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WO2011070030A1 - Dérivés sulfonamides hétérocycliques - Google Patents

Dérivés sulfonamides hétérocycliques Download PDF

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Publication number
WO2011070030A1
WO2011070030A1 PCT/EP2010/069099 EP2010069099W WO2011070030A1 WO 2011070030 A1 WO2011070030 A1 WO 2011070030A1 EP 2010069099 W EP2010069099 W EP 2010069099W WO 2011070030 A1 WO2011070030 A1 WO 2011070030A1
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WIPO (PCT)
Prior art keywords
fluoro
alkyl
difluoro
substituted
iodo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2010/069099
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English (en)
Inventor
Mark G. Bock
Dinesh Chikkanna
Clive Mccarthy
Henrik Moebitz
Chetan Pandit
Ramulu Poddutoori
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
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Novartis AG
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Publication date
Priority to EP10790407.0A priority Critical patent/EP2509964B1/fr
Priority to AU2010329940A priority patent/AU2010329940B2/en
Priority to GEAP201012745A priority patent/GEP20135998B/en
Priority to BR112012013735A priority patent/BR112012013735A2/pt
Priority to CN2010800556652A priority patent/CN102648188A/zh
Priority to ES10790407.0T priority patent/ES2484171T3/es
Priority to CA2781218A priority patent/CA2781218A1/fr
Priority to US13/514,208 priority patent/US8614239B2/en
Priority to EA201200823A priority patent/EA201200823A1/ru
Priority to MX2012006561A priority patent/MX2012006561A/es
Priority to JP2012542525A priority patent/JP5456908B2/ja
Priority to PH1/2012/501142A priority patent/PH12012501142A1/en
Application filed by Novartis AG filed Critical Novartis AG
Publication of WO2011070030A1 publication Critical patent/WO2011070030A1/fr
Priority to ZA2012/03324A priority patent/ZA201203324B/en
Priority to IL219635A priority patent/IL219635A0/en
Priority to TNP2012000242A priority patent/TN2012000242A1/en
Priority to CU2012000085A priority patent/CU20120085A7/es
Anticipated expiration legal-status Critical
Priority to MA35003A priority patent/MA33848B1/fr
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • the invention relates to heterocyclic sulfonamide compounds and pharmaceutical compositions thereof, in particular heterocyclic sulfonamide compounds that are specific inhibitors of kinase activity of MEK.
  • the invention also relates to the use of the compounds and compositions thereof in the management of hyperproliferative diseases like cancer and inflammation.
  • Hyperproliferative diseases like cancer and inflammation are receiving a lot of attention from the scientific community and there is a strong desire to discover compounds that provide therapeutic benefits with regard to treating hyperproliferative diseases. In this regard efforts have been made to identify and target specific mechanisms which play a role in proliferating the diseases.
  • MAP mitogen-activated protein
  • ERK mitogen-activated protein
  • MAP kinase cascade which is known to play an important role in cell proliferation and differentiation.
  • This pathway can be activated when a growth factor binds to its receptor tyrosine kinase. This interaction promotes RAS association with RAF and initiates a phosphorylation cascade through MEK (MAP kinase) to ERK. Inhibition of this pathway is known to be beneficial in treating hyperproliferative diseases.
  • MEK is an attractive therapeutic target because the only known substrates for MEK phosphorylation are the MAP kinases, ERKl and ERK2. Constitutive activation of MEK/ERK was been found in pancreatic, colon, lung, kidney and ovarian primary tumor samples.
  • Phosphorylation of MEK appears to increase its affinity and its catalytic activity toward ERK as well as is affinity for ATP.
  • This invention describes compounds that inhibit MEK activity by modulation of ATP binding, association of MEK with ERK by mechanisms that are competitive, and/or allosteric and/or uncompetitive.
  • Stroke see, e.g., Evidence of efficacy in stroke models significant neuroprotection against ischemic brain injury by inhibition of the ME described in J. Pharmacol. Exp. Ther. 304: 172. 2003; and Brain Res. 996:55, 2004
  • Diabetes see, e.g., Evidence in diabetic complications described in Am. J. Physiol. Renal.286, F120 2004
  • Inflammation see e.g., Evidence of efficacy in inflammation models described in Biochem Biophv. Res. Com. 268:647. 2000
  • Arthritis see, e.g, Evidence of efficacy in experimental osteoarthritis and arthritis as described in J. Clin. Invest. 1 16: 163. 2006).
  • the invention provides a compound of formula (I)
  • X is N or C(H);
  • R 1 is aryl or heteroaryl, optionally substituted by one or more substituents each independently selected from List 1 ;
  • R 2 is H or (Ci.C 6 )alkyl
  • R 3 is H, (C 1- C 6 )alkyl, halo- substituted (C
  • R 4 is H, halogen, (Ci_C 6 )alky1 or halo-substituted
  • R 5 is H, halogen, (Ci.C 6 )alkyl or halo-substituted (C,.C 6 )alkyl;
  • R 6 is H or (C,.C 6 )alkyl
  • R 7 is a chemical moiety selected from the group consisting of (Ci.C 6 )alkyl, (C 2- C 6 )alkenyl, (C 2- C6)alkynyl, (Ci.C6)alkylamino, di-((Ci.C 6 )alkyl)amino, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, wherein said chemical moiety is optionally substituted by one to three substituents each independently selected from halogen, cyano, (C 2- Ce)alkenyl, hydroxy!, (Ci.C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (Ci- C 6 )alkylthio, halo-substituted(Ci.C 6 )alkyl, amino, (C 1- C 6 )alkylamino, di-((Ci- Ce)alkyl)
  • List 1 is selected from hydroxyl, cyano, nitro, (C 2- C 6 )alkenyl, (C 2 . C6)alkynyl, (C 2- C6)alkenyloxy, (C 2- C 6 )alkynyloxy, halogen, (Ci.
  • C6)alkylcarbonyl carboxy, (Ci.Ceialkoxycarbonyl, amino, (Ci.C6)alkylamino, di-((Ci_ C 6 ))alkylamino, (Ci.C6)alkylaminocarbonyl, di-((Ci.C6)alkyl)aminocarbonyl, (Q.
  • Ceialkylcarbonylamino (Ci-C6)alkylcarbonyl((Ci-C 6 )alkyl)amino, (Ci- CeJalkylsulfonylamino, (Ci kylsulfonyKiQ.CeialkylJamino, (C,.C 6 )alkyl-S-, (Ci_ C 6 )alkylS(0)-, (C,.C 6 )alkyl-S0 2 -, NH 2 -S ⁇ 3 ⁇ 4-, (Ci.C6)alkylN(H)-S0 2 - and di-ttCi.
  • X is N.
  • X is C(H).
  • R 1 is an optionally substituted phenyl, more particularly, R 1 is phenyl, optionally substituted by one to three substituents, each independently selected from halogen (e.g. fluoro, bromo or iodo), (Ci VietnameseC 6 )alkyl, (C 2- C 6 )alkynyl, halo-substituted(Ci-C6)alkyl, and (Ci ⁇ alkylthio.
  • R l is phenyl substituted in the 2-, 4- and optionally 6- positions, preferably the 2- and 4- positions. Suitable substituted phenyl groups are 2-fluoro-4-bromophenyl or 2-fluoro-4-iodophenyl.
  • R 2 is H.
  • R 3 is H or (e.g. methyl).
  • R 4 is H or halogen (e.g. fluoro), more preferably halogen (e.g., fluoro).
  • R 5 is H or halogen (e.g. fluoro), more preferably halogen (e.g., fluoro).
  • R 6 is H.
  • R 7 is di-((Ci_C 6 )alkyl)amino (e.g. dimethylamino), (C 3- C 7 )cycloalkyl (e.g. cyclopropyl), substituted (C3-C 7 )cycloalkyl ((e.g. cyclopropyl substituted with (C 2 . C 6 )alkenyl or a (C).C6)alk l optionally substituted by one or two hydroxyl groups (e.g. 2,3-dihydroxypropyl) e.g., l-(2,3-dihydroxy-propyl)-cyclopropyl). More preferably, R 7 is cyclopropyl, l -(2,3-dihydroxy-propyl)-cyclopropyl, or N,N-dimethylamino.
  • R 7 is cyclopropyl, l -(2,3-dihydroxy-propyl)-cyclopropyl, or N,N
  • X is N or C(H);
  • R la is halogen
  • R lb is halogen
  • R 3 is H or (Ci.C 6 )alkyl
  • R 4 is halogen
  • R 5 is halogen
  • R 7 is (i) 3- to 6-membered cycloalkyl, where said cycloalkyl is optionally substituted with hydroxyl, (Ci-C 6 )alkyl, (C 2- C 6 )alkenyl, or (C 2- C 6 )alkynyl, wherein said (d-C6)alkyl, said (C 2- C 6 )alkenyl, and said (C 2- C 6 )alkynyl are optionally substituted with a benzyloxy or 1 to 3 hydroxyl,
  • R l is fluoro
  • R lb is bromo or iodo
  • R 4 is fluoro
  • R 5 is fluoro
  • R 7 is di-((C]-C6)alkyl)amino or (C3-C 7 )cycloalkyl, where the (C3.C 7 )cycloalkyl is optionally substituted by (C 2- C 6 )alkenyl or (C
  • X is N.
  • Representative compounds of Formula (la) where X is N include: Cyclopropanesulfonic acid [4,5-difluoro-6-(2-fluoro-4-iodo- phenylamino)-benzooxazoI-7-yl]-amide; Dimethylsulfamic acid [4,5-difluoro-6-(2- fluoro-4-iodo-phenylamino)-2-methyl-benzooxazoI-7-yl]-amide; Dimethylsulfamic acid [4,5-difluoro-6-(2-fluoro-4-iodo-phenylamino)-benzooxazol-7-yl]-amide;
  • X is C(H).
  • Representative compounds of Formula (la) where X is C(H) include: Cyclopropane sulfonic acid [4,5-difluoro-6-(2- fluoro-4-iodo-phenylamino)-benzofuran-7-yI]-amide; 1-(2,3-Dihydroxy-propyl)- cyclopropanesulfonic acid [4,5-difluoro-6-(2-fluoro-4-iodo-phenylamino)-benzofuran-7- yl]amide; l -(2-Hydroxy-ethyl)-cyclopropanesulfonic acid [4,5-difluoro-6-(2-fluoro-4- iodo-phenylamino)-benzofuran-7-yl]amide; and 2-Hydroxymethyl-cyclopropanesulfonic acid [4,5-difluoro-6-(2-fluoro-4-iodo-phenyl
  • composition which comprises any one of the compounds described above, or
  • alkyl refers to a hydrocarbon moiety of the general formula C n H 2 n+i .
  • the alkane group may be straight or branched.
  • (Ci-C6)alkyl refers to a monovalent, straight, or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like).
  • alkyl portion i.e., alkyl moiety of an alkoxy, alkylamino, dialkylamino, acyl (i.e., alkyl-C(0)- or alkylcarbonyl), alkylamido (i.e., alkyl-C(0)-NH-, alkyl-C(0)-N(alkyl)(H», alkylthio (i.e., alkyl-S-), alkylsulfinyl (i.e., alkyl-S(O)-), alkylsulfonyl (i.e., alkyl- S(0) 2 -), alkylsulfamyl (alkyl-NH-S0 2 -), alkyl sulfonami do (alkyl-S0 2 -NH-), etc.
  • alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or
  • Halo-substituted alkyl refers to an alkyl group having at least one halogen substitution.
  • alkenyl refers to an alkyl moiety containing at least one unsaturation in the alkyl group.
  • the alkenyl group may be straight or branched. For example, vinyl, prop-l-enyl, prop-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, and the like.
  • aryl refers to aromatic moieties having a single (e.g., phenyl) or a fused ring system (e.g., naphthalene, anthracene, phenanthrene, etc.).
  • a typical aryl group is a 6- to 14-membered aromatic carbocyclic ring(s).
  • a fused aromatic ring system may also include a phenyl fused to a partially or fully saturated cycloalkyl.
  • a preferred aryl is phenyl.
  • cycloalkyl or “partially or fully saturated cycloalkyl” refers to a carbocyclic ring which is fully hydrogenated (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.) or partially hydrogenated (e.g., cyclopropenyl, cyclobutenyl, cyclopentyl, cyclopenta-l ,3-dienyl, cyclohexenyl, cyclohexa-l ,3-dienyl, cyclohexa-l ,4-dienyl, etc.).
  • the cycloalkyl ring is generally a 3- to 12-membered ring which may be a single ring (as described above), a bicyclic ring (e.g., octahydropentalenyl, bicyclo[l . l . l ]pentanyl, bicyclo[2.1.1 ]hexanyl,
  • bicyclo[2.2.2]octanyl bicyclo[2.2.2]oct-2-enyl, bicyclo[2.2.2]octa-2,5-dienyl, etc.
  • a spiral ring e.g., spiro[2.2]pentanyl, etc.
  • Halogen or "halo” may be fluorine, chlorine, bromine or iodine.
  • heterocycle or “partially or fully saturated heterocycle” refers to a nonaromatic ring that is either partially or fully hydrogenated and may exist as a single ring, bicyclic ring (including fused rings) or a spiral ring.
  • the heterocyclic ring is generally a 3- to 12-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • Partially saturated or fully saturated heterocyclic rings include groups such as epoxy, aziridinyl, azetidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, 1 H-dihydroimidazolyJ, hexahydropyrimidinyl, piperidinyl, piperazinyl, pyrazoiidinyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl, oxazinyl, morpholino, thiomorpholino, tetrahydrothienyl, tetrahydrothienyl 1 ,1 -dioxide, oxazolidinyl, thiazolidinyl, octahydropyrrolo[3,2-b]pyrrolyl, and the like.
  • a partially saturated heterocyclic ring also includes groups wherein the heterocyclic ring is fused to an aryl or heteroaryl ring (e.g., 2,3-dihydrobenzofuranyl, indolinyl (or 2,3- dihydroindolyl), 2,3-dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl, 1 ,2,3,4- tetrahydroquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydropyrido[3,4- b]pyrazinyl, and the like).
  • spiral rings include 2,6-diazaspiro[3.3]heptanyl, 3-azaspiro[5.5]undecanyl, 3,9-diazaspiro[5.5]undecanyl, and the like.
  • heteroaryl refers to aromatic moieties containing at least one heteratom (e.g., oxygen, sulfur, nitrogen or combinations thereof) within a 5- to 10- membered aromatic ring system (e.g., pyrrolyl, pyridyl, pyrazolyl, indolyl, indazolyl, thienyl, furanyl, benzofuranyl, oxazolyl, imidazolyl, tetrazolyl, triazinyl, pyrimidyl, pyrazinyl, thiazolyl, purinyl, benzimidazolyl, quinolinyl, isoquinolinyl, benzothiophenyl, benzoxazolyl, lH-benzo[d][l,2,3]triazolyl, and the like.).
  • a 5- to 10- membered aromatic ring system e.g., pyrrolyl, pyridyl, pyrazolyl, in
  • the heteroaromatic moiety may consist of a single or fused ring system.
  • a typical single heteroaryl ring is a 5- to 6- membered ring containing one to three heteroatoms independently selected from oxygen, sulfur and nitrogen and a typical fused heteroaryl ring system is a 9- to 10-membered ring system containing one to four heteroatoms independently selected from oxygen, sulfur and nitrogen.
  • the fused heteroaryl ring system may consist of two heteroaryl rings fused together or a hetereoaryl fused to an aryl (generally, phenyl).
  • compounds of the present invention refers to compounds of Formula 1, la, I-A and I-B, and salts thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), tautomers, isotopically labeled compounds (including deuterium substitutions), and inherently formed moieties (e.g., polymorphs, solvates and/or hydrates).
  • the present invention provides compounds and pharmaceutical compositions thereof that are useful in the treatment of diseases, conditions and/or disorders modulated by the inhibition of kinase activity of ME .
  • Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.) s or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)).
  • reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are described below, those of skill in the art will appreciate that other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
  • Intermediate 1(a) may be prepared from the starting material (SM-1) where Z' is a suitable leaving group, such as F, with a desired amino compound (e.g., R'-NH 2 ) under suitable conditions, such as treatment with lithium bis(trimethylsilyl)amide (LHMDS) in a suitable solvent (e.g., tetrah drofuran) at reduced temperature, followed by treatment with a suitable metal alkoxide (e.g. sodium alkoxide, such as sodium methoxide, where R is methyl) at reduced temperature.
  • a suitable metal alkoxide e.g. sodium alkoxide, such as sodium methoxide, where R is methyl
  • the R group in subsequent steps acts as an O-protecting group.
  • intermediate 1(b) may be prepared by reduction of Intermediate 1(a) using standard reduction conditions well known to those of skill in the art, such as with Zn and hydrochloric acid.
  • Intermediate 1(c) may be prepared from Intermediate 1(b) by treatment with a suitable carbonylation agent (e.g., ⁇ , ⁇ -carbonyldiimidazole) in a suitable solvent (e.g., dichloromethane).
  • a suitable carbonylation agent e.g., ⁇ , ⁇ -carbonyldiimidazole
  • a suitable solvent e.g., dichloromethane
  • Intermediate 1(d) may be prepared from Intermediate 1(c) by treatment with a suitable nitrating agent (e.g., fuming nitric acid) at reduced temperature, followed by reduction of the nitro group under standard reduction conditions (e.g., Zn and
  • Ring formation to provide Intermediate 1(e) may be achieved by deprotecting the oxygen of Intermediate 1(d) (e.g., where R is alkyl, then treatment with borontribromide) followed by ring formation with the desired reagent R -C(OR) 3) where OR of the reagent acts as a leaving group.
  • Intermediate 1(f) may be prepared by reaction of intermediate 1(e) with the desired sulfonylating agent (e.g., R 7 S0 2 X, where X is a suitable leaving group (e.g., CI)).
  • desired sulfonylating agent e.g., R 7 S0 2 X, where X is a suitable leaving group (e.g., CI)
  • a compound of the present invention where R 2 and R 6 are H and X is N (I-A), may be prepared by removal of the amino protecting group introduced earlier using the appropriate reagents for the particular amino-protecting group used (e.g., potassium trimethylsilonolate).
  • the amino protecting group e.g., potassium trimethylsilonolate
  • Intermediate 2(a) may be prepared from starting material SM-2 where Z' is a suitable leaving group (e.g., F) with a desired amine (R'-NH 2 ) under suitable conditions, such as treatment with lithium bis(trimethylsilyl)amide (LHMDS) in a suitable solvent (e.g., tetrahydrofuran) at reduced temperature.
  • Z' is a suitable leaving group (e.g., F) with a desired amine (R'-NH 2 ) under suitable conditions, such as treatment with lithium bis(trimethylsilyl)amide (LHMDS) in a suitable solvent (e.g., tetrahydrofuran) at reduced temperature.
  • LHMDS lithium bis(trimethylsilyl)amide
  • Intermediate 2(b) may be prepared from Intermediate 2(a) under suitable condtions.
  • Intermediate 2(a) may be converted to Intermediate 2(b) by treating with an acetal or ketal protected hydroxy 1 acetaldehyde in presence of a base (e.g., sodium hydride or potassium carbonate) under suitable conditions appropriate for the leaving group (Z) employed.
  • a base e.g., sodium hydride or potassium carbonate
  • Intermediate 2(c) may be prepared by cyclization of Intermediate 2(b), for example, by treating Intermediate 2(b) with borontrifluoride diethyl etherate in the presence of a suitable acid reagent (e.g., acetic acid).
  • a suitable acid reagent e.g., acetic acid
  • Intermediate 2(c) can be prepared in trifluroacetic acid (TFA) or polyphophoric acid mediated cyclization under suitable conditions.
  • Intermediate 2(d) may be prepared by reduction of Intermediate 2(c) under suitable conditions, such as with Zn and hydrochloric acid.
  • Intermediate 2(e) may be prepared from Intermediate 2(d) by treatment with a suitable carbonylation agent (e.g., 1,1 '-carbonyldiimidazole) in a suitable solvent (e.g., dichloromethane).
  • a suitable carbonylation agent e.g., 1,1 '-carbonyldiimidazole
  • a suitable solvent e.g., dichloromethane
  • Intermediate 2(f) may be prepared by reacting Intermediate 2(e) with a the desired sulfonylating agent (R S0 2 X, where X is a suitable leaving group (e.g., CI)).
  • a the desired sulfonylating agent R S0 2 X, where X is a suitable leaving group (e.g., CI)
  • a compound of the present invention B where X is C(H) and R 2 and R 6 are H, may be prepared by removal of the amino protecting group introduced earlier using the appropriate reagents for the particular amino-protecting group used (e.g., potassium trimethylsilonolate).
  • the amino protecting group e.g., potassium trimethylsilonolate
  • R 3 -CH(OH)CH(OR) 2 , and R'-NH 2 are known or may be prepared by methods well- known to those skilled in the art. It will be appreciated that the compounds of Formula (I) may be prepared by the methods above in different sequence of reactions and that derivatives may be prepared from compounds of Formula (I- A) and (1-B) described above.
  • Pharmaceutically acceptable acid addition salts of the compound of formula I include those of inorganic acids, for example, hydrohalic acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1- hydroxynaphthalene-2-carboxylic acid or 3-hydroxynaphthaIene-2-carboxyIic acid, and sulfonic acids such as methanesulf
  • Compounds of Formula I or la are also capable of forming salts with bases, in particular pharmaceutically acceptable bases such as those well known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines, benzylamines or pyridine. These salts may be prepared by known salt- forming procedures.
  • the compounds exist in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic or diastereomeric mixtures.
  • the present invention embraces both individual optically active R and S isomers as well as mixtures, e.g. racemic or diastereomeric mixtures, thereof.
  • the present invention includes isotopically-labeled or -enriched compounds of the present invention.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 1 'C, l3 C and 14 C, chlorine, such as 36 C1, fluorine, such as l 8 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, l7 0 and l8 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • substitution with heavier isotopes such as deuterium, i.e. H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations Sections using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • solvates are considered pharmaceutical compositions, e.g., a compound of the present invention in combination with an excipient, wherein the excipient is a solvent.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.
  • Suitable excipients generally include binders, anti -adherents, disintegrants, fillers, diluents, flavors, colorants, glidants, lubricants, preservatives, sorbents and sweeteners or combination(s) thereof.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient.
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal.
  • GRAS solvents recognized by persons skilled in the art as safe
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • the bulk drug substance i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)
  • a suitable solvent in the presence of one or more of the excipients.
  • the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.
  • composition is generally formulated into various dosage forms selected from a group comprising tablet, troches, lozenges, aqueous or oily suspensions, ointment, patch, gel, lotion, dentifrice, capsule, emulsion, creams, spray, drops, dispersible powders or granules, emulsion in hard or soft gel capsules, syrups and elixirs.
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • Suitable containers are well- known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • the compounds of the present invention are useful as both prophylactic and therapeutic treatments for diseases or conditions related to the hyperactivity of MEK, as well as diseases or conditions modulated by the Raf/Ras/Mek pathway.
  • the invention relates to a method for treating a disease or condition related to the hyperactivity of MEK, or a disease or condition modulated by the MEK cascade, comprising administration of an effective therapeutic amount of a compound of the present invention.
  • the invention relates to a method for treating proliferative diseases, such as cancer, comprising administration of an effective amount of a compound of the present invention.
  • cancers include but are not limited to: angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma; bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, lymphoma, chondromatous hanlartoma, mesothelioma, esophageal squamous cell carcinoma, leiomyosarcoma, leiomyosarcoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, vipoma
  • adenomatoid tumors hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, hemangioma, osteogenic sarcoma
  • osteosarcoma malignant fibrous histiocytoma, chondrosarcoma, E wing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors, osteoma, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblasto
  • the invention relates to a method of treatment of a disorder selected from:
  • xenograft (cellos), skin, limb, organ or bone marrow transplant) rejection; osteoarthritis; rheumatoid arthritis; cystic fibrosis; complications of diabetes (including diabetic retinopathy and diabetic nephropathy); hepatomegaly; cardiomegaly; stroke (such as acute focal ischemic stroke and global cerebral ischemia); heart failure; septic shock; asthma; chronic obstructive pulmonary disorder; Alzheimer's disease; and chronic or neuropathic pain.
  • chronic pain for purposes of the present invention includes, but is not limited to, 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, and post-operative pain.
  • neurodegeneration pain is associated with numerous conditions which include, but are not limited to, inflammation, postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crush injury, constriction injury, tissue injury, limb amputation, and nerve injury between the peripheral nervous system and the central nervous system.
  • Compounds of the present invention may also be useful as antiviral agents for treating viral infections such as HIV, hepatitis (B) virus (HBV) human papilloma virus (HPV), cytomegalovirus (CMV], and Epstein-Barr virus (EBV).
  • viruses such as HIV, hepatitis (B) virus (HBV) human papilloma virus (HPV), cytomegalovirus (CMV], and Epstein-Barr virus (EBV).
  • Compounds of the present invention may also be useful in the treatment of restenosis, psoriasis, allergic contact dermatitis, autoimmune disease, atherosclerosis and inflammatory bowel diseases, e.g. Crohn's disease and ulcerative colitis.
  • An MEK inhibitor of the present invention may be usefully combined with another pharmacologically active compound, or with two or more other
  • a compound of the present invention may be administered simultaneously, sequentially or separately in combination with one or more agents selected from chemotherapy agents, e.g. mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine, and other anticancer agents, e.g. cisplatin, 5-fluorouracil or 5-fluoro-2-4(l H,3H)- pyrimidinedione (5FU), flutamide or gemcitabine.
  • chemotherapy agents e.g. mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine
  • anticancer agents e.g. cisplatin, 5-fluorouracil or 5-fluoro-2-4(l H,3H)- pyrimidinedione (5FU), flutamide or gemcita
  • Such combinations may offer significant advantages, including synergistic activity, in therapy.
  • a compound of the present invention may also be used to advantage in combination with other antiproliferative compounds.
  • antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors, such as LBH589; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors, such as RAD001 ; antineoplastic antimetabolites; plat in compounds;
  • antiproliferative antibodies include heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of FIt-3, such as P C4I2; Hsp90 inhibitors such as 17-AAG (17-allyIamino-gelda-namycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino- 17-demethoxy-geldana-mycin, NSC707545), IPI-504, CNFIOIO, CNF2024, CNFI OIO from Conforma Therapeutics and AUY922; temozolomide (TEMODAL); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; PI3 inhibitors, such as BEZ235; RAF inhibitor
  • tumor treatment approaches including surgery, ionizing radiation, photodynamic therapy, implants, e.g. with corticosteroids, hormones, or they may be used as radiosensitizers.
  • implants e.g. with corticosteroids, hormones, or they may be used as radiosensitizers.
  • anti-inflammatory and/or antiproliferative treatment combination with anti-inflammatory drugs is included. Combination is also possible with antihistamine drug substances, bronchodilatatory drugs, NSAID or antagonists of chemokine receptors.
  • aromatase inhibitor as used herein relates to a compound which inhibits the estrogen production, i.e. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atame-stane, exemestane and formestane and, in part-icular, nonsteroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark
  • AROMASIN Formestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark LENTARON. Fadrozole can be administered, e.g., in the form as it is marketed, e.g. un-der the trademark AFE A. Anastrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark ARIMIDEX. Letrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR. Amino glutethimide can be administered, e.g., in the form as it is marketed, e.g. under the trademark, OR1METEN.
  • a combination of the invention comprising a chemo-therapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g., breast tumors.
  • anti-estrogen as used herein relates to a compound which antagonizes the ef-fect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride.
  • Tamoxifen can be administered, e.g., in the form as it is marketed, e.g. under the trademark
  • Ralo-xifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under the trademark EVISTA.
  • Fulvestrant can be formulated as disclosed in US 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g. under the trademark FASLODEX.
  • a combination of the invention comprising a
  • chemotherapeutic agent which is an anti-estrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g. breast tumors.
  • anti-androgen as used herein relates to any substance which is capable of in-hibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX), which can be formulated, e.g. as disclosed in US 4,636,505.
  • CASODEX bicalutamide
  • gonadorelin agonist includes, but is not limited to abarelix, goserelin and goserelin acetate.
  • Goserelin is disclosed in US 4, 100,274 and can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZOLADEX.
  • Abarelix can be formulated, e.g. as disclosed in US 5,843,901.
  • topoisomerase 1 inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound Al in W099/ 17804).
  • Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark CAMPTOSAR.
  • Topotecan can be administered, e.g., in the form as it is marketed, e.g. under the trademark HYC ⁇ .
  • topoisomerase II inhibitor includes, but is not limited to the an-thracyclines such as doxorubicin (including liposomal formulation, e.g.
  • Etoposide can be administered, e.g. in the form as it is marketed, e.g. under the trademark ETOPOPHOS.
  • Teniposide can be administered, e.g. in the form as it is marketed, e.g. under the trademark VM 26-BRISTOL.
  • Doxorubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ADRIBLASTIN or ADRIAMYCI .
  • Epirubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark FARMORUB1CIN.
  • Idarubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZAVEDOS.
  • Mitoxantrone can be administered, e.g. in the form as it is marketed, e.g. under the trademark NOVANTRON.
  • microtubule active compound relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, e.g. paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine, discodermolides, cochicine and epothilones and derivatives thereof, e.g. epothilone B or D or derivatives thereof.
  • Paclitaxel may be administered e.g. in the form as it is marketed, e.g. TAXOL.
  • Docetaxel can be administered, e.g., in the form as it is marketed, e.g. under the trademark TAXOTERE.
  • Vinblastine sulfate can be
  • Epothilone A and/or B are Especially preferred.
  • alkylating compound includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).
  • Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark CYCLOSTIN. Ifosfamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark HOLOXAN.
  • histone deacetylase inhibitors or "HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes compounds such as sodium butyrate, LDH589 disclosed in WO 02/22577, especially N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(lH-indoI-3-yl)ethyI]- amino]methy 1] phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(2-methyI- 1 H-indoI-3- yl)-ethyl] -amino] methyI]phenyl]-2E-2-propenamide and pharmaceutically acceptable salts thereof, especially the lactate salt.
  • SAHA suberoylanilide hydroxamic acid
  • MS275 MS275
  • FK228 formerly FR9012228
  • trichostatin A compounds disclosed in US 6,552,065, in particular, N-hydroxy-3-[4-[[[2-(2-methyl-l H- indol-3-yl)-ethyl]-amino]-methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof.
  • antimetabolite includes, but is not limited to, 5- Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacy-ti-dine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.
  • Capecitabine can be administe-red, e.g., in the form as it is marketed, e.g. under the trademark XELODA.
  • Gemcitabine can be administered, e.g., in the form as it is marketed, e.g. under the trademark GEMZAR.
  • platinum compound as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark CARBOPLAT.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark
  • compounds targeting/decreasing a protein or lipid kinase activity includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g.,
  • PDGFR platelet- derived growth factor-receptors
  • compounds which target, decrease or inhibit the activity of PDGFR especially compounds which inhibit the PDGF receptor, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib, SU101, SU6668 and GFB- 1 11;
  • FGFR fibroblast growth factor-receptors
  • IGF-IR insulin-like growth factor receptor I
  • compounds which target, decrease or inhibit the activity of IGF-IR especially compounds which inhibit the kinase activity of IGF-I receptor, such as those compounds disclosed in WO 02/092599, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors;
  • compounds targeting, decreasing or inhibiting the activity of the it/SCFR receptor tyrosine kinase i.e C-kit receptor tyrosine kinases - (part of the PDGFR family)
  • compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family especially compounds which inhibit the c-Kit receptor, e.g.
  • imatinib compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase) and mutants, such as corn-pounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib or nilotinib (AM 107); PD 180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825)
  • a N-phenyl-2-pyrimidine-amine derivative e.g. imatinib or nilotinib (AM 107)
  • LY333531/LY379196 isochinoline compounds such as those disclosed in WO 00/09495; FTIs; BEZ235 (a P13K inhibitor) or AT7519 (CDK inhibitor);
  • compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC) or tyrphostin.
  • a tyrphostin is preferably a low molecular weight (mw ⁇ 1500) compound, or a pharmaceutically acceptable salt thereof, especially a compound selected from the benzylidenemalonitrile class or the S-arylbenzenemalonirile or bisubstrate quinoline class of compounds, more especially any compound selected from the group consisting of Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748;
  • k) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 97/02266, e.g. the compound of ex.
  • 96/30347 e.g. compound known as CP 358774
  • WO 96/33980 e.g. compound ZD 1839
  • WO 95/03283 e.g. compound ZM 105180
  • trastuzumab Herceptin
  • cetuximab Erbitux
  • Iressa Tarceva
  • OSI-774 Cl-1033
  • EKB-569 EKB-569
  • GW-2016 El .l, E2.4, E2.5, E6.2, E6.4, E2.1 1, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives which are disclosed in WO 03/013541; and
  • compounds targeting, decreasing or inhibiting the activity of the c-Met receptor such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF.
  • anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g.
  • TAALOMID thalidomide
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g., inhibitors of phosphatase 1, phosphatase 2A, or CDC25, e.g.
  • Compounds which induce cell differentiation processes are e.g. retinoic acid, or tocopherol or tocotrienol.
  • cyclooxygenase inhibitor as used herein includes, but is not limited to, e.g. Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a 5- alkyl-2-arylaminophenylacetic acid, e.g. 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • bisphosphonates as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark DIDRONEL.
  • Clodronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONEFOS.
  • titaniumudronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark S ELID.
  • “Pamidronic acid” can be administered, e.g. in the form as it is marketed, e.g. under the trademark ARED1A.
  • “Alendronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark FOSAM AX.
  • “lbandronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONDRANAT.
  • “Risedronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark ACTONEL.
  • "Zoledronic acid” can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZOMETA.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune), everolimus (CerticanO), CCI-779 and ABT578.
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation.
  • the term includes, but is not limited to, Pl-88.
  • biological response modifier refers to a lymphokine or interferons, e.g. interferon.
  • inhibitor of Ras oncogenic isoforms e.g. H-Ras, -Ras, or N-Ras
  • H-Ras, -Ras, or N-Ras refers to compounds which target, decrease or inhibit the oncogenic activity of Ras e.g. a "farnesyl transferase inhibitor” e.g. L-744832, D 8G557 or Rl 15777 (Zarnestra).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase.
  • Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, e.g. telomestatin.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • Compounds which target, decrease or inhibit the activity of methionine aminopeptidase are e.g. bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include e.g. Bortezomid (Velcade) and MLN 341.
  • matrix metal loproteinase inhibitor or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA21 1, MM1270B or AAJ996.
  • MMP matrix metal loproteinase inhibitor
  • FMS-like tyrosine kinase inhibitors e.g. compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors ⁇ Flt- 3R
  • interferon 1 -b-D-arabinofuransylcytosine (ara-c) and bisulfan
  • ALK inhibitors e.g. compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, e.g. P C412, TKI258, midostaurin, a staurosporine derivative, SU1 1248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90 e.g., 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds, and radicicol.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (Herceptin), Trastuzumab-DMl,erbitux, bevacizumab (Avastin), rituximab (Rituxan), PR064553 (anti-CD40) and 2C4 Antibody.
  • antibodies is meant e.g. intact monoclonal antibodies, polyclonal antibodies, multispe-cific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
  • compounds of formula (I) can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • compounds of formula (I) can be administered in combination with, e.g., farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC 12.
  • drugs useful for the treatment of AML such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC 12.
  • antigenemic compounds includes, for example, Ara-C, a pyrimidine analog, which is the 2-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.
  • Somatostatin receptor antagonists refers to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230
  • Tumor cell damaging approaches refer to approaches such as ionizing radiation.
  • ionizing radiation means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1 , pp. 248-275 (1993).
  • EDG binders refers a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
  • ribonucleotide reductase inhibitors refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluoro uracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy- 1 H-isoindole- 1 ,3-dione derivatives, such as PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned in Nandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961 (1994).
  • S-adenosylmethionine decarboxylase inhibitors includes, but is not limited to the compounds disclosed in US 5,461,076. Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF disclosed in WO 98/35958, e.g. l-(4-chloroanilino)-4-(4- pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, e.g.
  • anthranilic acid amides ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti- VEGF antibodies or anti-VEGF receptor antibodies, e.g. rhuMAb and RHUFab, VEGF aptamer e.g. Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGl antibody, Angiozyme (RPI 4610) and Bevacizumab (Avastin).
  • Photodynamic therapy refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers.
  • Examples of photodynamic therapy includes treatment with compounds, such as e.g. VISUDYNE and porfimer sodium.
  • Angiostatic steroids refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 1 1—
  • epihydrocotisol cortexolone, 17-hydroxyprogesterone, corticosterone,
  • Implants containing corticosteroids refers to compounds, such as e.g.
  • fluocinolone dexamethasone
  • “Other chemotherapeutic compounds” include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • biological response modifiers preferably lymphokines or interferons
  • antisense oligonucleotides or oligonucleotide derivatives preferably shRNA or siRNA
  • shRNA or siRNA or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • the structure of the active compounds identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index” or from databases, e.g. Patents International (e.g. IMS World Publications).
  • the compounds of the present invention may also be administered.
  • Anti IL-1 agents e.g:
  • Anakinra anti cytokine and anti-cytokine receptor agents, e.g. anti IL-6 R Ab, anti IL-15 Ab, anti 1L-17 Ab, anti IL-12 Ab; B-cell and T-cell modulating drugs, e.g. anti CD20 Ab; CTL4-Ig, disease-modifying anti-rheumatic agents (DMARDs), e.g. methotrexate, leflunamide, sulfasalazine; gold salts, penicillamine, hydroxychloroquine and
  • DMARDs disease-modifying anti-rheumatic agents
  • chloroquine chloroquine, azathioprine, glucocorticoids and non-steroidal antiinflammatories
  • NSAIDs e.g. cyclooxygenase inhibitors, selective COX-2 inhibitors, agents which modulate migration of immune cells, e.g. chemokine receptor antagonists, modulators of adhesion molecules, e.g. inhibitors of LFA-1 , VLA-4.
  • the pharmaceutical composition or combination of the present invention can be in unit dosage of about 1 -1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1 -500 mg or about 1 -250 mg or about 1 - 1 0 mg or about 0.5- 100 mg, or about 1 -50 mg of active ingredients.
  • suitable daily dosages for oral administration are from about 0.1 to about 10 mg/kg.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • the above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • the compounds of the present invention can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution.
  • the dosage in vitro may range between about 10 "3 molar and 10 "9 molar concentrations.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
  • a therapeutically effective amount of a compound of the present invention is administered to a patient in need of treatment.
  • a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a method for treating cancer in a mammal comprises administering to a mammal in need of such treatment an effective amount of a compound of the present invention.
  • the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. Preferably, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate.
  • the subject is a human.
  • the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers (i) to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof); (ii) to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient; or (iii) to preventing or delaying the onset or development or progression of the disease or disorder.
  • the term “treating” or “treatment” describes the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition or disorder.
  • a subject is "in need of a treatment if such subject would benefit biologically, medically or in quality of life from such treatment (preferably, a human).
  • Another aspect of the invention is a product comprising a compound of the present invention and at least one other therapeutic agent (or pharmaceutical agent) as a combined preparation for simultaneous, separate or sequential use in therapy to enhance apoptosis.
  • the compound of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manulacturers. Moreover, the compound of the present invention and the other therapeutic (or pharmaceutical agent) may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.
  • the invention provides the use of a compound of the present invention for treating a disease or condition by inhibiting the MAP kinase pathway, wherein the medicament is prepared for administration with another therapeutic agent.
  • the invention also provides for the use of another therapeutic agent, wherein the medicament is administered as a combination of a compound of the present invention with the other therapeutic agent.
  • CD1 1 , 1 -Carbonyldiimidazole
  • HPLC high pressure liquid chromatography or high performance liquid chromatography.
  • Intermediate I- 12a was prepared from l-(4-bromo-2-fluoro-phenyl)-6,7-difluoro- 4-methoxy-5-nitro-l,3-dihydro-benzoimidazol-2-one (2g, 0.00478 mol) and zinc powder (1.9g, 0.0287mol) using procedures analogous to those described above for the preparation of Intermediate I-l la to afford 1.7g of the product (95% yield).
  • Intermediate I- 18a was prepared from 5-amino-6,7-difluoro-l -(2-fluoro-4-iodo- phenyl)-4-hydroxy- 1 ,3-dihydro-benzoimidazol-2-one ( I- 13a: 550mg, 1.3mmol) in 1,1,1— triethoxy-ethane (5mL) and p-toluene sulfonic acid (20mg, O. Bmmol) using procedures analogous to those described above for Intermediate I- 16a to afford 3 lOmg of the product (53.6% yield).
  • TEA 4,5- difluoro-6-(2-fluoro-4-iodo-pheny l)-6,8-dihydro-i midazo [4',5 ': 3,4] benzo [ 1 ,2-d]oxazol-7- one (I-15a: 80mg, 0.178mmol) in dry DCM (5mL) at 0°C and the resulting mixture was stirred for i 5 minutes. This was followed by the addition of cyclopropanesulfonyi chloride (39mg, 0.27mmol) and stirring was continued for a further 3 hours at room temperature.
  • Intermediate I-25a was prepared from 6-(4-bromo-2-fluoro-phenyl)-4,5-difluoro- 6,8-dihydro-imidazo[4',5':3,4]benzo[l,2-d]oxazol-7-one (1-16a: 220mg, 0.57mmol), cyclopropanesulfonyl chloride (120mg, 0.86mmol) and NaH (34mg, 0.86mmol) using procedures analogous to those described above for Intermediate I- 19a to afford 135mg of the product (48.5% yield).
  • CDI (0.144g, 0.891 mmol) was added to a solution of 4,5-difluoro-N6-(2-fluoro-4- iodo-phenyl)-benzofuran-6,7-diamine fI-31 a: 0.240g, 0.5940mmol) in dry DCM (5mL).
  • the reaction mass was stirred 12-16 hours at 20-40°C.
  • the reaction was monitored by TLC (30% ethyl acetate in hexane).
  • the reaction mass was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate.
  • the organic layer was washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford the crude compound. Purification by column chromatography on silica gel (30% ethyl acetate in hexane) afforded 0.180g of the product (70% yield).
  • TEA 4,5-difluoro-3-(2-fluoro- 4 odophenyl)-lH-benzofuro[6,7-d]irnidazol-2(3H)-one (I-32a: 0.064g, 0.1488mmol) in dry DCM (5mL) at 0°C.
  • cyclopropanesulfonyl chloride 0.033 lg, 0.222mmol
  • the reaction mass was stirred for 3 hours at 20-40°C.
  • the reaction was monitored by TLC (25% ethyl acetate in hexane).
  • 2,6-Lutidine (0.077g, 0.7188mmol) and NaI0 4 (0.307g, 1.4376mmol) were added to a solution of l-allyl-N-(4,5-difluoro-6-(2-fluoro-4-iodophenylamino)benzofuran-7- yl)cyclopropane-l -sulfonamide d-35a: 0.190g, 0.3594mmol) in dioxane (lOmL).
  • osmium tetroxide 0.0045g, 0.0179mmol
  • TEA 0.094 lg, 0.930mmol
  • dry DCM 5mL
  • 2-benzyIoxymethyI- cyclopropanesulfonyl chloride 0.181g, 0.6976mmol
  • catalytic amount of DMAP 0.0 lOg
  • reaction was monitored by TLC (30% ethyl acetate in hexane).
  • the reaction mass was diluted with DCM (50mL) and partitioned between water and DCM.
  • the organic layer was washed with water, brine solution and concentrated under reduced pressure to afford the crude product.
  • Compound 2B was prepared from 4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-2- methyl-7-oxo-6,7-dihydro-imidazo[4',5':3,4]benzo[ 1 ,2-d]oxazole-8-sulfonic acid dimethylamide (I-23a: 60mg, 0.12mmol) and potassium trimethylsilonolate (30mg, 0.18mmol) using procedures analogous to those described above for Compound 1 A to afford 20mg of the product (31.7% yield).
  • Compound 1C was prepared from 4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-7-oxo- 6,7-dihydro-imidazo[4',5 , :3,4]benzo[l ,2-d]oxazole-8-sulfonic acid dimethylamide (60mg, 0.12mmol) and potassium trimethylsilonolate (30mg, 0.18mmol) using procedures analogous to those described above for Compound 1 A to afford 30mg of the product (49% yield). H !
  • Compound I E was prepared from 8-cyclopropanesulfonyl-4,5-diftuoro-6-(2- fluoro-4-iodo-phenyl)-2-methyl-6,8-dihydro-imidazo[4',5':3,4]benzo[ l ,2-d]oxazol-7-one (I-22a: 55mg, 0. 12mmol) and potassium trimethylsilonolate (30mg, 0.18mmol) using procedures analogous to those described above for Compound 1 A to afford 3mg of the product (5.66% yield).
  • Compound I F was prepared from 6-(4-bromo-2-fluoro-phenyl)-4,5-difluoro-7- oxo-6,7-dihydro-imidazo[4',5':3,4]benzo[l ,2-d]oxazole-8-sulfonic acid dimethylamide ( 24a: l OOmg, 0.203mmol) and potassium trimethylsilonolate (39mg, Q.305mmol) using procedures analogous to those described above for Compound I A to afford 30mg of the product (29% yield).
  • Compound 1G was prepared from 6-(4-bromo-2-fluoro-phenyl)-8- cyclopropanesulfonyl-4,5-difluoro-6,8-dihydro-imidazo[4',5':3,4]benzo[l,2-d]oxazol-7- one (1-25 a: 120mg, 0.245mmol) and potassium trimethylsilonolate (46mg, 0.368mmol) using procedures analogous to those described above for Compound 1 A to afford 20mg of the product (17.8% yield).
  • Compound IH was prepared from 6-(4-bromo-2-fluoro-phenyl)-8- cyclopropanesulfonyl-4,5-difluoro-2-methyl-6,8-dihydro-imidazo[4',5':3,4]benzo[l,2- d]oxazol-7-one (l-26a: lOOmg, 0.2mmol) and LiOH (50mg, 1.25mmol) in water (2mL) using procedures analogous to those described above for Compound I A to afford 30mg of the product (31.57% yield).
  • N-Methylmorpholine-N-oxide 34mg, 0.290mmol was added to a solution of 1- allyl-cyclopropanesulfonic acid [4,5-difluoro-6-(2-fluoro-4-iodo-phenylamino)- benzooxazol-7-yl] -amide (ID: 160mg, 0.290mmol) in THF (1 OmL). This was followed by the addition of osmium tetroxide (7.3mg, 0.0287mmol) and water (0.5mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and diluted with ethyl acetate.
  • Compound I K was prepared from 8-(2-benzyloxymethyl-cyclopropanesulfonyl)- 4,5-difluoro-6-(2-fiuoro-4-iodo-phenyl)-6,8-dihydro-imidazo[4 , ,5',3,4]benzo[l ,2- d]oxazoI-7-one (500mg, 0.77mmol) in THF (l OmL) was reacted with potassium trimethylsilonolate (198mg, 1.55mmol) to afford the crude product. Purification by column chromatography on silica gel (20-30% ethyl acetate in hexane) afforded 210mg of the product (43% yield).
  • Compound 1 L was prepared from 2-(benzyloxymethyl)-N-(4,5-difluoro-6-(2- fluoro-4-iodophenylamino) benzofd] oxazol-7-yl)cyclopropane-l -sulfonamide (150mg, 0.238mmol) in DCM (l OmL) was reacted with 1.0M solution of BC1 3 in DCM (0.9mL, 0.952mmol) to afford the crude product. The reaction mixture was quenched with methanol (0.5mL) and partitioned between water and ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous Na 2 S0 4 and concentrated.
  • N-methyl morpholine oxide (0.035g, 0.304 lmmol) was added to a solution of 1- allyl-cyclopropane sulfonic acid [4,5-difluoro-6-(2-fluoro-4-iodo-phenylamino)- benzofuran-7-yl] -amide (0.167g, 0.3041 mmol) in THF (5mL). This was followed by the addition of osmium tetroxide (0.0077g, 0.0304 lmmol) in water (ImL). The reaction mass was stirred for 16 hours at 30-40 °C. The reaction was monitored by TLC (10% methanol in chloroform).
  • a BRAF-MEK-ERK cascade assay is used to evaluate the effects of these compounds as inhibitors of the MAP kinase pathway.
  • An enzymatic cascade assay is set up using recombinant human activated BRAF (V599E) kinase (Cat No. 14-557), human full length unactive MEKl kinase (Cat No. 14-706) and human full length unactive MAP Kinase 2/ERK2 (Cat No. 14-536) enzymes procured from Upstate.
  • TR-FRET Time resolved fluorescence resonance energy transfer
  • the assay buffer solution contains 50 mM Tris pH 7.5, 10 mM MgC12 , 1 mM DTT, 0.01 % Tween 20, 0.1 nM activated BRAF, 2 nM unactive MEKl, 10 nM unactive ERK2, 100 ⁇ ATP and 500 nM long chain biotin-peptide substrate (LCB- FFKNIVTPRTPPP) in a 384 well format.
  • the kinase reaction is stopped after 90 minutes with 10 mM EDTA and Lance detection mix (2 nM Eu-labeled phospho- serine/threonine antibody (Cat. No.AD0176-Perkin Elmer), 20 nM SA-APC (Cat No. CR130-100-Perkin Elmer) is added.
  • the TR-FRET signal (Excitation at 340 nm, Emission at 615 nm and 665 nm) is read with 50 ⁇ delay time on a Victor3 V
  • the fluorimeter The data is calculated using the ratio of readings at 665nm to 615 nm. The final concentration of DMSO is 2.5 % in the assay. Compounds are screened at 10 ⁇ concentration with pre-incubation of the enzymes in the presence of test compound for 45 minutes.
  • Each individual IC50 is determined using a 10 point dose response curve generated by GraphPad Prism software Version 4 (San Diego, California, USA) using non linear regression curve fit for sigmoidal dose response (variable slope).
  • An in-vitro MAP kinase assay is set up using activated MAP kinase 2/ERK2 (Cat. No.14-550) obtained from Upstate. TR-FRET detection technology is used for the read out.
  • the assay buffer solution contains 50 mM Tris pH 7.5, 10 mM MgCI2 , I mM DTT, 0.01 % Tween 20, 1 nM activated ERK2, 100 ⁇ ATP and 500 nM long chain biotin-peptide substrate (LCB- FF NIVTPRTPPP) in a 384 well format.
  • the kinase reaction is stopped after 90 minutes with 10 mM EDTA and Lance detection mix (2 nM Eu-labeled phospho-serine/threonine antibody (Cat.No. AD0176-Perkin Elmer), 20 nM SA-APC (Cat. No. CR130-100-Perkin Elmer) is added.
  • the TR-FRET signal (excitation at 340 nm, emission at 615 nm and 665 nm) is read with 50 delay time on Victor3 V fluorimeter. The data is calculated using the ratio of readings at 665nm to 615 nm. The final concentration of DMSO is 2.5 % in the assay. Compounds are screened at 10 ⁇ concentration with pre-incubation of the enzymes in the presence of test compound for 45 minutes.
  • the radioactive filter binding assay is standardized using recombinant human activated BRAF (V599E) kinase (Cat No. 14-557) and kinase dead MEK1 (K97R) ( Cat No. 14-737) procured from Upstate.
  • the incorporation of 32P into ME 1 (K97R) by BRAF (V599E) is measured with final assay buffer conditions of 50 mM Tris pH 7.5, 10 mM MgCI2 , 1 mM DTT, 100 mM sucrose, 100 ⁇ sodium orthovanadate,5 ⁇ ATP and 2 ⁇ [ ⁇ 32P] ATP and 500 mg MEK I Kinase dead substrate.
  • the enzymatic reaction is stopped after 120 minutes with 8N HC1 (hydrochloric acid) and 1 mM ATP.
  • the solution is spotted on P81 filter paper and washed 4 times with 0.75 %
  • the cell viability assay in A375 cells is set up in a 96-well plate format using XTT.
  • XTT is a yellow tetrazolium salt that is cleaved to an orange formazan dye by the mitochondria of metabolically active cells. The procedure allows for rapid determination in a microtitre plate, to give reproducible and sensitive results.
  • A375 cells are grown in DMEM media containing 10% FBS and ImM sodium pyruvate. Cells are trypsinized and seeded at 1000 cells/well. After allowing the cells to adhere overnight, compound is added to the wells at the following final concentrations: 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.001, and 0.0001 ⁇ . The assay is set up in triplicates for each concentration. DMSO concentrations are kept at 0.5% /well. Three days after compound addition, the XTT assay is performed. Wells are washed once with PBS. 100 ⁇ !_, of DMEM media without phenol red or FBS is added to each well.
  • a working solution of XTT containing lmg/ml XTT and 100 of PMS (stock concentration 0.383 mg/ml) per 5ml is prepared. 50 ⁇ . of the working solution of XTT is added to each well. Absorbance of the plate is read at 465nm using a Spectramax 1 0 (Molecular Devices). The absorbance from wells with media and XTT alone, but without cells is considered the blank and subtracted from readings from all wells.
  • Percentage viability is calculated considering the blank subtracted value from wells treated with DMSO alone as 100% viable. G150 values are calculated using Graphpad Prism, using non-linear regression curve fit for sigmoidal dose response (variable slope).
  • the cell viability assay is further described in Scudiero, et. al., Cancer Research (1988) 48, 4827-4833; Weislow, et. al., J. Natl. Cancer Institute, (1989) 81, 577-586; and Roehm, et. al., J. Immunol. Methods [1991] 142:257-265.
  • the compounds of the above Examples were evaluated as inhibitors of the MAP kinase pathway in a BRAF-MEK-ERK enzymatic cascade assay and in a cell viability assay, the results of which are collated in Table 1 below.

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  • Vascular Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Molecular Biology (AREA)
  • AIDS & HIV (AREA)
  • Transplantation (AREA)

Abstract

La présente invention concerne des composés de formule (I) et des sels pharmaceutiquement acceptables de ceux-ci. Il a été démontré que les composés sont des inhibiteurs de MEK et par conséquent, peuvent être utiles dans le traitement de maladies hyperprolifératives (par exemple, le cancer et l'inflammation).
PCT/EP2010/069099 2009-12-08 2010-12-07 Dérivés sulfonamides hétérocycliques Ceased WO2011070030A1 (fr)

Priority Applications (17)

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JP2012542525A JP5456908B2 (ja) 2009-12-08 2010-12-07 ヘテロ環式スルホンアミド誘導体
GEAP201012745A GEP20135998B (en) 2009-12-08 2010-12-07 Heterocyclic sulfonamide derivatives
BR112012013735A BR112012013735A2 (pt) 2009-12-08 2010-12-07 derivados heterocícilicos de sulfonamida
CN2010800556652A CN102648188A (zh) 2009-12-08 2010-12-07 杂环磺酰胺衍生物
ES10790407.0T ES2484171T3 (es) 2009-12-08 2010-12-07 Derivados de sulfonamidas heterocíclicas
CA2781218A CA2781218A1 (fr) 2009-12-08 2010-12-07 Derives sulfonamides heterocycliques
US13/514,208 US8614239B2 (en) 2009-12-08 2010-12-07 Heterocyclic sulfonamide derivatives
EA201200823A EA201200823A1 (ru) 2009-12-08 2010-12-07 Гетероциклические производные сульфонамидов
MX2012006561A MX2012006561A (es) 2009-12-08 2010-12-07 Derivados de sulfonamida heterociclicos.
EP10790407.0A EP2509964B1 (fr) 2009-12-08 2010-12-07 Dérivés sulfonamides hétérocycliques
AU2010329940A AU2010329940B2 (en) 2009-12-08 2010-12-07 Heterocyclic sulfonamide derivatives
PH1/2012/501142A PH12012501142A1 (en) 2009-12-08 2010-12-07 Heterocyclic sulfonamide derivatives
ZA2012/03324A ZA201203324B (en) 2009-12-08 2012-05-07 Heterocyclic sulfonamide derivatives
IL219635A IL219635A0 (en) 2009-12-08 2012-05-07 Heterocyclic sulfonamide derivatives
TNP2012000242A TN2012000242A1 (en) 2009-12-08 2012-05-21 Heterocyclic sulfonamide derivatives
CU2012000085A CU20120085A7 (es) 2009-12-08 2012-05-31 Derivados de sulfamidas heterocíclicas
MA35003A MA33848B1 (fr) 2009-12-08 2012-06-25 Dérivés sulfonamides hétérocycliques

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012168884A1 (fr) * 2011-06-09 2012-12-13 Novartis Ag Dérivés de sulfonamide hétérocyclique
WO2013001372A3 (fr) * 2011-06-30 2013-04-25 University Of Oslo Procédés et compositions pour inhiber l'activation des lymphocytes t régulateurs
US8470878B2 (en) 2011-06-09 2013-06-25 Novartis Ag Heterocyclic sulfonamide derivatives
CN104822267A (zh) * 2012-02-29 2015-08-05 巴鲁克·S·布伦博格研究所 乙型肝炎病毒共价闭合环状dna形成的抑制剂及其使用方法
US9290468B2 (en) 2012-01-17 2016-03-22 Shanghai Kechow Pharma, Inc. Benzoheterocyclic compounds and use thereof

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Publication number Priority date Publication date Assignee Title
WO2017033113A1 (fr) 2015-08-21 2017-03-02 Acerta Pharma B.V. Associations thérapeutiques d'un inhibiteur de mek et d'un inhibiteur de btk

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012168884A1 (fr) * 2011-06-09 2012-12-13 Novartis Ag Dérivés de sulfonamide hétérocyclique
US8470878B2 (en) 2011-06-09 2013-06-25 Novartis Ag Heterocyclic sulfonamide derivatives
CN103748085A (zh) * 2011-06-09 2014-04-23 诺华股份有限公司 杂环磺酰胺衍生物
WO2013001372A3 (fr) * 2011-06-30 2013-04-25 University Of Oslo Procédés et compositions pour inhiber l'activation des lymphocytes t régulateurs
US9290468B2 (en) 2012-01-17 2016-03-22 Shanghai Kechow Pharma, Inc. Benzoheterocyclic compounds and use thereof
US9937158B2 (en) 2012-01-17 2018-04-10 Shanghai Kechow Pharma, Inc. Benzoheterocyclic compounds and use thereof
CN104822267A (zh) * 2012-02-29 2015-08-05 巴鲁克·S·布伦博格研究所 乙型肝炎病毒共价闭合环状dna形成的抑制剂及其使用方法

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EP2509964B1 (fr) 2014-04-30
CA2781218A1 (fr) 2011-06-16
CU20120085A7 (es) 2012-10-15
GT201200183A (es) 2014-03-27
KR20120102750A (ko) 2012-09-18
NI201200100A (es) 2012-08-13
AU2010329940A1 (en) 2012-05-31
US20120245209A1 (en) 2012-09-27
TN2012000242A1 (en) 2013-12-12
GEP20135998B (en) 2013-12-25
CO6551751A2 (es) 2012-10-31
PE20121384A1 (es) 2012-10-13
AU2010329940B2 (en) 2013-05-16
CL2012001485A1 (es) 2012-08-03
IL219635A0 (en) 2012-07-31
CR20120311A (es) 2012-10-04
JP2013512941A (ja) 2013-04-18
JP5456908B2 (ja) 2014-04-02
BR112012013735A2 (pt) 2019-09-24
MA33848B1 (fr) 2012-12-03
DOP2012000158A (es) 2012-09-30
ES2484171T3 (es) 2014-08-11
PH12012501142A1 (en) 2012-10-22
ECSP12011984A (es) 2012-07-31
EP2509964A1 (fr) 2012-10-17
US8614239B2 (en) 2013-12-24
CN102648188A (zh) 2012-08-22
MX2012006561A (es) 2012-07-04
EA201200823A1 (ru) 2013-02-28

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