MXPA02008103A - 5 amide substituted diarylamines as mex inhibitors. - Google Patents

5 amide substituted diarylamines as mex inhibitors.

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Publication number
MXPA02008103A
MXPA02008103A MXPA02008103A MXPA02008103A MXPA02008103A MX PA02008103 A MXPA02008103 A MX PA02008103A MX PA02008103 A MXPA02008103 A MX PA02008103A MX PA02008103 A MXPA02008103 A MX PA02008103A MX PA02008103 A MXPA02008103 A MX PA02008103A
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Mexico
Prior art keywords
methyl
alkyl
acid
mek
compound according
Prior art date
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MXPA02008103A
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Spanish (es)
Inventor
Haile Tecle
Original Assignee
Warner Lambert Co
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Publication of MXPA02008103A publication Critical patent/MXPA02008103A/en

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    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/20—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
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    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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Abstract

Diarylamines, such as 5 amide substituted diarylamines of formula (I) or formula (II) wherein A is hydroxy, C1 6 alkoxy, or NR6OR7; X is OR12, NR13R12, or NR14; inhibitors of MEK and are useful in the treatment of a variety of proliferative disease states, such as conditions related to the hyperactivity of MEK, as well as diseases modulated by the MEK cascade.

Description

DIARILAMINES SUBSTITUTED WITH 5-AM.DA AS MEK INHIBITORS The present invention relates to diarylamines, such as diarylamines substituted with 5-amide, and methods of using them. BACKGROUND OF THE INVENTION The kinase ERK mitogen enzymes ("MEK") are dual specific kinases involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis. Proliferative diseases are caused by a defect in the intracellular signaling system, or the mechanism of signal transduction of certain proteins. The defects include a change in either the intrinsic activity or the cellular concentration of one or more signaling proteins in the signaling cascade. The cell can produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continuously stimulates proliferation.
Mutations or overexpression of intracellular signaling proteins can lead to fictitious 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 it binds to GTP, and becomes inactive when it binds to GDP. The aforementioned growth factor receptors, and many other receptors t?. * f ** «ßBd ^ aia ^ tíA ^^ mitogenic, when activated, lead to Ras becoming from the state of union GDP to the state of union GTP. 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 leads to the following signaling cascade. Ras activating chronically. Activated ras in turn leads to the activation of a cascade of serine / threonine kinases. One of the groups of kmasas known to require an active Ras-GPT for its own activation is the Raf family. These in turn activate MEK (for example, MEKT and MEK2) which then activate the MAP kinase. ERK (ERKi and ERK2). The activation of the MAP kinase by mitogenesis seems to be essential for proliferation; The constitutive activation of this kinase is sufficient to induce cellular transformation. Obstruction of downstream Ras signaling, for example for use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, if induced from cell surface receptors or oncogenic Ras mutants. Although Ras is not a protein kinase by itself, Ras participates in the activation of Raf and other kmasas. most likely through a mechanism of phosphorylation Once activated, Raf and other MEK kinases phosphophonated in two closely adjacent serine residues, S218 and S222 in the case of MEK-1, which are the prerequisite for the activation of MEK as a kinase. MEK in turn phosphorylates kmasa MAP in both a tyrosine, Y185, and a threonine residue, T'83, separated by a single amino acid. This double phosphorylation activates MAP kinase at least 100 times. The activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including various transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activated by the target protein, such as a kinase, a transcription factor, or other cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK by itself appears to be a kinase that integrates the signal. The current understanding is that MEK is highly specific for MAP kinase phosphorylation. In fact, no substrate for MEK different from the MAP kinase, ERK, has been shown to date and MEK does not phosphopel peptides based on phosphorylation sequence of MAP kinase, or even phosphorylated denatured MAP kinase. MEK also seems to be strongly associated with MAP kinase before its phosphorylation, suggesting that phosphorylation of MAP kinase by MEK may require a strong prior interaction between the two proteins. Both of this requirement and the unusual specificity of MEK are suggested that it may have sufficient difference in its mechanism of action to other protein kinases whose selective inhibitors of MEK may possibly be found operating through allosteric mechanisms rather than through usual obstruction of the ATP binding site.
The compounds of the present invention have been found to be MEK inhibitors and are useful in the treatment of a variety of conditions of proliferative diseases, such as conditions related to the overactivity of MEK, as well as diseases modulated by the MEK cascade.
PREVIOUS ART The present invention provides compounds of the formula I and II: wherein Ri is hydrogen, C 1 a alkyl, C 1-8 alkoxy, halo, C 1-2 haloalkyl, or CN; R3 and R4 are each independently hydrogen, halo, haloalkyl of C1.2, alkyl of C? -8, alkoxy of C1-8, nitro, CN or (O or NH) k- (CH2) J-R9, wherein Rg is hydrogen, hydroxy, CO2H or j is 0 to 4; k is 0 or 1; R10 and R11 are each independently hydrogen or C? -8 alkyl, or together with the nitrogen to which they are attached form a cyclic ring of 3 to 10 members containing tf iÜWtoait I I lll l i! I! 11 11 lllr ir IÍI-ÍI-- II II II optionally one, two or three additional heteroatoms selected from the group consisting of O, S, NH and N-alkyl of A is hydroxy, C1.6 alkoxy or NR6OR; Rβ is hydrogen, C? .8 alkyl, (CO) -C1.8 alkyl, phenyl, naphthyl, phen i (to C 1), or C3.10 cycloalkyl; R7 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-10 cycloalkyl or C3 ° cycloalkyl optionally containing a heteroatom selected from the group consisting of O, S and NR9; X is OR12, NR13R? 2, or NR? 4; R 12 and R 13 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl > C2-6 alkynyl, C4.6 cycloalkyl, [(CH2) nY (CH2) m] qCH3, phenyl, naphthyl, (C6-6 alkyl) phenyl, - [(CH2) nY (CH2) m] qphenyl , C6 heteroaryl, (C6 alkyl) heterocyclic C2-6 radical. or [(CH2) pY (CH2) m] q heterocyclic radical of And it's N or O; R? taken with N is a 5- to 7-membered heterocyclic radical with from 0 to 3 additional heteroatoms or combinations of heteroatoms in the ring selected from the group consisting of O, S, SO, SO2, NH, and NMe; or < . n, m < _6, n + m; < 8, 1 £ 5.5; and wherein the above alkyl, alkenyl, alkyl or inyl, heterocyclic radical, aryl and cycloalkyl groups can be substituted optionally with 1 to 4 substituents independently selected from the group consisting of hydroxy, C? -4 alquiloalkyl, fluoro, chloro, iodo, bromo, amino, and C? -4 alco alkoxy and NRaRb; wherein Ra and Rb are each independently selected from the group consisting of hydrogen and alkyl of d.e; and the pharmaceutically acceptable salts thereof. The invention also provides a pharmaceutical composition comprising a compound of formula I or II and a pharmaceutically acceptable carrier. Additionally, the invention provides a method for treating a proliferative disease in a patient in need thereof comprising administering a therapeutically effective amount of a compound of formula I or II. The invention also provides the use of a compound of formula I or II for the manufacture of a medicament for the treatment of a proliferative disease. In addition, the invention provides methods for treating cancer, restenosis, psoriasis, autoimmune disease, atherosclerosis, osteoarthritis, rheumatoid arthritis, heart failure, chronic pain and neuropathic pain in a patient in need thereof comprising administering a therapeutically effective amount of a compound of the formula I or II The invention also provides the use of a compound of the formula I or II for the manufacture of a medicament for the treatment of cancer, restenosis. psoriasis, autoimmune disease, ater oscleros; : osteoartptis, rheumatoid arthritis. heart failure, chronic pain and neuropathic pain. Furthermore, the invention provides a method for treating cancer in a patient in need thereof comprising administering a therapeutically effective amount of a compound of formula I or II in co -ination with radiation therapy or at least one chemotherapeutic agent. The invention also exhibits intermediates and synthetic methods described herein. Other aspects of the invention are provided in the description, examples and following claims. DETAILED DESCRIPTION The invention exhibits diarylamine compounds. pharmaceutical compositions thereof, and methods for using such compounds and compositions. Certain terms are defined later and for use through this description. Alkyl groups, such as CA3 alkyl, include aliphatic chains (ie, hydrocarbyl or n-hydrocarbon radical structures containing hydrogen and carbon atoms) with a free valence. Aiquiio groups are understood to mean linear and branched caaena eslucinations. Examples include etuc ethyl procuo isoprconc utilo-outi I o, isobutyl. t-D plo .: a n t; soi ril 2. - d i n e 111 p i 'X 11 or 2.3-d? methylh? 1, 1 -d tmeti Ipenti lo, heptyl, and octyl. The term "Ci-s alkyl" includes within its definition the terms "alkyl of C-iA 'and Alkyl of C" -4". Cycloalkyl groups, such as cycloalkyl of C3.K) include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "cycloalkyl of C3.10" includes within its definition the terms "C6 cycloalkyl". The term "halo" as used herein refers to fluoro, chloro, bromo or iodo. The term "haloalkyl" as used herein refers to a straight or branched alkyl chain with 1, 2 or 3 halo atoms attached thereto. The term "C1-2 haloalkyl" as used herein refers to a straight or branched alkyl chain having one to two carbon atoms with 1, 2 or 3 halo atoms attached thereto. Typical C1-2 haloalkyl groups include chloromethyl, 2-bromoethyl, difluoromethyl, trifluoromethyl, and the like. The term "alkoxy" as used herein refers to a straight or branched alkyl chain attached to an oxygen atom. The term "C 1-8 alkoxy" as used herein refers to a linear or straight alkyl chain. branched chain having one to eight carbon atoms attached to an oxygen atom Typical C1.8 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. iA 'includes within its definition the terms "C.sub.6 alkoxy" and "C.sub.4 alkoxy". The alkyl and cycloalkyl groups can be substituted with 1, 2, 3 or more substituents which are independently selected from hydroxy, alkyl, halo, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical) oxy. Specific examples include fluoromethyl, hydroxyethyl, 2,3-dihydroxyethyl, (2- or 3-furanyl) methyl, cyclopropylmethyl, benzyloxyethyl, (3-pyridinyl) methyl, (2- or 3-furanyl) methyl, (2- thienyl) ethyl, hydroxypropyl, aminocyclohexyl, 2-dimethylaminobutyl, methoxymethyl, N-pipdinylethyl, diethylaminoethyl, and cyclobutylmethyl. In some embodiments, each above hydrocarbon radical is optionally substituted with 1 to 3 or more substituents independently selected from halo, hydroxyl or hydroxy, amino. (amino) sulfonyl and NO2. In another embodiment, each above heterocyclic radical is optionally substituted with from 1 to 3 or more substituents independently selected from halo, C? -4 alquilo alkyl, C3.6 cycloalkyl, C3.4 alkenyl, C3.4 alkynyl, phenyl , hydroxyl or hydroxy, C? (ammonium) sulfonyl, and NO2, wherein each alkyl, cycloalkyl, alkenyl, alkynyl or phenyl substituent is in turn optionally substituted with between 1 and 2 substituents independently selected from halo, C? 2 alkyl, > hydroxyl or hydroxy amino and NO2. * -y * - * - * - *** - * - and-? In general, more general forms of substituted hydrocarbon radicals include hydroxyalkylene. hydroxy Iqueni what. hydroxyalkynyl. hydroxycycloalkyl. mdroxiarilo. and corresponding forms for the amino- prefixes. halo-, nitro-, alkyl-, phenyl-, cycloalkyl-, and so on, or combinations of substituents. According to formula I and II, therefore, substituted alkyls include hydroxyalkyl. aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyls, such as methylpentyl), (cycloalkyl) alkyl. phenylalkyl, alkoxyalkyl, alkylaminoalkyl. dialkylaminoalkyl. Arylalkyl. aryloxyalicyl, aplaxkyloxyalkyl, (heterocyclic radical) alkyl, and (heterocyclic radical) oxyalkyl. R 1 thus includes hydroxyalkyl, hydroxyalkenyl. hydroxyalkynyl. hydroxycycloalkyl. hydroxyaplo, aminoalkyl, ammoalkyl. aminoalkynyl, aminocycloaikyl, aminoapyl, alkylalkyl. (rent? l) rent it. (haloaril) alkyl, • h i cl r o x i a r i I) a I q u i n 11 o, and so on In a similar way. Ra includes hydroxyalkyl and aminoaryl, and R .. includes hydroxyalkyl, ammoalkyl and hydroxalkyl (heterocyclic radical) alkyl. The alkenyl groups are analogous to alkyl groups. but they have at least one double bond (two carbon atoms), depending on the placement of a double union stit yents, and the geometry of the double union can be mgegen (?; or zusammen A; c; s J: rans. In a similar way. The alkynyl groups have for me a triple union - two (iii) adjacent carbon atoms) the unsaturated alkenyl or alkynyl groups may have one or more double or triple bonds respectively or a mixture thereof as alkyl groups unsaturated groups may be a straight or branched chain, and they can be substituted as both are described above for the alkyl groups throughout the description for example Examples of alkynynyl alkynyls and substituted forms include cis-2-bute'io or trans-2-butene or 3-butynyl. -fen? l-2-prop? n? lo 3- (2 Aluorofe A) -2-prop? n? lo 3-met? l (5-phen? l) -4-pent? n? lo 2-h ? drox? -2-prop? n? lo 2-met? l-2-p? Opinion 2-propenyl 4-hydroxyl-3-butyl 3- (3-fluo? ofenyl) -2-propylene and 2-methyl-2-propenyl In the formulas I and II alkenyls and alkynyls can be C? J C e O C2-8, for example and are preferably C: o C3 3 Heterocyclic radicals include but are not limited to heteroates such as C 8 and C 2 heylopels, including fuplo oxazoylo isoxazoyl tictenyl thiazolyl pyrrolyl, midazolyl 1,3-trolohydro, tetrazolin pipdinyl pipmidinyl, p patented indolyl and its aromatic counterparts Additional examples of heterocyclic radicals include p ipe rid i lo, auinonium isonazon, pipepdmilo norf or mio, piperazi or tetrahyarofuplo tetrahydropyrrronium pr "dichloro octahydroindohio octanid roDenzctiofuranyl and octanidroozofuranyl radicals neteroc? cl? ccs oueaen replace 3 e ^ - amóos are described The abovementioned for the alkyl groups and throughout the description for example The heterocyclic radicals include heteroatoms such as substituted or unsubstituted radicals of pyra no pyrazol, tpazol indazole, pnazine. oxadiazole oxathiadiazole, the heterocycles also include heteroalkyoids such as substituted or unsubstituted radicals of tetrahydropyran pyrrolidone, imidazoline. and tetrahydrothiophene The present invention includes pharmaceutically acceptable salts, amides and esters of the disclosed compounds. The invention also exhibits a pharmaceutically acceptable salt or Ci s ester of a described compound. For example, the described alcohol compounds can form esters having the structure obtained replacing e? H of a hydroxy group with an acyl group of -C (= 0) C - The invention provides the described compounds and strongly related pharmaceutically acceptable forms of the described compounds such as salts, esters, amides, hydrates or solvated forms thereof Masked or Drotected forms. and racemic mixtures or * purely enantiomeric forms The pharmaceutically acceptable salts esters and Incas include carboxylate ales and example C alkyl. s cicioalquno aplo neteroar o heterocoí cuco non aromatic) salts of addition of amino acid esters v am aas that are within a reasonable benefit / risk ratio, pharmacologically effective, and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and lauryl sulphonate. These may include alkali metal and alkaline earth cations such as sodium, potassium, calcium and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethylammonium, methylamine, trimethylamine, and ethylamine. See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66: 1-19 which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, C? -6 primary alkylamines and secondary di (C-i-beta) alkylamines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring portions containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, primary alkylamines of C? .3, and di (C-. 2 alkylamines). Pharmaceutically acceptable esters representative of the invention include C?. 7 alkyl, C5.7 cycloalkyl, phenyl, and phenylalkyl esters of (C ß). Preferred esters include methyl esters. The present invention includes compounds having one or more functional groups (eg, hydroxy, amino, or carboxyl) masked by a protecting group. Examples of protection groups used to protect the functional groups and their preparation are described by T.W. Green, "Protective Groups in Organic Synthesis," John Wiley & amp; amp;; Sons, 1981. The choice of the protection group used will depend on the substituent to be protected and the conditions that will be employed in the subsequent reaction steps where protection is required, and is well within the knowledge of one of ordinary skill in the art. . Protection groups include, but are not limited to, the list provided below. Hydroxyl protection groups Hydroxyl protection groups include: ethers, esters, and protection for 1,2- and 1,3-diols. Ether protecting groups include: methyl, substituted methyl esters, substituted ethylesters, substituted benzyl ethers, silyl ethers and conversion of silyethers to other functional groups. Substituted methyl esters include: methoxymethyl, methytiomethyl, ethyl, methyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl p-ethoxy-benzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl. r-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl. 2,2,2-trichloroethoxy? Methyl, bis (2-chloro- ethoxy?) methalo, 2- (tr? methylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydro-pyranyl, tetrahydroxypropyl nyl, 1-methoxycyclohexyl, 4-methox? tetrah? drop? ranyl, 4-methoxytetrahydrothio-pyranyl, - methoxytetrahydrothiopyranyl, S, S-dioxide, 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-ethanbenzofuran-2-yl. The substituted ethylethers include: 1-ethoxyethyl, 1- (2-chloroethoxy) ethylene, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, , 2,2-trichloroethyl, 2- tri-methyloxy, 2- (phenylenyl) ethyl, fb utyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl and benzyl. Substituted benzyl ethers include: p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3- methyl-2-picolyl A / -oxide, diphenylmethyl, p, p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenyl-methyl, p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri- (p-methoxy) or (I) met i lo, 4- (4'-bromophenacyloxy) phenyldiphenylmethyl, 4,4 ', 4"-tr? s (4,5-dichlorophthalimidophenyl) methyl, 4, 4', 4" -tris (levulinoyloxyphenyl) methyl, 4,4 ', 4"tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-ylmethyl) bis (4', 4" -dimet oxy nil) -m ethyl, 1, 1 -b (4- methox? phen? l) -1'-pyrenylmethyl, 9-anthryl, 9- (9-phenyl) xanthenium, 9- (9-phenol-10-oxo) antrolo. 1, 3-benzodithiolan-2-yl, and benzisothiazolyl S, S-dioxide Sihleters include imethylsilyl t-phenylsilyl. trusop ropi Isi 11, dimethylsopropylsilyl, diethyllisopropylsilyl, dime 1111 ex 11 s 1111 or r-butyldimethylsilyl-butyldiphenylsilyl-p-benzylsyl, tp-p-xylsilyl-3-phenylsilyl-diphenylmethylsilyl, and t-butyl-methoxyphenylsilyl Protection groups ester The ester protection groups include esters, carbonates, Differentiation of various esters and sulfonates. Examples of protective esters include formate. benzoylformate acetate chloroacetate dichloroacetate, tpcloroacetate, tpfluoroacetate methoxyacetate, tpfenylmethoxyacetate phenoxyacetate p-ciorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate 4-oxopentanoate (leuvilnate) 4- (et? iend? t? o) pentanoate. pivaloate, adamantoate, crotonate. 4-methoxyrotonate benzoate p-phenyoenzoate and 2,4-tpmethylbenzoate (mesitoate) Carbonates include methyl. 9-fluorophenone, ethyl 2-2,2-tr? -chloroether, 2- (tr? Met? L? L) e-? Io 2- (fen? L sulfon? L) et? Lo, 2- (tr? Phen? Lfosfon? O) et? Lo, isobutyl vinno aillo p-nitrophenyl. oencyl p-methoxybenzyl, 3,4-d? methoxy? benzyl o-nitrobenzyl p- "itrcoencyl thiocarbonate of S-oenc? 'or 4-ethoxy? -1-naphthyl and Methyl itiocarbonate Examples of assisted splitting orotection groups include 1-iodobenzoate ----, z? Do-but? Rato 4-n? Tro-¿ The methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy) ethylcarbonate, 4- (methylthiomethoxymethyl) benzoate, and 2- (methylthiomethoxymethyl) benzoate. In addition to the above classes, the various esters include: 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1-, 3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis (1, 1-dimethylpropyl) -phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (£) -2-methyl-2-butenoate (tigloate), o- (methoxycarbonyl) benzoate, pP-benzoate, a-naphthoate, nitrate, alkyl N, N, N ', N'-tetramethylphosphorodiamidate,? / - phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-dinitrofenyl sulfenate. Protective sulfates include: sulfate, methanesulfonate (mesylate), benzylsulfonate and tosylate. Protection for 1,2 and 1,3-diols Protection for 1,2 and 1,3-diols groups include: cyclic acetals and ketals, cyclic orthoesters and silyl derivatives. The cyclic acetals and ketals include: methylene, ethylidene, lead 1-f-butylethi, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene. Cyclic orthoesters include: methoxymethylene, ethoxymethylene, dimethoxy-methylene, 1-methoxyethylidene, 1-ethoxyethylidene, 1,2-d? Methox? Et? Lead, u-methoxybenzyldene, 1- (NN-dimethylamino) ethylidene derivative , <; /. - (? /./ V-dimethylamine) derivative benzylidene, and 2-oxacyclopentylidene. Protection for the Carboxyl Group The ester protection groups include: esters, substituted methyl esters, 2-substituted ethyl esters. substituted benzyl esters, silyl esters. Activated esters, various derivatives, and esianyl esters. The substituted methyl esters include: 9-fluorenylmethyl, methoxymethion. methithiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl. 2- (trimethylsilyl) ethoxymethyl, benzyloxymethyl, phenacyl, p-bromophenacyl, -methylphenacyl, p-methoxyphenacyl, carboxamidomethyl. and? / - phthalimidomethole. The 2-substituted ethylesters include: 2.2.2-trichloroethyl. 2-haloethyl, 1-chloroalkyl. 2- (trimethylsilyl) ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl. 2- (p-n-trofenylsulfenii) -ethyl. 2- (p-Toluenesulfon? I) ethyl, 2- (2'-pyridyl) ethylene, 2- (diphenyphosphino) ethyl, 1-methyl-1-phenylethyl,.-Butyl, cyclopentyl. cyclohexyl, allyl, 3-buten-1-yl, 4- (trimethylsilyl) -2-buten-1-yl, cinnamiy, (/ .methylcinnamyl, phenyl, p- (methyl mercapto) -thyl nyl and Benzyl Substituted benzyl esters include: triphenylmethyl, d-pentylmethyl, b? s (o-nitrophenyl (methyl, -antrilmethio- 2- (9.10-dioxoiantrilmethio, 5-dibenzo-subepio, 1 -pyrmethylmethyl, 2-? tr? fluoromet. (l) -6-Chromymethyl-2 -3-trimethylbenzyl, p-bromoDenzyl, o-nitrobenzyl, pn? trobenzyl, p-methoxybenzyl, 2.6- ..... ^^? J ^^ t? ^^ .. ^ ..-.....- a - ^ - a-i dimethoxybenzyl. 4- (Methylsulfinyl) benzene-sulfobenzyl. piperonyl and 4-P-benzyl. Silyl res include methylphenylsilyl. tpethylsilyl. t-butyldimethylsilyl, / -propyldimethylsilyl. Emldimethylsilyl and di-t-butylmethylsilyl. Various derivatives include oxazoles. Aalkyl-1, 3-oxazolines. 4-a! Quil-5-oxo-1, 3-oxazole? A? Nas, 5-alk? L-4-oxo-1, 3-dioxolanes, orthoesters, phenyl group, and pentaaminocobaite complex (III). Examples of stanilsters include: triethylstannyl and tri-butylstannyl. Amides and Hydrazides Amides include: N .. / -d imetium. pyrroiidinyl, piperidinyl, 5,6-dihydrophenanthridinyl. o-nitroanilides,? / - 7-nitroindolyl,? / - 8-nitro-1, 2,3,4-tetrah-ciroquinolyl, and p-P-benzenesulfonamides. Hydrazines include:? / - phenyl. • Diisopropyl and other dialkylhydrazides. Protection for the Amino Group The caroamates include: carca matos, substituted ethyl. assisted splitting, orotolithic splitting. urea derivatives, and various carbamates. The carbamates include methyl and ethyl, 9- f I u o n t i I m 111 o. 9- (2-sulfo) flu methyl, 9- (2.7 dibromo) fluo re nylmethyl. 2.7 - d i - f - b u 111 [9 - I0.10-dioxo-10,10,10.10-. t r a n d r o - í i o x a n 111 > ] m e 111 o and 4-methox? f? ?, o 11 o.
Ethyl substituted protecting groups include: 2,2,2-trichloroethyl, 2-trimethylsilythyl, 2-phenylethyl, 1- (1-adamantyl) -1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1- dimethyl il-2, 2-dibromoetyl, 1,1-dimethyl-2,2,2-tr? chloroethyl, 1-methi 1-1 - (4-biphenyl) ethyl, 1- (3,5-di-A) butylphenyl) -1-methylethyl, 2- (2'- and 4-pi ri di I) et i lo, 2- (N, N-icyclohexylcarboxamido) -ethyl, f-butyl, 1-adamantyl, vinyl, allyl, -isopropylallyl, connamyl, 4-nitrocinnamyl, quinolyl, N-hydroxypiperidinium, alkyldithium, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, and diphenylmethyl. The protection through assisted splitting includes: 2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1,3-dithianyl)] methyl, 4-methylthiophenyl, 2,4-dimethyl-thiophenyl . 2-Phosphonoethyl, 2-triphenylphosphonisoisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p- (dihydroxyboronyl) benzyl, 5-benzisoxazolyl-methyl, and 2- (trifluoromethyl) -6- chloromonylmethyl. The photolytic cleavage methods use groups such as: m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl (o-nitrophenyl) methyl. Examples of urea-type derivatives include: phenothiazine derivative i- (10) -carbonyl,? / '- p-toluenesulfonylaminocarbonyl, and ? / '- fen? laminot? ocarbonllo. In addition to the foregoing, various carbamates include f-amyl, S-benzylthiocarbamate, p-cyanobenzyl. cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxy-benzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o- (N, N-dimethyl-carboxamido) -benzyl, 1,1-dimethyl-3 - (? /, / V-dimethylcarboxamido) propyl, 1,1-dimethyl-propynyl, di (2-pyridyl) methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isont-chinyl, p (p-methoxyphenyl-azo) benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropyl-methyl, 1-methyl (3,5-dimethoxyphenyl) ethyl, 1-methyl-1- (p-henilazophenyl) -ethyl, 1-methyl-1 phenylethyl, 1-methyl-1- (4-pyridyl) ethyl, phenyl, p- (phenylazo) benzyl, 2,4,6-tri-f-butylphenyl, 4- (trimethylammonium) benzyl, and 2,4,6 -trimethylbenzyl. Amides Amides include:? / - formyl,? / - acetyl, N-chloroacetyl,? / - tr? Chloroacetyl,? / - trifluoroacetyl,? / - phenylacetyl, N-3-phenylpropionyl,? -picol indole,? / - 3-pyridyl carboxamide, derivative of? / - benzoylphenylalanyl,? / - benzoyl, and? / - p-phenylbenzoyl. Assisted splitting groups include: Non-nitrophenylacetyl,? / - o-nitrophenoxyacetyl,? / - acetoacetyl, (? Td? T? Obenc? Loxycarbonylamino) acetyl,? / - 3- (p-hydroxyphene I) propynyl, A / -3- (o-nitrophen? L) phenyl,? / - 2-methyl-2- (o-nitrophenoxy) pripionyl,? / - 2-methyl-2- (o-phenylazophenoxy) propionyl,? / - 4-chlorobutyryl, N-3-methyl-3-nitrobutyryl,? / - o -nitrocinnamoyl, derivative of? / - acetylmethionine,? / - o -nitrobenzoyl,? / - o- (benzoyloxymethyl) benzoyl, and 4,5-d ifen il-3-oxazolin-2-one.
Cyclic metric derivatives include 'N-phthalimide. N-dithiazuccinoyl,? / - 2,3-diphen-l-maleo? Lo? -2, 5 -di met i ipro I, adduct of? / - 1.1,4,4-tetramet? Ldisilylazac? Clopentane, i. 3-dimet? I-1,3,5-tr? Azacyclohexan-2-one 5-sust? Tu? to. 1, 3-di-benzyl-1, 3,5-triazacyclohexan-2-one 5-substituted. and 3,5-dinitro-4-pyridonyl 1-substituted. Protective -NH groups Protective groups for -NH include:? -alkyl and? / -arylamines. imine derivatives. enamine derivatives, and? / - heteroatom derivatives (such as / Ametal, N-N, N-P, N-Si, and N-S),? / - their ifen il, and? / - sulfonyl. The? / - alkyl and A / -arylamines include:? / -methyl, A-a lyl,? / - [2- (trimethylsilyl) ethoxy] methyl,? / - 3-acetoxy? Propyl. ? / - (1-isoprop? L-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl,? / - di (4-methoxyphenyl) methyl,? 5-dibenzosuberyl, N-triphenyl ii methyl,? / - (4-methoxyphenyl?) Diphenylmet? Io, A / -9-phenylfluorenyl. N-2.7-dichioro-9-fluorenylmethylene. ? / - ferrocen? lmethyl and? / '- N-2-picolylamine oxide. The imine derivatives include? / -1,1-dimethylthiomethylene. ? / - benzylidene. ? / - p-methoxybenzylidene. / V-diphenylmethylene, / V - [(2-p? R? Dyl) mesityl] m ethylene. ? / - (/ V.A / '- dimethylaminomethylene), N. N'- sopropilidene. / V-p-nitrobenzylidene? -saicyl idene,? / - 5-chlorosalicilidene,? / - (5-chloro-2-h? D-xxi-phenyl-methylene and N-cyclohexylidene.
J-. • ¿í í Í ---- Ü.
An example of an enamine derivative is? / - (5,5-dimethyl-3-oxo-1-cyclohexenyl). Derivatives / Ametal include: derivatives / V-borane, acid derivative / V-diphenylboronic acid. ZV-f phenyl (pentacarbonyl chromium-o-tungsten)] carbenyl, and chelate of / V-copper or / V-zinc. Examples of N-N derivatives include: A-nitro, / V-n-throso, and / V-oxide. Examples of N-P derivatives include: / V-difeniifosflnil, / V-dimethylthiophosphinyl, / V-diphenylthiophosphinyl,? / -dialkyphosphoryl, A / -dibenzylphosphoryl and N-diphenylphosphoryl. Examples of A / -sulfenyl derivatives include: N-benzenesulfenyl, A / - n -trobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, A / -pentachlorobenzenesulfenyl. ? / - 2-Nitro-4-methoxy-benzenesulfenyl,? -trifen-ylmethylsulphenyl and? / - 3-nitropyridinesulfenyl. The / V-sulfonyl derivatives include: N-p-toluenesulfonyl, A / -benzenesulfonyl. ? / - 2,3,6-trimet? L-4-methoxybenzenesulfonyl, ZV-2,4,6-trimethoxy-benzenesulfonyl, N-2,6-dimethyl-4-methoxy-benzenesul fonyl, N-pentamethylbenzenesul fonyl. N-2,3,5,6-tetramethyl-4-methoxybenzene sulfonyl. ? / - 4-methoxybenzenesulfonyl, A / -2,4,6-trimethyl? -benzenesulfonyl,? V-2,6-dimethoxy-4-methylbenzenesulfonyl? / - 2,2,5,7,8-pentamethylchroman-6-sulfonium, A / -methanesulfonyl,? / -? - trimet? isylylethanesulfonyl, A / -9-anthrancensul fonyl. A / -4- (4 ', 8'-dimethoxynaphthylmethyl) -benzenesul fonyl, A / -benzene sulfonyl, A / -trifluoromethyisulphonyl. and? -phenylalylsuiphenyl. The described compounds that are masked or protected can be pro-drugs, compounds metabolized or otherwise transformed in vivo to produce a compound '• * •• - • - * J¿M, h * MM -A¿ ^ * ~ ** ~ yy -------- é-y. - A ^? Utm,. ^, **. I described, for example, temporarily during metabolism. This transformation may be a hydrolysis or oxidation resulting from contact with a body fluid such as blood, or the action of acids, or liver, gastrointestinal or other enzymes. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediaries. The synthetic intermediates and processes described herein, and minor modifications thereof, are also within the scope of the invention. The compounds of formulas I and II can be prepared by techniques and procedures readily available to one of ordinary skill in the art, for example following the procedures set forth in the following Schemes or analogous variants thereof. These synthetic strategies are further exemplified in the following Examples 1-6. These Schemes are not intended to limit the scope of the invention in any way. As used herein, the following terms have the indicated meanings: "LiBIA" refers to lithium borohydride: "TMSCI" refers to trimethylsilyl chloride: "TBDPSCI" refers to fer-butyldiphenylsilyl chloride; "sBuLi" refers to sec-butyl lithium; "TBAF" refers to tetrabutylammonium fluoride; HOAc "refers to acetic acid." KMnO4"refers to potassium permanganate:" LiHMDS "refers to lithium 1,1,1,3,3,3-hexamethyldisilazane. substituents Unless otherwise indicated, they are previously defined. Reagents and starting materials are readily available to one of ordinary skill in the art. Scheme 1 provides a synthesis of the compound of structure (2).
SCHEME I In Scheme I, step a, the compound of structure (1), which is 2,3,4-trifluorobenzoic acid, is reduced with borane prepared in situ under conditions described in Angew. Chem. Int. Ed. (1989). 28. 218 to provide the corresponding alcohol. In Scheme I, stage b. the alcohol is protected with an appropriate hydroxyl protection group, such as tert-butyldiphenylsilyl chloride. A suitable hydroxyl protection group will be stable to basic conditions. In Scheme I. stage c. Metallization of the protected alcohol provides the anion. In step d, the resulting anion .- .., ^ ,, ... ^ »> - aMatü¿i is abruptly quenched with carbon dioxide to provide the monoacid. In Scheme I, steps e and f, the protected monoacid is deprotected and oxidized under conditions well known in the art to provide the symmetrical diacid (2) which is acidic. 4,5,6-tr? Fluoro-? Softálico. These synthetic strategies are further exemplified in Example 1, steps a-d. Scheme II provides a synthesis of the compounds of structure (4) s < SCHEME II • and, In Scheme II, step a, the compound of structure (3), which is 2,4-difluorobenzoic acid, is reduced with borane prepared m situ under conditions described in Angew. Chem Int Ed (1989), 28, 218 to provide the corresponding alcohol In Scheme II, step b, the alcohol is protected with a suitable hydroxyl protecting group, such as tertiary chloride. butyldiphenylsilyl. A suitable hydroxyl protection group will be stable to basic conditions. In Scheme II, step c, the directed metallization of the protected alcohol provides the anion. In Step d, the resulting anion is quenched with a silylating agent, such as trimethylsilyl chloride to provide the monoacid. In Scheme II, step e, the directed metallization of the protected alcohol provides the anion. In Step f, the resulting anion is quenched with carbon dioxide to provide the mono-acid. In Scheme II, steps g and h, the protected monoacid is deprotected and oxidized under conditions well known in the art to provide the symmetrical diacid (4) which is 4,6-difluoro-isophthalic acid. Scheme III provides a synthesis of the compounds of formula I, which includes formulas la and Ib, and formula II.
SCHEME (10) Formula Ib Jan! Esauema III etaoa - UÍ to adequate aniline (5). tai co or 4-yoao-2-methalan? l? na? - ctí o-2-chloroan? l? na. or 4 - y or d or - 2 - fluoroanilma is coupled with a symmetrical diacid (6) to provide the compound of structure (7). Examples of suitable diacids (6) include, but are not limited to compound (2) as shown in Scheme I compound (4) as shown in Scheme II and 4-fluoro-isophthalic acid which can be prepared by someone of experience in the art generally following the procedure described by Chuprina. G.N. et al., Uzh. Vses. Khim: O-va, 19. (5). 598-9 (1974). This is within the reach of someone of ordinary experience to identify additional diacids (6) useful in the preparation of compounds of the present invention. For example, the compound (6) and compound (5), in separate flasks, are each suspended in a suitable organic solvent. ial as tetrahydrofuran, at -78 ° C under nitrogen. Each suspension is treated with an excess of a suitable base. such as 2 equivalents of lithium 1,1,1,3,3,3-hexamethyldisilazane or lithium amide. After both solutions are stirred for approximately 30 minutes at -78 ° C, the diacid solution is transferred by cannula into the aniline solution and allowed to warm to room temperature. After stirring for about 4 to 12 hours, the mixture was extracted with a suitable solution, such as saturated HCt diethyl ether solution or combined with 1N HCl and extracted with ethyl acetate. The resulting precipitate was filtered and concentrated in vacuo to provide e! diacid _ > Anthranilic In the Scheme III, step B the acidic groups of the diacid (7) are differentiated by protection using suitable aldehyde, such as formalin or paratorm aldehyde when R 1 is methyl or using methyl bromide. v cesium fluoride when R1 is a halogen, such as chloride or muuride. For example, the diacid y), a suitable aldehyde, such as paraformaldehyde, and a suitable acid, such as para-toluenesulfonic acid monohydrate were combined in a suitable solvent, such as dichloromethane. In a round bottom flask attached with a Dean-Stark apparatus. The solution is allowed to reflux for about 3 hours. The resulting solution is concentrated and the residue is suspended in a suitable solvent, such as methanol. The aldehyde is removed by filtration, the filtrate is collected and concentrated under vacuum to provide the free acid (8). In Scheme III, stage C. e! free acid (8) is activated, such as by the addition of t-fluoroacetic acid and pneumoniae fluoroestransferase. For example, to a suspension of the free acid (8) in a suitable solvent. such as in? /./ V-aimetufformamide, pentafluorophenylester of pfluoroacetic acid and a suitable base are added as pipdma. The reaction mixture is stirred for about 4 hours, diluted with -i, suitable solvent, such as ethyl acetate JS, and washed with one or two solutions such as 3 times with 1.0 M HCl solution. 3 times with 50o of aqueous NaHCC solution. 2 times with water and one ez with a saturated salt solution. The organic extracts are combined, dried over sodium sulfate, filtered and concentrated under vacuum to provide the activated free ester (9). In Scheme III. stage d. the amines are added to! free ester (9) to provide the amide or the ester, which is a compound of the formula II. For example. the free ester (9) is suspended in a suitable solvent, such as tetrahydrofuran. An appropriate alcohol, such as methanol, or suitable amines, such as methylamine hydrochloride and a suitable tertiary amine base, such as tetylamine and N. A / -diisopropylethylamine, is added to the resulting suspension. After stirring for about 12 to 17 hours, the reaction mixture is diluted with a suitable solvent, such as ethyl acetate and washed using a series of solutions, such as 2 times with water and 2 times with saturated brine solution. The organic extracts are combined, dried over sodium sulfate, filtered and concentrated under vacuum to provide the amide of formula II. Examples of X may be derived by one of ordinary skill in the art from commercially available reagents including but not limited to. the following: trans-2-am? nccAohexane hydrochloride! 2 - a m i n o - 1, 3.4-t.iad? Azoi 3 - a m i n o - 1 - f e n i I - 2 - p i r a z o I i n - 5 - o < i a 5 - a m i n o - 3 - m e 11 i i s or x a z o! 3-amino-5-methylisoxazole 5-amino-3-phenyl-1,2,4-thiadiazole 2- (2-aminoethyl) -1-methylpyrrolidine 2- (aminomethyl) -1-ethylpyrrolidine 1- (2-aminophenyl) ) pyrrolidine pseudothiohydantoin 1- (3-aminopropyl) -2-pyrrolidinone furfurylamine 1-aminomethyl-1-cyclohexanol hydrochloride histamine 3-amino-1, 2,4-triazole 3-amino-5-mercapto-1,2,4 -triazole 3-amino-5-methytio-1,2,4-triazole 3-aminopyrazole 3-amino-4-carbethoxypyrazole 2-amino-2-thiazoline 2-am? not? azole 2-amino-4-methylthiazole 2- amino-4-ethyl thiazoleacetate d-cycloserine tetrahydrofurfurylamine thiophene-2-methylamine 2-aminopurine 2-Aminobenzimidazole 5-methoxytryptamine 6-methoxytryptamine 6-aminoindazole 8-azaadenine 2-aminobenzothiazole 2- (2-aminoethoxy) ethanol 2- (3,4-dimethoxyfe nyl) ethylamine 3-isopropoxypropylamine 3-aminothiophene-2- methyl carboxylate n- (3-aminopropyl) imidazole 3-aminopyrazine-2-carboxylic acid methyl ester -amino-1-ethylpyrazole 3-amino-5-hydroxypropyl 2-amino-5- (ethylthio) -1,3,4-thiadiazole dl-cycloserine 3-amino-5-methylprazole 4-chloro- n-methylaniline 2- (methylamino) ethanol 2-amino-5-mercapto-1,3,4-thiadiazole 2-amino-5-methyl-1,3,4-thiadiazole 2-amino-5-ethyl-1,3 4-thiadiazole 2-amino-6-methoxybenzothiazole 2-amino-6-ethoxybenzothiazole ..- MÍ¡ÍÜáM lÍÍteAÚÍ? M & j. -AAZ..AA- -. * Y * ~ M * zA * JYIA? Z and .. ArJ.JÉ..AM * ». * S *? 3 ?? fÍ? J 2-am? No-6 -met? lbenzot? azo! 2-am? No-4-met? Lbenzot? Azol 4-am? Nobenzo-2 1 3-t? Ad? Azoi 4-am? No-6-chloro-2-met? Lmercaotop? R? M? D? na 2-am? Nop? R? M? D? Na 2-amin or-4 6-d? H? Drox? P? R? M? 4-am? Nop? R? M? D? Not ammopyrazine 4-morpholinene 4- (2-aminophenyl) morpholine n- (3-aminopropyl) morpholine 5-aminophen-2-chloropyridone ? na 5-am? no-2-methox? p? r? d? na 2-am? nop? pd? na 2-am? nop? r? d? na 2- (am? nomet? l) p? r? d? na 2- (2-am? noet? l) p? r? d? na 3-am? nop? r? d? na 3- (am? nomet? l) p? r? d? na 4-am? Nop? R? D? Na 4-vam? Nomet? L) p? R? D? Na 3-amino-I 2 4 - riaz 'na 1- 2-arn? Noet? L) p? per? dta 3 4-et? lened? ox? an? l? na üHÉtMlMWt. - -. M *? ? + * m * -J- alcohol 2-am? nofenet? i? co N N-dimethyl-p-phenylenediamma N Nd? et? l-1 4-phen? lend? amma 2-am? nobenzenesulfonamide sulfanilamide 2 -am? no-1-methox? propane dl-2-ammo-1-pro panol 4-hydrox? p? pepd? na 4-p? per? d? netanol 1-met? l-4- (met ? lam? no) p? per? d? na N-metn-p-anisidine methylaminoacetaldehyde dimethylacetal (S) - (+) -2- (methox? met? l) p? rrol? a? 1-methyl piperazine dihydrochloride 3-h? drox? p? per? d? na dl-nomicotma hydrochloride hydrochloride 4-hydrox? p? per? a'na N N'-b? s (2-h? drox? et? ) et? lend? a diethanolamine 2- (but? lam? no) etant? ol 11 azo 11 oin l-prol? no? 3 - p i r ro i i d mol & amp; A-N-omega-methyltriptamine piperazine 1 -formylpiperazine 1 -methylpiperazine 1 -benzylpiperazine N- (2-hydroxyethyl) piperazine morpholine thiomorpholine 2-piperidinomethanol 2-piperidinoethanol 3-piper? dinomethanol 4- (1-pyrrolidinyl) piperidine N-ethylpiperazine d-prolinol tialdine (R) -3-hydroxypyrrolidine hydrochloride (R) - (-) - 3-pyrro ?? a? nol hydrochloride (R) - (+) - 3-h? drox? piperidine (S) -3-hydroxypyrrolidine tialdine In Scheme II !. Step E. If acid of the compound of α-formula II is deprotected under acidic conaicons using a polymer binding glycol as an extinguished reagent to rotate the compound of the formine la. For example, to one of the formulas of the formula 11 is a suitable entity, such as Tetrahydrofuran is added a suitable extinguishing agent such as a polymer bonding agent and a suitable acidic solution, such as approximately A ml of 10 M hydrochloric acid solution. After stirring for about 48 hours at room temperature, the The resin is removed by filtration and the filtrate is transferred to a separatory funnel and divided with a suitable solvent, such as ethyl acetate. The organic materials are washed using a series of solutions, such as twice with 1 0 M HCl and twice with saturated brine solution. The organic extracts are collected, dried over sodium sulfate, filtered and concentrated under vacuum to provide the compound of the formula la. In Scheme III, step F the deprotected acid of the formula is activated. such as by the addition of pentafluorophenylester of the tpfluoroacetic acid and is reacted with an appropriately substituted hydroxyamma, to allow the formation of the hydroxamate which is the compound of the formula Ib. For example, a suspension of the formula 1a in a suitable solvent, such as in N? Aaimethylformamide, is added pentafluorophenylester of tpfluoroacetic acid and a suitable base, such as pyridine. The reaction mixture is stirred for about 17 hours and diluted with a suitable solvent, such as ethyl acetate. and washed using a series of solutions such as 3 times with 10 μM HCi solution 3 times with 53u NaHCO-ac solution. bear 2 times with water and "" - ^^^^ M ME once with a saturated brine solution. The organic extracts are combined, dried over sodium sulfate, filtered and concentrated under vacuum to provide the activated free ester (10). In Scheme III, step G, the amines are added to the free ester (10) to provide the amide, which is a compound of the formula Ib. For example, the free ester (10) is suspended in a suitable solvent, such as tetrahydrofuran. To the resulting suspension, a suitable alcohol, such as methanol, or suitable amines, such as methylamine hydrochloride and cyclopropylmethylamine hydrochloride, and a suitable tertiary amine base, such as triethylamine and? /,? / - diisopropylethylamine, are added. After stirring from about 12 to 17 hours, the reaction mixture was partitioned between a suitable solvent, such as ethyl acetate and a suitable acid, such as 1.0M HCl solution. The organic layer was washed using a series of solutions, such as 2 times with water and 2 times with saturated brine solution. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated under vacuum to provide the hydroxamate of formula Ib. One aspect of the invention exhibits the disclosed compounds shown in formulas I and II. Preferred compounds of formulas I or II are those in which Ri is C? _8 alkyl or halo, preferably Ci-s alkyl, more preferably fluoro, chloro or methyl, and more preferably m »- .. -.« > -, MM | J ^ B | MttaaM My methyl; R3 and R4 are each independently hydrogen or halo, preferably fluoro; A is hydroxy or NR6OR7, X is NR13R.2 or NR 4; and R12 and R13 are each independently [(CH2) pY (CH2) m] qCH3, (C6-6 alkyl) phenyl, - [(CH2) nY (CH2) m] qphenyl or heterocyclic radical (C? .6 alkyl) of C2-6- Also preferred are compounds of the formula I or formula II wherein the heterocyclic radicals include heteroatoms such as substituted or unsubstituted radicals of pyrrole, furan, pyran, thiophene, pyrazole, imidazole, triazole, tetrazole, indole, isoxazole , indazole, pyridine, pyrazine, oxazole, thiazoi, oxadiazole, oxathiadiazole; heterocycles also include heteroalkyls such as substituted and unsubstituted radicals of morpholine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, pyrrolidone, imidazoline, and tetrahydrothiophene. Table I and Table II provide examples of preferred compounds of the present invention. i f niml j? ím? iíii.'i Table Table As used herein, the term "pacient" refers to any warm-blooded animal such as, but not limited to, human, horse, dog, guinea pig, or mouse. Preferably, the patient is human. The term "treatment" for purposes of the present invention refers to prophylaxis or prevention, reduction or elimination of a condition mentioned once the condition has been established. According to one aspect of the invention, the compounds are MEK inhibitors. MEK inhibition assays include in vitro cascade analysis for MAP kinase pathway inhibitors described in column 6, line 36 to column 7, line 4 of US Patent Number 5,525,625, and in vitro MEK analysis in column 7 , lines 4-27 of the same patent, the full description of which are incorporated for reference (see also Examples 163-173 below). Selective MEK 1 or MEK 2 inhibitors are those compounds that inhibit the MEK 1 or MEK 2 enzymes, respectively, without substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A, kinase phosphorylase, EGF, and PDGF receptor kinases, and C- src. In general, a select MEK 1 or MEK 2 inhibitor has an IC 50 for MEK 1 or MEK 2 which is at least one fiftieth (1/50) of its IC 50 for one of the other enzymes mentioned above. Preferably, an inhibitor The selective 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 your IC50 or one or more of the enzymes mentioned above. The compositions described are useful as prophylactic and therapeutic treatments for diseases or conditions related to the overactivity of MEK, as well as diseases or conditions modulated by the MEK cascade. Examples include, but are not limited to, stroke, septic shock, heart failure, osteoarthritis, rheumatoid arthritis, rejection of organ transplantation, and a variety of tumors such as ovarian, lung, pancreatic, brain, prostate, and colorectal cancer. rectal. 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 cancers related to MEK (including related ras), both solid or hematopoietic. Examples of cancers include brain, breast, lung, such as non-small cell lung, ovarian, pancreatic, prostate, renal, colo-rectal, cervical, acute leukemia, and gastric cancer. Additional aspects of the invention include methods to treat or reduce the symptoms of graft rejection (cell or cells, skin, limb, organ or bone marrow transplant), osteoartptis, rheumatoid arthritis, cystic fibrosis, -tjjri. »as? -if- '•• T" * -? -f, T' 'Ti complications of diabetes (including diabetic retinopathy and diabetic nephropathy)Hepatomegaly cardiomegaiia, apoplexy (such as acute focal ischemic stroke and global cerebral ischemia), heart failure, septic shock, Alzheimer's disease, and chronic or neuropathic pain. The compounds of the invention are also useful as antiviral agents to treat viral infections such as HIV, hepatitis B virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). ). 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 or therapeutically effective amount of a described compound or pharmaceutical composition thereof. The term "chronic pain" for purposes of the present invention includes, but is not limited to, neuropathic pain, idiopathic pain. and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism. Chronic pain is associated with numerous conditions including, but not limited to, inflammation, arthritis, and post-operative pain. As used herein, the term "neuropathic pain" is associated with numerous conditions including, but not limited to, inflammation, postoperative pain, artificial limb pain, pain from burning, gout, trigeminal neuralgia. acute herpetic pain and post-herpetic causalgia, diabetic neuropathy, avulsion of the plexus, neuroma. vasculitis, viral infection. traumatic injury, constriction injury, tissue injury, limb amputation, postoperative pain, arthritis pain, and nerve injury between the peripheral nervous system and the central nervous system, The invention also exhibits methods of combination therapy, such as a method of treating cancer, wherein the method further includes providing radiation therapy or chemotherapy, for example, with mitotic inhibitors such as a taxane or an alkaloid vinca. Examples of mitotic inhibitors include paclitaxel, docetaxel, vincristm. vinblastine, vinorelbine and vinflunine. Other therapeutic combinations include a MEK inhibitor of the invention and an anti-cancer agent such as cisplatin, 5-fluorouracil or 5-fluoro-2-4 (1 H, 3H) -p? Rimidinedione (5FU), flutamide, and gemcitabine. Chemotherapy or radiation therapy may be administered before, at the same time, or after administration of a compound described according to the needs of the patient. Those skilled in the art will be able to determine, according to known methods. the appropriate therapeutically effective amount or dose of a compound of the present invention for administration to a patient, taking into account such factors as age, weight, general health, the compound administered, the route of administration, the type of pain or condition it requires treatment and the presence of other medications. In general, an effective amount or a therapeutically effective amount will be between about 0.1 and about 1000 mg / kg per day, preferably between about 1 and about 300 mg / kg of body weight, and the daily doses will be between about 10 and about 5000 mg for an adult subject of normal weight. Commercially available capsules or other formulations (such as liquids and film-coated tablets) of 100 mg, 200 mg, 300 mg, or 400 mg may be administered according to the methods described. The compounds of the present invention are preferably formulated before administration. Therefore, another aspect of the present invention is a pharmaceutical composition comprising a compound of the formulas I or II and a pharmaceutically acceptable carrier. In making the compositions of the present invention, the active ingredient such as a compound of the formula I or the formula II. it will usually be mixed with a carrier, or diluted by a carrier or attached within a carrier. Dosage unit forms or pharmaceutical compositions include tablets, capsules, pills, powders, granules, aqueous and non-aqueous oral solutions and suspensions, and Parenteral solutions packaged in containers adapted for subdivision within individual doses. Dosage unit forms can be adapted for vain methods of administration including formulations of controlled release, such as subcutaneous implants Methods of administration include parenteral oral rectal (intravenous, subcutaneous intramuscular), intracisternal, intravaginal, intrapeptoneal, intravesical local (drops, powders, ointments, gels or cream), and by inhalation (or mouth or dew) nasal) Parenteral formulations include pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions, emulsions, and sterile powders for the preparation thereof. Examples of carriers include water, ethanol, pohols (polyethylene glycol, polyethylene glycol) plants, and injectable organic esters such as ethyl oleate. Fluency can be maintained or the use of a coating such as lecithin, a regulating agent or appropriate maintenance of particle size. The carriers for solid dosage forms include (a) fillers or extenders. , (b) binders, (c) humectants, (d) disintegrating agents (e) retarders of solution, (f) absorption accelerators, (g) adsorbents, (h) lubricants, (i) regulating agents and j) propellants The compositions may also contain adjuvants such as preservatives, wetting, emulsification and dispersion, antimicrobial agents such as parabens chlorobutanol, phenol and sorbic acid, isotonic agents such as a sugar or sodium chloride extension agents .uJJ - »- < j- * atrt | They include an absorption moiety such as aluminum monostearate and gelatin; and absorption enhancement agents. The following examples represent typical syntheses of the compounds of formula I and II as described in the foregoing generally. These examples are illustrative only, and are not intended to limit the invention in any way. Reagents and starting materials are readily available to one of ordinary skill in the art. As used herein, the following terms have the indicated meanings: "g" refers to grams; "mg" refers to milligrams, "ml" refers to milliliters; "mmol" refers to millimoles; "° C" refers to degrees Celsius; "APCI" refers to chemical ionization of atmospheric pressure; and "THF" refers to tetrahydrofuran; EXAMPLE 1 7,8-Difluoro-1- (4-vodo-2-methyl-phenyl) -4-oxo-1,4-dihydro-2H-benzo [d] f1,31-oxazine-6-carboxylic acid Step a: A suspension of (2,3,4-trifluoro-phenyl) -methanol (prepared as in Angew, Chem. Int. Ed. (1989), 28, 218) (8.7 g, 54 mmol) in 50 ml of dichloromethane was added tert-butyldiphenylsilyl chloride (15.4 ml, 59 mmol) and imidazole (4.02). g, 59 mmol). After 17 hours, the reaction was poured into 100 ml of 1 M HCl solution and extracted into dichloromethane. The organic layer was washed 2 times with 1 M HCl solution and 2 times with brine solution. The organic phase was collected and dried over Na 2 SO 4, filtered and concentrated in vacuo. The white, oily solid (18.8 g) was purified through silica column chromatography eluting with 9: 1 hexane: ethyl acetate to yield 14.37 g (68.5%) of re-butyl-diphenyl- (2.3, 4-trifluoro-benzyloxy) -silane. Step b: A suspension of re-butyl-diphenyl- (2,3,4-trifluoro-benzyloxy) -silane (7.42 g, 18.5 mmol) in freshly distilled tetrahydrofuran (50 ml) at -78 ° C under nitrogen was added 1.3 M sec-b was used in cyclohexane (18.5 ml, 24.0 mmoles). The reaction was allowed to stir at -78 ° C for 1 hour and quenched with CO2 gas (read bottle) directly into the solution for 30 minutes and the reaction mixture was brought slowly to room temperature. After 3 hours, the reaction was partitioned between ethyl acetate and a 1M HCl solution and washed with brine solution. The organic phase was collected and dried over Na2SO4, filtered and concentrated in vacuo to yield 8.17 g (99.6%) of 5- (re-butyldiphenyl-silanyloxymethyl) -2,3,4-trifluoro-benzoic acid as a solid. Waxy, white. Step c: To a suspension of 5- (fer-butyldiphenyl-silanyloxymethyl) -2,3,4-trifluoro-benzoic acid (8.17 g, 18.4 mmol) in freshly distilled THF (20 ml) was added a fluoride solution of tetrabutylammonium (1.0 M in THF, 40.0 ml, 40.0 mmol). After stirring at room temperature for 2 hours the reaction mixture was concentrated in vacuo and redissolved in ethyl acetate, transferred to a separatory funnel and washed with water. i ?? ? í irf inlttiii tilii ni i i lüÉiíimíilin r i ------------------------- ---------. times with 1M HCl solution 2 times with saturated brine solution. The organic layers were collected, dried over Na 2 SO 4, filtered and concentrated in vacuo. The resulting residue was added with hexanes producing a white solid which was washed several times with hexanes. was collected and dried m vacuo yielding 2-3,4-tr? fluoro-5-h? d acid? oxymethyl-benzoic acid (1 98 g, 52.2%) Step d: To a refluxing suspension of tr? uoro-5-hydroxymethyl-benzoic acid (1 90 g, 9 22 mmol) in acetone was added a solution of potassium permanganate (4 3 g, 27 7 mmol) in water (5 ml) After refluxing for 6 hours the reaction was allowed to cool and an aqueous solution of NaHS03 (5 ml, 10 M) and an aqueous solution of H2SO4 (5 ml, 1 OM) was added which clarified the reaction solution. This mixture was transferred to a separatory funnel and extracted several times with ethyl acetate. The organic layers were harvested by drying over Na2SO4., filter and concentrate m vacuo to yield 4-5-6-tpfiuoro-isophthalic acid as a light yellow solid (1 03 g, 50 7%) Step e A suspension of 4,5,6-tr? fluoro-? 0 (1 03 g, 4 68 mmol) in freshly distilled THF (20 ml) at -78 ° C under nitrogen is treated with 2.0 equivalents of freshly prepared 1M LiHMDS solution (HMDS, 2.07 ml, 9 83 mmol n- butyl lithium 3 5 ml 9 36 mmoies) in THF In a second flask, 4-iodo-2-methalanolin (1 09 g, 4 68 mmol) 5 in 20 ml of freshly distilled THF is cooled. at -78 ° C under nitrogen and treated with 2.0 equivalents of freshly prepared LiHMDS solution (HMDS, 2.07 ml, 9.83 mmole, n-butyllithium 3.5 ml, 9 36 mmole) in THF After both solutions were stirred for 30 minutes at -78 ° C, the benzoic acid solution was transferred by cannula into the aniline solution and allowed to slowly warm to room temperature. After stirring for 4 hours, the reaction mixture was poured into 200 ml of a saturated diethyl ether HCl solution yielding a white precipitate. The solid is removed by filtration and the remaining filtrate is collected and concentrated in vacuo to yield 4,5-difluoro-6- (4-iodo-2-methyl-phenylamino) -sophthalic acid (1.55 g, 77%). Step f: A suspension of 4,5-difluoro-6- (4-iodo-2-methyl-phenylamino) -isophthalic acid (1.1 g, 2.54 mmole), paraformaldehyde (5.0 g) and para-toluenesulfonic acid monohydrate (15.0 mg) in dichloromethane (250 ml) in a round bottom flask attached with a Dean-Stark apparatus was allowed to reflux for 3 hours. The cooled solution is then concentrated and the residue is redissolved in methanol and the paraformaldehyde is filtered off and the filtrate is collected and concentrated in vacuo yielding 7,8-difluoro-1- (4-yo-2-methyl) acid. phenyl) -4-oxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine-6-carboxylic acid as a red solid (0.80 g, 70.0%). ^^ ^^^ ^? ji .. - * "- **> -" * »•" -Muaiaiiniriiii i EXAMPLE 2 Methylamide of 7.8-Difluoro-1- (4-iodo-2-methyl-phenol) -4-oxo- 1.4-dih? Dro-2 / - / - benzo [d1í1, 31oxazin-6-carboxylic To a suspension of 7,8-difluoro-1- (4-iodo-2-methyl-phenyl) -4-oxo-1,4-dihydro-2-benzo [d] [1,3 ] oxazin-6-carboxylic acid (0.3 g, 0.67 mmol) in N, A / -dimethylformamide (3 ml) is added trifluoroacetic acid pentafluorophenylester (0.127 ml, 0.74 mmole) and pyridine (0.60 ml, 0.74 mmole) . After stirring for 4 hours the reaction mixture is diluted with ethyl acetate and washed 3 times with 1.0 M HCi solution, 3 times with 5% aqueous NaHC03 solution, 2 times with water and once with brine solution. saturated The organic layers were collected and dried over Na: S04, filtered and concentrated in vacuo to yield the pentafluorophenylester of 7,8-difluoro-1- (4-iodo-2-methyl-phenol). -4-oxo-1,4-dihydro-2H-benzo [d] [1, 3] oxaz? N-6-carboxyl? Co as a dark orange oil (0.3? G, 83.1%) To a suspension of the pentafluorophenyl 7,8-d? fluoro-1- (4-iodo-2-met? l-phen? l) -4-oxo-1,4-dihydro-2H-benzo [d] [1.3] oxaz? n-6- carboxyl? co (0 33 and 0.54 mmoles) in THF freshly distilled (10 ml) is added methylamine hydrochloride (0 037 g, 0 54 mmol) and? /,? / - d ?? soprop? let? lam? na (0 019 ml, 1 08 mmol) After shaking for 17 hours, the reaction mixture was diluted with ethyl acetate and washed 2 times with water and 2 times with saturated brine solution. The organic layers were collected and dried over Na 2 SO 4, filtered and concentrated in vacuo to yield 7,8-d? Fluoro-1- (4-iodo-2-methyl-phenyl) -4-oxo methylamide. -1,4-dihydro-2H-benzo [d] [1, 3] oxaz? N-6-carboxylic acid as a yellow solid (0.19 g, 76.9%); mp 219-223 ° C; NMR (400 MHz DMSO-d6) 8.40 (s 1H), 8 06 (d, 1H, J = 6 8), 7.74 (s 1H), 7 50 (d 1H, J = 8.4), 6.87 (d, 1H , j = 8.0), 5.61 (s 2H), 2.76 (d, 3H J = 4.4), 2.25 (s 3H); MS (APCI) m + 1 = 459, Analysis calculated / found for A-A3F2IN2O3 C 45.00 / 45.39, H 3.01 / 3 16. N 6 05/5 88. MEK assay m vitro: IC50 = 6 6 μM.
EXAMPLE 3 4,5-Difluoro-6- (4-vodo-2-methyl-phenolamine) -amide-isophthalamic acid To a suspension of 8-d? Fluoro-1- (4-iodo-2-met? L-phen?) -4-oxo-1 -d? H? Dro-2 / - / - benzoic acid methylamide [d] [1, 3] oxazine-6-carboxylic acid in THF (10 ml) is added polymer bound to glycerol, (0.33 g, 200-400 mesh) and 10 ml of 1.0 M HCl solution after stirring for 48 hours. hours at room temperature, the resin is removed by filtration and the filtrate is transferred to a separatory funnel and partitioned with ethyl acetate. The organic materials are washed twice with 1.0 M HCl, twice with saturated brine solution, collected, dried over Na 2 SO, filtered and concentrated in vacuo yielding 4,5-difluoro-6- (4-iodo) acid. 2-methyl-phenylamino) - / V-methyl-isophthalamic (0.11 g, 76.2%); mp 254-259 ° C; 1 H NMR (400 MHz, DMSO-d 6) 9.31 (s, 1 H), 8.19 (s, 1 H), 8.07 (d, 1 H, J = 7.2), 7.56 (s, 1 H) 6.69 (t, 1 H, J = 5.6 ), 2.74 (d, 3H, J = 4.4), 2.20 (s, 3H); MS (APCI) m + 1 = 447; Analysis calculated / found for C16H13F2lN2? 3, C 43.07 / 43.26, H 2.94 / 3.07, N 6.28 / 6.10. MEK in vi tro analysis: IC50 = 2.4 μM EXAMPLE 4 A / 7-Cyclopropylmethoxy-4,5-di fl uoro -6- (4-vodo-2-met il-f-enylamino) -N3-methyl i s or phthala m ida To a suspension of 4,5-difluoro-6- (4-iodo-2-methyl-phen-lamino) -A- -methyl-isophthalamic acid (0.13 g, 0.29 mmol) in ^^^^ tt ^^^ l N, A / -d? methylformamide (5 ml) was added pentafluorophenyl esters of trifluoroacetic acid (0.055 ml, 0.32 mmoles) and pyridine (0.03 ml, 0 32 mmoles). After stirring for 17 hours the reaction mixture is diluted with ethyl acetate and transferred to a separatory funnel, washed twice with 1.0 M HCl, twice with 5% aqueous NaHCO 3 solution, twice with water and once with saturated brine solution. The organic layers were collected and dried over Na 2 SO, filtered and concentrated in vacuo to yield 4,5-difluoro-6- (4-iodo-2-methyl-phenylamino) - / V-methyl-isophthalamic acid pentafluorophenyl ester ( 0.08 g, 45.2%). To a suspension of the 4,5-difluoro-6- (4-iodo-2-methyl-phenylamino) -A / -methyl-isophthalamic acid pentafluorophenylester (0.08 g, 0.13 mmol) in freshly distilled THF (3 ml) ) add cyclopropylmethylamine hydrochloride (0.016 g, 0.13 mmol), and N, N-diisopropylethylamine (0.07 ml, 0.39 mmol). After stirring at room temperature for 17 hours the reaction mixture was partitioned between ethyl acetate and 1M HCl solution. The organic layer was washed twice with water, twice with saturated brine solution, dried over MgSO 4, filtered and concentrated in vacuo. Purification was carried out by chromatography on a silica column in 2: 1 ethyl acetate: hexanes yielding α / 1-c-chloropropylmethoxy-4,5-difluoro-6- (4-iodo-2-methyl-phenylamino) - 3- methyl-isophthalamide (0.033, 42.8%); mp 198-202 ° C; 1 H NMR (400 MHz, DMSO-d 6) 8 59 (s, 1 H), 8.01 (s, 1 H), 7.44 (d, 1 H, J = 5.2), 7. 32 (s, 1H), 7.18 (d, 1H, J = 7.6), 6.36 (m.1H), 3.34 (d, 2H, J = 6.8), 2.56 (d, 3H, J = 4.0), 1.99 (s) , 3H), 0.82 (m, 1H), 0.27 (d, 2H, J = 8.4), 0.00 (m, 2H); MS (APCI) m + l = 516; Analysis calculated / found for C20H20F2IN3O3 C 47.08 / 46.85, H 4.22 / 4.02 N 7.68 / 7.29. MEK in vi tro analysis: IC50 = 1.1 μM.
EXAMPLE 5 7,8-Difluoro-1 - (4-vodo-2-methyl-phenyl) -4-oxo-1,4-dihydro-2 / - / - benzo [d] [1,3-loxazin-6-dimethylamide -carboxylic Prepared in the manner of Example 4 1 H NMR (400 MHz; CDCl 3) 7.96 (dd, 1 H, J = 2.2, 6.6), 7. 65 (t, 1H, J = 1.5), 7.48 (dd, 1H, J = 1.7, 8.3) 6.70 (d, 1H, J = 8.3), . 37 (s, 2H), 3.11 (s, 3H), 2.96 (s, 3H), 2.3 (s, 3H); MS (APCI) m + 1 = 473; Analysis calculated / found for C18F15F2IN2? 3 C 46.66 / 47.05, H 3.80 / 3.65, N 5.34 / 5.58. MEK analysis in vitro: IC50 = 5.8 μM ^ g ^ || EXAMPLE 6 A / '- C? Clopropylmethoxy? -4-5-d? Fluoro-6- (4-> / o-2-met? I-phen? Lam? No) -N3 AAdimethyl-isophthalamide (27 ) Prepared in the manner of Example 4 mp 78-80 ° C, 1 H NMR (400 MHz DMSO-d 6) 8 52 (s 1 H), 7 32 (s, 1 H), 7 15 (m 1 H), 6 39 (m, 1H) 3 35 (d 2H, J = 6 8), 2 79 (s, 3H) 2 72 (s 3H), 2 00 (s, 3H) 0 93 (m, 1H), 0 27 (d, 2H) , J = 8 0) 0 00 (m 2 H), MS (APCI) m + 1 = 530 MEK analysis m vitro IC5o = 3μM EXAMPLE 7 The following was prepared using parallel synthetic techniques in the following manner Step A A solution of pentafluorophenylester of the acid 7 8-d ifluoro- 1 - (4-iodo-2-methyl-An-1) -4- was prepared. oxo-1 4-d? -hydro-2H-benzo [d] [1 3] oxaz? n-6-carboxy? co in a mixture of 2 1 THF to N / Vd? met? lformam? da (0 32 M 19 36 p In the pre-weighing of glass flasks of 2 drachmas the corresponding amine was added 0 25 mmoles) v lueao the scluc.on of oentafluorofenilester oei% r > acid 7 8-d? f! uoro-1 - (4-iodo-2-meth? -phenol) -4-oxo-! 4-d? H? D-2H-benzo [d] [1 3] oxaz? N-6-carbox? lico (0 3 mmoles) To each bottle was added a morpholma polystyrene resin (0 2 g), covered with Teflon-coated lids and placed on an oixital shaker for 24 hours. The individual reactions were then loaded with styrene resin. of pohamin (0 2 g) and isocyanate polystyrene resin (0 1 g) and lycheloromethane (2 ml) and allowed to stir for another 17 hours The reactions were filtered and concentrated m vacuo to yield the acid amides 7,8 -d? fluo? o-1- (4-iodo-2-meth? l-phen?) -4-oxo-I -d? h? dro-2 / A benzo [d] [1, 3] oxaz ? n-6-carbox? l? co Se < eal? zo LC / MS on a CPI 120SE column (C18) (4 6 x 50 mm 5 μm) EXAMPLE 3 7 8-D? fluoro-6 ((R) -3-htdro xi-pyrro l? d? n-1-arbon? l) -1- (4-iodo-2-methyl I-phenyl?) - 1 2-dih id ro - 3 1 -benzoxaz? N-ona C.3 Hi- A I N - Oz MS (APCI) m = 515 tests MEK < nr / o 34% oe inhibition Z 'LIM EXAMPLE 9 7,8-Difluoro-1- (4-iodo-2-methyl-phenyl) -6 - ((S) -2-methoxymethyl-pyrrolidine-1-carbonyl) - 1,2-dihydro-3,1-benzoxazin-4-one C22 H2, F2 I N2 04, MS (APCI) m + 1 = 543 MEK test in vitro: 93% inhibition @ 1 μM EXAMPLE 10 7,8-Difluoro-1- (4-iodo-2-methyl-phenyl) -4-oxo-1,4-dihydro-2H-3 acid (2-piperidin-1-yl-ethyl) -amide, 1-benzoxazin-6-carboxylic acid C23 H24 F2 I N3 03, MS (APCI) m + 1 = 556 MEK test in vitro: 44% inhibition @ 1 μM ^ M¡ *? * ^ ** ^ - * .- ". * - EXAMPLE 11 (2-P? Rrol? D? N-1-? L-et? L) -amide of acid 7 8-d ? fl? o? o- I - (4-iodo-2-met? l-phen? l) -4-oxo-1 4-d? h? dro-2H-3 1-benzoxaz? n-6-carbox? l? co C2: H22 F2 I N3 03 MS (APCI) m + 1 = 542 test MEK tn vitio 33% inhibition @! μM EXAMPLE 12 [3- (2-Qxo-pyrrolidone-1-di-propyl-amide of 7-d-fluoro-1- (4-iodo-2-methyl-1-phenol) acid ) -4-oxo-1 4-d? H? Dro-2H-3 1 -benzoxaz? N-6-carboxy I co C-H :: F2 IN (A MS (APCI) mA = 57C or MEK wheel n viti 21% ce inhibition a.! EXAMPLE 13 (1-Hydroxy-cyclohexylmethyl-amide of acioo 7 8-d? Fluo? 1- (4-Vodo-2-methyl-phenol) -4-oxo-1 4-d? -hydro-2H-3 l-benzoxaz? N-6-carboxyl? Co C23 H23 F2 I N2 04 MS (APCI) m + 1 = 557 test MEK tn vitio 23% inhibition @ 1 μM EXAMPLE 14 (P? R? D? N-2-? Lmet?) - amide of the acid 7 8-d ifluoro- 1 - (4-iodo-2-met? Phen? L) -4-oxo- 1 4-d? H? Dro-2H-3,1-benzoxaz? N-6-carbox? L? Co C27 H24 F2 I N3 O3, MS (APCI) m + 1 = 604 EXAMPLE 15 7 8-d? Fluoro-1- (4-iodo-2-met? L-phen? L) -4-oxo-1 4-d? H? Dro-2H-3 benzoxaz? N-6-carbon ? lj-p? peraz? n-1-carPaldeh? do C 1 H. F2 I N O S (APCI) m + 1 = 54. '! I P l ~ MEK n > p? ' 13% 'nnib'cicr uM a -.-... -.- .AiA? iaiaíái? tlu? liáiikA »^^ m ^ EXAMPLE 16 Methyl- (1-methyl-p-peridin-4-yl) -amide of acid 7,8- difluoro-1 - (4-iodo-2-methyl-phenyl) -4-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-carboxylic acid C23 H24 F2 I N3 O3, MS (APCI) mA = 556 MEK test in vitro: 0% inhibition @ 1 μM EXAMPLE 17 7,8-Difluoro-1- (4-iodo-2-methyl-phenyl) -6- (4-methyl-piperazine-1 carbonyl) -1,2-dihydro-3,1-benzoxazin-4-one C21 H20 F2 I N3 03, MS (APCI) m + 1 = 528 MEK test in vitro: 78% inhibition @ 1 μM EXAMPLE 18, 7,8-difluoro-1- (2-methoxy-ethoxy) etyl-amide of 7,8-difluoro-1 - (4-oxo-2-methyl-n-1) -4-oxo-1,4- dihydro-2H-3,1-benzoxazin-6-carboxylic acid C20 H, 9 F2 I N2 O5, MS (APCI) m + 1 = 533 MEK test m vi tro 43% inhibition @ 1 μM EXAMPLE 19 f2- (1-Met? L? Rrol? D? N-2-? L) -et? Ll-amide of 7 8-d? Fluoro-1- (4-iodo-2-methyl) acid fen? l) -4-oxo-1,4-d? h? dro-2H-3 1-benzoxaz? n-6-carboxylic acid C :: H24 F2 I N3 03 MS (APCI) m + 1 = 556 MEK test m vitro 28% inhibition @ 1 μM EXAMPLE 20 (2-H? Drox? -et? L -met? L -amide of 7 8-d? Fluoro- - - (4-yoao-2-me 111 -phen 11) -? - o or - 1 4-d? h? dro-2H-3 1-bepzoxaz? n-6-carbox? l? co dc. H, 7 F2 I N2 04 MS (APCI) m + 1 = 503 MEK test m vitro 41% inhibition @ 1 μM EXAMPLE 21 1, 3,4-t-adiazole-2-? -lame of 7 8-d -ifluoro-1- (4-iodo-2-met? L-phenol) -4-oxo-4- d ih id ro-2 H-3, 1-benzoxaz? n-6-carboxyl? co Cis Hn F2 I N4 03 S, MS (APCI) m + 1 = 52G MEK test m vitro 31% inhibition Q) l μM EXAMPLE 22 (2-Methoxy? -1 -met? L-et? L) -amide of 7 8-d if luoro- 1 - (4-iodo-2-met? L-phen?) -4 -oxo-1 4-d? h? dro-2H-3.1-benzoxaz? n-6-carboxyl? co do H19 F2 I N2 04, MS (APCI) m + 1 = 517 MEK test m vitro: 46% inhibition @ 1 μM EXAMPLE 23 7-8-Difluoro-1- (4-vodo-2-methyl-phe nyl) -4-oxo-1,4-dihydro-2H-3 acid (4-methyl-benzothiazol-2-yl) -amide, 1-benzoxazin-6-carboxyl C24 Hie F2 I N3 03 S, MS (APCI) m + 1 = 592 MEK test in vitro: 26% inhibition @ 1 μM EXAMPLE 24 7,8-Difluoro-1- (4-methyl-2-methyl-phenyl) -4-oxo-1,4-dihydro-2H-3,1-4-methyl-thiazole-2-yl-amide -benzoxazin-6-carboxylic acid C20 H14 F2 I N3 03 S, MS (APCI) m + 1 = 542 MEK test m vi tro 20% inhibition @ 1 μM EXAMPLE 25 (5-et? Lsulfan? L-1 3 4-t? Ad? Azol-2-? L) -amide of 7-8-d? Fluoro- (4-iodo-2-met? L- acid) fen? l) -4-oxo-1 4-d? h? dro 2H-3 1-benzoxaz? n-6-carboxy I ico C20 H, 5 F2 I N4 03 S2 MS (APCI) m + 1 = 5 PX test MEK m vitio 5% inhibition @ I uM EXAMPLE 26 (5-et? L-1 3 4-t? Ad? Azole-2? L) -amide of the acid 7 8-d? Fluoro-1 - (4-iodo-2-met? I- fen? l) -4-oxo-1 4-d? h? dro-2H-3 1-benzoxaz? n-6-carbox? l? co C r H. FA A O S MS (APC!) M + 1 = 55"MEK m test came 20% inhibition at> 1 nM - "- ^" - and - * - - ^ *** - fS> k-Ír EXAMPLE 27 (5-Mercapto-1 3 4-t? Ad? Azole-2-? L-amide dei acid 7 3-d? fluoro- 1 - (4-iodo-2-meth? l-phen? i 1-4-0X0-1 4-d? h? dro-2H-3 1 -benzoxaz? n-6- carboxylic C? 8 Hn F2 I N4 03 S2, MS (APCI) m + 1 = 561 MEK test m vitro 27% inhibition @ 1 μM ? EXAMPLE 28 (??? 6-Etox -benzot azole-2- l) -am gives the ácioo Aug. 7-d fluoro- 1 -? (? 4-iodo-2-meth l-phen l) -4- oxo-1 4-d? h? dro-2H-3 1-benzoxaz? n-6-carboxyl? co C: 5 H? 8 F2 I N3 04 S MS (APCI) m + 1 = 622 MEK test? N vitro 9% of inhibition < a) 'uM Ite Éliiiiii 11111 i 111? I mu 111 iif "-" * - * - * ~ '"" "? MM A * EXAMPLE 29 Benzothiazol-2-ylamide of 7,8-difluoro-1- (4-vodo) acid -2-methyl phenol) -4-oxo-1,4-dihydro-2H-3, 3-benzoxazine-6-carboxylic acid C23 H14 F2 I N303 S, MS (APCI) m + 1 = 578 MEK test in vitro: 21% inhibition @ 1 μM EXAMPLE 30 F2- (2-Hydroxy-et l?) -fen¡p-amide 7,8-difluoro-1 acid - (4-methyl-2-vodo nil fe) -4 -oxo-1, 4- dihydro-2H-3,1-benzoxazin-6-carboxylic acid C24 H19 F2 I N2 O4, MS (APCI) m + 1 = 565 MEK test in vitro: 55% inhibition @ 1 μM ??? ^ -y ^ ^ y ^ í- -yyyy ^ X EXAMPLE 31 T azole-2- lam gives the acid Aug. 7-fluoro- d l - (4-iodo-2-meth l-fen? ) -4- oxo-1 4-d? H? Dro-2H-3 1 -benzoxaz? N-6-ca? boxyl Cig H12 F2 I N3 O3 S MS (APCI) m + 1 = 528 MEK test m vitro 32% inhibition @ 1 μM EXAMPLE 32 7 8-d? Fluoro-6-y2-, 2-h? Drox? -et? L) -p? Per? D? N-1-carbon? L.-1- (4-vodo-2- met i l-fen ii) - 1 2-dih id ro-3 1-benzoxaz? n-4-one C23 H23 F2 I N2 04 MS (APCI) m + 1 = 557 MEK m vitio test 76% inhibition @ 1 μM ? EXAMPLE 33 July 8 D-Fluoro-6- (2-h drox meth lp per d n-1 -carbonyl?????) - 1- (4-iodo-2-phen l got yl) - 1 2 -d? h? dro-3 1 -benzoxaz? n-4-one C22 H2? F2 I N2 O4. MS (APCI) m + 1 = 543 MEK test m vi tro '79% inhibition @ 1 μM EXAMPLE 34 Ethyl ester of 3- acid. { [7,8-difluoro-1- (4-iodo-2-metii-phene) -4-oxo-1,4-d? -hydro-2H-3-benzoxazin-6-carbon? Ll-am? no) -1H-p? razol-4-carboxylic C2 H17 F2 I N4 05 MS (APCI) m + 1 = 583 MEK test in vitro 72% inhibition @ 1 μM ????? Example 35 (5-meth l-lsulfan 1 H- 1, 2.4-tr azole-3- p-am gives the 7,8-difluoro-1-A-iodo-2-meth acid? - fen? l) -4-oxo-1,4-d? h? dro-2H-3,1-benzoxazin-6: aroox? neo C19 H14 F2 I N5 03 S, MS (APCI) m + 1 = 558 MEK test in vitro: 76% inhibition @ 1 μM EXAMPLE 36 (1 H-pyrazol-3-yl) -amide of 7,8-difluoro-1- (4-vodo-2-methyl-phenyl) -4-oxo-1,4-dihydro-2H-3amide, 1-benzoxazin-6-carboxylic acid C19 H13 F2 I N. 03, MS (APCI) m + 1 = 511 MEK test in vitro: 60% inhibition @ 1 μM EXAMPLE 37 7,8-Difluoro-1- (4-budo-2-methyl-phenyl) -4-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-carboxylic acid pyridin-3-ylamide IM-I ^ MÉ i i H14 F2 I N3 03 MS (APCI) m + 1 = 522 MEK test m vitro 20% inhibition @ 1 μM EXAMPLE 38 7 8-D? -fluoro-6- (3-hydroxy? -p? Per? D? N-1-carbon? L) -1- (4-iodo-2-methy fe n. 11) - 1 2-dihydro-3 1-benzoxaz? N-4-one C21 H19 F2 I N2 O4, MS (APCI) m + 1 = 529 MEK test m vitro 48% inhibition @ 1 μM EXAMPLE 39 7 8-d? Fluoro-6- (3-hydroxyethyl? Lp? Per? Din-1-carbon? L) -1- (4-iodo-2-met? L-phen? L) -1 2-d? H? Dro-3,1-benzoxaz? N-4-one d: H :, F2 I N2 O, MS (APCI) m + 1 = 543 test MEK tn vnro 71% inhibition @ 1 uM EXAMPLE 40 7 8-D? fluoro-6- (3-h? drox? -p 1-carbon-1-carbonyl) -1- (4-iodo-2-met? phen?) -1 2-d? h? dro-3 1 -benzoxaz? n-4-one C20 H17 F2 I N2 Od MS (APCI) m + 1 = 515 MEK test m vitro 42% inhibition @ 1 uM EXAMPLE 41 7 8-D? Fluoro-1- (4-iodo-2-met? L-phen? L) -6- (4-p? Rrol? D? N-1-? Lp? Per? D? N -1 carbon? H-1 2-dih id ro-3 1-benzoxaz? N 4-one of H: 5 F2 I N: 02 MS (APCI) m + 1 = 582 MEK test tn vttio 7% inhibition @ i uM EXAMPLE 42 (2-Morphine-4-? L-et? L, -amide of addo 7 8-d? -fluoro- I - (4-iodo-2-methyl-ren A-4-oxo-1) 4-d? H? Dro-2H-3 1-oe-? ZQxaz? N-6-carbox? L? Co iLiNiilliiiÉliiiiÉ ii wiiilittii-inr- - • - ^^ •• ' C22 H22 F2 I N3 04, MS (APCI) m + 1 = 558 MEK test tn vttro: 15% inhibition @ 1 μM EXAMPLE 43 7,8-Difluoro-6- (4-hydroxy-piperidine-1-carbonyl) -1- (4-iodo-2-methyl phenyl) -1,2-dihydro-3,1-benzoxazin-4-one C21 H19 F2 I N2 04, MS (APCI) m + 1 = 529 MEK test in vi tro: 52% inhibition @ 1 μM EXAMPLE 44 7.8-di fluoro -6- f4- (2-hydroxy-ethyl) -piperidin-1-carponill-1- (4-vodo-2-methyl-phenyl) -1,2-dihydro-3.1 -benzoxazin-4-one ID Üiiil i M iiÉliJÉil .- ^ .- ^ - ta? , ",, ^, Mtiaar 1 IÍG mu 11111. t. / d- H 3 F2 I N2 04, MS (APCI) m + 1 = 557 MEK m test vttto 69% inhibition @ l μM EXAMPLE 45 (6-Chloro-p? R? D? N-3-? L) -amide of 7.8-d if lu or ro- 1 - (4-iodo-2-methyl-phenyl) 4-oxo-1 4-dihydro-2H-3, 1-benzoxaz? N-6-carboxylic acid C21 H13 Cl F2 I N3 03, MS (APCI) m + 1 = 556 MEK test m vttro 62% inhibition @ 1 μM EXAMPLE 46 (6-methoxy-pyridin-3-yl) -amide of 7,8-difluoro-1- (4-iodo-2-met-1-phenol) -4-oxo- 1 4-dihydro-2H-3,1-benzoxazine-6-carboxylic acid C :: H, ß F2 I N3 04. MS (APCI) m + 1 = 552 test MEK m vttto 43% inhibition £! μM I - r É # É¡ r A ^ t¿fcAi > "- -????? tfiÜiÉÍ" llÉ.? i? i inunm mil iMiiirtulHir EXAMPLE 47 [2- (5-Methox? -1 H-? ndol-3-? l) -et? l. -amide of acid 7 8-d? Fluoro- 1 - (4-iodo-2-met? L-phen? L) -4-oxo-1 4-d? H? Dro-2H-3 l-benzoxaz? -6-carboxylic acid C27 H22 F2 I N3 04, MS (APCI) m + 1 = 618 MEK test in vttro 0% inhibition @ 1 μM EXAMPLE 48 [7- (6-Methoxy? -1H-? Ndol-3-? L) -et? -1. -amide of 7-8-d? Fluoro-1- (4-iodo-2-methyl? -fen? l) -4-oxo-1,4-d? h? dro-2H-3 1-benzoxaz? n-6-carboxylic acid C - H22 F2 I N3 04 MS (APCI) m + 1 = 618 oruePa MEK m vttro 12% inhibition @ I uM EXAMPLE 49 b? S- (2-hydroxy-et? L) -amide of the acid 7,8-difluoro-1 - (4-vodo-2-methy fe n? L) -4-oxo-1,4 -dihydro-2H-3,1-benzoxazin -6-carboxylic acid C20 H19 F2 I N2 05, MS (APCI) m + 1 = 533 MEK test in vttro: 50% inhibition @ 1 μM EXAMPLE 50 f2- (1 H-imidazol-4-yl) -ethyl-amide of 7.8-difluoro-1- (4-iodo-2-methyl-phenyl) -4-oxo-1,4-dihydro-2H-3 , 1-benzoxazin -6-carboxylic acid C2? H17 F2 I N4 03, MS (APCI) m + 1 = 539 MEK test in vitro: 44% inhibition @ 1 μM EXAMPLE 51 7,8-Difiuoro-1- (4-vodo-2-methyl-phenyl) -6- (morpholine-4-carbonii) -1,2-d? H? Dro-3.1-be nzox azin-4- ona do H17 F2 I N2 04 MS (APCI) m + 1 = 515 MEK test tn vttio 72% inhibition @ l μM EXAMPLE 52 (3-lm? Dazol-1-α-propyl) -amide of 7.8-d? Fluoro-1- (4-iodo-2-met? L-phen?) -4- acid oxo-1 4-d? h? dro-2H-3 1 -benzoxaz? n-6-carboxyl? co C2: H19 F2 I N4 03 MS (APCI) m + 1 = 553 test MEK tn vi tro 35% inhibition @ 1 μM EXAMPLE 53 7-D-Fluoro-1- (4-oxo-4-d-h? 2H-3 1-benzoxaz? N-6-carboxyl? Co TO - At -? A? TíéA. i - ^ i ^ -i ^ üM i-iii-llMifciÉlii C24 H20 F2 I N3 03, MS (APCI) m + 1 = 564 MEK test in vitro '61% inhibition @ 1 μM EXAMPLE 54 6- (4-Ethyl-piperazine-1-carbonyl) -7,8-difluoro-1- (4-yod or-2-methyl-n-ethyl) -1,2-dihydro-3, 1 -benzoxazin-4-one C22 H22 F2 I N3 03, MS (APCI) m + 1 = 542 MEK test in vttro: 56% inhibition @ 1 μM EXAMPLE 55 7,8-difluoro-1- (4-vodo-2-methyl-phenyl) -4-oxo-1 [2-M H-indol-3-yl] -ethyl] -methyl-amide , 4-dihydro-2H-3,1 -be nzoxazin-6-carboxylic acid C27 H22 F2 I N303, MS (APCI) m + 1 = 602 MEK m vttro test: 41% inhibition @ 1 μM EXAMPLE 56 7,8-Difluoro-1- (4-vodo-2-methyl-phene) -6- (piperazine-1-carbonyl) -1,2-dihydro-3,1-benzoxazin-4-one C20 H? 8 F2 I N303, MS (APCI) m + 1 = 514 MEK test in vitro: 1% inhibition @ 1 μM EXAMPLE 57 (7,8-difluoro-1- (4-vodo-2-methyl-phenyl) -4-oxo-1,4-dihydro-2H-3-tetrahydro-furan-2-methyl-amide. , 1-benzoxazin-6-carboxylic C21 H19 F2 I N2 04, MS (APCI) m + 1 = 529 MEK test in vitro: 35% inhibition @ 1 μM EXAMPLE 58 7.8-Difluoro-1- (4-iodo-2-met? L-phen? L ) -6- (t-Azolidin-3-carbonyl) -1.2-dihydro-3.1-benzoxazin-4-one C19 H15 F2 I N2 03 S, MS (APCI) m + 1 = 517 MEK test in vttro. 76% inhibition @ 1 μM EXAMPLE 59 7.8-Difluoro-1- (4-vodo-2-methyl-phenyl) -6- (thiomorpholine-4-carbonyl) -1,2-dihydro-3,1-benzoxazin-4-one C20 H17 F2 I N2 03 S, MS (APCI) m + 1 = 531 MEK test in vitro '75% inhibition @ 1 μM EXAMPLE 60 7.8-Difluoro-1- (4-budo-2-methyl-yenii) -4-oxo-1,4-dihydro-2H-3, 3-benzoxazin acid ((S) -2-hydroxyl-cydohexyl) -amide. -6-carboxylic i | i ^ yjj ^^ ni Mili n iiiüll i flirt) IIT * '"*' *" * - g ^^^ j C22 H21 F2 I N2 04, MS (APCI) m + 1 = 543 MEK in vi tro test: 30% inhibition @ 1 μM Step B: To each of the 2-drachma flasks containing the amides of 7,8-Difluoro-1- (4-iodo-2-methyl-phenyl) -4-oxo-1,4-d-hydroxide. 2H-bnzo [] [1, 3] oxain-6-carboxylic was added THF (1 mL) and aqueous HCl (1.0 M, 1 mL) and glycerol polystyrene resin (0.2 g), capped with Teflon-coated caps and allowed to stir in an orbital shaker at 50 ° C for 5 days. The reactions were filtered and washed with ethyl acetate (1.5 mL) and concentrated in vacuo. HPLC purification was performed in acetonitrile / water (0 05% TFA) on a YM C30 column (C18) (100 mm ODS-A) to give the corresponding isophthalamic acids. LC / MS was performed on a 120SE column (C18) (4 6x50mm, 5μm).
EXAMPLE 61 3,4-d? Fluoro-5- [1 - ((R) -3-h? Drox? -p? Rrol? D? N-1-? L) -methane? L] -2- (4- iodine-2-met? l-phen? lam? no) -benzo? co - .s ,, ^, - ^, ,,, - ^^. ÉÍ A J l C19 H17 F2 I N2 04, MS (APCI) m + 1 = 503 MEK test in vitro: 75% inhibition @ 1 μM EXAMPLE 62 4,5-Difluoro-6- (4-vodo-2-methyl-phenylamino) -? / - f3- (2-oxo-pyrrolidin-1-yl) -propyl-isophthalamic acid C22 H22 F2 I N304, MS (APCI) m + 1 = 558 MEK test in vitro: 78% inhibition @ 1 μM EXAMPLE 63 4,5-Difluoro-6- (4-iodo-2-methyl-phenylamino) -? / - (1-methyl p? Peridin-4-yl) -isophthalamic acid C22 H24 F2 I N3 O3, MS (APCI) m + 1 = 544 MEK test in vttro: 0% inhibition @ 1 μM EXAMPLE 64 3,4-d? Fluoro-2- (4-vodo-2-met? L-phenylamino) -5-M- (4-methyl piperaz? N-1-yl) -methanoyl-1-benzoic acid C20 H20 F2 I N3 03, MS (APCI) m + 1 = 516 MEK test in vttro: 57% inhibition @ 1 μM EXAMPLE 65 4,5-d? Fluoro-? Y-f2- (2-h? Drox? -etho?) -ethyl-1-6- (4-iodo-2-methyl-phenylamino) -β-softalmic acid C19 H19 F2 I N2 05, MS (APCI) m + 1 = 521 MEK test in vttro: 63% inhibition @ 1 μM MEK test in vitro: IC50 = 1.38 μM EXAMPLE 66 4,5-Di-fluoro-6- (4-iodo-2-methy1-phenylamino) -N- f2- (1-methyl-pyrrole-din-2-yl) -ethyl-isophthalamic acid C22 H24 F2 I N2 03. MS (APCI) m + 1 = 544 MEK test in vitro: 14% inhibition @ 1 μM EXAMPLE 67 4,5-Difluoro-6- (4-iodo-2-methyl-phenolamine) -A- (2- (2-pyridine-2-yl-t-yl) oft aja m i c o acid C22 H18 F2 I N3 O3, MS (APCI) m + 1 = 538 MEK test in vitro: 81% inhibition @ 1 μM MEK test in vitro: IC50 = 3.3 μM EXAMPLE 68 N-Butyl-4,5-difluoro-6- (4-vodo-2-methyl-phenylamino) -? / - acid (2-mercapto-etiP-isophthalic acid) C21 H23 F2 I N203 S, MS (APCI) m + 1 = 549 MEK test in vitro: 24% inhibition @ 1 μM EXAMPLE 69 Acid 3, 4-di fluoro -5-. { 1- [2- (2-Hydroxy-ethyl) -piperidin-1-yl-methanoyl) -2- (4-iodo-2-methyl-phenylamino) -benzoic acid C22 H23 F2 I N2 04, MS (APCI) m + 1 = 545 MEK test in vi tro 78% inhibition @ 1 μM MEK test tn vttio IC50 = 2 2μM EXAMPLE 70 Acid 3,4-d? Fluoro-5-f1- (2-hydrox? Met? Lp? Per? Din-1-? P-methane? L] -2- (4-iodo-2-met? L-phen) lam? no) -benzo? C21 H2? F2 I N2 04, MS (APCI) m + 1 = 531 MEK test m vttro 49% inhibition @ 1 μM EXAMPLE 71 Acid 4 5-d? Fluoro-6- (4-iodo-2-met? L-phen? Lam? No) -? / - p? R? D? N -3? Lmet? isophthalamic di H, 6 F2 I N3 03. MS (APCI) m + 1 = 524 MEK test tn vttro 86% inhibition @ 1 μM MEK test tn vttro. IC50 = 1.45μM EXAMPLE 72 Acid? / - (2,3-d? H? Dro-benzof1.4jdiox? N-6-? H-4,5-difluoro-6- (4-vodo-2-methyl-p-n-ylam) -isophthalamic acid C23 H F2 I N2 05, MS (APCI) m + 1 = 567 MEK test in vttro: 65% inhibition @ 1 μM EXAMPLE 73 3- ( { 1 - [5-carboxy-2,3-d? Fluoro-4- (4-iodo-2-methyl-phenolamine) -phen-1-methanoyl) -amino acid ester) -1H-p? Razol-4-carboxilico d- H.- F2 I N4 O5. MS (APCI) m + 1 = 571 MEK test // i vi tro 86% inhibition. © 1 μM MEK test in vttro: IC50 = 1.1μM EXAMPLE 74 4,5-Difluoro-6- (4-vodo-2-methyl-phenylamino) -N-pyridin-3-yl-isophthalamic acid C20 H14 F2 I N3 03, MS (APCI) m + 1 = 510 MEK test in vitro: 50% inhibition @ 1 μM EXAMPLE 75 1-f3,4-Difluoro-5- [1- (3-hydroxy-piperidin-1-yn-methanoyl-2- (4-vodo-2-methyl-phenylamino) - fe nill-et anona C20 H19 F2 I N2 04, MS (APCI) m + 1 = 517 MEK test in vitro: 92% inhibition @ 1 μM MEK test tn vttro: Ido = 0.465μM Ük. ^ MM iiiiii? I? mtain f - ^ - ^ * ^ - ^ - * - - iy - ^ - ^ z EXAMPLE 76 Acid 3 4-d? fluoro-5-f1- (3-h? drox? met? lp? per? d? n-1-? l) -methane? ll-2- (4-iodo-2-met? l-phen? lam? no) -benzo? co C21 H2? F2 I N2 04, MS (APCI) m + 1 = 531 MEK test in vitro 88% inhibition @ 1 μM MEK test tn vttro IC 0 = 0 300μM EXAMPLE 77 3,4-d? Fluoro-5-f1- (3-h? Drox? -p? Rrol? D? N-1-? L) -methane? L1-2- (4-iodo-2) acid met? l-fen? lam? no) -benzo? co C19 H17 F2 I N2 O4, MS (APCI) m + 1 = 503 test MEK tn vttro 83% inhibition @ 1 uM test MEK m vitio i C50 = 0 880uM liááÉÉÉ MttMÉl EXAMPLE 78 Acid 3,4-difluoro-2- (4-iodo-2-met? l-fen? lamino) -5-f1- (4-pyrrolidin-1-yl-piperidin-1-yl) -methane-M-benzoic acid C24 H26 F2 I N3 03, MS (APCI) m + 1 = 570 MEK test in vitro: 33% inhibition @ 1 μM EXAMPLE 79 4,5-Difluoro-6- (4-iodo-2-methyl-phen-lamino) - / V- (2-morpholin-4-yl-ethyl) -isophthalamic acid C21 H22 F2 I N3 O4. MS (APCI) m + 1 = 546 MEK test in vitro: 54% inhibition @ 1 μM MEK test in vitro: IC50 = 1.5 μM - «• ^^ - * ^^" titi, -r, - I ^ g ^^^^ i ^ EXAMPLE 80 4,5-Difluoro-6- (4-iodo-2-methyl-phenylamino) -N- acid pyridin-4-? lmeti isophthalamic C21 H16 F2 I N3 03, MS (APCI) m + 1 = 524 MEK test in vitro: 71% inhibition @ 1 μM MEK test in vttro: IC50 = 1.7 μM EXAMPLE 81 3,4-Difluoro-5- [1- (4-hydroxy-piperidin-1-yl) -methane-2- (4-vodo-2-methyl-phenylamino) -benzoic acid do H19 F2 I N2 04, MS (APCI) m + 1 = 517 MEK test in vttro: 86% inhibition @ 1 μM MEK test in vitro: IC50 = 1.8 μM - ^ U MZáit »*» * .- .. - A, ... ^ -. *** «*» * Z .-. Z EXAMPLE 82 Acid 4 5-d? Fluoro-6- (4-vodo-2-met? L-phen? Lam? No) -? / - (4-morphol? n-4-tl-phen? l) -? softalam? co C25 H2 F2 I N3 04 MS (APCI) m + 1 = 594 EXAMPLE 83 3-d-Fluoro-5- acid. { 1- [4- (2-hydroxy? -et? I) -p? Per? D? N-1-? 1-methane? L | -2- (4-iodo-2-met? L-phen lam? no) -benzo? C22 H23 F2 I N2 04 MS (APCI) mA = 545 test MEK m vttro 90% inhibition @ 1 uM test MEK tn vttro Ido = 0 150 μM EXAMPLE 84 N- (2-et? L-2H-p? Razol-3-? L) -4,5-difluoro-6- (4-vodo-2-met? PhenylaminoAsoftalmic acid) I il i nJ-Éái-iliÉHi - - ^ do H17 F2 I N4 03 MS (APCI) m + 1 = 527 MEK test tn vttio 79% inhibition @ I uM test MEK tn vttio Ido = O 960 μM EXAMPLE 85 Acid A / - (6-chloro-p? R? D? N-3-? L) -4 5-a? Fluoro-6- (4-iodo-2-met? L fen? Lam? No) -? softalam? co C20 H13 F2 I N3 03, MS (APCI) m + 1 = 544 MEK test tn vttro 90% inhibition @ l μM MEK test m vitro Ido = O 970 μM EXAMPLE 86 4-D-Fluoro-N- (1 H-? Ndazol-6? L) -6- (4-vodo-2-met? Phen? Lam?) -? Softalam? Acid? C22 H15 F2 I N4 03, MS (APCI) m + 1 = 549 MEK test in vttro: 77% inhibition @ 1 μM MEK test in vitro: IC50 = 1.1 μM EXAMPLE 87 4,5-Difluoro-? / - (2-Hydroxy-1-methyl-ethyl-6- (4-vodo-2-methyl-phenylamino) -isophthalamic acid Company H17 F2 I N2 04, MS (APCI) m + 1 = 491 MEK test in vitro: 66% inhibition @ 1 μM MEK test in vitro: IC50 = 2.2 μM EXAMPLE 88 4,5-Difluoro-N-f2- (1H-imidazol-4-yl) -ethyl-1-6- (4-vodo-2-methyl-phenylamino) -isophthalamic acid C20 H, 7 F2 I N4 03 MS (APCi) m + 1 = 527 MEK test in vttio 60% inhibition @ 1 μM MEK test in vitro Ido = 1 4 uM EXAMPLE 89 3-4-d? Fluoro-2- (4-iodo-2-met? L-phen? Lam? No) -5- (1-morpholine? 4-? L methanoiD-benzoic acid) C19 H17 F2 I N2 04, MS (APCI) m + 1 = 503 MEK test in vttro 89% inhibition @ 1 μM EXAMPLE 90 Acid 4 5-d? Fluoro-? / - (3-? M? Dazol-1-? L-orop? L) -6- (4-iodo-2-meth? FemlaminoAsoftalamico C ~ H10 F2 I N4 O3 MS (APCI) m + 1 = 541 MEK in vi tro test. 59% inhibition @ 1 μM EXAMPLE 91 4,5-Di-fluoro-6- (4-iodo-2-methyl-phenylamino) -N- (3-morph or lin-4-yl propiD-isophthalamic acid C22 H24 F2 I N3 04, MS (APCI) m + 1 = 560 MEK test in vitro: 58% inhibition @ 1 μM EXAMPLE 92 A / - (4-Dimethylamino-phenyl) -4,5-difluoro-6- (vodo-methyl phenylaminoHsophthalamic acid d: H20 F2 I N3 03. MS (APCI) m + 1 = 552 MEK in vi tro test '80% inhibition -g) 1 μM yt-yit - ^ EXAMPLE 93 Acid 5-f 1 - (4-et i I- piperazi n-1-yl) -methane 11-3.4-difluo ro-2- (4-iodo-2-methyl-fe n-amino) -benzoic acid C2? H22 F2 I N3 03, MS (APCI) m + 1 = 530 MEK test in vitro: 70% inhibition @ 1μM EXAMPLE 94 4,5-Difluoro-6- (4-vodo-2-methyl-phenylamino) -N- (4-methoxy-phenyl) -N-methyl-isophthalamic acid C23 H19 F2 I N2 04, MS (APCI) m + 1 = 553 MEK test in vitro: 92% inhibition @ 1 μM . -,.
EXAMPLE 95 Acid 4 5-d? Fluoro-N-2- (1H-? Ndol-3? L) -etip-6- (4-vodo-2-methyl phen? Lam) -N-met? L -? softalámico C26 H22 F2 I N3 03, MS (APCI) m + 1 = 590 MEK test in vitro: 77% inhibition @ 1 μM EXAMPLE 96 4,5-d? Fluoro-6- (4-iodo-2-met? L-phenylamino) -A- (4-sulfamoyl-phenyDisophthalamic acid) C21 H16 F2 I N3 04 S, MS (APCI) m + 1 = 588 MEK test in vitro '85% inhibition @ 1 μM , I ..., I, I ll? ll? I? jL "" -? ¡t * m ^? i - EXAMPLE 97 4,5-d? Fluoro-6- (4-vodo-2-met? l-phen? lam? no) -A / - (tetrahydro-furan-2? memethyl) -? C20 H19 F2 I N2 04, MS (APCI) m + 1 = 517 MEK test in vi tro: 81% inhibition @ 1 μM MEK test in vitro. IC50 = 0.150 μM EXAMPLE 98 3,4-Difluoro-2- (4-vodo-2-methyl-phen-lamino) -5- (1-thiazolid? N-3-yl-methanoyl) -benzoic acid C? 8 H15 F2 I N2 03 S. MS (APCI) m + 1 = 505 MEK test in vitro: 86% inhibition @ 1 μM MEK test in vitrc IC50 = 0.087 μM EXAMPLE 99 3,4-Difluoro-2- (4-budo-2-methyl-phenylamino) -5- (1-thiomorpholin-4-yl-methanoyl) -benzoic acid C19 H F2 I N2 03 S, MS (APCI) m + 1 = 519 MEK test in vitro: 82% inhibition @ 1 μM MEK test in vitro: IC50 = 0.150 μM EXAMPLE 100 4,5-Difluoro-N - ((S) -2-hydroxy-cyclohexyl) -6- (4-vodo-2-methyl-phenylamino) -isophthalamic acid C21 H21 F2 I N2 04, MS (APCI) m + 1 = 531 EXAMPLE 101 3,4-d? Fluoro-5-f1- (3-hydroxy-piperidin-1-yl) -methanoyl | -2- (4-vodo-2-met [l-phenamino]) -benzoic acid i ill lililí .- .. .. ^ ftf-f ^ flf - »- .. doH-aF2IN2? 4, MS (APCI) m + 1 = 517 MEK test in vitro '75% inhibition @ 1 μM EXAMPLE 102 4,5-Difluoro-6- (4-iodo-2-methyl-p-n-lamino) -N- (2-piperidin-1-ethyl) -isophthalamic acid C22H24F2IN303, MS (APCI) m + 1 = 544 MEK in vi tro test: 25% inhibition @ 1 μM EXAMPLE 103 3,4-Di- fluoro-2- (4-phenyl-2-methyl-p-n-ylamino) -5- acid. { 1-f2-met? L-4- (3-? Enox? -p? Rid? N-4-? L) -p? Peraz? N-1-? L] -methane A-benzoic acid EXAMPLE 104 2-Chloro-4- (4- (1- [2,3-difluoro-4- (4-iodo-2-meth? L-phen? Amalmo) -5-carbox? -phen? 1-methane acid l) -3-met? lp? peraz? n-1-? l) -benzo? co EXAMPLE 105 3,4-Difluoro-2- (4-iodo-2-met-1-phenylamino) -5-f 1 - (4-pyridin-2-l-piperazin-1-ii) acid - methanoyl] -benzoic acid EXAMPLE 106 5-f1- (4-Ethanesulfonyl-piperazine-1-yl) -methanoyl-3,4-di fluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid C21 H22F2 I N3 O35S, MS (APCI) m + 1 = 594 EXAMPLE 107 5- (1- [3- (2-Amino-ethyl) -2-oxo-β-midazolidin-1-yl] -rnetanoyl) -3,4-difluoro-2- (4-iodo-2-methyl) - phenylamino (-benzoic acid) I 1-ELLIS EXAMPLE 108 Acid 5-. { 1-f4- (2-Amino-ethyl) -piperazin-1-ill-methanoyl) -3,4-di-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid EXAMPLE 109 3,4-Di-fluoro acid-5-. { 1-f4- (2-Hydroxy-2-methyl-pro-pil) -pipera zin-1 -ill-methanoyl) -2- (4-iodo-2-methyl-phenylamino) -benzoic acid EXAMPLE 110 5- (1-f4- (2,4-Dimethoxy-phene-p-piperazin-1-ill-methanoyl) -3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid EXAMPLE 111 Acid 5-. { 1-f4- (2-carboxy-2-methyl-propyl) -piperazin-1-yl] -methanoyl) -3,4-difluoro-2- (4-budo-2-methyl-phenylamino) -benzoic acid EXAMPLE 112 3-4-Difluo-2- (4-iodo-2-met i-l-enylamino) -5- (1- (4- (3- (propan-1-sulfonyl) -phenyl-piperazine-1-acid -yl) -methanoyl) -benzoic acid EXAMPLE 113 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -5-f1- (3'-methyl) acid 2. 3.5.6-tetrahydro-f1.2'lbipyrazinyl-4-yl) -methanoyl] -benzoic acid ... -.- fmfflH i - "- '* -" ~ - rr? ii'fÍ? i "ttÍ? fflÉrl EXAMPLE 114 Acid 3 4-d? fluoro-2- (4-vodo-2-met? l-fen? lammo) -5-f1- (4- {2-f (p? r? d? n-2-? lmet? ll-am? no1-et? l) -p? peraz? n -1-? L) -methane? L] -benzo? Co C27 H28 F2 I N5 03, MS (APCI) m + 1 = 636 EXAMPLE 115 Acid 5-. { 1- [4- (3-d? Met? Lam? No-prop? L) -p? Peraz? N-1-? N-methane? L) -3.4-d? Fluoro-2- (4-vodo- 2-met? L-fen? Lam? No) -benzo? Co C24 H29 F2 I N4 03 MS (APCI) m + 1 = 587 ¡Jg a ^^ áJtít ^^. - Iiiiililitil 1 11111 I '? I Eiliin 11 EXAMPLE 116 3.4-Difluoro-5- Acid. { 1-f4- (6-hydroxy? -p? R? Din-2-yl) -p? Peraz? N-1-? N-methanoyl) -2- (4-iodo-2-methyl-phen? Lamino) -benzo? co EXAMPLE 117 5- (1- (4-f2- (2,5-Dimethyl-pyrro? -1-yl) -ethyl-1-p? Perazin-1-yt > -methanoyl) -3,4-difluoro-2- (4- iodine-2-methyl-phenylamino) -benzoic acid EXAMPLE 118 3,4-Difluoro-2- (4-iodo-2-methyl-phenamino) -5- acid. { 1-4- (3-phenoxy-pyridin-2-yl) -piperaz? N-1-yn-methanoyl) -benzoic acid EXAMPLE 119 3,4-Difluoro-2- (4-iodo-2-methyl-n-lamino) -5- acid. { 1- [4- (5-phenoxy-pyridin-2-yl) -piperazin-1-yl-1-methanoyl) -benzoic acid do H25 F2 I N4 O ?, MS (APCI) m + 1 = 671 EXAMPLE 120 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -5- acid. { 1- [4- (3-phenoxy-pyridin-4-yl) -f1,4ldiazepan-1-in-methane? L) -benzoic acid EXAMPLE 121 5- (1-f4- (3-Chloro-4-hydroxymethyl-phenyl) -piperazin-1-methanoyl} -3,4-difluoro-2- (4-vodo-2-methyl) acid phenylamino) -benzoic acid EXAMPLE 122 Acid 3, 4-di fluoro -2- (4-vodo-2-met il-f-enylamino) -5-ft- (8-tri-fluoro-methyl-3,4-dihydro-1H-benzo f4,51) midazof1, 2-alpira zin-2-yl) - methanoyl] -benzoic acid EXAMPLE 123 5- (1-f4- (5-Chloro-1,3-dimethyl-1-H-pyrazole-4-sulfonyl) -piperazin-1-yl-methanoyl) -3,4-difluoro-2- (4- vodo-2-methyl-phenylamino) -benzoic acid C24 H23CI F2 I N5 05 S, MS (APCI) m + 1 = 694 EXAMPLE 124 3,4-Difluoro-5- (1- (4-2 2 - (2-hydroxy-ethylsulfanyl) -phenin-p? Peraz? N-1-? L) -methane? L) -2- (4 -yodo-2-met? i-fen? lam? no) -benzoic acid C19 H17 F2 I N2 05 S, MS (APCI) m + 1 = 55 EXAMPLE 125 5- [1- (1,1-D? Oxo-16-thiomorpholin-4? L) -methane? L-3, 4-difluoro-2- (4-iodo-2-methyl-phen-lamino) acid -benzoic EXAMPLE 126 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -5- acid. { 1-f4- (1-methyl-piperidin-4-yl) -piperazin-1-yl-1-methanoyl) -benzoic acid C25 H29 F2 I N4, 03, MS (APCI) m + 1 = 599 EXAMPLE 127 3, 4-d? Fluoro-2- (4-iodo-2-methyl? N-nylamino) -5-f1- (4-OXO-1 phen? -1,3-tr? Aza- sp? rof4,51dec-8-? l) methane? ll-benzoic n - ^ - .-- £ - - ..
EXAMPLE 128 3-4-d? Fluoro-5-M-f4- (2-h? Drox? -et? L) -2 5-d? Met? Lp? Peraz? N-1? N-methane? L) acid -2- (4-iodo-2-met? L-fen? Lam? No) -benzo? Co C23 H26 F2 I N3 04, MS (APCI) m + 1 = 574 EXAMPLE 129 3,4-d? Fluoro-5- (1-f4- (2-hydrox? -et? L) -2,6-d? Met? Lp? Peraz? N-1? L-methane acid ? l.}. -2- (4-vodo-2-met? l-fen? lam? no) -benzo? co EXAMPLE 130 3,4-d? Fluoro-2- (4-iodo-2-met? L-phen? Lam? No) -5- [1- (4-? Soprop? L 2-met? Lp? Peraz acid. ? n-1-? l) -methane? l | -benzo? co EXAMPLE 131 Acid 5-. { 1-f4- (3-chloro-4-hydrox? Met? L-phen?) -2,6-d? Met? Lp? Peraz.n-1? L] -methane? L) -3 4 -d? fluoro-2- (4-iodo-2-met? i-fen? lam? no) -benzo? co EXAMPLE 132 3-d-Fluoro-5- acid. { 1-f4- (5-h? Drox? -pent? L) -p? Peraz? N- I -? L | - methane? L) -2- (4-iodo-2-met? L-fe nilammo) -benzoic EXAMPLE 133 3,4-Difluoro-5- (1 -. {4-f2- (2-hydroxy-ethoxy) -phenyl-piperazin-1-y-methanoyl) -2- (4-iodo-2-methyl) acid -phenylamino) -benzoic acid EXAMPLE 134 3,4-Difluoro-2- (4-vodo-2-methyl-phenylamino) -5- (1-f4- (4-methyl-pyridin-2-yl) -piperazin-1-ill-methanoyl) acid -benzoic EXAMPLE 135 Acid 5-. { 1-f4- (2-sec-butoxy-phenyl) -piperazin-1-ill-methanoyl) -3,4-difluoro-2- (4-vodo-2-methyl-phenylamino) -benzoic acid EXAMPLE 136 3,4-Difluoro-2- (4-vodo-2-methyl-phenylamino) -5- (1-f4- (2-isobutoxy-phenyl) -piperazin-1-methanoyl) -benzoic acid EXAMPLE 137 5-f1- (4-Benzothiazol-2-yl-piperazin-1-yl) -methanoin-3,4-difluoro-2- (4-budo-2-methyl-phenylamino) -benzoic acid EXAMPLE 138 5- (1-f4- (6-Ethoxy-pyridin-2-yl) -piperazin-1-yl-methanoyl) -3,4-difluoro-2- (4-iodo-2-methyl-phenylamino- benzoic ., i. EXAMPLE 139 5-f1- (4-Benzooxazol-2? L-p? Perazin-1-yl) -methanoin-3,4-difluoro-2- (4-iodo-2-methyl-phen-lamino) -benzoic acid EXAMPLE 140 3,4-Difluoro-2- (4-vodo-2-methyl-phenylamino) -5- (1- [4- (3-methyl-aminoxalin-2-? L) -piperazin-1-) acid in-methanoyl) -benzoic acid EXAMPLE 141 5-f1- (3'.6'-dimethyl-2,3,5,6-tetrahydro-f1.2'.bipyrazinyl-4-yl) -methanoyl-1, 3-4-difluoro-2- (4-iodo) acid -2-methyl-phenylamino) -benzoic acid EXAMPLE 142 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino) -5- acid. { 1-f4- (6-Methyl-pyridazin-3-yl) -piperazin-1-in-methanoyl} -benzoic EXAMPLE 143 3,4-Difluoro-5- (1-. {4-f3- (2-hydrox? -ethoxy) -phenyl] -piperazin-1-yl) -methane acid? -2- (4- iodine-2-methyl-phenylamino) -benzoic acid EXAMPLE 144 3,4-Difluoro-5-, 1- (2-hydrox? -ethyl) -imidazoiidin-2-ylidene-hydrazinocarbonyl-1-2- (4-vodo-2-methyl-phen-lamino) -benzoic acid Í-S..Jt.Éiíi ... i.é .: EXAMPLE 145 3,4-Difluoro-2- (4-vodo-2-met? L-phen? Lam? No) -5- (1-. {4-, 3- (propan-1-sulfon? L) acid) - phenyl] -p? peraz? n-1-? l) -methanoyl) -benzo? co C28 H28 F2 I N3 05 S, MS (APCI) m + 1 = 684 Example 146 3,4-difluoro-2- (4-vodo-2-methyl-fenilam? No) -5- (1-F4- (3-methanesulfonyl-phenyl) -piperazine-1-ill-methane? L) -benzoic EXAMPLE 147 3,4-d? Fluoro-2- (4-vodo-2-met? L-phenylamino) -5-.1-Í4-.2- (propan-1-sulfonyl) -phenyl acid -piperazin-1-? l) -methanoyl) -benzo? co EXAMPLE 148 Acid 5-. { 1-f4- (4,5-dimethyl-thiazol-2-yl) -p? Perazin-1-yl-methanoyl} -3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid EXAMPLE 149 Acid 5-. { 1-f4- (5-et? L-fA3.4] t? Adiazol-2- [l) -p? Perazin-1-? L. -methanoyl | -3.4-d? Fluoro-2- (4-iodine -2-methyl-phen? Lam? No) -benzoic acid j-1 -.- .. am-. • - »« '»- J > "a» * Jt-.A C23 H22 F2 I N5 O3 S, MS (APCI) m + 1 = 614 EXAMPLE 150 3,4-difluoro-5- (1-F4- (1-furan-2-yl-methanoyl) -piperazin-1-yl? Methanoyl) -2- (4-iodo-2-methylphenylamino) -benzoic C24 H20 F2 I N305, MS (APCI) m + 1 = 596 EXAMPLE 151 Acid 5-.1- (4-f4- (4,5-dihydro-1H-imidazol-2-yl) -butyl] -piperazin-1-ylV methanoyl) -3,4-difluoro-2- (4 -vodo-2-methyl-phenylamino) -benzoic acid EXAMPLE 152 3,4-Difluoro-2- (4-vodo-2-methy1-phenylamino) -5- (1-y4- (3-phosphono-propyl) -piperazin-1-yl-1-methanoyl acid} -benzoic EXAMPLE 153 3,4-Difluoro-5- { 1-f4- (2-hydrox? -et? l) -p? peraz? n-1-? l.-methano? l acid) - 2- (4-Vodo-2-methyl-phenylamino) -benzoic acid EXAMPLE 154 3,4-Di-fluoro-2- (4-iodo-2-methyl-hexa-n-lamino) -5-f1 - (5-methyl-hexahydro-pyrrolof3,4-c | pyrrole-2-acid il) -methane? l] -benzoic acid EXAMPLE 155 Acid? V- (1,1-dioxo-tetrahydro-1 At? Ofen-3-yl) -4,5-difluoro-6- (4-iodo-2-methyl-phen? Lamino) - / / -methyl-isophthalamic C20 H19 F2 I N2 05 S, MS (APCI) m + 1 = 565 EXAMPLE 156 3- ( { 1-f5-carboxy-2,3-difluoro-4- (4-vodo-2-meth? L-phenylamino) -phenn-methanoyl) -am? No. ) -tetrahydro-thiophene-3-carboxylic acid I i i itr I.ÉÜÍIT__llll ÉÜffl-rtititartH- EXAMPLE 157 4.5-difluoro Acid - / - (1-hydroxymethyl-cyclopentyl) -6- (4-vodo-2-methyl phenylamino) -isoftalámico EXAMPLE 158 4,5-Difluoro-N - (4-hydroxy-cyclohexyl) -6- (4-iodo-2-methyl-phenylamino) -isophthalamic acid EXAMPLE 159 4,5-Difluoro-A / - ((R) -2-hydroxy-cyclohexyl) -6- (4-vodo-2-methyl-phenylamino) -isophthalamic acid EXAMPLE 160 A / - (3-Cyclohexylamino-propyl) -4,5-difluoro-6- (4-iodo-2-methyl-phenylamino) -isophthalamic acid C24 H28 F2 I N3 03, MS (APCI) m + 1 = 572 EXAMPLE 161 4,5-Difluoro-6- (4-iodo-2-methyl-phenylamino) -N- (2-methylene-tetrahydro-thiophen-3-yl) -isophthalamic acid C19 H15 F2 I N204 S, MS (APCI) m + 1 = 533 EXAMPLE 162 Acid? / - (1,1-dioxo-tetrahydro-176-thiophen-3-yl) -4,5-difluoro-6- (4-vodo-2-methyl-phenylamino) -isophthalamic acid Biological examples EXAMPLE 163 Analysis cascade for inhibitors path MAP kinase 32P incorporation into the myelin basic protein (MBP) was analyzed in the presence of a fusion protein of glutathione S-transferase containing kinase p44MAP (GST-MAPK) and glutathione S-transferase fusion protein containing p45MEK (GST-MEK). The assay solution contains 20 mM HEPES, pH 7.4, 10 mM MgCl 2, 1 mM MnCl 2 of 1 mM EGTA, 50 mM [? -32P] ATP, 10 ug of GST-MEK, 0.5 GST-MAPK ug and 40 μg of MBP in a final volume of 100 μl. The reactions are stopped after 20 minutes by the addition of trichloroacetic acid and filtered through the filter GF / C mat. 32P withheld hir **** - * • "" "** on the mat filter is determined using a Beta 120S plate Compounds are evaluated at 10 μM for the ability to inhibit 32P incorporation To determine if compounds inhibit GST-MEK or GST MAP; Two additional protocols are used. In the first protocol, the compounds are added to the tubes containing GST-MEK, followed by the addition of GST-MAPK, MBP and [? -32P] ATP. In the second protocol, the compounds are added to tubes containing both GST-MEK and GST-MAPK, followed by MBP and [? -32P] ATP. Compounds showing activity in both protocols are classified as MAPK inhibitors, while compounds showing activity in only the first protocol are classified as MEK inhibitors.
EXAMPLE 164 Analysis of MAP kinase In vitro The inhibitory activity can be confirmed in direct analyzes. For MAP kmasa, 1 μg of GST-MAPK is incubated with 40 μg of MBP in the presence or absence of the test compound for 15 minutes at 30 ° C in a final volume of 50 μL containing 50 mM Tris (pH 7.5) , 10 μM of MgC12, 2 μM of EGTA, and 10 μM of [α -3A] ATP The reaction is stopped by the addition of the sample regulator Laemmh SDS and phosphorylated MBP resolved by electrophoresis in a 10% polyacrylamide gel. The rá if ÉÉ-l ... At? aaif *. *. TO . .. «*.,. > A - ~? ~ * .., A .., A. .. ... 4Kfaa ^. ^ JL Radioactivity incorporated in MBP is determined by auto-radiography and scintillation of bands removed by excision EXAMPLE 165 MEK In Vitro Analysis For the evaluation of direct MEK activity, 10 μg of GST-MEKi is incubated in the presence of absence of the test compound with 5 μg of a fusion protein of glutathione S-transferase containing p44MAP kinase with a lysine to the alanine mutation at position 71 (GST-MAPK-KA). This mutation eliminates MAPK kinase activity, thus only the kinase activity attributed to the remaining MEK aggregates. Incubations are 15 minutes at 30 ° C in a final volume of 50 μl containing 50 mM Tris (pH 7.5), 10 μM MgCl 2, 2 μM EGTA, and 10 μM [α-32 P] ATP. The reaction is stopped by the addition of the sample regulator Laemmli SDS. Phosphorylated GST-MAPK-KA was resolved by electrophoresis in a. 10% polyacrylamide gel. The radioactivity incorporated in GST-MAPK-KA is determined by autoradiography and subsequent scintillation counting of bands excised by excision. Alternatively, artificially activated MEK containing serine is used for glutamate mutations at positions 218 and 222 (GST-MEK-2E). When these two sites are phosphoresed, the MEK activity increases. Phosphorylation of these sites can be mimicked by mutation of septa to glutamate residues. For this analysis, 5 μg of GST-MEK-2E is incubated with 5 μg of GST-MAPK-KA for 15 minutes at 30 ° C in the same regulator of reaction as described above. The reactions are terminated and analyzed as in the previous.
EXAMPLE 166 Complete cell MAP kinase analysis To determine in case of block activation of MAP kinase compounds in whole cells, the following protocol is used. The cells were plated on multi-well plates and developed to confluence. The cells were stripped of the serum overnight. The cells were exposed to the desired concentrations of the compound or vehicle (DMSO) for 30 minutes, followed by the addition of a growth factor, for example, PDGF (100 ng / ml). After a 5 minute treatment with the growth factor, the cells are washed with PBS, and lysed in a regulator consisting of 70 mM NaCl, 10 mM HEPES (pH 7.4), 50 mM glycerol phosphate, and 1% Triton X-100. The lysates are clarified by centrifugation at 13,000 x g for 10 minutes. Five micrograms of the resulting supernatants are incubated with 10 μg of protein-2 (Map2) associated with microtubule for 15 minutes at 30 ° C in a final volume of 25 μl containing 50 mM Tris (pH 74), 10 mM MgCl 2, 2 mM EGTA and 30 μM [? -32P] ATP The reactions are terminated by the addition of the Laermm sample regulator. Map2 phospho- phate is resolved in 7.5% of acplamide gels and the incorporated radioactivity is determined by scintillation counting of bands removed by excision.
EXAMPLE 167 Monolayer Growth The cells were plated on multi-well plates of 10 to 20,000 cells / ml. Forty-eight hours after seeding, the test compounds are added to the cell growth medium and the incubation is continued for an additional 2 days. The cells are then removed from the wells for incubation with trypsin and enumerated with a Coulter counter.
EXAMPLE 168 Smooth aqar growth Cells are seeded in 35 mm dishes from 5 to 10,000 cells / dish using a growth medium containing 0.3% agar. After cooling to solidify the agar, the cells are transferred to a 37 ° C incubator. After 7 to 10 days of growth, the visible colonies are enumerated manually with the help of a vivisection microscope.
EXAMPLE 169 Collagen-induced arthritis in mice Arthritis induced by type II collagen (CIA) in mice is an experimental model of arthritis that has a number of pathological, immunological and genetic characteristics in common with rheumatoid arthritis. The disease is induced by immunization of DBA / 1 mice with 100 μg of type II collagen, which is a major component of binding cartilage, delivered intradermally in complete Freund's adjuvant. Disease susceptibility is regulated by the MHC class II gene site, which is analogous to the association of rheumatoid arthritis with HLA-DR4. A progressive and inflammatory arthritis developed in the majority of immunized mice, characterized by the width of the leg increases up to 100%. A test compound is administered to mice in a range of amounts, such as 20, 60, 100 and 200 mg / kg body weight / day. The duration of the test can be from several weeks to a few months, such as 40, 60 or 80 days. A clinical incision index is used to evaluate the progression of disease from erythema and edema (stage 1), joint distortion (stage 2) to joint ankylosis (stage 3). The disease is variable in that it can affect one or all of the legs in an animal, resulting in a total possible score of 12 for each mouse. The histopathology of an arthritic joint reveals synovitis, cataract formation, and erosions of cartilage and bone. All mouse strains that are susceptible to CIA are capable of responding to elevated antibodies to type II collagen, and there is a marked cellular Cll response.
EXAMPLE 170 SCart-induced monoarticular arthritis Arthritis is induced as described by Schwab, er al., Infection and Immunity, 59: 4436-4442 (1991) with minor modifications. Rats receive 6 μg of sonically induced SCW [in 10 μl of Dulbecco PBS (DPBS)] by an intraarticular injection in the right tibiotalar joint on day 0. On day 21, DTH was initiated with 100 μg of SCW (250 μg). μl) administered iv For studies of the oral compound, the compounds are suspended in vehicle (0.5% hydroxypropylmethylcellulose / 0.2% Tween 80), sonically induced, and administered twice daily (10 ml / kg by volume) beginning 1 hour before reactivation with SCW The compounds are administered in amounts between 10 and 500 mg / kg of body weight / day, such as 20, 30, 60, 100, 200 and 300 mg / kg / day. Edema measurements are obtained by determining the baseline volumes of the sensitized hind paw before reactivation on day 21, and comparing them with volumes at subsequent time points such as day 22, 23, 24 and 25. The volume Paw is determined by mercury plethysmography. iMltlii ^^ EXAMPLE 171 Fey mouse heart-ear transplant model, T.A. et al. describes methods for transplanting neonatal heart-spleen grafts into the ear pavilion of mice and rats (J. Pharm. and Toxic, Meth. 39: 9-17 (1998)). The compounds are dissolved in solutions containing combinations of absolute ethanol, 0.2% hydroxypropylmethylcellulose in water, propylene glycol, cremophor, and dextrose, or other solvent or suspension vehicle. Mice are dosed orally or intraperitoneally once, twice or three times daily from the day of transplantation (day 0) to day 13 or until the grafts have been rejected. The rats are dosed once, twice, or three times daily from day 0 to day 13. Each animal is anesthetized and an incision is made at the base of the recipient ear, cutting only the epidermis and dorsal dermis. The incision is spread open and below the cartilage parallel to the head, and wide enough to accommodate the appropriate undercut for a rat or insertion tool for a mouse. A neonatal mouse or rat puppy less than 60 hours old is anesthetized and dislocated cervically. The heart is removed from the chest, rinsed with saline, bisected longitudinally with a scalpel, and rinsed with sterile saline. The donor heart fragment is placed in the preformed tunnel with the insertion tool and air or residual fluid is expressed delicately from the tunnel with light pressure. No suturing, adhesive bonding, bandaging, or antibiotic treatment is required. The implants are examined in amplification 10-20 times with a stereoscopic dissection microscope without anesthesia. Containers whose grafts are not visibly beaten can be anesthetized and evaluated for the presence of electrical activity using pins of subdermal microelectrodes of Grass E-2 platinum placed in the pinna or directly on the graft and a tachograph. Implants can be examined 1-4 times a day for 10, 20, 30 or more days. The ability of a test compound to decrease the symptoms of transplant rejection can be compared to a control compound such as cyclosporin, tacrolimus, or orally administered lefluonomide.
EXAMPLE 172 Eosinophilia Induced by Mupno Ovalbumin Female C57BL / 6 mice are obtained from Jackson Laboratory (Bar Harbor, ME). All animals are given food and water ad libitum. Mice are sensitized with a single intrapeptoneal injection of OVA (Grade V, Sigma Chemical Company, St. Louis, MO) adsorbed to alum, (10 μg OVA + 9 mg alum in 200 μl saline) or control vehicle, ( 9 mg of alum in 200 μl of saline) on day 0. On day 14, the mice were emplaced with a 12 minute inhalation of an aerosol consisting of 1.5% OVA (weight / volume) in saline produced by a nebulizer (small particle generator, model SPAG-2, ICN Pharmaceuticals, Costa Mesa, CA). Groups of eight mice are dosed with oral vehicle (0.5% hydroxypropylmethylcellulose / 0.25% TWEEN-80), or a test compound of 10, 30 or 100 mg / kg in an oral vehicle, 200 μl per po mouse Dosing is performed once a day starting from day 7 or day 13, and extending through day 16. For the determination of pulmonary eosinophilia, three days after the first OVA aerosol site (day 17), the mice anesthetized with an ip injection of anesthetic (Ketamine / Acepromazine / Xylazine), and the trachea is exposed and cannulated. The lungs and upper airways are purged twice with 0.5 ml of cold PBS. A portion (200 μl) of the purged bronchoalveolar fluid (BAL) is enumerated using a Coulter counter model ZB1 (Coulter Electronics, Hiaieah, FL). The remaining BAL fluid is then centrifuged at 300 xg for five minutes, and the cells are resuspended in 1 ml of HBSS (Gibco BRL) containing 0.5% fetal calf serum (HyClone) and 10 mM HEPES (Gibco BRL) . The cell suspension is centrifuged in a cytospin (Shandon Southern Instruments, Sewickiey, PA), and stained by Diff Quick (American Scientific Products, McGraw Park, IL) to differentiate BAL leukocytes into subsets of neutrophil, eosinophil, monocyte or lymphocyte. The number of eosinophils in the BAL fluid is determined by multiplying the percentage of eosmophiles by the total ceiular count.
EXAMPLE 173 The experimental compounds are added to 96-well format plates with deep filter wells. Inactivated kinase ERK1 (K71R mutant) in HEPES regulator is then added to each well. After the subsequent addition of MEK1 (2D mutant) diluted in Tris buffer before being added to the plate, and the reaction is initiated by the addition of radioactive ATP, diluted in 0.05% Tween 20. After 1 hour of incubation at room temperature, 20% TCA cooled in ice is added to each well to stop the reaction and to precipitate the protein in the solution. The filtration is done the next day followed by scintillation counting of the incorporated radioactivity using a microbeta 1450 Perkm Elmer Wallac counter. Inhibition is expressed as a percentage of the control vehicle. From the above description and examples, and from the following claims, the essential features of the invention are readily apparent. The scope of the invention also encompasses various modifications and adaptations within the knowledge of a person with ordinary experience. Examples include a described compound modified by the z? A * M & to ^, t & amp; M * alb? M? < 2 addition or removal of a protecting group, or an ester, pharmaceutical salt, hydrate, acid or amide of a described compound. The publications cited herein are incorporated herein by reference in their entirety.

Claims (32)

  1. CLAIMS 1. A compound of formula I or formula II characterized in that Ri is hydrogen, C 1-8 alkyl, C 1-8 alkoxy, halo, C 1-2 haloalkyl, or CN; R3 and R4 are each independently hydrogen, halo, haloalkyl of C? -2, alkyl of Ci.β, alkoxy of Ci-a, nitro, CN, u (O or NH) k- (CH2), -R9, in wherein R9 is hydrogen, hydroxy, CO2H or NR10Rn; j is 0 to 4; k is 0 or 1; Rio and R11 are each independently hydrogen or C? -8 alkyl, or together with the nitrogen to which they are attached form a cyclic ring of 3 to 10 members optionally containing one, two or three additional heteroatoms selected from the group consists of O, S, NH, and N-C 8 alkyl, A is hydroxy, C 6 akoxy, or NR 6 OR 7; Re is hydrogen, β-alkyl, (CO) -alkyl of d.8, phenyl, naphthyl, phenyl I (Ci-β alkyl), or C3-10 cycloalkyl. R7 is hydrogen, d-8 alkyl, d-β alkenyl, C2-8 alkynyl, C3.10 cycloalkyl or C3.10 cycloalkyl optionally containing a heteroatom selected from the group consisting of O, S and NR9; X is OR12; NR13R12, or NR14; R 2 and R 13 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 1 6 alkoxy, C 4-6 cycloalkyl, [(CH 2) n Y (CH 2) m] q CH 3, phenyl, naphthyl, (C6_6 alkyl) phenyl, - [(CH2) nY (CH2) m] qphenyl, C2.6 heteroaryl, C2.6 heterocyclic radical (C6_6alkyl) or C2 heterocyclic radical -6 [(CH2) nY (CH2) m] q; And it's N or O; R 4 taken with N is a 5- to 7-membered heterocyclic radical with between 0 and 3 additional heteroatoms or combinations of heteroatoms in the ring selected from the group consisting of O, S, SO, S02, NH and NMe; 0 < . n, m < _6, n + m < .8, 1 ÍL q 5; and wherein the above alkyl, alkenyl, alkynyl, heterocyclic radical, aryl, and cycloalkyl groups may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of hydroxy, C 4 alkyl, fluoro, chloro, iodine, bromine, amino and C1-4 alkoxy, and NRaRbi wherein Ra and R are each independently selected from the group consisting of hydrogen and alkyl of d.6; Y the pharmaceutically acceptable salts thereof.
  2. 2. The compound according to claim 1, characterized in that Ri is alkyl of d.8 or halo.
  3. 3. The compound according to claim 2, characterized in that R is methyl.
  4. 4. The compound according to claim 1, characterized in that R3 and R are each independently selected from the group consisting of hydrogen and halo.
  5. 5. The compound according to claim 4, characterized in that halo is fluoro.
  6. 6. The compound according to claim 1, characterized in that A is NR6OR.
  7. 7. The compound according to claim 1, characterized in that X is NR? 3R? 2.
  8. 8. The compound according to claim 1, characterized in that X is NR14.
  9. 9. The compound according to claim 1, characterized in that R12 and R13 are each selected independently from the group consisting of [(CH2) nY (CH2) m] qCH3, d.6) phenyl alkyl, - [(CH2) nY (CH2) m] qphenyl, and heterocyclic radical (alkyl of
  10. 10. The compound according to claim 1, characterized in that the heterocyclic radical is a hetero-acyl í "& .t- ~ .A,., .., A- ^, selected from the group consisting of a substituted or unsubstituted radical of pyrrole, furan, pyran, thiophene, pyrazole, imidazole, triazole, tetrazole, indole, isoxazole, indazole , pyridine, pyrazine, oxazole, thiazole, oxadiazole, and oxathiadiazole.
  11. 11. The compound in accordance with the claim 1, characterized in that the heterocyclic radical is a heteroalkyl selected from the group consisting of a substituted or unsubstituted radical of morpholine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, pyrrolidone, imidazoline and tetrahydrothiophene.
  12. 12. The pharmaceutical composition characterized in that it comprises a compound according to claim 1 and a pharmaceutically acceptable carrier.
  13. 13. The method for treating a proliferative disease in a patient in need thereof characterized in that it comprises administering a therapeutically effective amount of a compound according to claim 1.
  14. 14. The method according to claim 13, characterized in that the proliferative disease is selected from the group consisting of cancer, restenosis, psoriasis, autoimmune disease and atherosclerosis.
  15. 15. The method for treating psoriasis in a patient in need thereof, characterized in that it comprises administering a therapeutically effective amount of a compound according to claim 1.
  16. The method for treating cancer in a patient in need thereof is characterized in that it comprises administering a therapeutically effective amount of a compound according to claim 1.
  17. 17. The method according to claim 16, characterized in that the cancer is related to MEK
  18. 18. The method according to claim 16, characterized in that the cancer is brain, breast, lung, ovarian, pancreatic, prostate, renal or cancer. colo-rectal
  19. 19. The method for treating osteoarthritis in a patient in need thereof characterized in that it comprises administering a therapeutically effective amount of a compound according to claim 1.
  20. 20. The method for treating rheumatoid arthritis in a patient in need of same, characterized in that it comprises administering a therapeutically effective amount of a compound according to claim 1.
  21. 21. The The method for treating heart failure in a patient in need thereof is characterized in that it comprises administering a therapeutically effective amount of a compound according to claim 1.
  22. 22. The method for treating chronic pain in a patient in need thereof characterized in that it comprises administering a therapeutically effective amount of a compound according to claim 1. AL4iS.il J ..-. n ^ ü ^^.
  23. 23. The method according to claim 22, characterized in that the chronic pain is selected from the group consisting of neuropathic pain, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia and hypothyroidism.
  24. 24. The method according to claim 22, characterized in that chronic pain is associated with inflammation.
  25. 25. The method according to claim 22, characterized in that chronic pain is associated with arthritis.
  26. 26. The method according to claim 22, characterized in that chronic pain is associated with postoperative pain.
  27. 27. The method for treating neuropathic pain in a patient in need thereof, characterized in that it comprises administering a therapeutically effective amount of a compound according to claim 1.
  28. 28. The method according to claim 27, characterized in that the neuropathic pain is associated with a condition selected from the group consisting of inflammation, postoperative pain, artificial limb pain, burn pain, gout, trigeminal neuralgia, acute and post-herpetic herpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma , vasculitis, viral infection, traumatic injury, constriction injury, tissue injury, limb amputation, postoperative pain, arthritis pain, and nerve injury between the peripheral nervous system and the central nervous system.
  29. 29. The method for treating cancer in a patient in need thereof, characterized in that it comprises administering a therapeutically effective amount of a compound according to claim 1, in combination with radiation therapy.
  30. 30. The method for treating cancer in a patient in need thereof, characterized in that it comprises administering a therapeutically effective amount of a compound according to claim 1, in combination with at least one chemotherapeutic agent. - * •:
  31. 31. The method according to claim 30, characterized in that the chemotherapeutic agent is a mitotic inhibitor.
  32. 32. The method according to claim 30, characterized in that the mitotic inhibitor is selected from the group consisting of paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinflunine.
MXPA02008103A 2000-03-15 2001-03-12 5 amide substituted diarylamines as mex inhibitors. MXPA02008103A (en)

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