (v) or (vi). One embodiment of this aspect, X, is NR 8 . An example would be 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1[(2' morpholinyl)-ethyl]-2-(phenyl)-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide. Embodiments of the invention also include compounds wherein Rio is 30 H; Rio is methyl or chloro; and where R 1 o is chloro. In some embodiments,

R

7 and R8 together have no more than 14 carbon atoms, exclusive of RL, RM, Rj and RK. Examples of this include compounds wherein R 7 and R 8 together 13 WO 01/05390 PCT/USOO/18345 have no more than 13 carbon atoms; no more than 7, 8, or 10 carbon atoms; between 4 and 8 carbon atoms; between 1 and 10 carbon atoms; between 1 and 8 carbon atoms; and no more than 6 carbon atoms. Preferably, where one of R 1 , R 2 , RA, RB, Rc, RD, RE, RF, RI, RJ, RK, RL, 5 Rm, RG, RH, RN, Ro, and Rp is an alkenyl or alkynyl group, its double or triple bond, respectively, is not adjacent the point of attachment. For example, where W is NR 2

OR

1 , R 2 is preferably prop-2-ynyl, or but-2 or 3-enyl, and less preferably prop-1 -ynyl or but-1-enyl. Listed below are some of the preferred structures which can be 10 synthesized utilizing Schemes 1, 2, 10, and 11. Free acids, free hydroxamic acids, and cyclopropylmethyl hydroxamates are grouped together. For example, compounds 1, 11, and 21 differ only by "W" (as defined in the claims); compounds 2, 12, and 22 are similarly related. Preferred compounds also include the 2-chloro (replacing 2-methyl) analogs of the listed 15 compounds. Examples of compounds include: 7-Fluoro-6-(4-iodo-2-methyl phenylamino)-1 H-benzoimidazole-5-carboxylic acid (APK IC 50 = 47±17 nM); 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzooxazole-5-carboxylic acid; 7 Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzothiazole-5-carboxylic acid; 7 20 Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo[1,2,5]thiadiazole-5-carboxylic acid; 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo[1,2,5]oxadiazole-5 carboxylic acid; 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-2-(2-hydroxyethyl) 1 H-benzoimidazole-5-carboxylic acid; 7-Fluoro-6-(4-iodo-2-methyl phenylamino)-2-(2-dimethylamino-ethyl)-1 H-benzoimidazole-5-carboxylic acid; 25 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-1-acetyl-benzoimidazole-5 carboxylic acid; 8-Fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-6 carboxylic acid; 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H-benzotriazole 5-carboxylic acid; 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-1

H

benzoimidazole-5-carboxylic acid hydroxyamide; 7-Fluoro-6-(4-iodo-2-methyl 30 phenylamino)-benzooxazole-5-carboxylic acid hydroxyamide; 7-Fluoro-6-(4 iodo-2-methyl-phenylamino)-benzothiazole-5-carboxylic acid hydroxyamide; 7 Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzo[1,2,5]thiadiazole-5-carboxylic 14 WO 01/05390 PCTUSOO/18345 acid hydroxyamide; 7-Fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5]oxadiazole-5-carboxylic acid hydroxyamide; 7-Fluoro-6-(4-iodo-2 methyl-phenylamino)-2-(2-hydroxyethyl)-1 H-benzoimidazole-5-carboxylic acid hydroxyamide; 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-2-(2-dimethylamino 5 ethyl)-1 H-benzoimidazole-5-carboxylic acid hydroxyamide; 7-Fluoro-6-(4-iodo 2-methyl-phenylamino)-1-acetyl-benzoimidazole-5-carboxylic acid hydroxyamide; 8-Fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-6 carboxylic acid hydroxyamide; 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-1H benzotriazole-5-carboxylic acid hydroxyamide; 7-Fluoro-6-(4-iodo-2-methyl 10 phenylamino)-1 H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy amide; 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzooxazole-5-carboxylic acid cyclopropylmethoxy-amide; 7-Fluoro-6-(4-iodo-2-methyl-phenylamino) benzothiazole-5-carboxylic acid cyclopropylmethoxy-amide; 7-Fluoro-6-(4 iodo-2-methyl-phenylamino)-benzo[1,2,5]thiadiazole-5-carboxylic acid 15 cyclopropylmethoxy-amide; 7-Fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5]oxadiazole-5-carboxylic acid cyclopropylmethoxy-amide; 7 Fluoro-6-(4-iodo-2-methyl-phenylamino)-2-(2-hydroxyethyl)-1

H

benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide; 7-Fluoro-6-(4 iodo-2-methyl-phenylamino)-2-(2-dimethylamino-ethyl)-1 H-benzoimidazole-5 20 carboxylic acid cyclopropylmethoxy-amide; 7-Fluoro-6-(4-iodo-2-methyl phenylamino)-1-acetyl-benzoimidazole-5-carboxylic acid cyclopropylmethoxy amide; 8-Fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-6-carboxylic acid cyclopropylmethoxy-amide; and 7-Fluoro-6-(4-iodo-2-methyl phenylamino)-1H-benzotriazole-5-carboxylic acid cyclopropylmethoxy-amide. 25 The following is a list of examples representing schemes 3-9. As above, free acids, free hydroxamic acids, and cyclopropylmethyl hydroxamates are grouped together. For example, compounds 31, 45, and 59 differ only by "W' (as defined in the claims); compounds 32, 46, and 60 are similarly related. Preferred compounds also include the 2-chloro (replacing 2 30 methyl) analogs of the listed compounds. Examples of compounds from schemes 3-9 include: 4-Fluoro-5-(4 iodo-2-methyl-phenylamino)-benzothiazole-6-carboxylic acid; 4-Fluoro-5-(4 15 WO 01/05390 PCTIUSOO/18345 iodo-2-methyl-phenylamino)-benzooxazole-6-carboxylic acid; 5-(2-Chloro-4 iodo-phenylamino)-6,7-difluoro-3H-benzoimidazole-4-carboxylic acid; 6,7 Difluoro-2-(2-hydroxy-ethyl)-5-(4-iodo-2-methyl-phenylamino)-3H benzoimidazole-4-carboxylic acid; 6,7-Difluoro-5-(4-iodo-2-methyl 5 phenylamino)-benzooxazole-4-carboxylic acid; 6,7-Difluoro-5-(4-iodo-2 methyl-phenylamino)-benzothiazole-4-carboxylic acid; 7,8-Difluoro-6-(4-iodo 2-methyl-phenylamino)-quinoxaline-5-carboxylic acid; 6-(4-lodo-2-methyl phenylamino)-8-nitro-quinoxaline-5-carboxylic acid; 5-(4-lodo-2-methyl phenylamino)-8-nitro-quinoxaline-6-carboxylic acid; 8-Chloro-5-(4-iodo-2 10 methyl-phenylamino)-quinoxaline-6-carboxylic acid; 3-Cyclopropyl-7-(4-iodo 2-methyl-phenylamino)-3H-benzoimidazole-4,6-dicarboxylic acid 4 dimethylamide; 7-Bromo-4-(4-iodo-2-methyl-phenylamino)-benzooxazole-5 carboxylic acid; 7-(2-Chloro-4-iodo-phenylamino)-4-fluoro-benzothiazole-6 carboxylic acid; 7-(4-lodo-2-methyl-phenylamino)-4-nitro-benzooxazole- 6 15 carboxylic acid; 4-Fluoro-5-(4-iodo-2-methyl-phenylamino)-benzothiazole-6 carboxylic acid hydroxyamide; 4-Fluoro-5-(4-iodo-2-methyl-phenylamino) benzooxazole-6-carboxylic acid hydroxyamide; 5-(2-Chloro-4-iodo phenylamino)-6,7-difluoro-3H-benzoimidazole-4-carboxylic acid hydroxyamide; 6,7-Difluoro-2-(2-hyd roxy-ethyl)-5-(4-iodo-2-methyl 20 phenylamino)-3H-benzoimidazole-4-carboxylic acid hydroxyamide; 6,7 Difluoro-5-(4-iodo-2-methyl-phenylamino)-benzooxazole-4-carboxylic acid hydroxyamide; 6,7-Difluoro-5-(4-iodo-2-methyl-phenylamino)-benzothiazole-4 carboxylic acid hydroxyamide; 7,8-Difluoro-6-(4-iodo-2-methyl-phenylamino) quinoxaline-5-carboxylic acid hydroxyamide; 6-(4-lodo-2-methyl 25 phenylamino)-8-nitro-quinoxaline-5-carboxylic acid hydroxyamide; 5-(4-lodo 2-methyl-phenylamino)-8-nitro-quinoxaline-6-carboxylic acid hydroxyamide; 8 Chloro-5-(4-iodo-2-methyl-phenylamino)-quinoxaline-6-carboxylic acid hydroxyamide; 3-Cyclopropyl-7-(4-iodo-2-methyl-phenylamino)-3H benzoimidazole-4,6-dicarboxylic acid 4-dimethylamide 6-hydroxyamide; 7 30 Bromo-4-(4-iodo-2-methyl-phenylamino)-benzooxazole-5-carboxylic acid hydroxyamide; 7-(2-Chloro-4-iodo-phenylamino)-4-fluoro-benzothiazole-6 carboxylic acid hydroxyamide; 7-(4-lodo-2-methyl-phenylamino)-4-nitro 16 WO 01/05390 PCT/USOO/18345 benzooxazole-6-carboxylic acid hydroxyamide; 4-Fluoro-5-(4-iodo-2-methyl phenylamino)-benzothiazole-6-carboxylic acid cyclopropylmethoxy-amide; 4 Fluoro-5-(4-iodo-2-methyl-phenylamino)-benzooxazole-6-carboxylic acid cyclopropylmethoxy-amide; 5-(2-Chloro-4-iodo-phenylamino)-6,7-difluoro-3H 5 benzoimidazole-4-carboxylic acid cyclopropylmethoxy-amide; 6,7-Difluoro-2 (2-hydroxy-ethyl)-5-(4-iodo-2-methyl-phenylamino)-3H-benzoimidazole- 4 carboxylic acid cyclopropylmethoxy-amide; 6,7-Difluoro-5-(4-iodo-2-methyl phenylamino)-benzooxazole-4-carboxylic acid cyclopropylmethoxy-amide; 6,7-Difluoro-5-(4-iodo-2-methyl-phenylamino)-benzothiazole-4-carboxylic acid 10 cyclopropylmethoxy-amide; 7,8-Difluoro-6-(4-iodo-2-methyl-phenylamino) quinoxaline-5-carboxylic acid cyclopropylmethoxy-amide; 6-(4-lodo-2-methyl phenylamino)-8-nitro-quinoxaline-5-carboxylic acid cyclopropylmethoxy amide; 5-(4-lodo-2-methyl-phenylamino)-8-nitro-quinoxaline-6-carboxylic acid cyclopropylmethoxy-amide; 8-Chloro-5-(4-iodo-2-methyl-phenylamino) 15 quinoxaline-6-carboxylic acid cyclopropylmethoxy-amide; 3-Cyclopropyl-7 (4-iodo-2-methyl-phenylamino)-3H-benzoimidazole-4,6-dicarboxylic acid 4 dimethylamide 6-cyclopropylmethoxy-amide; 7-Bromo-4-(4-iodo-2-methyl phenylamino)-benzooxazole-5-carboxylic acid cyclopropylmethoxy-amide; 7-(2-Chloro-4-iodo-phenylamino)-4-fluoro-benzothiazole-6-carboxylic acid 20 cyclopropylmethoxy-amide; and 7-(4-lodo-2-methyl-phenylamino)-4-nitro benzooxazole-6-carboxylic acid cyclopropylmethoxy-amide. 17 WO 01/05390 PCT/USOO/18345 C. Synthesis The disclosed compounds can be synthesized according to the following eleven Schemes, or variants thereof. These synthetic strategies are 5 further exemplified in Examples 1-22 below. Scheme 1 HO 0 HO 0 L H-XfR 8 a 9 LI H-0-R 1 2 0 2 N R 3 0 2 N R3 Catalyst H R, 8 9 '0 0 1 0 HN LI Base 2 N 0 2 N XR 3 7 0 2 N ,RRI H RH 9 R8g 9 Reducing Agent N L 2

R

7 R

H

2 N R 3

R

11 X R 3 RI, H R8 a9 R 7

R

8 9 0 0 R, 2 H lodinating Reagent N Deesterification y R 3 RI

R

7 R8 a 9 R2 HO 0 R RIs' N O H_ Ri N H N NI1 - R-RN-O-R 1 I N R II y R 3 RII

R

3 R R7 R8g a 9

R

7

R

8 , 9 18 WO 01/05390 PCT/USOO/18345 Scheme 2 ORI HO I L + H 2 N Base N 0 2 N R3 R0 2 N R3 R

NH

2

NH

2 0 O R1f0 0H Rif' HZR Rs-- N Reducing Agent N O 1 I2 2R ,IR- N R I HN 1( N R 3 Ri

NH

2 R3RiR R6 Rf H lodinating Reagent N N Deesterification R5 N R3 RI, R6 2 HO 0 R RI O'N 0 Rio H H ~ 0 N N NNH -O R5 R 3 Ri R N 3 RI 19 WO 01/05390 PCT/USOO/18345 Scheme 3 HO 0 HO 0 R13 L Li H-N-R 1 4

H-O-R

12 02N R3 Base 0 2 N R 3 Catalyst L2

R

13 ' R 14 R1fO O 0 RifOO R2" 0

H

2 N Base N L + R I B a eI 0 2 N R 3 R0 0 2 N ,R3 Ri N N R13' R14 R3' RI4 RIRO O nH RZ Rif H0R0 o Reducing Agent N 1) Diazotization N 7 2) HX 2

HX

2

H

2 N R3R R3I

R

13 RI4 R13 N R14 Deprotection N H R IX 7 L1 2 R(7 N

NH

2 X2N R3 RI R7 Rf H lodinating Reagent N Deesterification X2/ R3 Ri, R7 R2 HO 0 RIs -N O N H N R2-N-O-RI 1~ X2,. R3 RI, X 2 R3 RI, /-N N R7 R7 20 WO 01/05390 PCT/USOO/18345 Scheme 4 HO 0 HO 0 HO 0 L, L, Nitration LI L H-XR 8 or 9 R8o ' 2 R3ON R 3 0-,N; R 0 R2 0 H RIO

H-O-R

12

R

1 -, LI H-,N RIO Base R ) N R8o 9 + 8 or 7 Catalyst i__- R 3 OIN O-)N R4 R RI,- R4R 3 RI, R12 o 0 , R 1 ,N H3R R 4 H3R R7 L R R74\9 N HN R 3 R

R

3 R, RI O 0 HOH R,- -0 , R 7 4 I 1I N' N R4 R 3 R, I 3

R

1 02 WO 01/05390 PCTIUSOO/18345 Scheme 5 HO 0 HO 0 HO 0 ~ 1 Ntain L, LI H R13-N LI L 11LiNtaio -R 3--. R 1 ' R3 R 3 O-N;R43 R4 R4 R0< 0 RIO R 1 2< 0 0 HRI H--R R1N Base, R13-N N

R

1 + -_____ _R 1 4~ 14;7 OI Catalyst 0N - ~0N R 1 O-) 03 Rt2 H3R R4 RR4~ Reducing Agent R,3 TN N l)Diazotization R13-N N

H

2 N 4 R 3 RI, R R 3 RI I

HR

1 2Q0H 0 0~ HZ Deprotection H-N N L 2 AR7, N N 1 R7-< R11 HXI 4 R3 RII , R4R 3 R , R12 0010 0 loiatn eaet - Deesterification N N loinRig7eaen <N N R 7 -</ 7 I, X,

R

3 RI R R 3

R

1 1 R-) 0 R H H ' R,-N-0-RI N N R4

R

3

R,

11 22 WO 01/05390 PCT/USOO/18345 Scheme 6 HO 0 HO 0 HO 0 LI s LI Nitration L, L, NH 3 H2N LI R3 0,N R 3 ON R3 , 0 ,0 0

R

1 2 RoR 12 HRo H-0-R 1 2 H2N LI HN Base HN N Catalyst O-,N R 3 t ON R 3 Ri 0 ,00O ,0 0 Reducing Agent R 1 2 H R o R 5

R

1 2 H RIO H 2 N -N 0 R 5 N -N _0 I N I ; HN R 3 RI, N R 3 RII R4 R O 0 HO 0 R2 H R 1 Q HR lodinating Reagent R 1 N N Deesterification R 5 N N R5 N N N N N; 3R 3 RR RI R4 R3RR4 R, IIRisO'N O0 R R,-N-0-R, R 5 N N

R

6 XN N

R

3 RI, 23 WO 01/05390 PCT/USOO/18345 Scheme 7 HO 0 HO 0 HO 0

R

4 s LI Nitration R4 LI NH 3 R4 L R3 R3 NO2 R3 NO2 L L NH, R .2 0 O Rio Ri 'O O H0 H-O-Ri 1 R4 LI H 2 N Base R4 N Catalyst R3 NO 2 RR3 NO, R, NH.,

NH

2 0 O 0 H R6 R5 R6 R4 N Reducing A gent R4 N O R3 N R3 NHR 1 3 N R

NH

2 YR6 R5 R 0 H R H Rio lodinating Reagent N Deesterification R4 N R N N R, R,-N -O -Rj R 4sRR R(3 Na IN N NI

R

6 5R 24 WO 01/05390 PCTIUSOO/18345 Scheme 8 HO 0 HO 0 HO 0

R

4 Li Nitration R4 L, H-X2-R 8 or9 R4 R3 NO-,

R

3

NO

2 3 I L , H R8or9 RR O R ,2 O RH H-O-Ri 2 4 L H 2 N Base R4 N Catalyst R 3 NO R - R 3 NO2R H R8or9 H R8or9 R12 0 00 R 12,0 0 RI

R

1 , H RN Reducing Agent R4 N L R 7

R

4

R

3 NHR X R H R8or9 R 8 or 9

R

7 0 0 HO 0

R

1 H Rio H lodinating Reagent R4 Deesterification R 4 N R5N -a R 3 NR, X, RI, X R R8or9 R 7 R8 or 9 R 7 R, H

RI,.

0 N 0H RI

R

2 -N-O-R, R4 N R3 RN R8or9

R

7 25 WO 01/05390 PCT/USOO/18345 Scheme 9 HO 0 HO 0 HO 0

R

4 L, R 4 L, H R 4 L, Nitration , R 13

-N-R

1 4 R3 R3 NO, R 3 NO LL R,3'N R14 O 0 R 0 0

H-O-R

1 2 R4HN Base R 4 N Catalyst R 3 NO, R 3 INO N R N R1

R

1 3' R 14 R R 14 R,2R 0 H R H Reducing Agent R4 N 1) Diazotization 14 N R3 NH2R) R3 XIHRII 3 N, HI N,

R

13 R14

R

13 R14 O, 0 0 0 0 Deprotection H ' OA R7 R H R R3 XI R, R3 X 1 HR N R

NH

2 R Os O HO, R H 0 H R 0 lodinating Reagent R4 N Deesterification R 4 N R3 Xi iR3 XI R, N X RI, N R7 R7 R, RIO N 0 R H H 1 R,-N-0-RI R4 N RI R3) XI RI N: R7 26 WO 01/05390 PCT/USOO/18345 Scheme 10 2 H R0 R 0 2R N Reagents N A RI N / R 3 RI, N li

X

3 -N A=N0 2 or NH 2 ,0 0

R,

2 H RIO Iodinating Reagent - N Deesterification / R 3 R I X 3 -N R2 HO 0 RIs9N 0 H 10H N HN R R 2 -N-0-R N N / RR 11 ~N /RR,

X

3 -N

X

3 -N 27 WO 01/05390 PCT/USOO/18345 Scheme 11 R2"0 0H RI 1"0 0H RI

NRG-L

3 N H2N "GN IR 2 N R 3 RI, H N, I

R

3

'R

14 R 13 ~ R 14

R

1 2 H RIO Deprotection N Diazotization H NH3 RII R 2'0 0H RIOR 10 H RIO N lodinating Reagent N IRRGNN RG-N, 3 R1, 3

R

11 N=N Nq=N Deesteri fi cation N R 2 -N-0-R RG-N R 3 R, I N RG-N R 1 28 WO 01/05390 PCT/USO0/18345 D. Uses The disclosed compositions are useful as both prophylactic and 5 therapeutic treatments for diseases or conditions relating to chronic pain, 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 10 postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, 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 15 neuropathy can be treated with systemic administration (injection or orally) of 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 20 pharmaceutical agent, such as an anti-inflammatory, analgesic, muscle 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. 25 1. Dosages 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 30 between 0.1 and 1000 mg/kg per day, preferably between 1 and 300 mg/kg body weight, and daily dosages will be between 10 and 5000 mg for an adult subject of normal weight. Commercially available capsules or other 29 WO 01/05390 PCT/USOO/18345 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 Dosage unit forms include tablets, capsules, pills, powders, granules, 5 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. Administration methods include oral, rectal, parenteral (intravenous, 10 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 or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile 15 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 particle size. Carriers for solid dosage forms include (a) fillers or extenders, 20 (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, emulsifying, and dispensing agents; antimicrobial agents such as parabens, 25 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. 3. Related compounds The invention provides the disclosed compounds and closely related, 30 pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms. 30 WO 01/05390 PCTIUS0O/18345 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 5 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, 10 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, 15 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 20 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

.

6 )alkyl esters. Preferred esters include methyl esters. 25 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 acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also 30 within the scope of the invention. 31 WO 01/05390 PCT/USO0/18345 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 5 conversion of silyl ethers to other functional groups. Substituted Methyl Ethers Substituted methyl ethers include: methoxymethyl, methylthiomethyl, t utylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, t 10 butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloro- ethoxy)methyl, 2 (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydro-pyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4 methoxytetrahydrothio-pyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxido, 15 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, 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, 20 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2 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, 25 o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, ac-naphthyldiphenyl methyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri-(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxy)phenydiphenylmethyl, 30 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 32 WO 01/05390 PCTIUSOO/18345 methoxyphenyl)- 1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl) xanthenyl, 9-(9 phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S dioxido. Silyl Ethers 5 Silyl ethers include: trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenylsilyl. 10 ESTERS Esters protecting groups include: esters, carbonates, assisted cleavage, miscellaneous esters, and sulfonates. Esters Examples of protective esters include: formate, benzoylformate, acetate, 15 chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, 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, 20 and 2,4,6-trimethylbenzoate (mesitoate). 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 25 dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4 ethoxy-1-naphthyl, and methyl dithiocarbonate. Assisted Cleavage Examples of assisted cleavage protecting groups include: 2-iodobenzoate, 4 azido-butyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl) benzoate, 2 30 formylbenzene-sulfonate, 2-(methylthiomethoxy) ethyl carbonate, 4 (methylthiomethoxymethyl) benzoate, and 2-(methylthiomethoxymethyl) benzoate. 33 WO 01/05390 PCT/IUSOO/18345 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) phenoxyacetate, 2,4-bis(1,1-dimethylpropyl) phenoxyacetate, 5 chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2 butenoate (tigloate), o-(methoxycarbonyl) benzoate, p-P-benzoate, a-naphthoate, nitrate, alkyl NN,N ' N '-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate. 10 Sulfonates Protective sulfates includes: sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate. PROTECTION FOR 1,2- AND 1,3-DIOLS 15 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, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, 20 acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4 dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene. Cyclic Ortho Esters Cyclic ortho esters include: methoxymethylene, ethoxymethylene, dimethoxy 25 methylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1,2 dimethoxyethylidene, c-methoxybenzylidene, 1-(NN dimethylamino)ethylidene derivative, a-(N,N-dimethylamino) benzylidene derivative, and 2-oxacyclopentylidene. 30 34 WO 01/05390 PCT/USOO/18345 PROTECTION FOR THE CARBOXYL GROUP ESTERS Ester protecting groups include: esters, substituted methyl esters, 2 substituted ethyl esters, substituted benzyl esters, silyl esters, activated 5 esters, miscellaneous derivatives, and stannyl esters. Substituted Methyl Esters Substituted methyl esters include: 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahyd ropyranyl, tetrahyd rofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxy-methyl, benzyloxymethyl, phenacyl, p-bromophenacyl, 10 a-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N phthalimidomethyl. 2-Substituted Ethyl Esters 2-Substituted ethyl esters include: 2,2,2-trichloroethyl, 2-haloethyl, aX chloroalkyl, 2-(trimethylsily)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 15 2(p-nitrophenylsulfenyl)-ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2'-pyridyl)ethyl, 2 (diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsily)-2-buten-1-yl, cinnamyl, aX methylcinnamyl, phenyl, p-(methylmercapto)-phenyl, and benzyl. Substituted Benzyl Esters 20 Substituted benzyl esters include: triphenylmethyl, diphenylmethyl, 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, 25 piperonyl, and 4-P-benzyl. Silyl Esters Silyl esters include: trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, i propyldimethylsilyl, phenyldimethylsilyl, and di- t-butylmethylsilyl. Miscellaneous Derivatives 30 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. 35 WO 01/05390 PCT/USO0/18345 Stannyl Esters Examples of stannyl esters include: triethylstannyl and tri-n-butylstannyl. AMIDES AND HYDRAZIDES 5 Amides include: N,N-dimethyl, pyrrolidinyl, piperidinyl, 5,6 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. 10 PROTECTION FOR THE AMINO GROUP CARBAMATES Carbamates include: carbamates, substituted ethyl, assisted cleavage, photolytic cleavage, urea-type derivatives, and miscellaneous carbamates. 15 Carbamates 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 20 Substituted ethyl protective groups include: 2,2,2-trichloroethyl, 2 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, 25 vinyl, allyl, 1-isopropylallyl, connamyl, 4-nitrocinnamyl, quinolyl, N hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p bromobenzyl, p-chlorobenzyl, 2,4dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, and diphenylmethyl. 30 Assisted Cleavaqe Protection via assisted cleavage includes: 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 36 WO 01/05390 PCT/US0O/18345 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. 5 Photolytic Cleavage 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 10 Examples of of urea-type derivatives include: phenothiazinyl-(10)-carbonyl derivative, N '-p-toluenesulfonylaminocarbonyl, and N' phenylaminothiocarbonyl. Miscellaneous Carbamates In addition to the above, miscellaneous carbamates include: t-amyl, S-benzyl 15 thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, 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, di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p(p' 20 methoxyphenyl- azo)benzyl, 1 -methylcyclobutyl, 1 -methylcyclohexyl, 1 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. 25 37 WO 01/05390 PCT/US00/18345 AMIDES 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 Cleavaqe 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-dimethyl-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-(trimethylsilyi)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, 38 WO 01/05390 PCT/USOO/18345 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 10 methylene, and N-cyclohexylidene. Enamine Derivative An example of an enamine derivative is N (5,5-dimethyl-3-oxo-1-cyclohexenyl). N-Hetero Atom Derivatives 15 N-metal derivatives include: N-borane derivatives, N-diphenylborinic acid 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, 20 N-dialkyl phosphoryl, N-dibenzyl phosphoryl, and N-diphenyl phosphoryl. Examples of N-sulfenyl derivatives include: N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl, N-2-nitro-4-methoxy-benzenesulfenyl, N-triphenylmethylsulfenyl, and N-3-nitropyridinesulfenyl. N-sulfonyl 25 derivatives include: N-p-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl- 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, 30 N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl,

N

2,6-dimethoxy- 4-methylbenzenesulfonyl, N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl, 39 WO 01/05390 PCT/USOO/18345 N-p-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. 40 WO 01/05390 PCT/USOO/18345 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. 41 WO 01/05390 PCT/US0O/18345 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 ml/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 1h 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: Day 2: a.m.: PD 198306 Water 30 Vehicle p.m.: BL p.m.: BL 42 WO 01/05390 PCT/USO0/18345 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 Iniury 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 43 WO 01/05390 PCT/USOO/18345 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 tl 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 (1-30ptg, i.t.), vehicle (cremophor:ethanol:water, 1:1:8) or pregabalin (10pg, i.t). For oral administration experiments, static allodynia was assessed 44 WO 01/05390 PCTIUSOO/18345 with von Frey hairs, before (baseline, BL) and 1h 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, 1 h, 2h and 3h after administration for streptozocin treated animals. CCI animals were assessed before, 1h and 2h after administration 10 Druqs 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, 10pil and 15 100pl respectively. Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCl and administered intraperitoneally in a volume of 1ml/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). 45 WO 01/05390 PCT/USOO/18345 1.2. Effect of PD198306 on CC-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 (1-30pg) 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 pg. This antiallodynic effect lasted for 1h. 15 3. Effects of PD 198306 on static allodynia, following intraplantar administration An intrathecal administration of PD 198306 (30pg) 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 00p1l) directly 20 into the paw had no effect on streptozocin (FIG. 6) or CC-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 46 WO 01/05390 PCT/US00/18345 Example 3 Effect of other MEK inhibitors in a neuropathic pain model in the rat SUMMARY 5 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 (30pLg) had no significant effect on allodynia. This lack of effect may reflect the low affinity or solubility of the compounds. However, 10 intrathecal administration of PD 254552 or PD 184352 (30ptg), 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 the effect was similar for 30pg of PD 184352 and 100ptg of pregabalin. From 15 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. The animals and methods for developing chronic constriction injury in 20 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 30pg for all PD compounds and 100pg for pregabalin. Static allodynia was assessed with von Frey hairs, before (baseline, BL) and 0.5h, 1h and 2h after intrathecal 25 administration of the compounds Druqs used PD297447, PD219622, PD 254552, PD 184352 (CI-1040), and pregabalin were synthesised at Parke-Davis (Ann Arbor, MI, USA). PD297447, 30 PD219622, PD 254552 and PD 184352 were suspended in cremophor:ethanol:water (1:1:8) vehicle. Pregabalin was dissolved in water. All compounds were administered intrathecally in a 10pl volume. 47 WO 01/05390 PCTIUSO0/18345 Statistics Data were analysed using a Kruskall-Wallis ANOVA for non-parametric results, followed when significant by Mann-Whitney's t test vs vehicle group. 5 RESULTS Intrathecally administered PD297447 or PD219622 (30pg) had no significant effect on allodynia. This lack of effect may reflect the low affinity of the compounds (965nM and 1OOnM respectively). However, intrathecal 10 administration of PD 184352 or PD 254552 (30pg) 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 evident for 30min post-injection and thus, shorter than the one observed for pregabalin (100ptg). The magnitude of the effect was similar for 30pg of PD 15 184352 and 100pg of pregabalin. The results indicate 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. 48 WO 01/05390 PCT/USOO/18345 CHEMICAL EXAMPLES EXAMPLE 1 5 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole 5-carboxylic acid (PD 205293) (APK IC50 = 14 nM; colon 26 cells, IC50 = > 10 micromolar) Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid 10 To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension 15 was extracted with diethyl ether (3 x 200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78 % yield; m.p. 1 H-NMR (400 MHz; DMSO) 8 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); '3C 20 NMR (100 MHz; DMSO) 8 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F= 2 5 3

.

4 Hz), 133.95, 123.30 (d, Jc

F=

2

.

2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 1 9 F-NMR (376 MHz; DMSO) 6 120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m). 25 Step b: Preparation of 4-amino-2,3-difluoro-5-nitrobenzoic acid Solid 5-nitro-2,3,4-trifluorobenzoic acid (0.75 g, 0.00339 mol) was dissolved in concentrated ammonium hydroxide (25 ml) to give instantly a yellow solution. A precipitate began to form within five minutes, after which time the mixture was acidified to pH 0 with concentrated aqueous hydrochloric 30 acid. A yellow precipitate rapidly formed. The mixture was heated to boiling and was filtered hot. The yellow solids were washed with 10 % aqueous hydrochloric acid and were suction dried to afford 0.47 g of a yellow powder; 64 % yield; 1 H-NMR (400 MHz; DMSO) 6 13.32 (s, 1H), 8.36 (d, 1H, J=7.6 49 WO 01/05390 PCT/USOO/18345 Hz), 7.98 (s, 2H); 1 9 F-NMR (376 MHz; DMSO) 8 -128.69 to -128.76 (m), 153.60 (d). Step c: Preparation of methyl 4-amino-2,3-difluoro-5-nitrobenzoate 5 Hydrogen chloride gas was dissolved in anhydrous methanol (30 ml) until the solution was warm. The solid 4-amino-2,3-difluoro-5-nitrobenzoic acid (0.47 g; 0.00215 mol) was dissolved in this solution and the reaction mixture was brought to reflux with vigorous stirring for 23 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool slowly on the 10 bench. A yellow precipitate formed and was collected by vacuum filtration and dried with suction to afford 0.35 g of yellow microfilaments; 70 % yield; m.p. 183.5-184 *C; 1 H-NMR (400 MHz; DMSO) 8 8.36 (dd, 1H, J=7.3, 1.7 Hz), 8.06 (s, 2H), 3.78 (s, 3H); 1 9 F-NMR (376 MHz; DMSO) 6 -128.85 to -128.92 (m), -153.29 (d); MS (APCI-) 231 (M-1, 100); IR (KBr) 3433, 3322, 1700, 15 1650, 1549, 1343, 1285 cm'; Anal. calcd/found for: C 8

H

6

F

2

N

2 0 4 C, 41.39/41.40; H, 2.61/2.50; N, 12.07/11.98; F, 16.37/16.58. Step d: Preparation of methyl 4-amino-3-fluoro-2-(2-methyl-phenylamino)-5 nitrobenzoate 20 The solid methyl 4-amino-2,3-difluoro-5-nitrobenzoate (0.087 g, 3.7 x 10-4 mol) was dissolved in ortho-toluidine (3 ml, 0.028 mol). The reaction mixture was stirred at 200 0 C for 35 minutes under a nitrogen atmosphere. The mixture was then partitioned between diethyl ether (150 ml) and 10 % aqueous hydrochloric acid (150 ml). The ether phase was dried with 25 anhydrous magnesium sulfate and was concentrated in vacuo to a crude solid. The crude product was dissolved in 5 ml of dichloromethane and was filtered through a flash silica plug. Elution with dichloromethane afforded 0.0953 g of a yellow solid; 81 % yield; m.p. 164-168 *C; 1 H-NMR (400 MHz; DMSO) 6 9.20 (s, 1H), 8.52 (d, 1H, J=1.7 Hz), 7.57 (s, 2H), 7.19 (d, 1H, J=7.3 30 Hz), 7.12-7.08 (m, 1H), 7.02-6.98 (m, 1H), 6.95-6.91 (m, 1H), 3.78 (s, 3H), 2.21 (s, 3H); 1 9 F-NMR (376 MHz; DMSO) 6 -141.13 (s); MS (APCI+) 320 (M+1, 100); (APCI-) 318 (M-1, 100); IR (KBr) 3467, 3346, 1690, 1305 cm 1 ; 50 WO 01/05390 PCT/US0O/18345 Anal. calcd/found for: C 15

H

14

FN

3 0 4 0.21 H 2 0 C, 55.77/55.97; H, 4.50/4.55; N, 13.01/12.61; F, 5.88/5.95. Step e: Preparation of methyl 4,5-diamino-3-fluoro-2-(2-methyl 5 phenylamino)benzoate To a mixture comprised of methyl 4-amino-3-fluoro-2-(2-methyl phenylamino)-5-nitrobenzoate (2.52 g, 0.00789 mol), tetrahydrofuran (50 ml), methanol (50 ml) and washed Raney nickel (0.5 g) was initially applied 48.6 psi of hydrogen gas at 30.2 0C in a shaker for 4 hours 48 minutes. The 10 mixture was filtered and the filtrate concentrated in vacuo to afford 2.20 g of a salmon-colored amorphous solid; 96 % yield; 1 H-NMR (400 MHz; DMSO) 6 7.84 (s, 1H), 7.04 (d, 1H, J=7.1 Hz), 6.98 (d, 1H, J=1.2 Hz), 6.95-6.91 (m, 1H), 6.68-6.64 (m, 1H), 6.40-6.36 (m, 1H), 5.39 (s, 2H), 4.73 (s, 2H), 3.66 (s, 3H), 2.21 (s, 3H); 1 9 F-NMR (376 MHz; DMSO) 8 -139.66 (s). 15 Step f: Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-1

H

benzoimidazole-5-carboxylate A stirring solution comprised of methyl 4,5-diamino-3-fluoro-2-(2 methyl-phenylamino)-benzoate (1.78 g, 0.00615 mol) in formic acid (Aldrich, 20 95-97 %, 100 ml, 2.5 mol) was brought to reflux for 3 hours followed by concentration in vacuo to give a crude brown solid. The crude product was triturated with chloroform (40 ml) and subsequently collected by vacuum filtration. The solids were dried with suction to afford 1.09 g of a light-lavender powder. The filtrate was concentrated in vacuo to a crude solid which was 25 triturated with 10 ml of chloroform-dichloromethane. These solids were collected by vacuum filtration, rinsed with dichloromethane, and were suction dried to give an additional 0.55 g of a light-lavender powder (total yield: 1.64 g); 87 % yield; m.p. 259-262 0C; 1 H-NMR (400 MHz; DMSO) 6 8.42 (s, 1H), 8.03 (s, 1H), 7.93 (broad s, 1H), 7.12 (d, 1H, J=7.0 Hz), 6.99-6.95 (m, 1H), 30 6.75-6.71 (m, 1H), 6.48-6.44 (m, 1H), 3.81 (s, 3H), 2.30 (s, 3H); 19 F-NMR (376 MHz; DMSO) 8 -132.84 (s); MS (APCI+) 300 (M+1, 100); (APCI-) 298 (M-1, 51 WO 01/05390 PCTIUSOO/18345 100); IR (KBr) 3322, 1689, 1437, 1326, 1218 cm-1; Anal. calcd/found for:

C

16

H

14

FN

3 02 -0.32 H 2 0 C, 62.99/63.01; H, 4.84/4.61; N, 13.77/13.70. Step g: Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenvlamino)-1 H 5 benzoimidazole-5-carboxylate A stirring mixture comprised of methyl 7-fluoro-6-(2-methyl phenylamino)-1H-benzoimidazole-5-carboxylate (0.2492 g, 8.326 x 10 -4 mol), benzyltrimethylammonium dichloroiodinate (Aldrich, 95 %, 0.3934 g, 0.00113 mol), and zinc chloride (0.1899 g, 0.00139 mol) in glacial acetic acid (20 ml) 10 was brought to reflux for 15 minutes. The hot suspension was filtered to isolate the precipitate which was dried in the vacuum oven (90 C, ca. 10 mm Hg) overnight to afford 0.2392 g of a green powder; 68 % yield; m.p. 219-220 0C DEC; 1 H-NMR (400 MHz; DMSO) 5 8.71 (s, 1H), 8.02 (s, 1H), 7.85 (broad s, 1H), 7.43 (d, 1H, J=1.7 Hz), 7.24 (dd, 1H, J=8.5, 2.2 Hz), 6.24 (dd, 1H, 15 J=8.5, 5.4 Hz), 3.76 (s, 3H), 2.22 (s, 3H); 1 9 F-NMR (376 MHz; DMSO) 5 132.86 (s); MS (APCI+) 426 (M+1, 48), 169 (100); (APCI-) 424 (M-1, 100); IR (KBr) 1704,1508, 1227 cm- 1 . Step h: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1

H

20 benzoimidazole-5-carboxylic acid To a stirring solution comprised of methyl 7-fluoro-6-(4-iodo-2-methyl phenylamino)-1H-benzoimidazole-5-carboxylate (0.2035 g, 4.786 x 1 0 ~4 mol) in tetrahydrofuran (20 ml) was added solid potassium trimethylsilanolate (0.315 g, 0.00246 mol). The reaction mixture was stirred at ambient 25 temperature under argon for 16 hours. An additional 0.082 g (6.39 x 10 -4 mol) of potassium trimethylsilanolate was added and the mixture stirred 30 minutes. The reaction mixture was concentrated in vacuo to one-third volume and was treated with diethyl ether (50 ml). The off-white precipitate formed was collected by vacuum filtration, giving a hygroscopic solid. The wet solid 30 was dissolved in a 4:1 (v/v) ethyl acetate-methanol solution (500 ml). The solution was washed with 0.84 M aqueous citric acid (50 ml), dried (MgSO 4 ), and concentrated in vacuo to a yellow liquid. The liquid was redissolved in 52 WO 01/05390 PCT/USOO/18345 fresh ethyl acetate-methanol. The solution was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was redissolved in chloroform and reconcentrated to afford 1.55 g of a viscous yellow residue which was comprised mainly of citric acid; MS (APCI-) 191 (M-1, 100). The 5 residue was dissolved in water (50 ml). Insoluble material was extracted into 1:1 (v/v) ethyl acetate-diethyl ether (250 ml). Upon separation, the aqueous phase remained strongly acidic (pH 0). The organic phase was washed with a fresh portion of water (150 ml). Upon separation, this wash was only slightly acidic (pH 4.5). The organic phase was dried (MgSO4), concentrated in 10 vacuo, and chased with chloroform to give a tan semisolid. The product was triturated with hexanes. Vacuum filtration and suction-drying afforded 0.0839 g of a tan powder. A portion of the product (0.050 g) was recrystallized from boiling ethanol (1 ml). While cooling and moderate scratching, an off-white solid formed. This product was isolated by vacuum filtration and dried under 15 high vacuum (23 0C) to afford 0.018 g of an off-white powder; 9 % yield; m.p. 247-248 *C DEC; 1 9 F-NMR (376 MHz; DMSO) 8 -132.87 (s); MS (APCI+) 412 (M+1, 100); (APCI-) 410 (M-1, 100); IR (KBr) 3322, 1689, 1437, 1326, 1218 cm 1 ; Anal. calcd/found for: C 1 5

H

1 1

FIN

3 0 2 -0.61 C 2

H

6 0 -0.59 H 2 0 (91.4 % parent) C, 43.30/43.30; H, 3.55/3.34; N, 9.34/9.15. 20 EXAMPLE 2 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenvlamino)-1H-benzoimidazole 5-carboxylic acid cyclopropylmethoxy-amide (PD 254552) (APK IC50 < 10 nM 25 (n = 2); colon 26 cells, 1 hour pretreatment, IC5o = 20 nM) Step a: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenvlamino)-1

H

benzoimidazole-5-carboxylic acid pentafluorophenyl ester (PD 254551) (APK ICo = 120 nM (n=2)) 30 To a stirring suspension comprised of 7-fluoro-6-(4-iodo-2-methyl phenylamino)-1H-benzoimidazole-5-carboxylic acid (0.844 g, 2.05x10 3 mol) in ethyl acetate (4 ml) was added a solution comprised of pentafluorophenol (0.375 g, 2.04x10 3 mol) in N,N-dimethylformamide (10 ml). Solid 53 WO 01/05390 PCT/USOO/18345 dicyclohexylcarbo-diimide (0.415 g, 1.99x1 0-3 mol) was then added and the reaction mixture was stirred for 22 hours. The reaction mixture was vacuum filtered to remove the precipitate that had formed. The filtrate was diluted with ethyl acetate (400 ml), and that solution was washed with water (3x400 ml), 5 was dried (MgSO 4 ), and was concentrated in vacuo to afford 1.7 g of a yellow foam. The crude product was purified by flash silica column chromatography. Elution with a gradient (CHCl 3 to 0.5 % methanol in CHC 3 ) afforded 0.69 g of the yellow amorphous product; 60 % yield; 'H-NMR (400 MHz; CDCl 3 ) 8 8.54 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H), 7.49 (d, 1H, J=1.7 Hz), 7.36 (dd, 1H, J=8.2, 10 1.7 Hz), 6.57 (dd, 1H, J=8.4, 6.5 Hz), 2.31 (s, 3H); 1 9 F-NMR (376 MHz; CDCl 3 ) 8 -132.02 (s), -152.35 (d, J=18.3 Hz), -157.26 (t, J=21.4 Hz), -161.96 (dd, J=21.3, 18.3 Hz); MS (APCI+) 578 (M+1, 57), 394 (100); (APCI-) 576 (M 1, 44), 409 (100), 393 (95), 392 (82), 378 (55), 183 (97), 165 (68), 127 (53); IR (KBr) 1731 cm 1 (C=O stretch). 15 Step b: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1

H

benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide To a stirring solution comprised of 7-fluoro-6-(4-iodo-2-methyl phenylamino)-1 H-benzoimidazole-5-carboxylic acid pentafluorophenyl ester 20 (0.63 g, 1.09x10 3 mol) in anhydrous tetrahydrofuran (5 ml) was added solid cyclopropylmethoxylamine hydrochloride (0.14 g, 1.13x10 3 mol) and diisopropylethylamine (0.6 ml, 3.4x10 3 mol). The reaction mixture was stirred for one week. The solvent was removed and the evaporate was treated with 10 % aqueous hydrochloric acid (200 ml) and was extracted with diethyl ether 25 (200 ml). A biphasic suspension resulted, and the precipitate was isolated by vacuum filtration. The crude product was recrystallized from absolute ethanol to afford 0.18 g of a green-yellow powder; 35 % yield; mp 168-172 *C; 1

H

NMR (400 MHz; DMSO) 8 11.48 (s, 1H), 8.37 (s, 1H), 7.50 (broad s, 1H), 7.45 (s, 1H), 7.24 (s, 1H), 7.07 (d, 1H, J=8.4 Hz), 6.03-5.97 (m, 1H), 3.38 (d, 2H, 30 J=6.5 Hz), 2.04 (s, 3H), 0.85-0.75 (m, 1H), 0.30-0.22 (m, 2H), 0.00 (s, 2H); 1 9 F-NMR (376 MHz; DMSO) 8 -133.23 (s); MS (APCI+) 481 (M+1, 77), 409 (100); (APC1-) 480 (M, 22), 407 (100); IR (KBr) 1659, 1632, 1493 cm 1 ; Anal. 54 WO 01/05390 PCT/USOO/18345 calcd/found for: C 19

H

1 8

FIN

4 0 2 0.50 HCI (96.3 % parent) C, 45.78/45.74; H, 3.74/3.84; N, 11.24/10.88. EXAMPLE 3 5 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H-benzoimidazole 5-carboxylic acid hydroxyamide Step a: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H 10 benzoimidazole-5-carboxylic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide A solution comprised of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H benzoimidazole-5-carboxylic acid, 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (1.25 equiv.), benzotriazole-1-yl-oxy-tris-pyrrolidino phosphonium hexafluorophosphate (1.25 equiv.), and diisopropylethylamine 15 (3 equiv.) in 1:1 v/v tetrahydrofuran-dichloromethane is stirred for 30 minutes. The reaction mixture is concentrated in vacuo and the residue is purified by flash chromatography; elution with dichloromethane affords the desired product. The product may be recrystallized with an appropriate solvent like methanol if further purification is necessary. 20 Step b: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1

H

benzoimidazole-5-carboxylic acid hydroxyamide The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1

H

benzoimidazole-5-carboxylic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide is 25 dissolved in an appropriate hydrogen chloride-saturated solvent like methanol or ethanol. Once homogeneous, the solution is concentrated in vacuo to give the desired product. The product may be triturated with an appropriate solvent like chloroform or dichloromethane if further purification is necessary. 30 55 WO 01/05390 PCT/USOO/18345 EXAMPLE 4 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole 5-carboxylic acid cyclopropylmethoxy-amide 5 Step a: Preparation of 0-cyclopropylmethylhydroxylamine hydrochloride Step i: Preparation of 2-cylcopropylmethoxy-isoindole-1,3-dione 10 To a stirring solution/suspension comprised of N-hydroxyphthalimide (Aldrich, 57.15 g, 339.8 mmol), cyclopropanemethanol (Aldrich, 25.10 g, 341.1 mmol), and triphenylphosphine ("DEAD," Aldrich, 91.0 g, 344 mmol) in 1.00 L of tetrahydrofuran under a nitrogen atmosphere and cooled to 6 *C (internal mixture temperature) with an ice-water bath was added diethyl 15 azodicarboxylate (Aldrich, 56 ml, 356 mmol) dropwise over 20 minutes via addition funnel. The reaction mixture temperature was kept below 20 *C during the addition. Following addition of the DEAD, the cold bath was removed and the reaction mixture was stirred for 15 hours. The mixture was concentrated to a paste under reduced pressure. Chloroform (ca. 300 ml) 20 was added and the mixture swirled to loosen all solids. Vacuum filtration removed the insolubles. The filtrate was likewise filtered to remove white precipitate that formed and to give a clear filtrate. Concentration under reduced pressure afforded a clear oil. Flash filtration through silica gel (100 % chloroform) gave filtrates containing unseparated product. These filtrates 25 were combined and concentrated under reduced pressure to afford 127.4 g of a clear oil. The oil was dissolved in absolute ethanol (400 ml) and the solution was refrigerated for two hours. A white crystalline solid had precipitated and was subsequently collected by vacuum filtration. The product was dried in the vacuum oven (60 0C) to afford 42.66 g (58 %) of the desired material; m.p. 71 30 77 0C; 1 H-NMR (400 MHz; CDC1 3 signal offset to 6 6.96) 8 7.54-7.43 (m, 4H), 3.74 (d, 2H, J=7.6 Hz), 1.02-0.95 (m, 1H), 0.34-0.30 (m, 1H), 0.04-0.00 (m, 1H). 56 WO 01/05390 PCT/USOO/18345 Step ii: Preparation of 0-cyclopropylmethylhydroxylamine hydrochloride To a stirring solution comprised of 2-cyclopropylmethoxy-isoindole-1,3-dione (42.64 g, 196.3 mmol) in 150 ml of dichloromethane under ambient conditions 5 was carefully added methyihydrazine (Aldrich, 10.7 ml, 197 mmol). A white precipitate began to form almost instantly. After 15 minutes of vigorous stirring, the suspension was vacuum filtered. The filtrate was likewise filtered to remove additional precipitate. The resulting clear filtrate was concentrated carefully (volatile product) under reduced pressure to afford a clear liquid/solid 10 mixture. The white solids were removed when an ether (200 ml) solution of the product was made and vacuum filtered. The filtrate was acidified with gaseous hydrogen chloride, affording instantly a white precipitate. Collection of the solid by vacuum filtration and vacuum-oven drying (55 0C) afforded 18.7 g (77 %) of the white powder product; m.p. 165-168 OC; 'H-NMR (400 MHz; 15 DMSO) 8 10.77 (broad s, 2H), 3.57 (d, 2H, J=7.3 Hz), 0.84-0.74 (m, 1H), 0.31 0.25 (m, 2H), 0.04-0.00 (m, 1H); 13 C-NMR (100 MHz; DMSO) 6 75.39, 5.52, 0.00. Step b: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H 20 benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide A solution comprised of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H benzoimidazole-5-carboxylic acid, 0-cyclopropylmethylhydroxylamine hydrochloride (1.25 equiv.), benzotriazole-1-yl-oxy-tris-pyrrolidino phosphonium hexafluorophosphate (1.25 equiv.), and diisopropylethylamine 25 (3 equiv.) in 1:1 v/v tetrahydrofuran-dichloromethane is stirred for 30 minutes. The reaction mixture is concentrated in vacuo and the residue is taken up into diethyl ether. The ether phase is washed with dilute aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, is dried (MgSO 4 ), and is concentrated in vacuo to afford the desired product. The product may be 30 recrystallized with an appropriate solvent like methanol or chloroform if further purification is necessary. 57 WO 01/05390 PCT/USOO/18345 EXAMPLE 5 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H-benzooxazole-5 carboxylic acid 5 Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid Same as for Example 1, Step a. Step b: Preparation of 2,3-difluoro-4-hydroxy-5-nitrobenzoic acid 10 The solid 5-nitro-2,3,4-trifluorobenzoic acid (1.00 g, 0.00452 mol) was dissolved in 10 wt. % aqueous sodium hydroxide solution. The mixture was clear deep orange. After standing under ambient conditions for several minutes, the mixture was quenched with concentrated aqueous hydrochloric acid until strongly acidic (pH 0). A white solid precipitated which was isolated 15 by vacuum filtration and dried with suction to afford 0.40 g of an off-white solid. This solid was recrystallized from chloroform (20 ml) to afford 0.22 g of an off-white crystalline powder; 22 % yield; MS (APCI-) 218 (M-1, 100). Step c: Preparation of methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate 20 Anhydrous hydrogen chloride gas was dissolved in anhydrous methanol (50 ml) until the solution was warm. The microcrystalline solid 2,3 difluoro-4-hydroxy-5-nitrobenzoic acid 0.22 g, 0.00100 mol) was dissolved in the methanolic hydrogen chloride solution. The stirring reaction mixture was brought to reflux under nitrogen for 16 hours. The mixture was concentrated 25 in vacuo to give a white solid. The product was dried under high vacuum to afford 0.213 g of a white powder; 91 % yield; m.p. 108-109.5 *C; 1 H-NMR (400 MHz; DMSO) 6 8.25 (dd, 1H, J=7.7, 2.2 Hz), 3.83 (s, 3H); (CDCl 3 ) 6 10.83 (s, 1H), 8.66 (dd, 1H, J=7.0, 2.2 Hz), 3.98 (s, 3H); 1 9 F-NMR (376 MHz; DMSO) 8-127.85 (s), -154.32 (d, J=19.8 Hz); (CDCl 3 ) 6 -118.31 to -118.37 30 (m), -152.38 (d, J=18.3 Hz); MS (APCI-) 232 (M-1, 100); IR (KBr) 3264, 1731, 1640, 1546, 1307, 1286, 1160 cm 1 . 58 WO 01/05390 PCTIUSOO/18345 Step d: Preparation of 1-adamantyl 4-carboxymethyl-2,3-difluoro-6-nitrophenyl carbonate To a solution comprised of 1-adamantyl fluoroformate (2.0 M) and pyridine (2.0 M) in tetrahydrofuran is added a stirred solution comprised of 5 methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate (0.96 equiv., 0.384 M) in anhydrous tetrahydrofuran at ambient temperature. The reaction mixture is stirred for 6 hours and the solvent is removed in vacuo. The residue is dissolved in dichloromethane. The organic solution is washed with dilute aqueous hydrochloric acid, dilute aqueous sodium carbonate, and water, is 10 dried (MgSO 4 ), and is concentrated in vacuo to give the desired product. Step e: Preparation of 1-adamantyl 4-carboxymethyl-2-fluoro-3-(2-methyl phenylamino)-6-nitrophenyl carbonate The compound 1-adamantyl 4-carboxymethyl-2,3-difluoro-6-nitrophenyl 15 carbonate is dissolved in excess ortho-toluidine. The reaction mixture is stirred at 200 0C for 6 hours. The mixture is allowed to cool and is dissolved in diethyl ether. The organic phase is washed with dilute aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, is dried (MgSO4), and is concentrated in vacuo to afford the desired product. The 20 product is purified by flash chromatography as necessary. Step f: Preparation of methyl 3-fluoro-4-hydroxy-2-(2-methyl-phenylamino)-5 nitrobenzoate The compound 1-adamantyl 4-carboxymethyl-2-fluoro-3-(2-methyl 25 phenylamino)-6-nitrophenyl carbonate is dissolved in excess trifluoroacetic acid at ambient temperature. The mixture is stirred for 20 minutes. The TFA is removed under reduced pressure. The residue is subjected to vacuum pump to remove adamantan-1-ol to give the desired product. 59 WO 01/05390 PCTIUSOO/18345 Step g: Preparation of methyl 5-amino-3-fluoro-4-hydroxy-2-(2-methyl phenylamino)-benzoate The compound methyl 3-fluoro-4-hydroxy-2-(2-methyl-phenylamino)-5 nitrobenzoate is treated as in Step e, Example 1. 5 Step h: Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-1 H benzooxazole-5-carboxylate The compound 5-amino-3-fluoro-4-hydroxy-2-(2-methyl-phenylamino) benzoate is treated as in Step f, Example 1. The product may be 10 recrystallized with an appropriate solvent like chloroform or ethanol if further purification is necessary. Step i: Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H benzooxazole-5-carboxylate 15 A stirring mixture comprised of methyl 7-fluoro-6-(2-methyl phenylamino)-1 H-benzooxazole-5-carboxylate (0.042 M), benzyltrimethylammonium dichloroiodinate (Aldrich, 95 %, 0.057 M, 1.36 equiv.), and zinc chloride (0.070 M, 1.67 equiv.) in glacial acetic acid is brought to reflux for 15 minutes. The mixture is concentrated in vacuo and the 20 residue taken up into diethyl ether. The ether solution is washed with dilute aqueous hydrochloric acid, water, and brine, is dried (MgSO 4 ), and is concentrated in vacuo to obtain the desired product. The product may be purified by recrystallization with an appropriate solvent like ethanol. 25 Step j: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H benzooxazole-5-carboxylic acid To a stirring solution comprised of methyl 7-fluoro-6-(4-iodo-2-methyl phenylamino)-1H-benzooxazole-5-carboxylate (0.024 M) in tetrahydrofuran is added solid potassium trimethylsilanolate (5.14 equiv.). The reaction mixture 30 is stirred at ambient temperature under argon for 16 hours. An additional equivalent of potassium trimethylsilanolate is added and the mixture stirred 30 minutes. The reaction mixture is concentrated in vacuo to give a residue that 60 WO 01/05390 PCTIUSOO/18345 is then taken up into 1:1 (v/v) ethyl acetate-diethyl ether. The organic phase is washed with dilute aqueous hydrochloric acid, water, and brine, is dried (MgSO4), is concentrated in vacuo, and chased with chloroform to give a crude product. Recrystallization from an appropriate solvent like ethanol gives 5 the purified desired product. EXAMPLE 6 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H-benzooxazole-5 10 carboxylic acid hydroxyamide Step a: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenvlamino)-1 H benzooxazole-5-carboxylic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H 15 benzooxazole-5-carboxylic acid is treated as in Step a, Example 2. Step b: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H benzooxazole-5-carboxylic acid hydroxyamide The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H 20 benzooxazole-5-carboxylic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide is treated as in Step b, Example 2. EXAMPLE 7 25 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzooxazole-5 carboxylic acid cyclopropylmethoxy-amide The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1

H

benzooxazole-5-carboxylic acid is treated as in Step b, Example 3. 61 WO 01/05390 PCT/US0O/18345 EXAMPLE 8 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenlamino)-1 H-benzothiazole-5 carboxylic acid 5 Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid Same as for Example 1, Step a. Step b: Preparation of 2,3-difluoro-4-hydroxy-5-nitrobenzoic acid 10 Same as for Example 4, Step b. Step c: Preparation of methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate Same as for Example 4, Step c. 15 Step d: Preparation of 4-dimethylthiocarbamoyloxy-2,3-difluoro-5-nitro benzoic acid methyl ester A solution of methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate in N,N 20 dimethylformamide is treated with one molar equivalent of cesium carbonate and warmed to 85 *C for 30 minutes. The stirring mixture is then treated dropwise rapidly with a solution comprised of a slight excess of N,N dimethylthiocarbamoyl chloride in N,N-dimethylformamide. The reaction mixture is stirred at room temperature for one hour, or may be warmed over a 25 steam bath for one hour. The mixture is then poured into water and extracted with ethyl acetate. The organic phase is washed with 5 % aqueous sodium hydroxide, water, and brine, and is then dried with a drying agent like magnesium sulfate of sodium sulfate. The solvent is then removed in vacuo to give a crude product. The compound is purified by ordinary methods such 30 as chromatography or crystallization from an appropriate solvent. 62 WO 01/05390 PCT/USOO/18345 Step e: Preparation of 4-Dimethylthiocarbamoyloxy-3-fluoro-5-nitro-2-o tolylamino-benzoic acid methyl ester The compound 4-dimethylthiocarbamoyloxy-2,3-difluoro-5-nitro-benzoic 5 acid methyl ester is dissolved in excess o-toluidine. The stirring mixture is brought to 200 0C for one hour. The mixture is then poured into 5 % aqueous hydrochloric acid. The aqueous mixture is extracted with diethyl ether. The organic phase is washed with water and brine, is dried over magnesium sulfate, and is concentrated in vacuo. The crude product is purified by 10 ordinary methods such as chromatography or crystallization from an appropriate solvent. Step f: Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-1 H benzothiazole-5-carboxylate 15 The compound methyl 5-amino-3-fluoro-4-mercapto-2-(2-methyl phenylamino)-benzoate is treated as in Step h, Example 4. Step g: Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H benzothiazole-5-carboxylate 20 The compound methyl 7-fluoro-6-(2-methyl-phenylamino)-1 H benzothiazole-5-carboxylate is treated as in Step i, Example 4. Step h: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H benzothiazole-5-carboxylic acid 25 The compound methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H benzothiazole-5-carboxylate is treated as in Step j, Example 4. EXAMPLE 9 30 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H-benzothiazole-5 carboxylic acid hydroxyamide 63 WO 01/05390 PCTUSOO/18345 Step a: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H benzothiazole-5-carboxylic acid O-(tetrahydro-2H-pyran-2-yl)-oxvamide The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H benzothiazole-5-carboxylic acid is treated as in Step a, Example 2. 5 Step b: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenVlamino)-1 H benzothiazole-5-carboxylic acid hydroxyamide The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H benzothiazole-5-carboxylic acid O-(tetrahyd ro-2H-pyran-2-yl)-oxyamide is 10 treated as in Step b, Example 2. EXAMPLE 10 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzothiazole-5 15 carboxylic acid cyclopropylmethoxy-amide The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H benzothiazole-5-carboxylic acid is treated as in Step b, Example 3. EXAMPLE 11 20 Preparation of 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-6 carboxylic acid Step a: Preparation of 8-fluoro-7-(2-methyl-phenylamino)-quinoxaline-6 25 carboxylic acid The compound methyl 4,5-diamino-3-fluoro-2-(2-methyl-phenylamino) benzoate (from Step e, Example 1) is dissolved in 2:1:1.2 v/v/v of 2.0 M acetic acid-4.0 M sodium acetate-methanol. The suspension is warmed to 65 *C (or until homogeneous) and the clear solution is poured into a 0.078 M aqueous 30 sodium glyoxal bisulfite (Aldrich, monohydrate, 1.05 equiv.) solution which is warmed to 70 0C. The reaction mixture is stirred gently between 55-75 0C for one hour, and is then cooled to 12 *C with an ice-water bath. Pulverized 64 WO 01/05390 PCT/USOO/18345 sodium hydroxide pellets (27 equiv.) are added to the cold solution. The mixture is gently warmed to 30 0C and stirred for 45 minutes. The temperature is raised to 70 0C for 15 minutes. The mixture is allowed to cool and is treated with ethyl acetate. The biphasic mixture is treated with 5 concentrated aqueous hydrochloric acid to achieve pH 0 in the aqueous phase. The organic phase is separated, dried (MgSO4), and concentrated in vacuo to give the desired product. The product may be triturated with an appropriate solvent like dichloromethane or recrystallized from a solvent like ethanol for further purification as necessary. 10 Step b: Preparation of 8-fluoro-7-(4-iodo-2-methyl-phenvlamino)-quinoxaline 6-carboxylic acid The compound 8-fluoro-7-(2-methyl-phenylamino)-quinoxaline-6 carboxylic acid is treated as in Step i, Example 4. 15 EXAMPLE 12 Preparation of 8-fluoro-7-(4-iodo-2-methyl-phenvlamino)-quinoxaline-6 carboxylic acid hydroxyamide 20 Step a: Preparation of 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline 6-carboxylic acid O-(tetrahydro-2H-pyran-2-yl)-oxvamide The compound 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline 6-carboxylic acid is treated as in Step a, Example 2. 25 Step b: Preparation of 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline 6-carboxylic acid hydroxyamide The compound 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline 6-carboxylic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide is treated as in Step 30 b, Example 2. 65 WO 01/05390 PCT/USOO/18345 EXAMPLE 13 Preparation of 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline-6 carboxylic acid cyclopropylmethoxy-amide 5 The compound 8-fluoro-7-(4-iodo-2-methyl-phenylamino)-quinoxaline 6-carboxylic acid is treated as in Step b, Example 3. EXAMPLE 14 10 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5lthiadiazole-5-carboxylic acid Step a: Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino) benzo[ 1,2,51thiadiazole-5-carboxylate 15 To a stirring solution comprised of methyl 4,5-diamino-3-fluoro-2-(2-methyl phenylamino)-benzoate (from Step e, Example 1) and diisopropylethylamine (2 equiv.) in an appropriate solvent like diethyl ether or toluene is added a reagent like N-thioaniline or thionyl chloride (1.35 equiv.). The reaction mixture is brought to reflux for one hour. The mixture is quenched with dilute 20 aqueous hydrochloric acid. The organic phase is washed with saturated aqueous sodium bicarbonate and brine, is dried (MgSO4), and is concentrated in vacuo to afford the desired product. The product may be recrystallized with an appropriate solvent like chloroform or ethanol, or may be chromatographed if further purification is necessary. 25 Alternative method: The compound methyl 4,5-diamino-3-fluoro-2-(2-methyl phenylamino)-benzoate is added to a stirring solution of sulfur monochloride (6 equiv.) in N,N-dimethylformamide and the mixture is gradually heated to 75-80 0 C. After 5 hours the mixture is cooled to 10 *C, water is slowly added. 30 The mixture is extracted with a solvent like diethyl ether or dichloromethane. The organic extract is dried (MgSO 4 ) and is concentrated in vacuo to afford the desired product. The product may be recrystallized with an appropriate 66 WO 01/05390 PCT/USOO/18345 solvent like chloroform or ethanol, or may be chromatographed if further purification is necessary. Step b: Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino) 5 benzo[1,2,5thiadiazole-5-carboxylate The compound methyl 7-fluoro-6-(2-methyl-phenylamino) benzo[1,2,5]thiadiazole-5-carboxylate is treated as in Step i, Example 4. Step c: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino) 10 benzo[1,2,5]thiadiazole-5-carboxylic acid The compound methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5]thiadiazole-5-carboxylate is treated as in Step j, Example 4. EXAMPLE 15 15 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5thiadiazole-5-carboxylic acid hydroxyamide Step a: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino) 20 benzo[1,2,5]thiadiazole-5-carboxylic acid O-(tetrahydro-2H-pyran-2-vl) oxyamide The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5]thiadiazole-5-carboxylic acid is treated as in Step a, Example 2. 25 Step b: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5]thiadiazole-5-carboxylic acid hydroxyamide The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5]thiadiazole-5-carboxylic acid O-(tetrahydro-2H-pyran-2-yl) oxyamide is treated as in Step b, Example 2. 30 67 WO 01/05390 PCT/USO0/18345 EXAMPLE 16 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,51thiadiazole-5-carboxylic acid cyclopropylmethoxy-amide 5 The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5]thiadiazole-5-carboxylic acid is treated as in Step b, Example 3. EXAMPLE 17 10 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5loxadiazole-5-carboxylic acid Step a: Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino) benzorl,2,51oxadiazole-5-carboxylate 2-oxide 15 See Takakis, I. M.; Hadjimihalakis, P. M., J. Heterocyclic Chem., 27, 177 (1990). A mixture comprised of methyl 4-amino-3-fluoro-2-(2-methyl phenylamino)-5-nitrobenzoate (from Step d, Example 1) and iodosobenzenediacetate (1.76 equiv.) in benzene is stirred at ambient 20 temperature for 5 hours. The mixture is concentrated in vacuo and the residue purified by column chromatography to give the desired product. Alternative method: A solution comprised of methyl 4-amino-3-fluoro-2-(2 methyl-phenylamino)-5-nitrobenzoate (0.86 M) in tetrahydrofuran is diazotized 25 and the diazonium salt is treated in situ with sodium azide as described by Smith, P. A. S.; Boyer, J. H., Org. Synth., 31, 14 (1951) and references 4 and 8 cited therein. Thermolysis of this intermediate in ethylene glycol at 110-120 'C for one hour affords the desired product. 30 Step b: Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino) benzo[1,2,5]oxadiazole-5-carboxylate 68 WO 01/05390 PCT/USOO/18345 A solution comprised of methyl 7-fluoro-6-(2-methyl-phenylamino) benzo[1,2,5]oxadiazole-5-carboxylate 2-oxide and sodium azide (1.38 equiv.) in ethylene glycol is heated to 140-150 0C for 30 minutes to obtain, after column chromatography, the desired product. 5 Step c: Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo( 1, 2,5]oxadiazole-5-carboxylate The compound methyl 7-fluoro-6-(2-methyl-phenylamino) benzo[1,2,5]oxadiazole-5-carboxylate is treated as in Step i, Example 4. 10 Step d: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenvlamino) benzo[1,2,5]oxadiazole-5-carboxylic acid The compound methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5]oxadiazole-5-carboxylate is treated as in Step j, Example 4. 15 EXAMPLE 18 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5]oxadiazole-5-carboxylic acid hydroxyamide 20 Step a: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5]oxadiazole-5-carboxylic acid O-(tetrahyd ro-2H-pyran-2-yl) oxyamide The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino) 25 benzo[1,2,5]oxadiazole-5-carboxylic acid is treated as in Step a, Example 2. Step b: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5]oxadiazole-5-carboxylic acid hydroxyamide The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino) 30 benzo[1,2,5]oxadiazole-5-carboxylic acid O-(tetrahydro-2H-pyran-2-yl) oxyamide is treated as in Step b, Example 2. 69 WO 01/05390 PCT/USOO/18345 EXAMPLE 19 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzof1,2,5loxadiazole-5-carboxylic acid cyclopropylmethoxy-amide 5 The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5]oxadiazole-5-carboxylic acid is treated as in Step b, Example 3. EXAMPLE 20 10 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H-benzotriazole-5 carboxylic acid Step a: Preparation of methyl 7-fluoro-6-(2-methyl-phenylamino)-1 H benzotriazole-5-carboxylate 15 The compound methyl 4,5-diamino-3-fluoro-2-(2-methyl-phenylamino) benzoate (from Step e, Example 1) is diazotized by ordinary methods. Workup gives the desired product. Step b: Preparation of methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H 20 benzotriazole-5-carboxylate The compound methyl 7-fluoro-6-(2-methyl-phenylamino)-1 H benzotriazole-5-carboxylate is treated as in Step i, Example 4. Step c: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H 25 benzotriazole-5-carboxylic acid The compound methyl 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H benzotriazole-5-carboxylate is treated as in Step j, Example 4. EXAMPLE 21 30 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenytamino)-1H-benzotriazole-5 carboxylic acid hydroxyamide 70 WO 01/05390 PCT/USOO/18345 Step a: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenvlamino)-1 H benzotriazole-5-carboxylic acid O-(tetrahvdro-2H-pyran-2-vl)-oxvamide The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H 5 benzotriazole-5-carboxylic acid is treated as in Step a, Example 2. Step b: Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H benzotriazole-5-carboxylic acid hydroxyamide The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H 10 benzotriazole-5-carboxylic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide is treated as in Step b, Example 2. EXAMPLE 22 15 Preparation of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H-benzotriazole-5 carboxylic acid cyclopropylmethoxy-amide The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H benzotriazole-5-carboxylic acid is treated as in Step b, Example 3. 20 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 25 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 30 entirety. What is claimed is: 71

Claims (32)

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 the following formula (1): O H RIO W Q' R, 1 I (I) wherein 10 W is OR 1 , NR 2 0R 1 , NRARB, NR 2 NRARB, O(CH 2 ) 2 -4NRARB, or NR 2 (CH 2 ) 2 -4 NRARB; R 1 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 3.8 cycloalkyl, phenyl, 15 (phenyl)-C 1-4 alkyl, (phenyl)C 3.4 alkenyl, (phenyl)C 3-4 alkynyl, (C 3-8 cycloalkyl)C 1-4 alkyl, (C 3-8 cycloalkyl)C 3.4 alkenyl, (C 3-8 cycloalkyl)C 3-4 alkynyl, C 3.8 heterocyclic radical, (C 3-8 heterocyclic radical)C 1-4 alkyl, (C 3-8 heterocyclic radical)-C 3.4 alkenyl, (C 3-8 heterocyclic radical)C 3-4 alkynyl or (CH 2 ) 2 -4 NRcRD; 20 R 2 is H, C 1-4 alkyl, phenyl, C 3-6 cycloalkyl, C 3-6 heterocyclic radical, or (C 3-6 cycloalkyl) methyl; RA is H, C 1-6 alkyl, C 3-8 alkenyl, C 3.8 alkynyl, C 3-8 cycloalkyl, phenyl, (C 3-8 25 cycloalkyl)C 1-4 alkyl, (C 3-8 cycloalkyl)C 34 alkenyl, (C 3-8 cycloalkyl)C 3-4 alkynyl, C 3-8 heterocyclic radical, (C 3-8 heterocyclic radical)C 1.4 alkyl, (aminosulfonyl)phenyl, [(aminosulfonyl)phenyl]C 1-4 alkyl, (aminosulfonyl)C 1-6 72 WO 01/05390 PCT/USOO/18345 alkyl, (aminosulfonyl)C 3-6 cycloalkyl, [(aminosulfonyl)C 3.6 cycloalkyl]C 1-4 alkyl, or (CH 2 ) 2 -4 NRcRD; RB is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 3-8 cycloalkyl, or phenyl; 5 Q is one of the following formulae (i) - (iii): R3 R3 ~z Z R4 R4 10 R 3 is H or F; R 4 is halo, NO 2 , SO 2 NRO(CH 2 ) 2 -4NRERF, SO2NRERF, or (CO)T; T is C 1-8 alkyl, C 3-8 cycloalkyl, (NRERF)C 1-4 alkyl, ORF, -NRo(CH 2 ) 2 -4 NRERF, 15 or NRERF; Z is one of the following formulae (iv) - (viii): N N N- X X 2 N R5 gR7 R7 R 5 R 6 (iv) (v) (vi) 20 73 WO 01/05390 PCT/USOO/18345 N, -N N, -N (vii) (viii) 5 one of R 5 and R 6 is H or methyl and the other of R 5 and R 6 is H, C1.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, benzyl, or -M-E-G; 10 M is 0, CO, SO 2 , NRA, (CO)NRH, NRH (CO), NRH (SO 2 ), (S02)NRH, or CH 2 ; E is (CH 2 ) 1 - 4 or (CH 2 )m O(CH 2 )p where 1 (each of m and p) s 3 and 2 s (m + p) s 4; or E is absent; G is RK, OR, or NRjRK, provided that if p = 1, then G is H; 15 R 7 is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3.6 cycloalkyl, phenyl, 2 pyridyl, 3-pyridyl, 4-pyridyl, (CH 2 )1- 2 Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, SO 2 NRH(CH 2 ) 2 -4 NRjRK, (CO)(CH 2 ) 2 4NRjRK or (CO)NRH(CH 2 ) 2 -4NRRK; 20 X 1 is 0, S, NR 8 , or CHR 9 ; X 2 is 0, S, or CHR9; and X 3 is 0 or S; where if X 1 or X 2 is CHR 9 , said compound may also be a tautomerized indole; R 8 is H, C 1-4 alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, (CH 2 )1- 2 Ar, where Ar 25 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or (C 2-4 alkyl)NRLRM; provided R 7 and R 8 together have no more than 14 carbon atoms, exclusive of RL, RM, RJ and RK; 74 WO 01/05390 PCT/USOO/18345 RG is C 1-4 alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C 34 alkenyl, C 34 alkynyl, C 3-6 cycloalkyl, (CO)ORp, (C 2-4 alkyl)NRLRM, (CO)NRN(CH 2 ) 2 4NRLRM, (CO)NRLRM, (CO)(CH 2 ) 2 -4 -NRLRM, or (CH 2 ) 1 - 2 Ar, where Ar is phenyl,

2-pyridyl, 3-pyridyl, or 4-pyridyl; 5 R 9 is C 1-4 alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, (CO)ORp, (C 2-4 alkyl)NRLRM, (CO)NRN(CH2)2-4NRLRM, (CO)NRLRM, (CO)(CH 2 ) 2 -4 -NRLRM, or (CH 2 ) 1 - 2 Ar', where Ar' is phenyl, 2 10 pyridyl, 3-pyridyl, or 4-pyridyl; Rp is H, C 1-6 alkyl, phenyl, C 34 alkenyl, C 34 alkynyl, C 3-6 cycloalkyl, or (CH 2 ) 2 - 4 NRLRM; 15 R 1 0 is H, methyl, halo, or NO 2 ; R 11 is H, methyl, halo, or NO 2 ; each of Rc, RD, RE, RF, RI, Rj, RK, RL and RM is independently selected from 20 H, C 1.4 alkyl, C 3-4 alkenyl, C 3-4 alkynyl, C 3-6 cycloalkyl, and phenyl; each of NRcRD,NRERF, NRJRK, and NRLRM can also independently be morpholinyl, piperazinyl, pyrrolidinyl, or piperadinyl; and 25 each of RH, RN, and Ro is independently H, methyl, or ethyl; wherein each hydrocarbon radical or heterocyclic radical 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, 30 amino, (amino)sulfonyl, and NO 2 , wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 3 75 WO 01/05390 PCT/USOO/18345 substituents independently selected from halo, C 1-2 alkyl, hydroxyl, amino, and NO 2 ; or a pharmaceutically acceptable salt or C 1-7 ester thereof. 5 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 10 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, 15 vasculitis, 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. 20

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

6. The method of claim 2, wherein said chronic pain is associated with idiopathic pain. 25

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 30 with arthritis. 76 WO 01/05390 PCT/USOO/18345

9. The method of claim 1, wherein said chronic pain is associated with post-operative pain. 5

10. A method of claim 1, wherein Q is formula (i).

11. A method of claim 10, wherein R 3 is H or fluoro.

12. A method of claim 11, wherein R 4 is fluoro, chloro, or bromo. 10

13. A method of claim 1, wherein R 10 is hydrogen, methyl, fluoro, or chloro.

14. A method of claim 1, wherein R 1 1 is methyl, chloro, fluoro, nitro, 15 or hydrogen.

15. A method of claim 14, wherein R 11 is H.

16. A method of claim 14, wherein R 1 1 is fluoro. 20

17. A method of claim 13, wherein each of R 1 0 and R 11 is fluoro.

18. A method of claim 1, wherein R 1 is H, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, phenethyl, allyl, C 3-5 alkenyl, C 3-6 cycloalkyl, (C 3-s 25 cycloalkyl)C 1-2 alkyl, (C 3-S heterocyclic radical)C 1-2 alkyl, or (CH 2 ) 2 - 4 NRcRD.

19. A method of claim 18, wherein R 1 is H or (C 3-4 cycloalkyl)C 1-2 alkyl. 30

20. A method of claim 1, wherein R 2 is H or methyl. 77 WO 01/05390 PCT/USOO/18345

21. A method of claim 1, wherein RA has at least one hydroxyl substituent.

22. A compound of claim 1, wherein RA is H, methyl, ethyl, isobutyl, 5 hydroxyethyl, phenyl, 2-piperidin-1-yl-ethyl, 2,3-dihydroxy-propyl, 3-[4-(2 hydroxyethyl)-piperazin-1 -yl]-propyl, 2-pyrrolidin-1 -yl-ethyl, or 2-diethylamino ethyl; and RB is H; or where RB is methyl and RA is phenyl.

23. A method of claim 1, wherein W is NRARB or NR 2 NRARB. 10

24. A method of claim 1, wherein W is NR 2 (CH 2 ) 2 -4 NRARB or O(CH 2 ) 2 - 3 NRARB.

25. A method of claim 1, wherein W is NR 2 OR 1 . 15

26. A method of claim 1, wherein W is OR 1 .

27. A method of claim 1, wherein Z is formula (v). 20

28. A method of claim 27, wherein X 1 is NR 8 , and R 7 is H.

29. A method of claim 1, wherein said MEK inhibitor has a structure selected from: 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H-benzoimidazole 5-carboxylic acid. 25

30. A method of claim 1, wherein said MEK inhibitor has a structure selected from: 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1 H-benzoimidazole 5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzooxazole-5 carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-benzothiazole-5 30 carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino) benzo[1,2,5]thiadiazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl phenylamino)-benzo[1,2,5]oxadiazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2 78 WO 01/05390 PCTIUSO0/18345 methyl-phenylamino)-2-(2-hydroxyethyl)-1 H-benzoimidazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-2-(2-dimethylamino-ethyl)-1 H benzoimidazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino) 1-acetyl-benzoimidazole-5-carboxylic acid; 8-fluoro-7-(4-iodo-2-methyl 5 phenylamino)-quinoxaline-6-carboxylic acid; and 7-fluoro-6-(4-iodo-2-methyl phenylamino)-1 H-benzotriazole-5-carboxylic acid; and the corresponding hydroxamic acids and cyclopropylmethyl hydroxamates.

31. The method of claim 1 wherein said MEK inhibitor has a structure 10 selected from: 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole 5-carboxylic acid cyclopropylmethoxy-amide; 7-fluoro-6-(4-iodo-2-methyl phenylamino)-6,7-dihydro-1 H-benzoimidazole-5-carboxylic acid (hydrochloride); 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H benzoimidazole-5-carboxylic acid; 7-fluoro-6-(4-iodo-2-methyl-phenylamino) 15 3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide; 6-(2-chloro-4 iodo-phenylamino)-7-fluoro-1H-benzoimidazole-5-carboxylic acid; and 7 fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid pentafluorophenyl ester. 20

32. The method of claim 1 wherein said MEK inhibitor has a structure selected from: 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole 5-carboxylic acid cyclopropylmethoxy-amide; and 7-fluoro-6-(4-iodo-2-methyl phenylamino)-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide. 25 79