ZA200105219B

ZA200105219B - 1-Heterocycle substituted diarylamines.

Info

Publication number: ZA200105219B
Application number: ZA200105219A
Authority: ZA
Inventors: Haile Tecle; Alexander James Bridges; Stephen Douglas Barrett; Lu-Yan Zhang
Original assignee: Warner Lambert Co
Priority date: 1999-01-13
Filing date: 2001-06-25
Publication date: 2002-09-25
Also published as: UA72239C2; JP2000204077A

Description

’ i 1-HETEROCYCLE SUBSTITUTED DIARYLAMINES

This invention relates to diaryl amines such as 1-heterocycle substituted diarylamines.

BACKGROUND

MEK enzymes are dual specificity kinases involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis.

Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins. Defects include a change either in the intrinsic activity or in the cellular 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 in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to

GDP. The above-mentioned growth factor receptors, and many other mitogenic receptors, when activated, lead to Ras being converted from the GDP-bound state to the GTP-bound state. This signal is an absolute prerequisite for proliferation in most cell types. Defects in this signaling system, especially in the deactivation of the Ras-GTP complex, are common in cancers, and lead to the signaling cascade below Ras being chronically activated.

Activated Ras leads in turn to the activation of a cascade of serine/threonine kinases. One of the groups of kinases known to require an active Ras-GTP for its own activation is the Raf family. These in turn activate

MEK (e.g., MEK4 and MEKj) which then activates MAP kinase, ERK (ERK; and

ERK). 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. 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, $218 and 8222 in the case of MEK-1, which are the prerequisite for activation of

MEK as a kinase. MEK in turn phosphorylates MAP kinase on both a tyrosine,

Y185, and a threonine residue, T183, 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. 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, no substrate for MEK other than the

MAP kinase , ERK, has been demonstrated to date and MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase. MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins. Both this requirement and the unusual specificity of

MEK are suggestive that it may have enough difference in its mechanism of action to other protein kinases that selective inhibitors of MEK, possibly operating through allosteric mechanisms rather than through the usual blockade of the ATP binding site, may be found.

to SUMMARY

The invention features a compound having the formula (1) below: w Rs

R, R; I

R2

W is one of the following formulae (i) — (xiii):

X NR + on Neg rd

N=“*2 RsN NNR; \ O- \ et oe No hE oy Lhe Ny 0) (i) (ii) vw (vi) (vii

N- NF Ney N-NR Su. ) NR, [ By AN pn Rs Xi—N - ) { \

Myo My Rx, “x, Yh Gx (viii) (ix) (x) (xi) (xii) (xiii)

HO 0) 0 — 0) 0 N—N

N ) \ > \ I \

X; NPS Xi oN Xi Non

TY

(xiv) (xv) (xvi) (xvii)

X1is O, S, or NRg. X,is OH, SH, or NHR:. Eachof Re and Reis Hor

C 14 alkyl; each of Ry and R; is independently selected from H, F, NO,, Br and

Cl; Ry can also be SO;NRgRy, or R; and R; together with the benzene ring to which they are attached constitute an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzthioazole. Rj is selected from

Hand F; each of Rg, Ru, and Ry is independently selected from H, Cl and CHs.

Rsis Hor C 14 alkyl. Each hydrocarbon radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, hydroxyl, amino, (amino)sulfonyl, and NO,. Each heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo,

C 14 alkyl, C 3.6 cycloalkyl, C 34 alkenyl, C 3.4 alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO, wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 2 substituents independently selected from halo, C 1.; alkyl, hydroxyl, amino, and — NOz. The invention also features a pharmaceutically acceptable sattor € 15 ester of a disclosed compound. For example, the disclosed alcohol compounds may form esters having the structure obtained by replacing the H of a hydroxy! group with a —C(=0)C 1.7 acyl group.

The invention also relates to a pharmaceutical composition including (a) a compound of formula (I) and (b) a pharmaceutically-acceptable carrier.

The invention further relates to a method for treating proliferative diseases, such as cancer, restenosis, psoriasis, autoimmune disease, and atherosclerosis.

Other aspects of the invention include methods for treating MEK-related (including ras-related) cancers, whether solid or hematopoietic. Examples of cancers include colorectal, cervical, breast, ovarian, brain, acute leukemia, gastric, non-small cell lung, pancreatic, and renal cancer. Further aspects of the invention include methods for treating or reducing the symptoms of xenograft _ (cell(s), skin, limb, organ or bone marrow transplant) rejection, osteoarthritis, rheumatoid arthritis, cystic fibrosis, complications of diabetes (including diabetic retinopathy and diabetic nephropathy), hepatomegaly, cardiomegaly, stroke (such as acute focal ischemic stroke and global cerebral ischemia), heart failure, septic shock, asthma, and Alzheimer's disease. Compounds of the invention are also “useful as antiviral agents for treating viral infections such as HIV, hepatitis (B) virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV), and Epstein-

Barr virus (EBV). These methods include the step of administering to a patient in need of such treatment, or suffering from such a disease or condition, a pharmaceutically-effective amount of a disclosed compound or pharmaceutical composition thereof.

The invention also features methods of combination therapy, such as a method for treating cancer, wherein the method further includes providing radiation therapy or chemotherapy, for example, with mitotic inhibitors such as a taxane or a vinca alkaloid. Examples of mitotic inhibitors include paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinflunine. Other therapeutic combinations include a MEK inhibitor of the invention and an anticancer agent such as cisplatin, 5-fluorouracil or 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide, and gemcitabine.

The chemotherapy or radiation therapy may be administered before, concurrently, or after the administration of a disclosed compound according to the needs of the patient.

The invention also features synthetic intermediates and methods disclosed herein.

Other aspects of the invention are provided in the description, examples, and claims below.

DETAILED DESCRIPTION

The invention features diaryl amine compounds, pharmaceutical compositions thereof, and methods of using such compounds and compositions.

According to one aspect of the invention, the compounds are MEK inhibitors. MEK inhibition assays include the in vitro cascade assay for inhibitors of MAP kinase pathway described at column 6, line 36 to column 7, line 4 of U.S.

Patent Number 5,525,625 and the in vitro MEK assay at column 7, lines 4-27 of the same patent, the entire disclosure of which is incorporated by reference (see also Examples 9-12 below).

A. Terms

Certain terms are defined below and by their usage throughout this disclosure.

Alkyl groups include aliphatic (i.e., hydrocarbyl or hydrocarbon radical 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-dimethylhexy!, 1,1-dimethylpentyi, heptyl, and octyl. Cycloalky! groups include cyclopropyl, 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 — finoromethyt, hydroxyethyl, 2,3-dihydroxyethyt, (2- or 3-furanyl)methyl, N ) cyclopropylmethyl, benzyloxyethyl, (3-pyridinyl)methyl, (2- or 3-furanyl)methyl, (2-thienyl)ethyl, hydroxypropy!, aminocyclohexyl, 2-dimethylaminobutyl, methoxymethyl, N-pyridinylethyl, diethylaminoethyl, and cyclobutylmethyl.

Alkeny! groups are analogous to alkyl groups, but have at least one double bond (two adjacent sp 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 (2), cis, or trans. Similarly, alkynyl groups have at least one triple bond (two adjacent sp carbon atoms). Unsaturated alkenyl! or alkyny! : groups may have one or more double or triple 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 forras include cis-2-butenyl, trans-2-butenyl, 3-butynyl, 3-phenyl-2- propynyl, 3-(2-7luorophenyl)-2-propynyl, 3-methyl(5-phenyl)-4-pentynyl, 2- hydroxy-2-propynyl, 2-methy!-2-propynyl, 2-propenyl, 4-hydroxy-3-butynyl, 3-(3- 6 fluorophenyl)-2-propynyl, and 2-methyl-2-propeny!. In formula (1), alkenyls and alkynyls can be C ,4 or C 2.5, for example, and are preferably C 34 or C as.

More general forms of substituted hydrocarbon radicals include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, 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, alkylaminoalky!, dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, (heterocyclic radical)alkyl, and (heterocyclic radical)oxyalkyl. R; thus includes hydroxyalkyl, hydroxyalkeny:, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl)alkyl, (haloaryl)alkyl, (hydroxyaryi)alkynyl, and so forth. Similarly, Ra includes hydroxyalkyl and aminoaryl, and Rg includes hydroxyalkyl, aminoalkyl, and hydroxyalkyl(heterocyclic radical)alkyl.

Heterocyclic radicals, which include but are not limited to heteroaryls, include: furyl, oxazolyl, iscxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, 1,3,4- triazolyl, tetrazolyl, pyridiny!, pyrimidinyl, pyridazinyl, indolyl, and their nonaromatic counterparts. Further examples of heterocyclic radicals include ~ piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl, and octahydrobenzofuranyl.

Selective MEK 1 or MEK 2 inhibitors are those compounds which 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 ICs, for MEX 1 or MEK 2 that is at least one-fiftieth (1/50) that of its ICs for one of the above-named othar enzymes. Preferably, a selective inhibitor has aniCs that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/500C or less than that of its ICs, or one or more of the above-named enzymes.

Claims

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 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 entirety.

What is claimed is:

1. A compound of formula (1): w Rs R, Ry R2 0) Wi is one of the following formulae (i) — (xiii): X, RN N-NR ~~ oN No ¢ 2 5; N- N 5 \ \ O- \

NK . Nx Ae oy Lh Ne (i) (ii) (iii) (iV) (v) (vi) (vii) _ X, X, BESET WERE § = iat 0 N Rs x Px Yo Xi (viii) (ix) (x) (xi) (xii) (xiii) HO 0) 0 —N 0) 0 N—N \ \ \ // 3 X; xX Ny Xi N Nex T (xiv) (xv) (xvi) (xvii) X1is O, S, or NRg; Xz is OH, SH, or NHRg; is each of Re and Rr is H or C 14 alkyl: . ; each of R; and R; is independently selected from H, F, NO, Br and Ci; Rs: can also be SO,NRgRy, or Ry and R; together with the benzene ring to which they are attached constitute an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzthioazole: RizisHorF; each of Rg, Ry, and R4 is independently selected from H, Cl and CHa; Rs is H or C 34 alkyl; and wherein each hydrocarbon radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, hydroxyl, amino, (amino)sulfonyl, and NO,; and wherein each heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C 3.4 alkyl, C 35 cycloalkyl, C34 alkenyl, C 34 alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO,, wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 2 substituents independently selected from halo, C 1. alkyl, hydroxyl, amino, and NO; or a pharmaceutically acceptable salt or C 1.8 ester thereof.

2. A compound of claim 1, wherein R; is bromo or chloro.

3. A compound of claim 1, wherein R; is fluoro. 4, A compound of claim 1, wherein Rj is H.

5. A compound of claim 4, wherein each of R; and Rs is H.

6. A compound of claim 1, wherein each of R; and Rj is fluoro.

7. A compound of claim 6, wherein R; is bromo.

8. A compound of claim 6, wherein Rj is fluoro.

9. A compound of claim 1, wherein R; is nitro.

10. A compound of claim 8, wherein R; is H.

11. A compound of claim 1, wherein R, is chloro.

12. A compound of claim 1, wherein Ry is methyl.

13. A compound of claim 1, wherein Rs is H.

14. A compound of claim 1, wherein Rg is CHa.

16. A compound of claim 1, wherein X; is O or S.

16. A compound of claim 1, wherein X; is NH or NCH.

17. A compound of claim 1, wherein X; is OH, SH, or NH.

18. A compound of claim 1, wherein X, is NHCH3 or OH.

19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically-acceptable carrier.

3 WO 00/42029 PCT/US99/30416 \ 20. A compound of claim 1, having a structure: [5-fluoro-2-(1H- tetrazol-5-yl)-phenyl}-(4-iodo-2-methyl-phenyl)-amine: [2,3-difluoro-6-(1H-tetrazol- 5-yl)-phenyl}-(4-iodo-2-methyl-phenyl)- amine: (4-iodo-2-methyi-phenyl)-[2,3.4- trifluoro-6-(1H-tetrazol-5-yl)-phenyl}-amine; [4-bromo-2,3-difl uoro-6-(1H-tetrazol- 5-yl)-phenyl]-(4-iodo-2-methyl-phenyl)-amine; {5-fluoro-4-nitro-2-(1H-tetrazol-5- yl)-phenyl}-(4-iodo-2-methyl-phenyl)-amine; (2-(4,4-dimethyl-4,5-dihydro-oxazol- 2-yl)-5-fluoro-phenyl]-(4-iodo-2-methyl-phenyl)-amine: [6-(4,4-dimethyl-4,5- dihydro-oxazol-2-yl)-2,3-difluoro-phenyl)-(4-iodo-2-methyl-phenyl)-amine; [6-(4,4- dimethyl-4,5-dihydro-oxazol-2-yl)-2,3 4-trifluoro-phenyl]-(4-iodo-2-methyl-phenyl)- amine; [4-bromo-6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2, 3-difluoro-phenyl]-(4- iodo-2-methyl-phenyl)-amine; [2-(4.4-dimethy|-4,5-dihydro-oxazol-2-yl)-5-fluoro-4- nitro-phenyl]-(4-iodo-2-methyl-phenyl)-amine; S-[4-fluoro-2-(4-iodo-2-methyi- phenylamino)-phenyl}-[1,3,4]thiadiazol-2-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl}-[1,3,4]thiadiazol-2-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl}-[1,3,4]thiadiazol-2-ol: 5-[5-bromo-3,4-difluoro-2-(4-iodo-2- methyl-phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ol: 5-[4-fluoro-2-(4-iodo-2-methyi- phenylamino)-5-nitro-phenyi}-[1,3,4]thiadiazol-2-ol: 5-[4-fluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl}-[1,3,4Joxadiazol-2-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl}-[1 ,3,4Joxadiazol-2-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl}-[1 ,3,4]Joxadiazol-2-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2- methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ol; 5-[4-fluoro-2-(4-iodo-2-methyl- phenylamino)-5-nitro-phenyl}-[1,3,4]oxadiazol-2-ol: 5-[4-fluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl}-4H-[1,2,4]triazol-3-ol: 5-[3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl]-4H-[1,2,4]triazol-3-ol: 9-[3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl}-4H-[1,2,4]triazol-3-ol: 5-[5-bromo-3,4-difluoro-2-(4-iodo-2- methyl-phenylamino)-phenyl}-4H-[1,2 4}triazol-3-ol; or 5-[4-fluoro-2-(4-iodo-2- methyl-phenylamino)-5-nitro-phenyl}-4H-[1,2 4]triazol-3-ol.

21. A compound of claim 1, having a structure: 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-{1,3,4]thiadiazol-2-ylamine: : 5-[3,4-Difluoro-2-(4-iodo-2-methyi-phenylamino)-pheny!]-[1 ,3,4]thiadiazol-2- ylamine; 5-[3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl}-

[1,3,4]thiadiazol-2-ylamine; 5-[5-bromo-3,4-d ifluoro-2-(4-iodo-2-methyl- -phenylamino)-phenyl]-[1,3,4]thiadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl- -phenylamino)-5-nitro-phenyl}-[1,3,4}thiadiazol-2-ylamine; 5-[4-Fluoro-2-(4-iodo-2- : methyl-phenylamino)-phenyl}-[1,3 4]oxadiazol-2-ylamine; 5-[3,4-difluoro-2-(4- iodo-2-methyl-phenylamino)-phenyl}-[1,3,4]oxadiazol-2-ylamine; 5-[3,4,5-trifluoro- 2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazol-2-ylamine; 5-[5-bromo- 3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1 .3,4]oxadiazol-2-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-[1,3,4]oxadiazol-2- ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-[1,2,4]triazol-3- ylamine; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyi}-4H- [1,2,4]triazol-3-ylamine; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)- phenyl]-4H-[1,2 4]triazol-3-ylamine; 5-[3-bromo-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl]-4H-[1,2 4]triazol-3-ylamine; 5-[4-fluoro-2-(4-iodo-2-methyl- phenylamino)-5-nitro-phenyl]-4H-[1,2,4]triazol-3-ylamine; 5-[4-fluoro-2-(4-iodo-2- methyl-phenylamino)-phenyl]-[1,3 4]thiadiazole-2-thiol; 5-[3,4-difluoro-2-(4-iodo-2- = methyl-phenylamino)-phenyl}-[1,3:4}thiadiazole-2-thiot; 5-[3,4,5-trifluoro-2-(4-iodo- 2-methyl-phenylamino)-phenyl}-[1,3,4]thiadiazole-2-thiol; 5-[5-bromo-3,4-difluoro- 2-(4-iodo-2-methyl-phenylamino)-phenyl}-[1,3,4]thiadiazole-2-thiol; 5-[4-fluoro-2- (4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-{1,3,4]thiadiazole-2-thiol; 5-[4- fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl}-{1,3,4]oxadiazole-2-thiol; 5-[3,4- difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-{1,3,4Joxadiazole-2-thiol; 5-

[3.4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl}-[1,3,4]oxadiazole-2-thiol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- [1,3,4]oxadiazole-2-thiol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro- phenyl]{1,3 4]oxadiazole-2-thiol; 5-{4-fluoro-2-(4-iodo-2-methyl-phenylamino)- phenyl]-4H-[1,2,4]triazole-3-thiol; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- phenyl]-4H-[1,2,4}triazole-3-thiol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-phenyli]-4H-[1,2 4ltriazole-3-thiol; 5-[5-bromo-3,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-phenyl}-4H-[1,2 4]triazole-3-thiol; or 5-[4-fluoro-2-(4-iodo- 2-methyl-phenylamino)-5-nitro-phenyl}-4H-[1,2,4]triazole-3-thiol.

N WO 00/42029 PCT/US99/30416

22. A compound of claim 1, having a structure: 5-[4-fluoro-2-(4-iodo-2- methyl-phenylamino)-phenyll-isothiazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl}-isothiazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl}-isothiazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-phenyi}-isothiazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl- phenylamino)-5-nitro-phenyl}-isothiazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl]-isoxazol-3-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl]-isoxazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl]-isoxazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl}-isoxazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)- 5-nitro-phenyi}-isoxazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenyiamino)- phenyl]-1H-pyrazol-3-of; 5-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- 1H-pyrazol-3-ol; 5-[3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl}- 1H- pyrazol-3-ol; 5-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl}- 16 1 H-pyrazol-3-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl}-1H- pyrazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl}-isothiazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl}-isothiazol-3-ol; 4-[3,4,5- trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-isothiazol-3-ol; 4-[5-bromo-3,4- difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl}-isothiazol-3-ol; 4-[4-fluoro-2-(4- iodo-2-methyl-phenylamino)-5-nitro-phenyl]-isothiazol-3-ol; 4-[4-fluoro-2-(4-iodo- 2-methyl-phenylamino)-phenyl}-isoxazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2-methyi- phenylamino)-phenyl}-isoxazol-3-ol; 4-[3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl]-isoxazol-3-ol; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl}-isoxazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)- 5-nitro-phenyl]-isoxazol-3-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)- phenyl}-1-methyl-1H-pyrazol-3-ol; 4-[3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl]-1-methyl-1H-pyrazol-3-ol; 1-methyl-4-[3,4,5-trifluoro-2-(4- iodo-2-methyl-phenylamino)-phenyl}-1H-pyrazol-3-ol; 4-[5-bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-phenyl}-1-methyl-1H-pyrazol-3-ol; or 4-[4-fluoro-2- (4-iodo-2-methyl-phenylamino)-5-nitro-phenyl}-1-methyl-1H-pyrazol-3-ol.

1, WOO00/42029 PCT/US99/30416

23. A compound of claim 1, having a structure: 5-[2-(2-amino-4-iodo- phenylamino)-4-fluoro-phenyl]-1-methyl-1H-[1,2,3]triazol-4-ol; 5-[2-(2-amino-4- iodo-phenylamino)-3,4-difluoro-phenyl]-1 -methyl-1H-[1,2,3]triazol-4-ol; 5-[2-(2- amino-4-iodo-phenylamino)-3,4,5-trifluoro-phenyl]-1 -methyl-1H-[1,2,3]triazol-4-ol: 5-[2-(2-amino-4-iodo-phenylamino)-5-bromo-3,4-difluoro-phenyl}-1-methyl-1H- [1,2,3]triazol-4-ol; 5-[2-(2-amino-4-iodo-phenylamino)-4-fluoro-5-nitro-phenyl}-1- methyl-1H-[1,2,3]triazol-4-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)- phenyl]-3-methyl-3H-[1,2,3]triazol-4-ol; 5-[3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-phenyl]-3-methyl-3H-{1,2, 3]triazol-4-ol; 3-methyl-5-[3,4,5-trifluoro-2- (4-iodo-2-methyl-phenylamino)-phenyl}-3H-[1,2,3]triazol-4-ol: 5-[5-bromo-3,4- difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl}-3-methyl-3H-[1 ,2,3]triazol-4-ol; 5-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl]-3-methyl-3H- [1,2,3]triazol-4-ol; 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-2-methyl- 2H-pyrazol-3-of; 4-(3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl}-2- methyl-2H-pyrazol-3-ol; 2-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl- - phenytamino)-phenyl}-2H-pyrazol-3-of: 4-[5=bromo-3,4-diftluoro-2-(4-iodo=-2- methyl-phenylamino)-phenyl}-2-methyi-2H-pyrazol-3-ol; 4-{4-fluoro-2-(4-iodo-2- methyl-phenylamino)-5-nitro-phenyl}-2-methyl-2H-pyrazol-3-ol; 1-{4-fluoro-2-(4- iodo-2-methyl-phenylamino)-phenyl]-4-methyl- 1 .4-dihydro-tetrazol-5-one; 1-[3,4- difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4-methyl-1,4-dihydro-tetrazol-5- one; 1-methyl-4-[3,4,5-trifluoro-2-(4-iodo-2-methyl-p henylamino)-phenyl]-1,4- dihydro-tetrazol-5-one: 1-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one; 1-[4-fluoro-2-(4-iodo-2-methyl- phenylamino)-5-nitro-phenyl]-4-methyl-1,4-dihydro-tetrazol-5-one: 1-[4-fluoro-2- (4-iodo-2-methyl-phenylamino)-phenyl]-1H-[1 .2,3]triazol-4-ol; 1-[3,4-difluoro-2-(4- iodo-2-methyl-phenylamino)-phenyl}- 1H-[1 ,2,3]triazol-4-ol; 1-[3,4,5-trifluoro-2-(4- iodo-2-methyl-phenylamino)-phenyl}-1H-[1,2,3]triazol-4-ol; 1-[5-bromo-3,4- difluoro-2-(4-iodo-2-methyl-phenylamino)-pheny!}-1 H-[1,2,3]triazol-4-ol; or 1-[4- fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl}-1 H-[1,2,3]triazol-4-ol.

24. A compound of claim 1, having a structure: 3-[4-fluoro-2-(4-iodo-2- methyl-phenylamino)-phenyl]-2H-isoxazol-5-one; 3[3,4-difluoro-2-(4-iodo-2-

PCT/US99/30416 [ methyl-phenylamino}-phenyll-2H-isoxazol-5-one; 3-[3,4,5-trifluoro-2-(4- iodo-2-methyl-phenylamino)-phenyl]l-2H-isoxazol-5-one; 3-[5-bromo-3,4- difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyll-2H-isoxazol-5-one; 3-[4- fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyll-2H-isoxazol-5-one; [5-fluoro-2-(2-oxo-2,3-dihydro-21> 4 -[1 .2,3,5]oxathiadiazol-4-yl)-phenyl}- (4-iodo-2-methyl-phenyl)-amine; [2,3-difluoro-6-(2-ox0-2,3-dihydro-21>4 _- [1,2,3,5)oxathiadiazol-4-yl)-phenyll-(4-iodo-2-methyl-phenyl)-amine; (4- lodo-2-methyl-phenyl)-[2,3,4-trifluoro-6-(2-oxo0-2,3-dihydro-2l >4 - [1 ,2,3,5]oxathiadiazol-4-yl)-phenyl]-amine; [4-bromo-2,3-difluoro-6-(2-oxo- 2,3-dihydro-21>4_-[1 '2,3,5]oxathiadiazol-4-yl)-phenyl]-(4-iodo-2-methyl- phenyl)-amine; [5-fluoro-4-nitro-2-(2-oxo-2,3-dihydro-2I >4 - [1 12.3, 5]oxathiadiazol-4-yl)-phenyll-(4-iodo-2-methyl-phenyl)-amine; 4-(4- fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H-isoxazol-5-one; 4-[3,4- difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]l-4H-isoxazol-5-one; 4- (3,4, 5-trifluoro-2-(4-iodo-2-methyl-phenylamino)-phenyll-4H-isoxazol-5- one; 4-[5-bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-4H- isoxazol-5-one; or 4-[4-fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro- phenyl]-4H-isoxazol-5-one.

25. Use of a compound of claim 1 in the manufacture of a medicament for treating a proliferative disease.

26. Use of claim 25, wherein said proliferative disease is selected from psoriasis, restenosis, autoimmune disease, and atherosclerosis.

27. Use of a compound of claim 1 in the manufacture of a medicament for treating cancer.

28. Use of claim 27, wherein said cancer is MEK-related.

29. Use of claim 27, wherein said cancer is brain, breast, lung, ovarian, pancreatic, prostate, renal, or colorectal cancer. AMENDED SHEET

: PCT/US99/30416 ® 30. Use of a compound of claim 1 in the manufacture of a medicament for treating, or ameliorating the sequelae of, a stroke.

31. Use of a compound of claim 1 in the manufacture of a medicament for treating, or ameliorating the sequelae of, heart failure.

32. Use of a compound of claim 1 in the manufacture of a medicament for treating or reducing the symptoms of xenograft rejection.

33. Use of a compound of claim 1 in the manufacture of a medicament for treating osteoarthritis.

34. Use of a compound of claim 1 in the manufacture of a medicament for treating rheumatoid arthritis.

35. Use of a compound of claim 1 in the manufacture of a medicament for treating cystic fibrosis.

36. Use of a compound of claim 1 in the manufacture of a medicament for treating hepatomegaly. :

37. Use of a compound of claim 1 in the manufacture of a medicament for treating cardiomegaly. j

38. Use of a compound of claim 1 in the manufacture of a ; medicament for treating Alzheimer’s disease.

39. Use of a compound of claim 1 in the manufacture of a medicament for treating a complication of diabetes.

40. Use of a compound of claim 1 in the manufacture of a medicament for treating septic shock. AMENDED SHEET ]

86 .

PCT/US99/30416 [ 41. Use of a compound in the manufacture of a medicament for treating a viral infection.

42. Use of claim 41, wherein said infection is an infection of HIV.

43. Use of a compound of claim 1 in the manufacture of a medicament for use with a therapy selected from radiation therapy and chemotherapy, for treating cancer. 44, Use of claim 43, wherein said chemotherapy comprises a mitotic inhibitor.

45. Use of claim 44, wherein said mitotic inhibitor is selected from paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinflunine.

46. A substance or composition for use in a method for treating a proliferative disease, said substance or composition comprising a compound of claim 1, and said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of said substance or composition.

47. A substance or composition for use in a method of treatment of claim 46, wherein said proliferative disease is selected from psoriasis, restenosis, autoimmune disease, and atherosclerosis.

48. A substance or composition for use in a method for treating cancer, said substance or composition comprising a compound of claim 1, and said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of said substance or composition. ;

49. A substance or composition for use in a method of treatment of ~~ AMENDED SHEET

PCT/US99/30416 ® claim 48, wherein said cancer is MEK-related.

50. A substance or composition for use in a method of treatment of claim 48, wherein said cancer is brain, breast, lung, ovarian, pancreatic, prostate, renal, or colorectal cancer.

51. A substance or composition for use in a method for treating, or ameliorating the sequelae of a stroke, said substance or composition comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of said substance or composition.

52. A substance or composition for use in a method for treating, or ameliorating the sequelae of heart failure, said substance or composition comprising a compound of claim 1, and said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of said substance or composition.

53. A substance or composition for use in a method for treating or reducing the symptoms of xenograft rejection, said substance or composition comprising a compound of claim 1, and said method comprising administering to an organ transplant, limb transplant, skin transplant, cell(s) transplant, or bone marrow transplant patient a pharmaceutically-effective amount of said substance or composition.

54. A substance or composition for use in a method for treating osteoarthritis, said substance or composition comprising a compound of claim 1, and said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of said substance or composition.

55. A substance or composition for use in a method for treating rheumatoid arthritis, said substance or composition comprising a compound AMENDED SHEET )

PCT/US99/30416 ® of claim 1, and said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of said substance or composition.

56. A substance or composition for use in a method for treating cystic fibrosis, said substance or composition comprising a compound of claim 1, and said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of said substance or composition.

57. A substance or composition for use in a method for treating hepatomegaly, said substance or composition comprising a compound of claim 1, and said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of said substance or composition.

58. A substance or composition for use in a method for treating ] cardiomegaly, said substance or composition comprising a compound of claim 1, and said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of said substance or composition.

59. A substance or composition for use in a method for treating Alzheimer’s disease, said substance or composition comprising a compound of claim 1, and said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of said substance or composition.

60. A substance or composition for use in a method for treating a complication of diabetes, said substance or composition comprising a ; compound of claim 1, and said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of said AMENDED SHEET . 89 i

PCT/US99/30416 ® substance or composition.

61. A substance or composition for use in a method for treating septic shock, said substance or composition comprising a compound of claim 1, and said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of said substance or composition.

62. A substance or composition for use in a method for treating a viral infection, said substance or composition comprising a compound of claim 1, and said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of said substance or composition. }

63. A substance or composition for use in a method of treatment of claim 62, wherein said infection is an infection of HIV.

64. A substance or composition for use with a therapy selected from radiation therapy and chemotherapy, in a method for treating cancer, said substance or composition comprising a compound of claim 1, and said method comprising administering to a patient in need of such treatment a pharmaceutically-effective amount of said substance or composition, and administering the selected therapy.

65. A substance or composition for use in a method of treatment of claim 64, wherein said chemotherapy comprises a mitotic inhibitor.

66. A substance or composition for use in a method of treatment of claim 65, wherein said mitotic inhibitor is selected from paclitaxel, docetaxel, vincristine, vinorelbine, and vinflunine.

67. A compound as claimed in claim 1, substantially as herein AMENDED SHEET

PCT/US99/30416 ® described and illustrated.

68. A composition as claimed in claim 19, substantially as herein described and illustrated.

69. Use as claimed in any one of claims 25, 27, 30 to 41 or 43, substantially as herein described and illustrated.

70. A substance or composition for use in a method of treatment as claimed in any one of claims 46 to 66, substantially as herein described and illustrated.

71. A new compound, a new composition, a new use of a compound as defined in claim 1, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET 91 i